JPS646190B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel azetidinone compounds with antibacterial activity. More specifically, the present invention provides novel azetidinone compounds, particularly compounds having various substituted carboxyalkyl groups at the 1-position of the azetidine nucleus and compounds having various substituents at the 4-position of the azetidine nucleus. Conventionally, the following compounds are known as azetidinone compounds, but these compounds either have almost no antibacterial activity, or have antibacterial activity only against certain Gram-negative bacteria, such as Pseudomonas aeruginosa. It has the following. As a result of intensive research, the inventors succeeded in synthesizing an azetidinone compound that has antibacterial activity against not only Gram-negative bacteria but also Gram-positive bacteria, and completed this invention. The azetidinone compound of this invention is represented by the following general formula (). [In the formula, R ¹ is amino, substituted amino, substituted hydroxy, azide, or halogen atom, and R ² is hydrogen atom, hydroxymethyl, aralkoxyiminomethyl, aryl, aralkenyl, formyl, carboxy, or the remainder of a nucleophilic compound. group, and
R ³ is a group

[Formula] (In the group, R ⁴ means an aryl, aralkyl, arylthioalkyl or heterocyclic group, and R ⁵ means a carboxy group or a derivative thereof) or a group

[Formula] (In the group, R ⁶ is alkyl, haloalkyl, heterocyclic thioalkyl or arylthio, and R ⁷
means a hydrogen atom, haloalkyl or heterocyclic thioalkyl, and R ⁵ has the same meaning as above)
respectively, and when R ¹ is an acylamino group having an acyl moiety derived from amino or an organic carboxylic acid or an organic sulfonic acid, and R ² is a hydrogen atom, R ³ is a group

[Formula] (In the group, R ⁴ is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
means an aralkyl, arylthioalkyl, or heterocyclic group, and R ⁵ has the same meaning as above),
base

[Formula] (In the group, R ⁶ means alkyl, haloalkyl or heterocyclic thioalkyl, R ⁷ means haloalkyl or heterocyclic thioalkyl, and R ⁵ has the same meaning as above) or a group

[Formula] (in the group, R ⁸ means arylthio, R ⁵ has the same meaning as above), and R ¹ is amino, substituted amino or azido,
and when R ² is the residue of an aryl, halogen or sulfur nucleophilic compound, R ³ is a group

[Formula] (In the group, R ⁴ means aryl, aralkyl, arylthioalkyl or a heterocyclic group, and R ⁵ has the same meaning as above), group

[Formula] (In the group, R ⁶ means alkyl or heterocyclic thioalkyl, R ⁷ means heterocyclic thioalkyl, and R ⁵ has the same meaning as above) or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above), and each group defined in the above formula has one or more alkane, arene, and heterocycle in any position thereof. ] The azetidinone compound () of the present invention has one or more optical and/or ) May have geometric isomers. The azetidinone compound () of the present invention can be produced by various methods shown in the following formulas, among which Processes 1 to 10 and Process
21 is a basic synthesis method for azetidinone compounds. (1) Process 1: [In the formula, R ¹ ' is substituted amino, substituted hydroxy,
azide or halogen atom, and n is 1 to 3
R ³ has the same meaning as above,
When R ¹ ' is an acylamino group having an acyl moiety derived from an organic carboxylic acid or an organic sulfonic acid, R ³ is a group

[Formula] (In the group, R ⁴ is phenyl having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
naphthyl, aralkyl, arylthioalkyl,
or a heterocyclic group, R ⁵ has the same meaning as above), a group

[Formula] (In the group, R ⁶ means alkyl, haloalkyl or heterocyclic thioalkyl, R ⁷ means haloalkyl or heterocyclic thioalkyl, and R ⁵ has the same meaning as above) or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above)] (2) Process 2: [In the formula, R ² _a is an aryl, aralkenyl or a residue of a nucleophilic compound, and R ³ _a is a group

[Formula] (in the group, R ⁴ _a means aryl, R ⁵ has the same meaning as above), and R ¹ ' has the same meaning as above] (3) Process 3: [In the formula, R ² _b is a hydrogen atom, hydroxymethyl,
aryl, aralkenyl or the residue of a nucleophilic compound, R ³ _b is a group

[Formula] (in the group, R ⁵ _a means carboxy or a derivative thereof or alkyl having carboxy or a derivative thereof,
R ⁴ has the same meaning as above) or a group

[Formula] (in the group, R ⁵ , R ⁶ and R ⁷ have the same meanings as above)] (4) Process 4: [In the formula, R ¹ _a is a protected amino, and R ³ _c
is the base

[Formula] (in the group, R ⁴ and R ⁵ have the same meanings as above), group

[Formula] (In the group, R ⁶ _a means alkyl, haloalkyl or heterocyclic thioalkyl, R ⁷ _a means haloalkyl or heterocyclic thioalkyl, and R ⁵ has the same meaning as above) or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above), and when R ² _b is a hydrogen atom, R ³ is a group

[Formula] (In the group, R ⁴ is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
means an aralkyl, arylthioalkyl, or heterocyclic group, and R ⁵ has the same meaning as above),
base

[Formula] (In the group, R ⁵ , R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above)] (5) Process 5: [In the formula, R ¹ _b means acylamino, R ² _b and R ³ _c have the same meanings as above, and when R ² _b is a hydrogen atom, R ³ _c is a group

[Formula] (In the group, R ⁴ is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
means an aralkyl, arylthioalkyl, or heterocyclic group, and R ⁵ has the same meaning as above),
base

[Formula] (in the group, R ⁵ , R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (In the group, R ⁵ and R ⁸ have the same meanings as above)] (6) Process 6: (wherein R ¹ _c is dialkylamino-substituted methyleneamino or aralkylideneamino, and
R ⁹ means dialkylamino or aryl;
R ³ _a has the same meaning as above) (7) Process 7: [In the formula, R ¹ _a is acylamino or azide,
and R ² _c means a group -CH=CH-R ¹⁰ (in the group, R ¹⁰ means aryl), and R ³ _a has the same meaning as above] (8) Process 8: [In the formula, R ¹¹ is aralkyl, and R ² _d is a group -
^{( 9} ₎ ^{Process 9} _: (In the formula, R ³ _a has the same meaning as above) (10) Process 10: (In the formula, R ¹ _b and R ³ _a have the same meanings as above.) (11) Process 11: (In the formula, R ¹ _e means an aralkylamino, azide or halogen atom, and R ³ _c has the same meaning as above.) (12) Process 12: (In the formula, R ¹ _f is an acylamino group having at least one group selected from protected amino, protected hydroxy and protected carboxy, and R ¹ _g is selected from amino, hydroxy and carboxy. an acylamino group having at least one group, and R ³ _d is a group

[Formula] (In the group, R ⁴ _b means a phenyl, naphthyl, aralkyl, arylthioalkyl, or heterocyclic group having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy, and R ⁵ is as defined above. have the same meaning), base

[Formula] (in the group, R ⁵ , R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above)] (13) Process 13: [In the formula, R ³ _e is a group

[Formula] (In the group, R ⁵ _b means esterified carboxy, R ⁴ has the same meaning as above), group

[Formula] (In the group, R ⁵ _b , R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (in the group, R ⁵ _b and R ⁸ have the same meanings as above), and R ³ _f is a group

[Formula] (In the group, M means a hydrogen atom or an inorganic or organic cation, and R ⁴ has the same meaning as above),
base

[Formula] (in the group, M, R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (in the group, M and R ⁸ have the same meanings as above), R ¹ and R ² _b have the same meanings as above, and when R ² _b is a hydrogen atom, R ³ _e is the base

[Formula] (In the group, R ⁴ is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
aralkyl, arylthioalkyl, or heterocyclic group, R ⁵ _b has the same meaning as above),
base

[Formula] (in the group, R ⁵ _b , R ⁶ _a and R ⁷ _a have the same meanings as above) or a group

[Formula] (In the group, R ⁵ _b and R ⁸ have the same meanings as above), and
R ³ _f is the base

[Formula] (In the group, R ⁴ means a phenyl, naphthyl, aralkyl, arylithioalkyl, or heterocyclic group having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy, and M has the same meaning as above. ), base

[Formula] (in the group, R ⁶ _a , R ⁷ _a and M have the same meanings as above) or a group

[Formula] (in the group, R ⁸ and M have the same meanings as above)] (14) Process 14: [In the formula, R ³ _g is a group

[Formula] (In the group, R ⁴ _c means an aralkyl group having at least one group selected from protected amino, protected hydroxy and protected carboxy, and R ⁵ has the same meaning as above. ), and R ³ _h is the group

[Formula] (in the group, R ⁴ _d means aralkyl having at least one group selected from amino, hydroxy and carboxy, R ⁵ has the same meaning as above), and R ¹ represents (15) Process 15: (In the formula, R ² _e is alkylthio, aralkylthio,
a residue of a nucleophilic compound selected from arylthio and heterocyclic thio, and R ² _f means a halogen atom, R ¹ and R ³ _a have the same meanings as above) (16) Process 16: (In the formula, R ² _g means a residue of a nucleophilic compound excluding halogen, and R ¹ , R ² _f and R ³ _a have the same meanings as above.) (17) Process 17: [In the formula, R ³ _i is a group

[Formula] (In the group, R ¹² and R ¹³ each mean alkyl, R ⁵
has the same meaning as above), and R ³ _j is the group

[Formula] (in the group, R ⁶ _b means alkyl or haloalkyl, R ⁷ _b means haloalkyl, R ⁵ has the same meaning as above), and R ¹ has the same meaning as above] (18) Process 18: [In the formula, R ³ _k is a group

[Formula] (in the group, R ⁶ _c means alkyl or heterocyclic thioalkyl, R ⁷ _c means heterocyclic thioalkyl, and R ⁵ has the same meaning as above), R ¹ and R ³ _j has the same meaning as above] (19) Process 19: [In the formula, R ³ _l is a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above), and R ³ _n is a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above), and R ¹ has the same meanings as above] (20) Process 20: (In the formula, R ¹ _h means a halogen atom, and R ³ _a has the same meaning as above.) (21) Process 21: [In the formula, R ¹ _i is a group R ¹⁴ −COCONH− (in the group, R ¹⁴
means substituted or unsubstituted aryl),
and R ¹ _j is the group

[Formula] (in the group, R ¹⁴ has the same meaning as above), R ² _b and R ³ _c have the same meaning as above, and when R ² _b is a hydrogen atom, R ³ _c is base

[Formula] (In the group, R ⁴ is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy,
means an aralkyl, arylthioalkyl or heterocyclic group, R ⁵ has the same meaning as above), a group

[Formula] (in the group, R ⁵ , R ⁶ _a and R ⁷ _a have the same meanings as above), or a group

[Formula] (in the group, R ⁵ and R ⁸ have the same meanings as above)]. In the above processes 1 to 21, in the formula (a), the group R ⁶
and R ⁷ , R ⁶ _a and R ⁷ _a , R ⁶ _b and R ⁷ _b , R ⁶ _c and
It is assumed that R ⁷ _c and R ¹² and R ¹³ are bonded to the same carbon atom. The alkane, arene, and heterocyclic moieties in the group defined in formula (b) may be substituted with one or more suitable substituents, and examples of such substituents include those described below for the acyl moiety of acylamino. The exemplified substituents can be listed as they are. (c) The carboxy group defined as R ⁵ in the above formula may be led to a salt thereof, and examples of such salts include alkali metal salts such as sodium salts and potassium salts, calcium salts, and magnesium salts. with inorganic or organic bases such as alkaline earth metal salts, ammonium salts, methylamine salts, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, pyridine salts, ethanolamine salts, diethanolamine salts, N,N-dimethylaniline salts, etc. I can give you salt. Furthermore, the amino group, which is a substituent for each group defined in the formula, may be converted into a salt with an acid. Examples of such salts include inorganic acids such as hydrochloric acid, bromic acid, and sulfuric acid. , salts with inorganic or organic acids such as dilic acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid. Examples of each of the above definitions are as follows. 1 Regarding substituted amino groups [R ¹ and R ¹ ′]: Substituted amino groups in R ¹ and R ¹ ′ include acylamino, aralkylamino, dialkylamino-substituted methylene amino, aralkylidene amino,
Specific examples of such groups will be described in detail below. a Acylamino group; Here, the acylamino group refers to aliphatic acylamino, aromatic acylamino, aromatic substituted aliphatic acylamino, heterocyclic acylamino, heterocyclic substituted aliphatic acylamino, and groups

[Formula] (in the group, Q means oxy or aryl methylene, X ³ means carbonyl or imino, and Z means oxo, aryl or heterocyclic substituted methylene) or a group

It includes acylamino represented by the formula: (wherein R means aryl). The acyl moiety in the above acylamino is an acyl derived from organic carboxylic acid, organic sulfonic acid, and organic phosphoric acid, and examples of such acyl include aliphatic acyl, aromatic acyl, aromatic substituted aliphatic acyl, heterocyclic acyl, and heterocyclic acyl. It is a ring-substituted aliphatic acyl, and more detailed examples are as follows. Examples of aliphatic acyl include formyl, acetyl, propionyl, butyryl, isobutyryl,
Alkanoyl groups such as valeryl, isovaleryl, pivaloyl, lauroyl, palmitoyl, alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, isocrotonoyl, alkyloxalyl groups such as methyloxalyl, ethyloxalyl, propyloxalyl, isopropyloxalyl, mesyl, ethanesulfonyl, propane Alkanesulfonyl groups such as sulfonyl and butanesulfonyl, alkenesulfonyl groups such as ethylenesulfonyl and propenesulfonyl, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Examples include alkoxycarbonyl groups such as tertiary butoxycarbonyl and pentyloxycarbonyl, and dialkylphosphoryl groups such as dimethylphosphoryl, diethylphosphoryl and diisopropylphosphoryl. Examples of the aromatic acyl include aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, and phthaloyl, aryloxalyl groups such as phenyloxalyl, tolyloxalyl, and naphthyloxalyl, and arenes such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, and naphthalenesulfonyl. Examples include sulfonyl groups and diarylphosphoryl groups such as diphenylphosphoryl. Examples of aromatic substituted aliphatic acyl include phenylacetyl, tolylacetyl, xylylacetyl, naphthylacetyl, biphenylylacetyl,
Phenylpropionyl, tolylpropionyl, naphthylpropionyl, 2-methyl-3-phenylpropionyl, 2-methyl-2-phenylpropionyl, 2-methyl-3-naphthylpropionyl, phenylbutyryl, naphthylbutyryl, phenylvaleryl, tolylvaleryl, naphthyl Aralkanoyl groups such as valeryl, diphenylacetyl, diphenylpropionyl, benzyloxalyl,
Aralkyloxalyl groups such as phenethyloxalyl and phenylpropyloxalyl, aralkanesulfonyl groups such as phenylmesyl, tolylmesyl, naphthylmesyl, phenylethanesulfonyl, naphthylethanesulfonyl, phenylpropanesulfonyl, and phenylbutanesulfonyl, phenylethylene Sulfonyl, tolylethylenesulfonyl,
Aralkenesulfonyl groups such as naphthylethylenesulfonyl, phenylpropenesulfonyl, naphthylpropenesulfonyl, phenylbutensulfonyl, benzyloxycarbonyl, phenyloxycarbonyl, phenylpropoxycarbonyl,
Examples include aralkoxycarbonyl groups such as diphenylmethoxycarbonyl and dialkylphosphoryl groups such as dibenzylphosphoryl. Examples of the heterocyclic acyl include a 3- to 6- (preferably 5)-membered monocyclic or fused polycyclic heterocyclic carbonyl group containing at least one hetero atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom; Examples of such heterocyclic carbonyl groups include aziridine carbonyl, azetidine carbonyl, pyrrole carbonyl, 2H-pyrrole carbonyl, imidazole carbonyl, pyrazole carbonyl, pyridine carbonyl, pyrazine carbonyl, piperidine carbonyl, piperazine carbonyl, pyrimidine carbonyl, pyridazine carbonyl, triazole carbonyl, thiazoline carbonyl, triazine carbonyl, pyrrolidine carbonyl, imidazolidine carbonyl, oxirane carbonyl, furoyl,
pyrancarbonyl, thenoyl, morpholinecarbonyl, furazanecarbonyl, oxazolecarbonyl, isoxazolecarbonyl, thiazolecarbonyl, thiadiazolecarbonyl, oxadiazolecarbonyl, indolecarbonyl,
3H-indole carbonyl, isoindole carbonyl, indolizine carbonyl, 1H-indazole carbonyl, purine carbonyl, benzimidazole carbonyl, benzotriazole carbonyl, quinoline carbonyl, isoquinoline carbonyl, naphthyridine carbonyl, quinoxaline carbonyl, quinazoline carbonyl, benzofuran carbonyl, chromene carbonyl, Isobenzofurancarbonyl, benzothiophenecarbonyl, xanthenecarbonyl, benzoxazolecarbonyl, benzisoxazolecarbonyl, benzothiazolecarbonyl, etc., and heterocyclic oxalyl groups include, for example, thienyloxalyl, furyloxalyl, pyridyloxalyl,
Specific examples include purinyloxalyl and tetrazolyloxalyl. Examples of the heterocyclic aliphatic acyl include thienyl acetyl, furylacetyl, pyridylacetyl, (pyridyl-1-oxide)acetyl, pyrrolyl acetyl, imidazolylacetyl, pyrazolylacetyl, triazolyl acetyl, tetrazolylacetyl, and oxazolyl. Ruacetyl, oxadiazolyl acetyl, thiazolyl acetyl, thiazolinyl acetyl, thiadiazolyl acetyl, morpholinyl acetyl, pyranyl acetyl, pyrrolidinyl acetyl, pyrrolinylacetyl, thienylpropionyl, furylpropionyl, pyridylpropionyl, imidazolylpropionyl, oxazolylpropionyl, oxadiazolylpropionyl, thiazolylpropionyl, thiadiazolylpropionyl, benzothienyl acetyl, benzoxadiazolyl acetyl, benzothiazolylacetyl, benzoxazolyl acetyl, benzisoxazolyl Acetyl, benzotriazolylacetyl, indolyl acetyl, purinyl acetyl,
Examples include heterocyclic-substituted alkanoyl groups such as purinylpropionyl and indolylpropionyl, and heterocyclic-substituted alkyloxalyl groups such as thenyloxalyl, furfuryloxalyl, pyridylmethyloxalyl, tetrazolylmethyloxalyl, and thiadiazolylmethyloxalyl. The aliphatic hydrocarbon moieties (e.g. alkane or alkene moieties), aromatic hydrocarbon moieties (e.g. arene moieties) and heterocyclic moieties in the acyls mentioned above may have one or more suitable substituents; Such substituents include, for example, methyl, ethyl, propyl, isopropyl, butyl,
Alkyl groups such as isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, alkenyl groups such as vinyl, propenyl, isopropenyl, butenyl, aryl groups such as phenyl, tolyl, xylyl, mesityl, naphthyl, methylnaphthyl,
Mono- or dialkylamino groups such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, diethylamino, arylamino groups such as anilino, toluidino, xylidino, naphthylamino, benzylamino, phenethylamino, diphenylmethylamino, tritylamino Aralkylamino groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Alkoxy groups such as pentyloxy, isopentyloxy, neopentyloxy, aryloxy groups such as phenoxy, tolyloxy, xylyloxy, naphthoxy, aralkoxy groups such as benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, diphenylmethoxy, methylthio, ethylthio , alkylthio groups such as propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, neopentylthio, arylthio groups such as phenylthio, tolylthio, xylylthio, naphthylthio, benzylthio, phenethylthio, phenylpropylthio, phenylbutylthio , aralkylthio groups such as diphenylmethylthio, alkanesulfonamide groups such as mesylamino, ethanesulfonamide, propanesulfonamide, alkanamide groups such as formamide, acetamide, propionamide, butyramide, isobutyramide, carbamoyl group, N-methylcarbamoyl , N-alkylcarbamoyl groups such as N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, carbazoyl, N-methylcarbazoyl, N-ethylcarbazoyl, N-propyl N-alkylcarbazoyl groups such as carbazoyl and N-isopropylcarbazoyl, alkoxyimino groups such as methoxyimino, ethoxyimino, and propoxyimino, hydroxyl groups, hydroxyimino groups, carboxy groups, nitro groups, halogens, sulfo groups, cyano group, a mercapto group, an amino group, an imino group, or a group formed by combining these substituents, and the alkane and arene moieties of the above substituents may be substituted with appropriate substituents. Examples of substituents include amino, mono- or dialkylamino as exemplified above, hydroxy, carboxy, nitro, halogen, sulfo, cyano, and the like.
Among such substituents, amino, imino, hydroxy (including hydroxy in hydroxyimino) mercapto and carboxy groups may be protected with suitable protecting groups, such as the following: can give. Amino and imino protecting groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, chloromethoxycarbonyl, bromoethoxycarbonyl, tribromoethoxycarbonyl,
Substituted or unsubstituted alkoxycarbonyl groups such as trichloroethoxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, diphenylmethoxycarbonyl, nitrobenzyloxycarbonyl, bromobenzyloxycarbonyl, methoxybenzyloxycarbonyl, dinitrobenzyloxycarbonyl, etc. or unsubstituted aralkoxycarbonyl group, halogen-substituted alkanoyl group such as trifluoroacetyl, substituted or unsubstituted aralkyl group such as benzyl, diphenylmethyl, trityl, bromobenzyl, nitrobenzyl, phenylthio, nitrophenylthio,
Substituted or unsubstituted arylthio groups such as dinitrophenylthio, ethylidene, isopropylidene,
Substituted or unsubstituted alkylidene groups such as 2-methoxycarbonyl-1-methylethylidene (or its tautomer 2-methoxycarbonyl-1-methylvinyl), substituted or unsubstituted aralkylidene groups such as benzylidene, salicylidene, etc. Examples of the hydroxy group and mercapto protecting group include those exemplified above as the amino and imino protecting groups, and further include acetyl, propionyl, butyryl, isobutyryl, valeryl, bromoacetyl, dichloroacetyl, Specific examples thereof include substituted or unsubstituted alkanoyl groups such as trifluoroacetyl, substituted or unsubstituted aroyl groups such as benzoyl, toluoyl, xyloyl, nitrobenzoyl, bromobenzoyl, and salicilloyl, and aroylmethyl groups such as phenacyl. Carboxy protecting groups include, for example, silyl esters, aliphatic esters, and esters containing an aromatic or heterocyclic ring, and specific examples of such esters include the esters in carboxyl group derivatives. Representative examples of acyl defined above include bromoacetyl, dichloroacetyl, glycoloyl, glycyl, phenylglycoloyl, phenylglycyl, 2-hydroxyimino-2-phenylacetyl, 2-hydroxyimino- 2-(4-hydroxyphenyl)acetyl, 4
-Hydroxyphenylglycyl, N-(2,2,
2-trichloroethoxycarbonyl)-2-phenylglycyl, N-benzyloxycarbonyl-
2-pyranylglycyl, 3,5-dinitrobenzoyl, azidoacetyl, 3-amino-3-phenylpropionyl, 2-bromo-2-phenylacetyl, methoxyacetyl, 2-(2-amino-2
-carboxyethoxy)acetyl, methylthioacetyl, 2-(2-amino-2-carboxyethylthio)acetyl, phenoxyacetyl, naphthoxyacetyl, phenylthioacetyl, methoxybenzoyl, 4-methoxyphenylglyoxyloyl, 4-Hydroxyphenylglyoxyloyl, 5-methylisoxazolecarbonyl, 2
-Hydroxyimino-2-(4-methoxyphenyl)acetyl, 2-(3-mesylaminophenyl)glycyl, cyanoacetyl, 2-(2-amino-4-thiazolyl)acetyl, 2-(2-imino- 4-thiazolin-4-yl)acetyl, 2-
Hydroxyimino-2-[4-(3-tertiary-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]acetyl, 2-hydroxyimino-2-[4-(3-phthalimide-3-)
methoxycarbonylpropoxy)phenyl]acetyl, 4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxyloyl, 4-(3-phthalimide-
3-methoxycarbonylpropoxy) phenylglyoxyloyl, 2-benzoyloxyimino-
2-[4-(3-tertiary-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenyl]acetyl, 4-[3-(4-methoxybenzyloxycarbonyl)-3-tertiary-butoxycarbonylaminopropoxy]phenyl Examples include enylglyoxyloyl, 2-[3-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetyl, 3-(3-amino-3-carboxypropoxy)phenylglyoxyloyl, etc. Ru. A more preferred example of the acyl defined above is phthalimide or an acyl represented by the following formula.

[Formula] R ^d -CO- or (R ^e O) ₂ PO- (wherein, R ^a is a hydrogen atom or alkoxy which may be substituted with an amino group and/or a carboxy group, and R ^b is a hydrogen atom or an amino group, R ^c is a hydrogen atom, or R ^b and R ^c together represent oxo or hydroxyimino, R ^d is aryloxyalkyl, heterocyclic substituted alkyl, substituted or unsubstituted aryl, aralkoxy, and R ^e means alkyl, amino,
Hydroxyimino and carboxy may be protected with a suitable protecting group, and examples of such protecting groups include the same as the above-mentioned amino, hydroxy and carboxy protecting groups). Here, the alkoxy in R ^a includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, pentyloxy, isopentyloxy, etc., and the aryloxyalkyl in R ^d includes, for example, Examples include phenoxymethyl, phenoxyethyl, tolyloxymethyl, xylyloxymethyl, naphthoxymethyl, etc., and examples of the heterocycle of the heterocycle-substituted alkyl in R ^d include the heterocycle group in the above-mentioned heterocycle-substituted aliphatic acyl. Examples of the alkyl moiety include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like. In addition, as the alkyl in R ^e ,
Examples of the alkyl moiety of aryloxyalkyl in R ^d above can be cited as they are. The alkanes, arenes and heterocycles in the preferred acyl represented by the above formula may have a suitable substituent at any position, and such substituents include the specific substituents mentioned for the acyl above. I can just give you an example. b Aralkylamino group; Specific examples of the aralkyl moiety in the aralkylamino group include benzyl, diphenylmethyl, trityl, phenethyl, phenylpropyl, phenylbutyl, 4-methylbenzyl, 3,
4-dimethylbenzyl, 4-methylphenethyl,
Naphthylmethyl, etc., and such groups may have one or more suitable substituents at any position, such as the substituents exemplified in the acyl of the above-mentioned acylamino group. Specific examples of the groups can be listed as they are. c dialkylamino-substituted methyleneamino group; Specific examples of the dialkylamino moiety in the dialkylamino-substituted methyleneamino group include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dihexylamino, N-ethyl-N-methyl Examples include N,N-dialkylamino groups such as amino, and polymethyleneamino groups such as ethyleneamino, trimethyleneamino, tetramethyleneamino, pentamethyleneamino, hexamethyleneamino, heptamethyleneamino, and octamethyleneamino. d Aralkylidene amino group; Examples of the aralkylidene moiety in the aralkylidene amino group include benzylidene, tolylmethylene, xylylmethylene, naphthylmethylene, etc.
It may have one or more suitable substituents, and examples of such substituents include the specific examples of the substituents exemplified for the acyl of acylamino. 2 Regarding acylamino groups [R ¹ _b , R ¹ _d , R ¹ _f and R ¹ _g ]; As specific examples of the acyl moiety in the acylamino group, the examples for the acyl moiety of the acylamino group described in Section 1 a) above can be used as is. I can give it to you. 3 Regarding substituted hydroxy groups [R ¹ and R ¹ ']; Substituted hydroxy groups include alkoxy, aralkoxy, aryloxy, acyloxy, etc., and each of these groups will be described in detail below. a Alkoxy group Examples of the alkyl moiety in the alkoxy group include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, and the like. b Aralkoxy Group Specific examples of the aralkyl moiety in the aralkoxy group include the same examples as the aralkyl moiety of the aralkylamino group described in item 1 b) above. c Aryloxy group Specific examples of the aryl moiety in the aryloxy group include phenyl, tolyl, xylyl, naphthyl, etc., and these groups have one or more suitable substituents at any position thereof. Examples of such substituents include the specific examples of the substituents exemplified for the acyl moiety of the acylamino group described in item 1 a) above. d Acyloxy Group Specific examples of the acyl moiety in the acyloxy group include the examples of the acyl moiety in the acylamino group described in section 1 a) above. 4 Halogen [R ¹ , R ¹ ′, R ¹ _e , R ¹ _h , R ² and R ² _f ]
Concerning: Here, specific examples of halogen include fluor, chloro, bromine, and iodine. 5 Regarding the protected amino group [R ¹ _a ]: Preferred examples of the amino protecting group in the protected amino group include alkoxycarbonyl, dialkylphosphoryl, aralkoxycarbonyl, dialkylphosphoryl, aroyl, aralkylamino, etc. Specific examples of such groups include the specific examples of the acyl moiety of the acylamino group exemplified in item 1 a) above, and further examples of groups such as

[Formula] (In the ^group , diazolidin-3-yl) and groups

[Formula] (in the group, R has the same meaning as above) can be mentioned. 6 Regarding the dialkylamino-substituted methyleneamino group [R ¹ _c ]: Specific examples of the dialkylamino moiety in the dialkylamino-substituted methyleneamino group include the dialkylamino moiety of the dialkylamino-substituted methyleneamino group described in Section 1 c) above. A concrete example can be given as is. 7 Regarding the aralkylidene amino group [R ¹ _c ]: Specific examples of the aralkylidene moiety in the aralkylidene amino group include the above-mentioned item 1 d).
Specific examples of the aralkylidene moiety of the aralkylidene amino group mentioned above can be cited as they are. 8 Aralkyl moieties in aralkylamino group [R ¹ _e ], aralkoxyiminomethyl group [R ² ], and aralkylthio group [R ² _e ], and aralkyl group [R ⁴ , R ⁴ _b , R ⁴ _c , R ⁴ _d and R ¹¹ ]: Specific examples of the aralkyl moiety and aralkyl group in the above group include, for example, the above item 1 b)
Specific examples of the aralkyl moiety of the aralkylamino group described in 2 can be cited as they are. 9 Protected amino group, protected hydroxy group and protected carboxy group [R ¹ _f and
R ⁴ _c ]: Examples of the protecting groups for each of the protected amino group, protected hydroxy group, and protected carboxy group include amino in the acyl moiety of the acylamino group mentioned in item 1 a) above,
Specific examples of hydroxy and carboxy protecting groups can be mentioned directly. 10 Aryl group [R ² , R ² _a , R ² _b , R ⁴ , R ⁴ _a , R ⁹ ,
R ¹⁰ and R ¹⁴ ] and arylthio group [R ² _e ,
R ⁶ and R ⁸ ] and the aryl moiety in the arylthioalkyl group [R ⁴ and R ⁴ _b ]: Specific examples of the aryl group and aryl moiety in the above groups include phenyl, tolyl,
Examples include xylyl, mesityl, naphthyl, etc., and such groups may have one or more suitable substituents at any position thereof. Examples of such substituents include ) The specific examples of the substituents in the acyl moiety mentioned in 2.) can be cited as they are, and further include N-phenylglyoxyloyl mesylamino, N-phenylglyoxyloyl ethanesulfonamide, and N-tolylglyoxyloylpropanesulfonamide. , N-arylglyoxyloylalkanesulfonamide groups such as N-naphthylglyoxyloylmesylamino, N-(benzamideacetyl)mesylamino, N-(phthalimidoacetyl)mesylamino, N-(benzamideacetyl)ethanesulfonamide, N- (phthalimidoacetyl)propanesulfonamide,
N-(aroylaminoalkanoyl) alkanesulfonamides such as N-(phthalimidopropionyl)mesylamino, aroyl alkoxy such as phenacyloxy, benzoylethoxy, benzoylpropoxy, toluoylmethoxy, toluoylethoxy, xyloylmethoxy, naphthoylmethoxy, etc. Mention may be made of N-substituted alkanesulfonamides such as the radicals. 11 Regarding aralkenyl groups [R ₂ , R ² _a and R ² _b ]: Here, specific examples of aralkenyl groups include styryl, cinnamyl, tolyruvinyl, xylyl vinyl, naphthyl vinyl, etc., and the arene moiety of such groups may have one or more suitable substituents at any position thereof, and examples of such substituents include the specific examples of the substituents on the acyl moiety described in item 1 a) above. I can give it to you. 12 Residues of nucleophilic compounds [R ² , R ² _a , R ² _b and
R ² _g ]: The residues of the above nucleophilic compounds are the residues of nitrogen-nucleophilic compounds such as halogens, disubstituted aminos, azides, etc.
Examples include residues of oxygen-nucleophilic compounds such as alkoxy, aryloxy, and aralkoxy; residues of sulfur-nucleophilic compounds such as alkylthio, arylthio, aralkylthio, and heterocyclic thio; The heterocyclic group may have one or more suitable substituents at any position thereof, and such substituents include, for example, the first
Specific examples of the substituents in the acyl moiety mentioned in section a) can be listed as they are. Here, the above-mentioned di-substituted amino group includes, for example, dimethylamino, N-ethyl-N-methylamino,
Dialkyl amino groups such as N-methyl-N-propylamino, diethylamino, N-ethyl-N-propylamino, diisopropylamino, dipropylamino, N-methylanilino, N-ethylanilino, N-propylanilino, N-isopropylamino Reno, N-methyltoluidino, N-ethyltoluidino, N-propyltoluidino, N-methylxylidino, N-ethylxylidino, N-methyl-N-naphthylamino, N-ethyl-N-naphthylamino, N-propyl-N -N-alkyl-N-arylamino group such as naphthylamino, N-benzyl-N-methylamino, N-benzyl-N-
ethylamino, N-benzyl-N-propylamino, N-diphenylmethyl-N-methylamino,
N such as N-diphenylmethyl-N-ethylamino
Examples include -aralkyl-N-alkylamino group. Further, as specific examples of the halogen in the above group, the specific examples of the halogen described in the above section 4 can be cited as they are. Further, as specific examples of the alkyl moiety of alkoxy and alkylthio, for example, the above-mentioned item 3 a)
Specific examples of the alkyl moiety of the alkoxy group mentioned above can be cited as they are. Further, as specific examples of the aralkyl moiety of aralkoxy and aralkylthio, for example, the first
Specific examples of the aralkyl moiety of the aralkylamino group mentioned in item b) can be cited as they are. Further, as specific examples of the aryl moiety in aryloxy and arylthio, the specific examples of the aryl moiety in the aryloxy group described in Section 3 (c) above can be cited as they are. Examples of the heterocycle of the heterocycle thio group include specific examples of the heterocycle in the heterocycle acyl mentioned in item 1 a) above. 13 Heterocyclic groups [R ⁴ and R ⁴ _b ] and heterocyclic thio groups [R ² _e ] and heterocyclic thioalkyl groups [R ⁶ , R ⁶ _a , R ⁶ _c , R ⁷ , R ⁷ _a and R ⁷ _c Regarding the heterocyclic moiety in ]: Specific examples of the heterocycle in the above group include the specific examples of the heterocycle in the heterocyclic acyl described in item 1 a) above. 14 Alkyl groups [R ⁵ _b , R ⁶ , R ⁶ _a , R ⁶ _b , R ⁶ _c , R ¹² and R ¹³ ] and alkylthio groups [R ² _e ], arylthioalkyl groups [R ⁴ and R ⁴ _b ] and heterocyclic thioalkyl groups [R ⁶ , R ⁶ _a , R ⁶ _c , R ⁷ , R ⁷ _a
and R ⁷ _c ]: Specific examples of alkyl in the above groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, neopentyl, hexyl, etc. , such a group may have one or more suitable substituents at any position thereof, and such substituents include, for example, the substituents on the acyl moiety described in item 1 a) above. I can give you a concrete example. 15 Regarding the N-substituted or unsubstituted alkanesulfonamide moiety in phenyl [R ⁴ and R ⁴ _b ] having an N-substituted or unsubstituted alkanesulfonamide: Specific examples of the N-substituted alkanesulfonamide in the above group include, for example. , Specific examples of the N-substituted alkanesulfonamide as a substituent of the aryl group in item 10 above can be cited as they are,
Further, as specific examples of unsubstituted alkanesulfonamides, the specific examples of alkanesulfonamides exemplified for the substituents on acyl mentioned in Section 1 a) above can be cited as they are. 16 Phenyl with aroyl alkoxy [R ⁴
Regarding the aroyl alkoxy moiety in [and R ⁴ _b ]: Specific examples of aroyl alkoxy in the above group include specific examples of aroyl alkoxy in the aryl substituent described in Section 10 above. . 17 Regarding carboxy group derivatives [R ⁵ and R ⁵ _a ]: Here, as carboxy group derivatives, for example,
Examples include acid amides, esters, nitriles, etc., and specific examples of these derivatives include the following. a Acid amide: N-unsubstituted amide, N-alkyl amide such as N-methylamide, N-ethylamide, N,N- such as N,N-dimethylamide, N,N-diethylamide, N-ethyl-N-methylamide, etc. Examples include acid amides such as dialkylamide and N-phenylamide, as well as acid amides with pyrazole, imidazole, 4-alkylimidazole, and the like. b Ester: Examples of esters include silyl esters, aliphatic esters, esters containing aromatic rings or heterocycles, and esters with N-hydroxy compounds. Examples of the silyl ester include trimethylsilyl,
Examples include triethylsilyl. Examples of aliphatic esters include saturated or unsaturated, cyclic or acyclic (including linear and branched) aliphatic esters, typical examples of which include methyl ester, ethyl ester, propyl ester, and isopropyl. ester,
Alkyl esters such as butyl ester, tertiary butyl ester, octyl ester, nonyl ester, undecyl ester, vinyl ester, 1-
Examples include alkenyl esters such as propenyl ester, allyl ester, and 3-butenyl ester, alkynyl esters such as 3-butynyl ester and 4-pentynyl ester, and cycloalkyl esters such as cyclopentyl ester, cyclohexyl ester, and cyclopeptyl ester. . Examples of esters containing an aromatic ring include aryl esters such as phenyl ester, tolyl ester, xylyl ester, naphthyl ester, indanyl ester, and dihydroanthryl ester; aralkyl esters such as benzyl ester and phenethyl ester; and phenoxymethyl. ester, aryloxyalkyl ester such as phenoxyethyl ester, phenoxypropyl ester, arylthioalkyl ester such as phenylthiomethyl ester, phenylthioethyl ester, phenylthiopropyl ester, benzenesulfinylmethyl ester , arenesulfinyl alkyl esters such as benzenesulfinyl ethyl ester, aroyl alkyl esters such as phenacyl ester, and toluoyl ethyl ester. Examples of esters containing a chlorine ring include saturated or unsaturated, monocyclic or fused ring, oxygen,
1 to 4 heteroatoms such as sulfur and nitrogen atoms
Examples of such esters include esters having a 3- to 10-membered heterocycle, such as
Pyridyl ester, piperidinyl ester, 2-
Examples include heterocyclic esters such as pyridon-1-yl ester, tetrahydropyranyl ester, quinolyl ester, and pyrazolyl ester, and heterocyclic-substituted alkyl (e.g., methyl, ethyl, propyl, etc.) esters substituted with the above-mentioned heterocycles. It will be done. N in esters with N-hydroxy compounds
-Hydroxy compounds include, for example, N,N-dialkylhydroxylamines such as N,N-dimethylhydroxylamine, N,N-diethylhydroxylamine, N,N-dipropylhydroxylamine, propanal oxime, butanam oxime, Examples include aldoximes or ketoxime such as acetone oxime, and N-hydroxyimide compounds such as N-hydroxyphthalimide and N-hydroxysuccinimide. Such silyl esters, aliphatic esters,
The ester moiety, such as an ester containing an aromatic ring or a heterocycle, or an ester with an N-hydroxy compound, may have one or more suitable substituents at any position, such substituents include, for example, Methyl, ethyl, propyl, isopropyl, butyl,
Alkyl such as tertiary butyl, cycloalkyl such as cyclopropyl, cyclohexyl, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, alkanoyloxy such as acetoxy, propionyloxy, pivaloyloxy, methylthio, ethylthio ,
Alkylthio such as propylthio, alkanesulfinyl such as methanesulfinyl, ethanesulfinyl, propanesulfinyl, alkanesulfonyl such as mesyl, ethanesulfonyl, halogen such as phenylazo, chlor, bromo, iodo, cyano, nitro, etc. The following substituents are mentioned. Specific examples of esters having the above substituents include chloromethyl ester, bromoethyl ester, dichloromethyl ester, 2,
Monos such as 2,2-trifluoroethyl ester,
Di- or trihaloalkyl ester, cyanoalkyl ester such as cyanomethyl ester, cyanoethyl ester, 4-chlorophenyl ester, 3,5-dibromophenyl ester, 2,
4,5-trichlorophenyl ester, 2,4,
Examples include mono-, di-, tri-, tetra- or pentahalophenyl esters such as 6-trichlorophenyl ester and pentachlorophenyl ester, and cycloalkyl-substituted alkyl esters such as 1-cyclopropylethyl ester. 18 Regarding the ester in the esterified carboxyl group [R ⁵ _b ]: Examples of the ester in the above group include the specific examples of the ester in the carboxy group derivative described in the above item 17. 19 Regarding haloalkyl groups [R ⁶ , R ⁶ _a , R ⁶ _b , R ⁷ , R ⁷ _a and R ⁷ _b ]: Here, specific examples of haloalkyl groups include chloromethyl, bromomethyl, iodomethyl, 1-bromoethyl, 1-bromopropyl, 1
-Chlorobutyl, 1-iodoethyl, 1-bromohexyl, etc. 20 Regarding inorganic or organic cations [M]: Specific examples of inorganic or organic cations include metal cations (e.g., alkali metal cations such as sodium cations and potassium cations, alkaline earth metal cations such as calcium cations and magnesium cations, etc.). ), inorganic cations such as ammonium ion, methylammonium ion, trimethylammonium ion, triethylammonium ion, dicyclohexylammonium ion, pyridinium ion, 2-hydroxyethylammonium ion, bis(2-hydroxyethyl)ammonium ion, N,N-
Examples include organic cations such as dimethyl-N-phenylammonium ion. 21 Regarding the dialkylamino group [R ⁹ ]: Specific examples of the above dialkylamino group include the specific examples of the dialkylamino moiety in the dialkylamino-substituted methyleneamino group described in Section 6 above. 22 Regarding the aryl group [R ⁹ ]: As specific examples of the above aryl group, the specific examples of the aryl group in the aralkylidene amino group described in the above section 7 can be cited as they are. 23 Regarding the residue [R ² ] of the sulfur nucleophilic compound: As a specific example of the residue of the sulfur nucleophilic compound mentioned above, the sulfur nucleophilic compound in the residue of the nucleophilic compound described in Section 12 above is Specific examples of residues of chemical compounds can be listed as they are. The starting materials of this invention include known and novel compounds, and these compounds can be produced, for example, by the following methods. (a) Method for producing the starting material () in Process 1: The starting material () in Process 1, for example, is an amino acid represented by the formula R ³ -NH ₂ (wherein R ³ has the same meaning as above). It can be produced by reacting with formaldehyde. R ³ −NH ₂ +HCHO—→ [CH ₂ =N−R ³ ] _o (wherein, R ³ and n have the same meanings as above) Here, the raw material amino acid (R ³ −NH ₂ )
includes novel compounds, which can be produced, for example, by conventional amino acid synthesis methods.
The amino acid represented by the formula R ³ -NH ₂ can be used in the form of a salt with an acid or a base, and examples of the salt with an acid include inorganic salts such as hydrochloride and hydrobromide. Salts with acids, right salts, acetates, P-
Examples include salts with organic acids such as toluenesulfonate, and examples of salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, and magnesium salts, trimethylamine salts, and dicyclohexylamine salts. , pyridine salts, picoline salts, lutidine salts, ethanolamine salts, morpholine salts, and other salts with organic bases. This reaction is usually carried out in a solvent, and water, methanol, ethanol, diethyl ether, etc. are often used.
Other common organic solvents that do not adversely affect this reaction can also be used. Further, the reaction temperature is not particularly limited, but it is usually carried out under cooling or heating conditions in many cases. (b) Method for producing the starting material () in Process 2: An example of producing the starting material () is as follows. (c) Manufacturing method of starting material () in Process 11: Of this starting material (), compound ( _A )
The production examples of (B) and ( _B ) are as follows. (d) Method for producing starting material () in Process 17: One production example of this starting material () is as follows. Next, each process of the method for producing the azetidinone compound of the present invention described above will be explained in detail. (1) About process 1: This process is carried out by reacting compound () with 2-substituted acetic acid () or a reactive derivative thereof in the presence of a Lewis acid and a base. Representative examples of reactive derivatives of 2-substituted acetic acid () used in this process include, for example:
Examples include acid anhydrides, esters, acid halides, acid amides, azides, etc., and specific examples thereof are shown below. Acid anhydride: Mixed acid anhydride or symmetric acid anhydride with dialkyl phosphoric acid, monoaryl or diaryl phosphoric acid, dialkyl phosphoric acid, halophosphoric acid, dialkyl phosphorous acid, sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid, aromatic carboxylic acid, etc. Preferred examples of these acid anhydrides include diethyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, ethyl carbonate, tertiary butyl carbonate, trichloroethyl carbonate, pivalic acid, trichloroacetic acid, trifluoroacetic acid, and benzoic acid. Examples include mixed acid anhydrides with etc. Ester: Active esters are commonly used as esters, and examples of such active esters include alkyl esters with substituents such as cyanomethyl ester and methoxymethyl ester, alkenyl esters such as allyl ester, and alkynyl esters such as propargyl ester. ester, 4-nitrophenyl ester, 2,4-
Aryl esters with substituents such as dinitrophenyl esters and pentachlorophenyl esters, trimethylsilyl esters, dimethyl-
In addition to silyl esters such as methoxy-silyl ester, esters with N-hydroxy compounds such as acetoxime, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-6-chloro-1H-benzotriazole can be mentioned. Acid amide: As the acid amide, active amides are usually used, and examples of such active amides include amides with pyrazole, imidazole, 4-methylimidazole, and the like. Acid halide: Examples include acid chloride and acid bromide. The Lewis acids used in this process include:
Examples include metal halides and non-metals, and preferred examples of such Lewis acids include, for example,
Boron trihalides such as boron trifluoride, boron trichloride, and boron tribromide, boron trihalides and ethers (e.g., diethyl ether, etc.), alcohols (e.g., methanol, etc.), carboxylic acids ( Coordination compounds with solvents such as acetic acid, aluminum halides such as aluminum chloride and aluminum bromide, zinc halides such as zinc chloride, tin halides such as tin chloride, iron halides such as iron chloride, chloride Examples include titanium halides such as titanium, silicon tetrahalides such as silicon tetrachloride, and antimony halides such as antimony chloride. Among these Lewis acids, boron trifluoride diethyl etherate is the most effective in this reaction. is the most suitable. In addition, examples of bases used in this reaction include trialkylamines (e.g., trimethylamine, triethylamine, tributylamine, etc.),
N,N-dialkylaniline (e.g. N,N-
dimethylaniline, N,N-diethylaniline, etc.), N,N-dialkylbenzylamine (e.g., N,N-dimethylbenzylamine, etc.), N-
Substituted or unsubstituted heterocyclic compounds (e.g. N-
Methylmorpholine, N-methylpiperidine, pyridine, dimethylaminopyridine, picoline, lutidine, quinoline, 1,5-diazabicyclo[4,
Examples include organic bases such as 3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, and 1,8-diazabicyclo[5,4,0]-8-undecene. This reaction is usually carried out under mild conditions such as cooling or room temperature. In addition, this reaction is usually carried out in a solvent, and dichloromethane, chloroform, carbon tetrachloride, diethyl ether, dioxane, pyridine, dimethylformamide, or a mixed solvent thereof is often used, but other solvents that do not adversely affect this reaction General organic solvents can also be used.
Furthermore, when the Lewis acid and base are liquids, they can also be used as a solvent. In this reaction, during the reaction or during the post-treatment of the reaction, for example, if the carboxy group in the compound ( ¹ ') or () is converted to its derivative, and if the derivative of the carboxy group is converted to a free carboxy group, ○ (b) If the amino group, monosubstituted amino group, alkanesulfonamide group, mercapto group, and hydroxy group in R ³ of compound () is
○C When the amino group in R ³ of the compound () is converted to the corresponding acylamino group, N-substituted acylamino group, N-acylalkanesulfonamide group, acylthio group, and acyloxy group, ,
When forming a salt with an inorganic acid such as hydrobromic acid, or an organic acid such as acetic acid, acetic acid, fumaric acid, maleic acid, or P-toluenesulfonic acid, R ¹ ′ of compound () or ( ¹ ′) and
Side reactions may occur, such as when the protecting groups on the amino, imino, hydroxy, mercapto, and carboxy groups in R ³ are removed and converted to free amino, imino, hydroxy, hydroxyimino, mercapto, and carboxy groups, respectively. , such cases are also included within the scope of this process. Compound produced by this process ( ¹ ′)
may be produced as a mixture of two stereoisomers due to the asymmetric carbon at the 3-position of the azetidine nucleus, and in such cases, each can be separated by conventional optical resolution, if desired. (2) Regarding process 2: This process is carried out by reacting the compound ( ) with 2-substituted acetic acid ( ) or a reactive derivative thereof. As a representative example of the reactive derivative of 2-substituted acetic acid (2) used in this process, the same examples of the reactive derivative of 2-substituted acetic acid mentioned in Process 1 above can be cited. This reaction is carried out by a conventional method, for example, the reaction conditions are cooling to room temperature, and the solvent is usually ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, etc.
Dimethylformamide, water, and the like are often used, but other common organic solvents that do not adversely affect this reaction can also be used. Further, this reaction is usually preferably carried out in the presence of a base, and examples of such a base include the bases mentioned in Process 1 above, but also sodium carbonate, potassium carbonate, magnesium carbonate, and carbonate. Examples include inorganic bases such as calcium, calcium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and calcium hydroxide. This reaction may be carried out in the presence of a Lewis acid, and examples of such a Lewis acid include the specific examples of the Lewis acid described in Process 1 above. (3) Regarding process 3: This process is carried out by reducing the acid group of the compound (). The starting material () in this process can be produced, for example, by processes such as processes 1, 2, and 7 described above. The reduction method in this process is, for example, a conventional method such as chemical reduction or catalytic reduction. Examples of reducing agents used for chemical reduction include:
Metals such as tin, zinc, iron, etc. or metal compounds such as chromium chloride, chromium acetate, hydrochloric acid, hydrobromic acid, diconic acid, acetic acid, propionic acid, trifluoroacetic acid, P
- Examples include combinations with inorganic or organic acids such as toluenesulfonic acid. Catalysts used for catalytic reduction include, for example, platinum catalysts such as platinum plates, platinum sponges, platinum black, platinum colloids, platinum oxide, platinum wires, palladium sponges, palladium black, palladium oxide,
Palladium catalysts such as palladium on carbon, palladium colloid, palladium barium sulfate and palladium barium carbonate, nickel catalysts such as reduced nickel, nickel oxide and Raney nickel, reduced cobalt,
Examples include cobalt catalysts such as Raney cobalt, reduced iron, iron catalysts such as Raney iron, copper catalysts such as reduced copper, and Ullmann copper. Chemical reduction is usually carried out in a solvent, such as water, methanol, ethanol, propanol, or a mixed solvent of these solvents and other general organic solvents. In some cases, it can also be used as a solvent. Catalytic reduction is also usually carried out in a solvent, and specific examples thereof include diethyl ether, dioxane, tetrahydrofuran, and mixed solvents thereof in addition to the solvents mentioned in the above chemical reduction. This reaction is usually carried out under mild conditions such as cooling or heating. In this process, a protected amino, protected hydroxy, protected carboxy or esterified carboxy group in the compound () is converted into the corresponding free amino, hydroxy or carboxy group during the reaction or post-treatment of the reaction. However, such cases are also included in this process. The target substance of this process, 3-aminoazetidinone compound ( ³ ), includes new and known compounds, and is a compound of various antibacterial compounds, such as 2-aminoazetidinone compound (3).
[3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamide]-2-oxo-1-azetidinyl]-2-(4-hydroxyphenyl)acetic acid or 2 - Manufactures [3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamide]-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid, etc. It is useful as a synthetic intermediate. (4) Regarding process 4: This process is carried out by subjecting the compound () to an elimination reaction of its amino protecting group. Methods for removing the amino protecting group used in this process include hydrolysis, reduction, and the use of an iminohalogenating agent and then an iminoetherifying agent, followed by hydrolysis if necessary. This will be explained in detail next. B. Hydrolysis: Here, hydrolysis refers to solvolysis such as hydrolysis, acidolysis, alcohololysis, amineolysis, and hydrazinolysis. Hydrolysis is usually carried out in the presence of an acid or a base, such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acidic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, etc. In addition to organic acids such as , P-toluenesulfonic acid, acidic ion exchange resins can also be used. Examples of bases include hydroxides, carbonates, or hydrogen carbonates of alkali metals or alkaline earth metals (e.g., sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, calcium hydroxide, magnesium hydroxide, etc.), hydroxides, etc. Inorganic bases such as ammonium, alkali metal or alkaline earth metal alkoxides or phenoxides (e.g. sodium methoxide, sodium ethoxide, lithium phenoxide, etc.), mono-, di- or trialkylamines (e.g. methylamine, ethylamine, propyl amine, isopropylamine,
butylamine, N,N-dimethyl-1,3-propanediamine, trimethylamine, triethylamine, etc.), unsubstituted or mono(or di)substituted arylamines (e.g., aniline, N-methylaniline, N,N-dimethylaniline, etc.) , heterocyclic compounds (e.g. pyrrolidine, morpholine,
N-methylmorpholine, N-methylpiperidine,
In addition to organic salts such as hydrazines (eg, hydrazine, methylhydrazine, ethylhydrazine, etc.), basic ion exchange resins, etc. can be mentioned. The reaction temperature for this hydrolysis is usually carried out under mild conditions such as cooling or heating.
This reaction is usually carried out in a solvent such as water, methanol, ethanol, propanol, dimethylformamide, tetrahydrofuran, dioxane,
Hydrophilic solvents such as dimethyl sulfoxide or mixed solvents thereof are often used, but when the acid or base exemplified above is liquid, it can also be used as a solvent. ○B Reduction: Here, the reduction reaction is carried out by conventional methods such as chemical ring element and catalytic reduction. The reaction conditions can also be listed as they are. ○ Regarding the method of hydrolyzing as necessary after the action of an iminohalogenating agent and an iminoetherifying agent: In this method, when the amino protecting group in R ¹ _a of the compound () is an organic carboxamide, the carboxamide bond is more easily cleaved and removal of the amino protecting group is more likely to occur. The first step (iminohalogenation) and the second step (iminoetherification) of this process are carried out at relatively low temperatures in an anhydrous solvent, for example, an aprotic solvent such as dichloromethane, chloroform, diethyl ether, dioxane, etc. solvents are often used. The reactions of the first, second and third stages (hydrolysis) of this process are preferably carried out in one system without isolation. Examples of the iminohalogenating agent in this method include phosphorus compounds such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, and phosphorus oxychloride, thionyl chloride, and phosgene. Examples of the iminoetherification agent in this method include alkanols such as methanol, ethanol, propanol, isopropanol, butanol, and tertiary butanol, alkoxy-substituted alkanols such as methoxyethanol and ethoxyethanol, and alkanethiols such as methanethiol and ethanethiol. , and alkali or alkaline earth metal salts of the above-mentioned alkals and alkanethiols (eg, sodium methoxide, potassium ethoxide, magnesium ethoxide, lithium methoxide, potassium methanethiolate, etc.). Compounds obtained by the action of iminohalogenating agents and iminoetherifying agents are hydrolyzed by conventional methods as necessary, but the hydrolysis is usually carried out under cooling or at room temperature; Alternatively, the reaction can proceed by simply adding a mixture of water and a hydrophilic solvent such as methanol or ethanol;
If necessary, an acid or base as mentioned in ◯B above may be added. In this method, when the amino protecting group in R ¹ _a of compound () is a group such as phthalimide, the removal of the protecting group does not proceed completely and a phthalamic acid or phthalamide type intermediate is generated. However, in such cases, compound ( ⁴ ) can be obtained by further reaction. Certain substituents (e.g., N _- substituted or ^{unsubstituted alkanesulfonamides} , carbamoyl, protected hydroxy, protected (carboxy, protected amino, etc.) may be converted to the respective corresponding alkanesulfonamide, amino, hydroxy, or carboxy, and such cases are also included in this process. (5) Regarding process 5: This process is carried out by reacting the compound () with an acylating agent. In this reaction, the amino group in the 3-amino-2-azetidinone compound () used as a raw material may be activated, and such activated amino groups include, for example, isocyanate, isothiocyanate, Conventional methods such as Schiff's base, salts with acids such as hydrochloric acid and hydrobromic acid, silyl compounds such as trimethylsilyl chloride, groups produced by the reaction of phosphorus compounds such as phosphorus oxychloride, and amino groups, etc. Mention may be made of reactive derivatives of the group. The acylating agent used in this reaction is an organic acid such as organic carboxylic acid, organic carbonic acid, organic carbamic acid, organic sulfonic acid, or organic phosphoric acid, and the acyl moiety of the organic acid is The acyl moieties mentioned in paragraph 1 a) may be mentioned as such, and such acyl moieties may consist of aliphatic, aromatic, aromatic-substituted aliphatic, heterocyclic and heterocyclic-substituted aliphatic acyls. be. Organic acids as acylating agents as mentioned above are usually converted into their reactive derivatives, such as the reactive derivative in 2-substituted acetic acid () mentioned in Process 1 above. Specific examples can be given as they are; in such cases, it is usually preferable to carry out the reaction in the presence of a base, and such bases include those described in Process 1 above.
The specific examples of the bases mentioned in Process 2 can also be cited as they are. When using a free organic acid as an acylating agent, it is preferable to carry out the reaction in the presence of a condensing agent, such as N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-phospholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1
-Alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxa Zolium salt, 2-ethyl-5-(3-sulfophenyl)isoxazolium hydroxide, (chloromethylene)dimethylammonium chloride, 2,2,4,4,6,6-hexachloro-1,3,5, Examples include condensing agents formed by combining 2,4,6-triazatriphosphine and triphenylphosphine with carbon tetrahalides such as carbon tetrachloride and carbon tetrabromide, or halogens such as chlorine, bromine, and iodine. . This reaction is usually carried out in a solvent, and water, acetone, dichloromethane, chloroform, dimethylformamide, etc. are often used, but other general organic solvents that do not have an adverse effect on this reaction can also be used, and the bases and Among the condensing agents, liquid ones can be used also as a solvent. In this process, during the reaction or during the post-treatment of the reaction, for example, amino in the compound (),
It is also included in this process that monosubstituted amino, hydroxy and mercapto groups are acylated with an acylating agent. (6) Regarding process 6: This process is carried out by reacting the compound () with a formyl compound represented by the formula ^R9 -CHO (wherein ^R9 has the same meaning as above) or a reactive derivative thereof. Here, examples of reactive derivatives of the formyl group of the formyl compound include the group

[Formula] (In the group, R ¹⁵ and R ¹⁶ each mean an alkyl group) Acetal (e.g., dimethyl acetal, diethylacetal, dipropylacetal, etc.), group

[Formula] (base, X¹Oyo BiX²each means a halogen atom)
Dihalogen compounds (e.g. dichloride, dib
romido, etc.). This reaction can be carried out in a conventional manner, for example as described in Process 5 above.
In addition to sticky condensing agents, phosgene, thionyl chloride
Presence of Lewis acids such as phosphorus chloride, phosphorus oxychloride, and phosphorus tribromide
It is preferable to do this below. (7) About process 7: This process replaces the compound () with a substitution at its 4-position.
The carbon-carbon double bond of the aralkenyl group is
This is done by chemically subjecting it to a cleavage reaction. This oxidation reaction is carried out by a conventional method, for example,
Permanganates, triacids such as potassium permanganate
Metal oxides such as chromium chloride, osmium tetroxide, etc.
Presence of oxidizing agents such as dinitrogen oxide, hydrogen peroxide, ozone, etc.
It can be done in your presence. (8) Regarding process 8: This process converts the compound () to the formula R¹¹O−NH₂
(In the formula, R¹¹is the same meaning as above)
to act on a compound having a group by a conventional method.
This is done by Compounds having the above amino group (R¹¹O−NH₂)
For example, the amino group in
Acid, acid, acetic acid, P-toluenesulfonic acid, etc.
It may be converted into a salt with organic acid, and such
If compounds are used, they are usually alkali metal compounds.
substances (e.g., sodium hydroxide, potassium hydroxide)
Mu, sodium carbonate, potassium carbonate, sodium bicarbonate
thorium, potassium phosphate, etc.) or alkaline earth
metals (e.g. calcium hydroxide, mag hydroxide)
nesium etc.) under alkaline conditions.
Preferably, the reaction is carried out. (9) About process 9: This process works on compounds with formyl groups.
(XI) was subjected to the reduction reaction of the formyl group by a conventional method.
This is done by Examples of reducing agents used in this reduction reaction include
For example, sodium borohydride, borohydride
Examples include boron hydride metals such as lithium. (10) About process 10: This process works on compounds with formyl groups.
(XII) was added to the carboxy group of the formyl group using a conventional method.
This is done by subjecting it to an oxidation reaction. The oxidizing agent used in this oxidation reaction is
For example, permanganic acids such as potassium permanganate
Salt, chromium trioxide, nitric acid, hydrogen peroxide, organic peracid
or its salts (e.g. perbenzoic acid, m-
Chloroperbenzoic acid, peracetic acid, etc., or their sodium
(or potassium salts, etc.), metals such as silver oxide, etc.
Examples include oxides. (11) About process 11: This process involves the compound () or its
Reactive derivatives at the carboxy group of compounds are always
It is carried out by subjecting it to an intramolecular ring-closing reaction according to the method.
be exposed. Reaction in the carboxy group of the above compound ()
As the reactive derivative, 2 mentioned in the above process 1 is used.
-Specific examples of reactive derivatives of substituted acetic acid ()
I can leave it to you. This reaction is carried out in the presence of a condensing agent and a base.
It is preferred that the condensing agent and base
As a specific example, as described in Processes 1 and 2 above,
Specific examples of the bases described in Process 5 above
Specific examples of condensing agents can be given, and
Additionally, acetic anhydride, ethylmagnesium bromide,
Grignard test such as enylmagnesium bromide
Drugs, trial alkaline compounds such as triisobutylaluminum, etc.
metals, etc. can also be mentioned. (12) About process 12: This process converts the compound () to
Amino, hydroxy and carboxy protection in
This is carried out by subjecting the group to an elimination reaction. Methods for removing this protecting group include, for example, hydrolysis,
reduction, metal halide, metal mercaptide, metal
Using metal salts such as cyanide and metal thiocyanate
This method is carried out using conventional methods such as
reaction reagents, reaction conditions (e.g. reaction solution)
medium, reaction temperature, etc.) are the same as in Processes 3 and 4 above.
The explanation for each corresponding method described in
I can give it to you. Through this reaction, R of compound ()¹ _fIndicated by
a protected amino group in an acylamino group,
Protected hydroxy groups and protected carboxyl groups
The xy group is the corresponding free amino group,
Converts to hydroxyl group. (13) About process 13: This process consists of R of the compound ()³ _ein
By subjecting it to the elimination reaction of the carboxy protecting group
will be held. Removal of carboxy protecting group in this process
Methods include, for example, hydrolysis, reduction, gold halide
genus, metal mercaptide, metal cyanide, metal titanium
Conventional methods such as methods using metal salts such as oceanate
The reaction test in this method is
agent, reaction conditions (e.g., reaction solvent, reaction temperature, etc.)
etc. are the corresponding ones mentioned in processes 3 and 4 above.
I can give you the exact explanation for each method.
Ru. (14) About process 14: This process is based on the amino acid in the compound ().
Removal of hydroxyl and carboxy protecting groups
This is done by attaching appropriate information. An example of how to remove the protecting group in this process is
For example, it is carried out by conventional methods such as hydrolysis and reduction.
The reaction reagents and reaction conditions (e.g.
(e.g., reaction solvent, reaction temperature, etc.)
Explanation for each corresponding method described in 3 and 4
You can give it as is, in this way
So, R of the compound ()³ _gProtection on the inner aralkyl
Protected amino groups, protected hydroxy groups and
and the protecting group on the protected carboxy group is removed.
and the corresponding free amino group, hydroxy group or
and converted into a carboxy group. (15) About process 15: This process involves converting the compound () into
This is done by halogenation. Examples of halogenating agents used here include
, halogens such as chlorine, bromine, iodine, penta-salts
Inorganic chemicals such as phosphorous chloride, thionyl chloride, cuprous chloride, etc.
halogen compounds, N-halamides (e.g.
lomoacetamide, N-iodoacetamide, etc.),
N-haloimide (e.g. N-chlorosuccinimide)
mido, N-bromosuccinimide, N-chlorof
talimide, etc.), pyridinium bromide, perv
Organic halogens such as romide, dioxane, bromide, etc.
Compound, hypochlorous acid, tertiary butyl hypochlorous acid
Hypohalous acid such as Stell, or its alkyl
ester, benzenesulfenyl chloride,
Sulfenes such as Norin-2-sulfenyl chloride
Examples include nil halide. (16) About process 16: This process consists of a compound (¹⁵) to the formula R² _g-H
(In the formula, R² _ghas the same meaning as above)
This is done by reacting compounds in a conventional manner.
be exposed. formula R² _gThe nucleophilic compound represented by -H is hydrogen nitride.
Acids, nitrogen-nucleophilic compounds such as amines, aliphatic, aromatic
Aliphatic or aromatic hydroxylation of aromatic substitution
compounds (e.g. alkanol, aralkanol,
Oxygen-nucleophilic compounds such as phenols, etc.), fats
group, aromatic substituted aliphatic, aromatic or heterocyclic ring
Thiol compounds (e.g. alkanethiols, alkanethiols)
lane thiol, aralkane thiol, heterocyclic thiol
Contains sulfur-nucleophilic compounds such as
Specifically, in the formula of the above nucleophilic compound, R² _gHowever, the above
Compound (¹⁶) of R² _gCompounds that are the groups exemplified in
I can give things away. Nucleophilic compounds such as those mentioned above include alkali metals,
It is used in the form of salts of metals such as alkaline earth metals.
Such alkali metals or
Examples of the alkaline earth metal include sodium,
Potassium, magnesium, calcium, etc.
It will be done. In addition, hydronitride acid is usually made of sodium, etc.
Often used in the form of salts with alkali metals
stomach. (17) About process 17: This process involves converting the compound () into
This is done by halogenation. Examples of halogenating agents used here include
, halogens such as chlorine, bromine, iodine, N-
Haloacetamides (e.g., N-bromoacetamide)
(mido, etc.), N-halolactam (e.g., N-bromo),
mochaprolactam, etc.), N-haloimide (e.g.,
N-chlorosuccinimide, N-bromosuccinimide
imide, N-bromophthalimide, etc.) N-halohi
Dantoin (e.g., N-chlorohydantoin,
N-haloamides such as N-bromohydantoin, etc.)
etc. can be mentioned. This halogenation reaction is carried out by a conventional method,
Ultraviolet irradiation or catalytic amount of radical reaction initiation
Preferably, it is carried out in the presence of an initiator. Here, as an initiator for the radical reaction, for example,
For example, benzyl peroxide, m-chloroperbenzoic acid,
Peroxides such as tertiary butyl hydroperoxide,
Azobis (isobutyronitrile), α,α′-azo
Azo compounds such as isobutanoic acid methyl ester, or
Or the above peroxides (e.g. tertiary butyl hydride)
cobalt (robar oxide) and organic carboxylic acids
Alternatively, a combination of copper salts may be used. (18) About process 18: This process uses halogenated compounds (
¹⁷) by reacting with a heterocyclic thiol.
be called. The heterocyclic thiol used here has the formula R¹⁷−
SH (in the formula, R¹⁷means a heterocyclic group)
R, R¹⁷The heterocyclic group defined in
The complex mentioned in the acyl part of the first term a) in
Specific examples of heterocyclic groups in ring acyl as they are
I can give it to you. This process consists of starting materials (¹⁷) of R⁶ _band
(or) R⁷ _bThe haloalkyl group defined above is
reacts with a heterocyclic thiol to form a heterocyclic thioalkyl
This is a reaction that forms This reaction is carried out in a conventional manner, for example,
The reaction is preferably carried out in the presence of a base;
Examples of such bases include those described in Process 1 and
I will give you the specific examples of bases mentioned in Sections 2 and 2.
can be done. (19) In process 19: This process halogenates the compound ()
by subsequently subjecting it to a dehydrohalogenation reaction.
will be held. In this process, first the compound ()
By halogenating, the compound shown in the following formula
is obtained. (In the formula, R¹and R⁸has the same meaning as above,
X^Fourmeans a halogen atom such as chlorine or brome
) Here the halogenation used in the halogenation reaction
Examples of agents include halogens such as chloro and brome.
sulfuryl chloride, sulfuryl chloride, etc.
N-haloamine such as de, N-bromoacetamide, etc.
Do, N-bromosuccinimide, N-bromophtha
N-haloimide such as limide, N-chloro-1H
-benzotriazole, 1,3,5-trichloro
-2,4,6-trioxoperhydrotriazine
N-haloheterocyclic compounds such as phenyl iodochloride
Halo compounds such as lido and pyridinium iodobromide
Complex compounds of substances and halogens, metals such as cupric chloride
Examples include halides, and other sulfur atoms.
Conventional method that allows halogenation of adjacent carbon atoms
Halogenating agents can be used. Dehalogenation of the compounds thus produced
By hydrogenation, the target compound (¹⁹) get
However, this dehydrohalogenation reaction is carried out by a conventional method.
For example, we usually get good results when we do it in the presence of a base.
I often get . Here, a specific example of a base is
For example, in the hydrolysis described in Process 4 above,
Specific examples of the bases described above can be listed. (20) About process 20: This process is 3-halo-2-azetidinone formation.
Hydrogen nitride acid or its salts is applied to the compound ().
It is done by letting The hydronitridic acid salts used in this process and
For example, alkaline substances such as sodium and potassium
salts with potassium metals, calcium, magnesium, etc.
Examples include salts with alkaline earth metals. (21) About process 21: This process converts the compound () into hydroxy
By acting with ruamine or its salts
It is done. Hydroxylamine used in this process
Examples of salts include inorganic acids such as hydrochloric acid and sulfuric acid.
salts, dinic acid, acetic acid, trifluoroacetic acid, P-tolu
Examples include salts with organic acids such as ensulfonic acid. This reaction is usually carried out in the presence of a base;
Specific examples of such bases include, for example, the bases described above.
The specific examples of bases mentioned in steps 1 and 2 can be used as they are.
can be given. This reaction is usually carried out in a solvent, including water, methane,
alcohol, ethanol, propanol, dimethylform
Muamide or mixed solvents thereof are often used.
However, there are other commonly available substances that do not adversely affect this reaction.
Organic solvents can also be used. The temperature of this reaction is room temperature or moderate temperature.
This is often done under certain conditions. Target compounds obtained by the above processes 1 to 21
Products are isolated and purified using conventional methods, and each process
The resulting compound can be used in the next step without being isolated or purified.
It can also be used as a starting material for processes. The azetidinone compound () of this invention has antibacterial activity.
It is useful as a medicine and has other antibacterial properties.
useful as a synthetic intermediate for producing substances with
be. That is, azetidinone compound ()
For example, 3-acylamino-2-azetidinone
The compounds exhibit antibacterial activity as shown in the table below and are used as pharmaceuticals.
It is also useful as 3-phthalimide, 3
-Azide- and 3-amino-2-azetidinone
The compound is the above 3-acylamino-2-azetidi
It is useful as a synthetic intermediate for producing non-compounds.
Ru. Here, the azetidinone compound of this invention ()
Antibacterial activity (minimum inhibitory concentration) for typical examples of
The expression is as follows. Test method Take one platinum loop from the slant of the test bacteria and place it in a 5ml buoy.
Inoculate into a medium-sized test tube containing Yon and leave it at 30℃ overnight.
Cultivate. 1% of this cultured bacteria was
Add to Tong medium (1% agar) and add to 8cm diameter shear plate.
Dispense in 10ml portions. Obtained by this invention as shown below
Add the target substance to 10mg/ml in water and 2% carbonate.
Diluted in sodium hydrogen aqueous solution or methanol
Interpret. Apply this to 8mm long diameter pulp and test.
M.I.C. (minimum
(inhibitory concentration). M.I.C. Compound of Example 91: Against Escherichia coli
0.25γ, Pseudomonas aeruginosa
4γ for Compound of Example 108: Against Escherichia coli
0.5γ, Compound of Example 114: Staphylococcus au
3.75γ for Reus, Pseudomonas
15γ against S. aeruginosa, Essie
15γ against Lychia coli, Bacillus
15γ for P. suburitis; Compound of Example 115: Staphylococcus au
60γ for Reus, Next, the present invention will be explained with reference to examples. Manufacture of new raw materials: Manufacturing example 1 1,3,5-tris [D-1-methoxycarbo
Nyl-1-(2-thienyl)methyl]-perhy
Production of Dro-1,3,5-triazine: D-2-(2-thienyl)glycine methyl es
Dissolve 25.0g of Teru hydrochloride in 130ml of water,
250 ml of benzene was added dropwise to the liquid. Add ice to this mixture.
Drop 120ml of 1N sodium hydroxide aqueous solution under cooling.
Then add 9.9 ml of 37% formaldehyde aqueous solution.
I got it. The mixture was then stirred for 2 hours at the same temperature.
Ta. Separate the benzene layer from the reaction solution and remove the remaining aqueous layer.
was extracted with ethyl acetate. Separate this extract first
Combine the benzene layer, wash with water, and add magnesium sulfate.
It was dried. The solvent was distilled off under reduced pressure and the residue was diluted.
When recrystallized from sopropyl ether, 1,3,5
-Tris[D-1-methoxycarbonyl-1-
(2-thienyl)methyl]-perhydro-1,3,
16.5 g of 5-triazine was obtained. Infrared absorption spectrum (hereinafter referred to as IR) νcm^-1(Nujiyor) 1739 NMR absorption spectrum (hereinafter referred to as NMR) (Internal standard: Tetramethylsilane, hereinafter TMS
) δppm (CDCl₃) 3.69 (9H, s), 3.78 (6H, s), 4.89 (3H, s),
6.80~7.43 (9H, m) The corresponding amino acid was prepared in substantially the same manner as in Preparation Example 1.
By reacting a carbon derivative with formaldehyde,
The following compounds were produced. Manufacturing example 2 1,3,5-tris (D-α-methoxycarbo
Nyl-3-mesylaminobenzyl)-perhydro
-1,3,5-triazine. IR νcm^-1(film) 3550 (broad), 3240, 1730 NMR (TMS) 4.00~4.24 (2H, m) 4.05 (1H, d, J=2
Hz) 5.18 (1H, s) 4.56 (1H, d, J=2
Hz) 7.30 (5H, s) 5.34 (1H, s) 7.30
(5H, s) Example 33 2-[3-amino-4-(5-methyl-1,
3,4-thiadiazol-2-ylthio)-2-
Oxo-1-azetidinyl]-2-phenylacetic acid
Methyl [two at the 3rd and 4th positions of the azetidine ring
mixture of trans isomers]. IR νcm^-1(film) 3280, 1770, 1640 Example 34 2-[3-amino-4-(5-methyl-1,
3,4-thiadiazol-2-ylthio)-2-
Oxo-1-azetidinyl]-2-phenylacetic acid
Methyl [two at the 3rd and 4th positions of the azetidine ring
mixture of cis isomers]. IR νcm^-1(film) 3350, 1765, 1740 Example 35 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetate ben
Zyl [two at positions 3 and 4 of the azetidine ring
mixture of trans isomers]. IR νcm^-1(film) 3400～3300, 1770, 1740, 1680 Example 36 2-(3-amino-2-oxo-1-azetidi
nyl)-2-(2-thienyl)acetic acid. IR νcm^-1(Nujiyor) 2750-2250, 1760 (shoulder), 1745, 1620 Example 37 2-(3-amino-2-oxo-1-azetidi
nyl)-2-(2-furyl)acetic acid. IR δppm (CDCl₃) 3.08 (3H, s), 3.61 (5H, broad s), 4.53
(1H, s), 7.0-7.6 (4H, m), 7.71 (1H, Brochure)
code) Manufacturing example 3 1,3,5-tris [dl-1-methoxycarbo
Nyl-1-(1-naphthyl)methyl]-perhydride
Rho-1,3,5-triazine, mp148-151℃. Manufacturing example 4 1,3,5-tris (dl-1-methoxycarbo
Nyl-2-phenylthioethyl)-perhydro-
1,3,5-triazine. NMR (TMS) δppm (CDCl₃) 3.10~3.90 (15H, m), 3.68 (9H, s), 7.1~
7.5 (15H, m) Manufacturing example 5 1,3,5-tris(4-benzyloxy-α
-methoxycarbonylphenethyl)-perhydro
-1,3,5-triazine, mp106-109℃. Manufacturing example 6 1,3,5-tris [dl-erythro-α-meth
xycarbonyl-β-methoxyphenethyl)-p
-hydro-1,3,5-triazine. Manufacturing example 7 1,3,5-tris [dl-1-(2-frill)
-1-methoxycarbonylmethyl]-perhydro
-1,3,5-triazine. NMR (TMS) δppm (CDCl₃) 3.5-3.8 (12H, m), 4.74 (3H, s), 6.28 (6H,
m), 7.32 (3H, m) Manufacturing example 8 1,3,5-tris[methoxycarbonylmethy]
)-perhydro-1,3,5-triazine. IR νcm^-1(film) 1740-1755 NMR (TMS) δppm (CDCl₃) 3.48 (6H, s), 3.73 (15H, s) Manufacturing example 9 1,3,5-tris[ethoxycarbonylmethy]
)-perhydro-1,3,5-triazine. IR νcm^-1(film) 1730-1750 NMR (TMS) δppm (CDCl₃) 1.25 (9H, t, J=6Hz), 3.45 (6H, s),
3.73 (6H, s), 4.17 (6H, q, J = 6Hz) Manufacturing example 10 1,3,5-tris[benzyloxycarboni
(methyl)-per-hydro-1,3,5-triazid
hmm. IR νcm^-1(film) 1740 NMR (TMS) δppm (CDCl₃) 3.44 (6H, s), 3.69 (6H, s), 5.10 (6H, s),
7.40 (15H, s) Manufacturing example 11 1,3,5-Tris [D-α-methoxycarbo
nylbenzyl)-perhydro-1,3,5-tri
Azine, mp148-155℃. IR νcm^-1(Nujiyor) 1730 NMR (TMS) δppm (CDCl₃) 3.49 (9H, s), 3.51 (6H, s), 4.50 (1H, s),
7.42~6.90 (15H, m) Manufacturing example 12 1,3,5-tris[D-4-benzyloxy
-α-methoxycarbonylbenzyl)-perhydride
Rho-1,3,5-triazine, mp141-145°C. IR νcm^-1(Nujiyor) 1725 NMR (TMS) δppm (CDCl₃) 3.58 (15H, s), 4.50 (3H, s), 5.04 (6H,
s), 6.80 (6H, d, J=9Hz), 7.29 (6H, d,
J=9Hz), 7.40 (15H, s) Manufacturing example 13 1,3,5-tris[D-4-benzyloxy
Carbonyloxy-α-methoxycarbonylben
Zyl)-perhydro-1,3,5-triazine. IR νcm^-1(film) 1740, 1710 NMR (TMS) δppm (CDCl₃) 3.50 (15H, s), 4.42 (3H, s), 5.23 (6H,
s), 6.99 (6H, d, J=9Hz), 7.23 (6H, d,
J=9Hz), 7.27 (15H, s) Manufacturing example 14 1,3,5-tris [dl-2-methoxycarbo
Nyl-1-phenylethyl)-perhydro-1,
3,5-triazine, mp92-96°C. IR νcm^-1(Nujiyor) 1735 Manufacturing example 15 1,3,5-tris[4-methoxycarbonyl
phenyl)-per-hydro-1,3,5-triazid
temperature, mp208-209.5℃ (decomposed). IR νcm^-1(Nujiyor) 1710 Manufacturing example 16 1,3,5-tris[D-α-benzyloxy
carbonylbenzyl)-perhydro-1,3,5
-Triazine, mp118-119°C. IR νcm^-1(Nujiyor) 1730, 1740 (shoulder) NMR (TMS) δppm (CDCl₃) 3.57 (6H, s), 4.52 (3H, s), 4.95 (6H, s),
6.95~7.45 (30H, m) Manufacturing example 17 1,3,5-Tris [D-α-methoxycarbo
Nyl-3-nitrobenzyl)-perhydro-1,
3,5-triazine. IR νcm^-1(liquid film) 1740 NMR (TMS) δppm (CDCl₃) 3.65 (15H, broad s), 4.65 (3H, s), 7.45
~8.2 (12H, m) Manufacturing example 18 1,3,5-tris[D-α-benzyloxy
Carbonyl-4-benzyloxybenzyl)-p
-Hydro-1,3,5-triazine, mp108~
110℃. IR νcm^-1(Nujiyor) 1745, 1735, 1720 NMR (TMS) δppm (CDCl₃) 3.55 (6H, s), 4.47 (3H, s) 4.92 (12H, s)
6.76 (6H, d, J=8Hz), 7.00~7.44 (36H,
m) Manufacturing example 19 1,3,5-tris[4-phenathyloxy-
α-phenatyloxycarbonylbenzyl)-
Production of per-hydro-1,3,5-triazine: N-tertiary butoxycarbonyl-2-(4-hybrid)
Droxyphenyl) glycine 9.18g, fenatil
Promide 6.86g and sodium hydroxide 1.37g
Dissolve each in 100ml of N,N-dimethylformamide.
The dissolved solution was stirred at room temperature for 4 hours. reaction mixture
Pour the material into 500ml of water and use 50ml each of ethyl acetate.
Extracted three times. Combine the extracts, wash with water, and soak with sulfuric acid macerate.
Dried with gnesium. Evaporate the solvent under reduced pressure;
Oily N-tertiary butoxycarbonyl-2-(4
-Hydroxyphenyl) glycine phenacyl es
13.19 g of tel was obtained. IR νcm^-1(film) 3400 (broad), 1750, 1710, 1690 3.56 g of the compound obtained above, phenacyl bromide
1.84 g of potassium carbonate and 1.28 g of potassium carbonate were dried in a drying oven.
A solution dissolved in 71 ml of setone was heated under reflux for 7 hours.
Ta. Insoluble materials were removed from the reaction mixture and the filtrate was placed under reduced pressure.
Evaporate to dryness and dissolve the resulting residue in chloroform.
Dissolved. Wash the chloroform solution with water and place it in a sulfuric acid mug.
dried with nesium. Distill the chloroform under reduced pressure.
A residue was obtained. Diisopropyl ether to the residue
When added, N-tertiary butoxycarbonyl-2-
(4-phenatyloxyphenyl) glycine phenylene
4.12 g of crystals of natyl ester were obtained. This product
Pure product with mp125-126℃ when recrystallized with ethanol
was gotten. Dissolve 1 g of the compound obtained above in 10 ml of ethyl acetate.
and a mixture of hydrobromic acid and acetic acid (4:1 by volume)
2 ml was added and the reaction mixture was stirred at room temperature for 30 minutes.
Ta. Filter the precipitated crystals and wash with ethyl acetate.
and 2-(4-phenatyloxyphenyl)glycide
830 mg of nphenate hydrobromide was obtained.
This product can be mixed with ethanol, methanol and diethyl ether.
When recrystallized with a mixture of
0.55g of product was obtained. 9.5 g of the compound thus obtained and 37% formua
Substantially the same as in Production Example 1, 6 ml of aldehyde aqueous solution was added.
When reacted by the method, 1,3,5-tris[4
-Phenatyloxy-α-Phenatyloxycal
(bonylbenzyl)-perhydro-1,3,5-t
7.25 g of riazine was obtained. mp80~90℃. NMR (TMS) δppm (CDCl₃) 3.70 (6H, s), 4.65 (3H, s), 5.19 (6H, s),
5.23 (6H, s), 6.86-8.04 (42H, m). Manufacturing example 20 D-2-(4-benzyloxyphenyl)-N
-Methylthiomethyleneglycine benzyl ester
Manufacture of: 3.9 g of triethylamine in dry chloroform 10
ml of D-2-(4-benzyl alcohol).
xyphenyl) glycine benzyl ester p-
20 g of toluene sulfonate in dry chloroform
It was added dropwise to a 400 ml solution while stirring under ice cooling. blood
Add 5.21 g of oxformic acid O-ethyl ester to dry chloroform.
Mix the solution dissolved in 10 ml of lum at the same temperature as described above.
It dripped onto things. The reaction mixture was then kept at room temperature overnight.
Stir and pour into 400ml of ice water, then filter off insoluble matter.
did. The organic solution layer was treated with 1% phosphoric acid aqueous solution and water, respectively.
After washing, dry with magnesium sulfate, then reduce
The solvent was evaporated to dryness under pressure. 13.1g of residue is silica
Developed on a chromatograph using 100g of gel and added benzene.
It was eluted. Combine the fractions containing the target substance and dissolve
When the solvent is distilled off under reduced pressure, D-2-(4-benzi
oxyphenyl)-N-thioformylglycine
3.66 g of benzyl ester crystals were obtained. This product
recrystallize from a mixture of benzene and n-hexane.
A pure product with a mp of 124 to 126°C was obtained. D-2-(4-benzyloxyphenyl)-N
-Thioformylglycine benzyl ester 3.56
g, potassium carbonate 0.63 g and methyl iodide 3.89 g.
Add the mixture to 35 ml of dry acetone and leave at room temperature for 23 hours.
Stirred. Filter off the solid and evaporate the filtrate under reduced pressure.
It was dried and solidified. The residue was dissolved in chloroform and washed with water.
Dry with magnesium sulfate and then evaporate to dryness under reduced pressure.
Upon solidification, a crystalline material was obtained. This product contains diisopropylene.
After adding ether and crushing it and collecting it by filtration, D-2-
(4-benzyloxyphenyl)-N-methylthi
Obtained 3.08g of omethyleneglycine benzyl ester.
It was done. mp78~80℃ when recrystallized with ethanol
I got a pure product. IR νcm^-1(Nujiyor) 1730, 1610 NMR (TMS) δppm (CDCl₃) 2.36 (3H, s), 5.00 (2H, s), 5.08 (1H, s),
5.10 (2H, s), 6.78-7.56 (14H, m), 8.25
(1H, s) By substantially the same method as Production Example 20, the following chemical reaction was carried out.
Compounds (Production Examples 21 and 22) were produced. Manufacturing example 21 D-2-(4-benzyloxyphenyl)-N
-Methylthiomethyleneglycine methyl ester. NMR (TMS) δppm (CDCl₃) 2.40 (3H, s), 3.65 (3H, s), 5.01 (1H, s),
5.06 (1H, s), 6.83~7.53 (9H, m), 8.28
(1H, s) Manufacturing example 22 D-N-methylthiomethylene-2-phenylg
Lysine methyl ester. NMR (TMS) δppm (CDCl₃) 2.36 (3H, s), 3.60 (3H, s), 5.03 (1H, s),
7.25 (5H, s), 8.20 (1H, s) Manufacturing example 23 D-N-benzylidene-2-(4-hydroxy
Production of phenyl)glycine methyl ester: D-2-(4-hydroxyphenyl)glycine
16.8g methyl ester and 9.86g benzaldehyde
Dissolved in 250ml of methanol and heat for 1 hour.
It refluxed. Methanol was distilled off under reduced pressure, and the residue was
Dissolved in 200ml of benzene. Filter the precipitated crystals
When recrystallized with benzene, D-N with mp128℃ is obtained.
-benzylidene-2-(4-hydroxyphenylene)
21.0 g of glycine methyl ester was obtained. By substantially the same method as Production Example 23, the following
Compounds (Production Examples 24 and 25) were produced. Manufacturing example 24 D-N-Benzylidene-2-phenylglycine
Methyl ester. IR νcm^-1(Nujiyor) 1740, 1635 Manufacturing example 25 D-N-cinnamylidene-2-phenylglycide
Methyl ester. IR νcm^-1(film) 1740, 1635 NMR (TMS) δppm (CDCl₃) 3.66 (3H, s), 5.05 (1H, s), 6.93~7.08
(2H, m), 7.16-7.60 (10H, m), 8.05 (1H,
q) Production of target compound: Example 1 Dissolve 480 mg of pyridine in 2 ml of dichloromethane,
1.34g of 2-phthalimidoacetic acid chloride in dichloromethane
-35~-30℃ solution dissolved in 20ml of lomethane.
The mixture was added dropwise over a period of 15 minutes at room temperature. On the other hand 1, 3,
5-Tris [D-1-(2-thienyl)-1-meth
Toxycarbonylmethyl]-perhydro-1,
Diesel of 3,5-triazine 550mg and boron trifluoride
430 mg of thyl ether complex compound in dichloromethane 10
ml, and this solution was heated at -60°C.
Then, it was added dropwise to the previously obtained solution over a period of 15 minutes. anti
The reaction mixture was stirred at the same temperature for 2 hours, then further stirred on ice for 30 minutes.
Stirring was continued for a minute. Evaporate the reaction mixture to dryness under reduced pressure.
Once solidified, 30 ml of ethyl acetate and 30 ml of water were poured into the residue.
After that, insoluble matter was filtered off. Separate the ethyl acetate layer from the filtrate.
The mixture was separated and the remaining aqueous layer was extracted with ethyl acetate. acetic acid
Combine the ethyl layers and dilute sodium bicarbonate with dilute hydrochloric acid 3 times.
Rinse with sulfuric acid mug three times and once with water.
dried with nesium. Obtained by distilling off the solvent under reduced pressure.
The resulting residue was subjected to column chromatography using 20 g of silica gel.
Expanded into a graph. Perform elution with chloroform.
Then, fractions containing the target substance were collected. From this concentrated liquid
When chloroform is distilled off under reduced pressure, oily D-
2-(2-oxo-3-phthalimido-1-acetate)
Tidinyl)-2-(2-thienyl)methyl acetate
720mg was obtained.
is a mixture of two isomers). thus obtained
When the obtained compound is recrystallized from ethanol, the above compound is obtained.
One of the isomers of the compound was obtained in crystalline form (300
mg). mp167~170℃. In substantially the same manner as in Example 1, the corresponding pattern
-Hydro-1,3,5-triazine derivative and 2-
By reacting substituted acetic acid chloride, the following
Compounds (Examples 2 to 15) were prepared. Example 2 D-2-(3-azido-2-oxo-1-aze
Tidinyl)-2-phenylacetate methyl
A mixture of isomers (a) and (b) at the 3-position of the ring
ratio of approximately 3:1)]. IR νcm^-1(film) 2080, 1760, 1730. NMR (TMS) δppm (CDCl₃) Isomer (a); 2.93 (1H, q, J = 2Hz, 6Hz) 3.73 (3H, s) 3.86 (1H, t, J=6Hz) 4.63 (1H, q, J = 2Hz, 6Hz) 5.56 (1H, s) 7.28 (5H, s) Isomer (b); 3.26-3.76 (2H, m) 3.80 (3H, s) 4.50 (1H, q, J = 2Hz, 5Hz) 5.60 (1H, s) 7.33 (5H, s) Example 3 dl-2-(2-oxo-3-phthalimide-1
-Azetidinyl)-3-phenylthiopropion
Acid methyl ester [at the 3-position of the azetidine ring]
A mixture of isomers (a) and (b) (mixing ratio of about 3:2)]. IR νcm^-1(Nujiyor) 1785, 1770, 1735, 1715 NMR (TMS) δppm (CDCl₃) Isomer (a); 3.1~3.9 (4H, m) 3.76 (3H, s) 4.64 (1H, d, d, J=8.5, 5Hz) 5.20 (1H, d, d, J=6,3Hz) 7.30 (5H, m) 7.70 (4H, m) Isomer (b); 3.1~3.9 (4H, m) 3.76 (3H, s) 4.64 (1H, d, d, J=8.5, 5Hz) 5.40 (1H, t, J=6Hz) 7.30 (5H, m) 7.70 (4H, m) Example 4 dl-2-(1-naphthyl)-2-(2-oxo
-3-phthalimido-1-azetidinyl)acetic acid
Chill, mp200.5~201.5℃. IR νcm^-1(Nujiyor) 1724, 1740, 1750, 1782 NMR (TMS) δppm (CDCl₃) 3.16 (1H, d, d, J = 6, 3Hz), 3.80 (3H,
s), 3.89 (1H, t, J=6Hz), 5.50 (1H, d,
d, J=6.3Hz), 6.45 (1H, s), 7.3~8.3
(7H, m) Example 5 dl-erythro-3-methoxy-3-phenyl-
2-(2-oxo-3-phthalimido-1-aze
Tidinyl) methyl propionate [two isomers (a)
and (b) mixture (mixing ratio of about 3:2)]. Isomer (a); mp150~155℃ IR νcm^-1(Nujiyor) 1785 (shoulder), 1760, 1735, 1715 NMR (TMS) δppm (CDCl₃) 3.24 (3H, s), 3.86 (3H, s), 4.56 (1H, d,
J=8Hz), 4.84 (1H, d, J=8Hz), 5.08
(1H, d, d, J=3,6Hz), 7.37 (5H,
s), 7.6-7.8 (4H, m) Isomer (b): NMR (TMS) δppm (CDCl₃) 3.36 (3H, s), 3.68 (3H, s), 4.71 (1H, d,
J=6Hz), 4.95 (1H, d, J=6Hz), 5.38
(1H, d, d, J=6,4Hz), 7.40 (5H,
s), 7.6-7.9 (4H, m) Example 6 dl-3-(4-benzyloxyphenyl)-2
-Oxo-3-phthalimide-1-azetidine
) Methyl propionate (mixture of two stereoisomers)
compound). IR νcm^-1(Nujiyor) 1780, 1760, 1738, 1705 Example 7 D-2-(3-azido-2-oxo-1-aze
Tidinyl)-2-(2-thienyl)acetate
[Mixture of isomers (a) and (b) at the 3-position of the azetidine ring]
mixture (mixing ratio of approximately 1:1)]. NMR (TMS) δppm (CDCl₃) Isomer (a); 3.17 (1H, d, d, J=2.5, 6Hz) 3.80 (3H, s) 3.95 (1H, t, J=6Hz) 4.70 (1H, d, d, J=2.5, 6Hz) 5.88 (1H, s) 7.05 (2H, m) Isomer (b); 3.60 (2H, m) 3.82 (3H, s) 4.53 (1H, d, d, J=2.5, 6Hz) 5.87 (1H, s) 7.05 (2H, m) 7.26 (1H, m) Example 8 D-2-[2-oxo-3-(2-oxo-
4,5-diphenyl-4-oxazoline-3-y
Ru-1-azetidinyl]-2-(2-thienyl)
Methyl acetate [isomer at the 3-position of the azetidine ring]
A mixture of (a) and (b) (mixing ratio of about 2:1)]. NMR (TMS) δppm (CDCl₃) Isomer (a): 3.67 (1H, d, d, J=2.5, 6Hz) 3.76 (3H, s) 3.84 (1H, t, J=6Hz) 4.92 (1H, d, d, J=2.5, 6Hz) 5.82 (1H, s) 6.88~7.62 (13H, m) Isomer (b): 3.60 (1H, t, J=6Hz) 3.80 (3H, s) 4.08 (1H, d, d, J=2.5, 6Hz) 4.80 (1H, d, d, J=2.5, 6Hz) 5.78 (1H, s) 6.88~7.62 (13H, m) Example 9 D-2-(2-oxo-3-phthalimide-1
-Azetidinyl)-2-(4-phenatyloxy
phenyl) phenatyl acetate [3-position of azetidine ring
A mixture of isomers (a) and (b) in (mixing ratio approximately 2:
1)]. IR νcm^-1(film) 1780 (shoulder), 1760, 1720, 1700, 1680 (shoulder) NMR (TMS) δppm (CDCl₃): Isomer (a); 3.43 (1H, d, d, J = 3Hz, 5Hz) 3.82 (1H, t, J=5Hz) 5.30~5.54 (5H, m) Isomer (b); 3.55 (1H, t, J=5Hz) 4.06 (1H, d, d, J = 3Hz, 5Hz) 5.30~5.54 (5H, m) Example 10 Dl-2-(2-furil)-2-(2-oxo
-3-phthalimido-1-azetidinyl)acetic acid
Chil [Mixture of two isomers (a) and (b) (mixture ratio approx.
4:1)], mp176-178℃. IR νcm^-1(Nujiyor) 1770. (shoulder), 1760, 1730, 1710 Example 11 D-2-(3-azido-2-oxo-1-aze
Tidinyl)-2-(4-benzyloxyphenylene)
) Benzyl acetate [at the 3-position of the azetidine ring]
A mixture of isomers (a) and (b). IR νcm^-1(film) 2100, 1765, 1735 NMR (TMS) δppm (CDCl₃) Isomer (a); 2.94 (1H, d, d, J = 2Hz, 5Hz) 3.84 (1H, t, J=5Hz) 4.62 (1H, d, d, J = 2Hz, 5Hz) 5.03 (2H, s) 5.13 (2H, s) 5.61 (1H, s) 7.09 (4H, AB-q, J=8Hz) 7.12~7.56 (10H, m) Isomer (b); 3.35 (1H, t, J=5Hz) 3.56 (1H, d, d, J = 2Hz, 5Hz) 4.46 (1H, d, d, J = 2Hz, 5Hz) 5.03 (2H, s) 5.18 (2H, s) 5.58 (1H, s) 7.09 (4H, AB-q, J=8Hz) 7.12~7.56 (10H, m) Example 12 Dl-2-(3-benzyloxy-2-oxo
-1-Azetidinyl]-2-phenylacetic acid benzene
[Mixture of two isomers (a) and (b) (mixture ratio approximately 5:
2)]. IR νcm^-1(film) 1760, 1740 NMR (TMS) δppm (CDCl₃): Isomer (a); 3.18 (1H, d, d, J = 4Hz, 5Hz) 4.02 (1H, d, d, J=5Hz, 6Hz) 5.17 (4H, s) 5.27 (1H, d, d, J = 2Hz, 5Hz) 5.75 (1H, s) 6.8~7.4 (15H, m) Isomer (b); 3.52 (1H, d, d, J = 4Hz, 5Hz) 3.78 (1H, d, d, J = 2Hz, 4Hz) 5.12 (1H, d, d, J = 2Hz, 6Hz) 5.17 (4H, s) 5.72 (1H, s) 6.8~7.4 (15H, m) Example 13 D-2-(3-phenoxy-2-oxo-1-
azetidinyl)-2-phenylacetate methyl
Mixture of isomers (a) and (b) at position 3 of the tidine ring
(Mixing ratio approximately 1:1)]. IR νcm^-1(film) 1790, 1740 NMR (TMS) δppm (CDCl₃) Isomer (a); 3.15 (1H, d, d, J = 2Hz, 6Hz) 3.70 (3H, s) 5.28 (1H, d, d, J = 2Hz, 5Hz) 5.67 (1H, s) 6.8~7.4 (10H, m) Isomer (b); 3.52 (1H, d, d, J = 5Hz, 6Hz) 3.70 (3H, s) 5.06 (1H, d, d, J = 2Hz, 5Hz) 5.63 (1H, s) 6.8~7.4 (10H, m) Example 14 D-2-(3-chloro-2-oxo-1-aze
Tidinyl)-2-phenylacetate methyl
A mixture of isomers (a) and (b) at the 3-position of the ring
ratio of approximately 1:1)]. IR νcm^-1(film) 1770 (broad), 1740 NMR (TMS) δppm (CDCl₃) Isomer (a); 3.14 (1H, d, d, J = 2Hz, 6Hz) 3.75 (3H, s) 4.81 (1H, d, d, J = 2Hz, 5Hz) 5.64 (1H, s) 7.2~7.5 (5H, m) Isomer (b); 3.60 (1H, t, J=6Hz) 3.78 (3H, s) 4.77 (1H, d, d, J = 2Hz, 6Hz) 5.61 (1H, s) 7.2~7.5 (5H, m) Example 15 D-2-(3-diethylphosphorylamino-2
-oxo-1-azetidinyl]-2-phenyl vinegar
Methyl acid [isomer at the 3-position of the azetidine ring]
blend〕. IR νcm^-1(film) 3450, 1750, 1710, 1270 Example 16 1,3,5-tris (D-α-methoxycarbo
Nyl-3-mesylaminobenzyl) perhydro-
2.53 g of 1,3,5-triazine was added to Example 1.
2-phthalimidoacetic acid chloride in the same manner as above.
React with 8.38 g of D-2 [3
-{N-Mesyl-2-(phthalimide)acetami
phenyl]-2-(2-oxo-3-phthal
2.2 g of methyl imido-1-azetidinyl) acetate
Obtained. IR νcm^-1(Nujiyor) 1780 (shoulder), 1770, 1730, 1720 NMR (TMS) δppm (CDCl₃) 3.57 (3H, s), 3.74 (1H, m), 3.85 (3H, s),
4.03 (1H, t, J=6Hz), 4.22 (2H, s),
5.54 (1H, d, d, J = 6Hz, 3Hz), 5.93
(1H, s), 7.60 (12H, m) Example 17 D-2-(4-benzyloxyphenyl)-N
-Methylthiomethyleneglycine benzyl ester
Dissolve 2.67 g in methylene chloride. On the other hand
Add 1.47 g of thalimidoacetic acid chloride to methylene chloride.
Dissolve in 10 ml of Ride and add this solution to the solution obtained earlier.
The mixture was added dropwise over 10 minutes while stirring at 0 to 5°C. same temperature
After stirring for an additional 15 minutes at
A solution of 0.67g dissolved in 10ml of methylene chloride
was added dropwise to the above mixture at room temperature and stirred for 40 minutes.
continued. The reaction mixture was mixed with water, dilute hydrochloric acid, and sodium bicarbonate.
Rinse with magnesium sulfate solution, then water, and then rinse with magnesium sulfate.
After drying with aluminum, the mixture was evaporated to dryness under reduced pressure. residue
3.69g was applied to a chromatograph using 110g of silica gel.
The mixture was opened and eluted with chloroform. Combine each elution fraction.
and evaporated to dryness to form an oily D-2-(4-benzyl
oxyphenyl)-2-(4-methylthio-2-
oxo-3-phthalimido-1-azetidinyl)
3.15 g of benzyl acetate was obtained. This product has two 3 and 4
- Same as approximately 1:1.7 mixture of trans isomers (a) and (b)
Established. IR νcm^-1(film) 1780, 1770, 1740, 1720 NMR (TMS) δppm (CDCl₃) Isomer (a); 2.10 (3H, s) 4.69 (1H, d, J = 2.5Hz) 5.01 (2H, s) 5.30 (1H, d, J = 2.5Hz) 5.57 (1H, s) 6.69~7.52 (14H, m) 7.56-7.94 (4H, m) Isomer (b); 1.83 (3H, s) 5.02 (2H, s) 5.29 (2H, s) 5.40 (1H, s) 6.69~7.52 (14H, m) 7.56-7.94 (4H, m) In substantially the same manner as Example 17, the corresponding group
Reacting lysine derivative with 2-substituted acetic acid chloride
The following compounds (Examples 18-29) were prepared by
Manufactured. Example 18 D-2-(4-benzyloxyphenyl)-2
-(4-methylthio-2-oxo-3-phthalyl
Mid-1-azetidinyl) acetic chloride
Two trans-isomers at positions 3 and 4 of the thidine ring
A mixture of sex substances (a) and (b) (mixing ratio of about 2:1)]. IR νcm^-1(film) 1780, 1770, 1740, 1720 NMR (TMS) δppm (CDCl₃) Isomer (a); 2.14 (3H, s) 3.79 (3H, s) 4.71 (1H, d, J = 2.5Hz) 5.04 (2H, s) 5.33 (1H, d, J = 2.5Hz) 5.54 (1H, s) 6.86~7.54 (9H, m) 7.58-7.96 (4H, m) Isomer (b); 1.87 (3H, s) 3.81 (3H, s) 5.05 (2H, s) 5.30 (2H, s) 6.86~7.54 (9H, m) 7.58-7.96 (4H, m) Example 19 2-(3-azido-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetic acid methyl
[Two torsions at positions 3 and 4 of the azetidine ring]
mixture of lance isomers (a) and (b)]. IR νcm^-1(film) 2120, 1778, 1750 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.73 (3H, s) 3.74 (3H, s) 4.54 (1H, d, J=2Hz) 4.82 (1H, d, J=2Hz) 5.40 (1H, s) 7.40 (5H, s) Isomer (b); 1.98 (3H, s) 3.74 (3H, s) 4.38 (1H, d, J=2Hz) 4.54 (1H, d, J=2Hz) 5.28 (1H, s) 7.38 (5H, s) Example 20 2-(3-azido-4-methylthio-2-ox
So-1-azetidinyl]-2-phenylacetate ben
Zyl [two at positions 3 and 4 of the azetidine ring
mixture of trans isomers (a) and (b)]. IR νcm^-1(film) 2110, 1780, 1740 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.67 (3H, s) 4.45 (1H, d, J=2Hz) 4.80 (1H, d, J=2Hz) 5.26 (2H, s) 5.43 (1H, s) 7.30 (5H, s) 7.35 (5H, s) Isomer (b); 1.93 (3H, s) 4.33 (1H, d, J=2Hz) 4.48 (1H, d, J=2Hz) 5.26 (2H, s) 5.30 (1H, s) 7.27 (5H, s) 7.32 (5H, s) Example 21 2-(3-azido-4-methylthio-2-ox
So-1-azetidinyl)-2-(4-benzyl)
xyphenyl) methyl acetate [3-position of azetidine ring
and a mixture of the two trans isomers (a) and (b) at position 4.
Compound]. IR νcm^-1(film) 2120, 1775, 1745 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.74 (3H, s) 3.76 (3H, s) 4.49 (1H, d, J=2Hz) 4.80 (1H, d, J=2Hz) 5.04 (2H, s) 5.24 (1H, s) 6.92~7.56 (9H, m) Isomer (b); 2.00 (3H, s) 3.76 (3H, s) 4.36 (1H, d, J=2Hz) 4.49 (1H, d, J=2Hz) 5.04 (2H, s) 5.24 (1H, s) 6.92~7.56 (9H, m) Example 22 2-(3-azido-2-oxo-4-phenyl
-1-Azetidinyl)-2-phenylacetate methyl
[Mixture of stereoisomers]. IR νcm^-1(film) 2100, 1770, 1740 Example 23 2-(3-benzyloxycarbonylamino-
2-oxo-4-phenyl-1-azetidinyl]
-2-Methyl phenyl acetate [mixture of stereoisomers]
thing〕. IR νcm^-1(film) 3320, 1770, 1740, 1720 NMR (TMS) δppm (CDCl₃) 3.56, 3.70 (3H, each s), 4.86 (2H, s), 5.08 ~
5.52 (2H, m), 5.52 (1H, s), 6.68-7.50
(15H, m) Example 24 2-(2-oxo-3-phenoxy-4-feu
Nyl-1-azetidinyl)-2-phenylacetic acid
Chil [mixture of stereoisomers]. IR νcm^-1(film) 1770, 1740 Example 25 D-2-(3-azido-2-oxo-4-aze
Tidinyl)-2-(4-hydroxyphenyl) vinegar
methyl acid [2 at the 3- and 4-positions of the azetidine ring
mixture of two cis isomers (a) and (b)]. Isomer (a); mp 138-142℃. IR νcm^-1(CHCl₃) 3300, 2120, 1765, 1745 NMR (TMS) δppm (CDCl₃) 3.67 (3H, s), 4.94 (1H, d, J=5Hz),
5.06 (1H, d, J=5Hz), 5.38 (1H, s),
6.56 (2H, d, J = 8Hz), 6.90 (2H, d, J =
8Hz), 7.12 (5H, m) Isomer (b); mp 67~71℃ IR νcm^-1(CHCl₃) 3300, 2120, 1765, 1750 NMR (TMS) δppm (CDCl₃) 3.60 (3H, s), 4.82 (1H, d, J=5Hz),
4.90 (1H, d, J=5Hz), 5.12 (1H, s),
6.72 (2H, d, J = 8Hz), 7.08 (2H, d, J =
8Hz), 7.36 (5H, s) Example 26 D-2-[4-trans-styryl-2-oki
So-3-phthalimido-1-azetidinyl]-2
-Methyl phenyl acetate [3- and 4-positions of azetidine ring
mixture of two cis isomers at position], mp144
~145℃. IR νcm^-1(Nujiyor) 1770, 1740 (shoulder), 1720 Example 27 D-2-[3-azido-4-trans-styli
Ru-2-oxo-1-azetidinyl]-2-hue
Methyl nylacetate [at the 3rd and 4th positions of the azetidine ring]
mixture of two cis isomers]. IR νcm^-1(film) 2120, 1780, 1770, 1750 NMR (TMS) δppm (CDCl₃) 3.68, 3.75 (3H, each s), 4.12-4.94 (2H, m),
5.48, 5.60 (1H, each s), 6.28-6.52 (2H, m),
7.36 (5H, s) Example 28 In substantially the same manner as in Example 17, trifluoride
In the presence of the pure diethyl ether complex, the reaction
When doing this, 2-(3-azido-2-oxo-4
-Phenyl-1-azetidinyl]-2-phenyl
Methyl acetate [one of two trans isomers
] was obtained. IR νcm^-1(film) 2120, 1770, 1740 NMR (TMS) δppm (CDCl₃) 3.59 (3H, s), 4.30 (1H, d, J=2.5Hz),
4.35 (1H, d, J=2.5Hz), 5.22 (1H, s),
6.84~7.55 (10H, m) Example 29 2-[3-azido-4-(5-methyl-1,
3,4-thiadiazol-2-ylthio)-2-
Oxo-1-azetidinyl]-2-phenylacetic acid
Methyl [two at the 3rd and 4th positions of the azetidine ring
mixture of trans isomers], mp81-84℃. Example 30 D-2-(3-azido-2-oxo-1-aze
Tidinyl)-2-(2-thienyl)methyl acetate
Dissolve 3.4g in 34ml of dioxane and touch this solution.
10% palladium-carbon was added as a medium. reaction mixture
The compound was heated at room temperature using a solvent pressurizer under a hydrogen gas flow.
The mixture was subjected to a reduction reaction for 3 hours. Filter off the catalyst and remove the mother liquor.
was evaporated to dryness under reduced pressure to obtain 2.98 g of oily residue.
It was done. Column chromatography using 50g of silica gel
It was developed on a graph and eluted with chloroform. the purpose
Combine the fractions containing the substance and remove the solvent under reduced pressure.
Then, D-2-(3-amino-2-oxo-1
-Azetidinyl)-2-(2-thienyl)acetic acid
Chyl [two isomers at the 3-position of the azetidine ring
2.60 g of mixture] was obtained. IR νcm^-1(film) 3390, 1765, 1740 In substantially the same manner as in Example 30, the azido group was
The following compound is obtained by reducing the corresponding compound containing
(Examples 31 to 45) were obtained. Example 31 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl]-2-(4-benzyl)
xyphenyl) methyl acetate [3-position of azetidine ring
and a mixture of the two trans isomers (a) and (b) at position 4.
Compound]. IR νcm^-1(film) 3400, 1770, 1740 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.71 (2H, s) 2.01 (3H, s) 3.78 (3H, s) 4.03~4.28 (2H, m) 5.07 (2H, s) 5.23 (1H, s) 6.80~7.60 (9H, m) Isomer (b); 1.72 (3H, s) 1.80 (2H, s) 3.78 (3H, s) 4.15 (1H, d, J=2Hz) 4.63 (1H, d, J=2Hz) 5.07 (2H, s) 5.37 (1H, s) 6.80~7.60 (9H, m) Example 32 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetic acid methyl
[Two torsions at positions 3 and 4 of the azetidine ring]
mixture of lance isomers (a) and (b)]. IR νcm^-1(film) 3380, 1770, 1740 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.95 (2H, s) 1.98 (3H, s) 3.70 (3H, s) Isomer (b); 1.70 (3H, s) 1.80 (2H, s) 3.74 (3H, s) νcm^-1(Nujiyor) 1725, 1640 Example 38 2-(3-amino-2-oxo-1-azetidi
Methyl-2-(1-naphthyl)acetate. IR νcm^-1(film) 3380, 3000, (shoulder), 1740 (broad) Example 39 2-(3-amino-2-oxo-1-azetidi
Nyl)-2-(3-mesylaminophenyl)acetic acid
Methyl. IR νcm^-1(film) 3350 (shoulder), 3150 (broad), 1730 (broad) Example 40 Erythro-2-(3-amino-2-oxo-1-
azetidinyl)-3-methoxy-3-phenylp
Methyl ropionate. IR νcm^-1(film) 3380, 1750 Example 41 2-(3-amino-2-oxo-1-azetidi
methyl)-3-phenylthiopropionate. IR νcm^-1(film) 3380, 3300 (shoulder), 1740 (broad) Example 42 2-(3-amino-2-oxo-1-azetidi
Methyl)-3-(phenylthio)acrylate
Le. IR νcm^-1(film) 3380, 3320 (shoulder), 1760, 1740, 1720. Example 43 2-(3-amino-2-oxo-1-azetidi
3-(4-hydroxyphenyl)propylene
Methyl onate. IR νcm^-1(film) 3200, 1750, 1720 Example 44 2-(3-amino-2-oxo-1-azetidi
3-(4-benzyloxyphenyl)-3-(4-benzyloxyphenyl)
Methyl ropionate. IR νcm^-1(Nujiyor) 3300, 1750, 1740, 1720. Example 45 2-(3-amino-4-trans-styryl-
2-oxo-1-azetidinyl)-2-phenyl
Methyl acetate [at the 3rd and 4th positions of the azetidine ring]
mixture of two cis isomers]. IR νcm^-1(film) 3350, 1770, 1740, 1660 Example 46 2-(2-oxo-3-phthalimido-1-a
Zetidinyl)-2-(2-thienyl)acetic acid 2.22g
Add this to 30 ml of methanol and 18 ml of chloroform.
Add N,N-dimethyl-1,3-propane to the mixture of
Add 1.32 g of amine and then let the mixture cool to room temperature.
Stirred overnight. After the reaction, the reaction mixture was evaporated under reduced pressure.
It was dried and the residue was dissolved in ethyl acetate. This solution
with an aqueous solution consisting of 6.4 ml of 1N hydrochloric acid and 10 ml of water.
Extract times. Combine the extracts and add sodium bicarbonate
The pH was adjusted to 8 and saturated with sodium chloride. this
The liquid was extracted with ethyl acetate, and the extract was diluted with saturated sodium chloride.
Washed with magnesium aqueous solution and dried with magnesium sulfate.
Ta. This solution was evaporated to dryness under reduced pressure, leaving a residue of 1.57 g.
was developed on a column chromatograph using 25 g of silica gel.
did. Contains the target substance by elution with chloroform
When the fractions are combined and the solvent is distilled off under reduced pressure, 2-
(3-amino-2-oxo-1-azetidinyl-
0.96 g of methyl 2-(2-thienyl)acetate was obtained. IR νcm^-1(film) 3390, 1765, 1740 NMR (TMS) δppm (CDCl₃) 2.00, 2.09 (2H, each s), 2.98, 3.35 (1H, each d,
d, J = 2.5, 6Hz), 3.53, 3.86 (1H, each t,
J=6Hz), 3.73 (3H, s), 4.05, 5.12 (1H,
each d, d, J = 2.5, 6Hz), 5.83 (1H, s),
6.75~7.55 (3H, m) Phthalimide in substantially the same manner as Example 46
Corresponding compounds containing groups and N,N-dimethyl
- When reacting with 1,3-propanediamine, the following
The following compounds (Examples 47-63) were obtained. Example 47 2-(3-amino-2-oxo-1-azetidi
nyl)-2-(2-thienyl)acetic acid. IR νcm^-1(Nujiyor) 2750-2250, 1760 (shoulder), 1745, 1620. NMR [Internal standard: 2,2,3,3-tetra deuterium-
Sodium 3-(trimethylsilyl)propionate
(hereinafter simply referred to as TMSP) δppm(D₂O) 3.13, 3.45 (1H, each q, J = 2Hz, 5Hz),
3.54, 3.82 (1H, each t, J = 5Hz), 4.21, 4.31
(1H, each q, J = 2Hz, 5Hz), 5.54, 5.56
(1H, each s), 7.10 (2H, m), 7.46 (1H, m) Example 48 2-(3-amino-2-oxo-1-azetidi
nyl)-2-(2-furyl)acetic acid. IR νcm^-1(Nujiyor) 1725, 1640 NMR (TMSP) δppm(D₂O) 3.36 (1H, d, d, J = 2Hz, 6Hz), 3.90
(1H, d, d, J = 6Hz, 5Hz), 5.41 (1H,
s), 6.49 (2H, m), 7.37 (1H, m) Example 49 2-(3-amino-2-oxo-1-azetidi
methyl)-2-(1-naphthyl)acetate. IR νcm^-1(film) 3380, 3000 (shoulder), 1740 (broad). NMR (TMS) δppm (CDCl₃) 1.70 (2H, s), 2.48, 3.37 (1H, each d, d, J
=3Hz, 6Hz), 3.02, 3.84 (1H, each d, d, J
=3Hz, 6Hz), 3.91, 4.21 (1H, each d, d, J
=3Hz, 6Hz), 3.74, 3.75 (3H, each s), 6.43,
6.44 (1H, each s), 7.2~8.2 (7H, m) Example 50 2-(3-amino-2-oxo-1-azetidi
Nyl)-2-(3-mesylaminophenyl)acetic acid
Methyl. IR νcm^-1(film) 3350 (shoulder), 3150 (broad), 1730 (broad). Example 51 Erythro-2-(3-amino-2-oxo-1
-azetidinyl)-3-methoxy-3-phenyl
Methyl propionate. IR νcm^-1(film) 3380, 1750. NMR (TMS) δppm (CDCl₃) 1.57 (2H, s), 3.23, 3.32 (3H, each s), 3.71,
3.78 (3H, each s), 4.65 (1H, d, J = 5Hz),
4.85 (1H, d, J=5Hz), 7.36 (5H, s). Example 52 2-(3-amino-2-oxo-1-azetidi
methyl)-3-phenylthiopropionate. IR νcm^-1(film) 3380, 3300 (shoulder), 1740 (broad). NMR (TMS) δppm (CDCl₃) 2.98-3.76 (4H, m), 3.68 (3H, s), 4.04,
4.15 (1H, each d, d, J = 6Hz, 3Hz), 4.54
(1H, d, d, J=10Hz, 5Hz), 7.2~7.5
(5H, m) Example 53 2-(3-amino-2-oxo-1-azetidi
methyl)-3-phenylthioacrylate. IR νcm^-1(film) 3380, 3320 (shoulder), 1760, 1740, 1720. NMR (TMS) δppm (CDCl₃) 1.94 (2H, s), 3.55 (1H, d, d, J = 6Hz,
3Hz), 3.76 (3H, s), 3.95 (1H, t, J=6
Hz), 4.33 (1H, d, d, J = 6Hz, 3Hz), 7.2
~7.6 (6H, m) Example 54 2-(3-amino-2-oxo-1-azetidi
Nyl)-3-methyl-3-(5-methyl-1,
3,4-thiadiazol-2-ylthiomethyl)
Methyl acrylate [cis isomer* and trans isomer
body※※mixture]. IR νcm^-1(film) 1780, 1760, 1720. As shown in the chemical structural formula above, trans isomerism
In the body, azetyl at position 2 in acrylic ester
The dinone ring and the methyl group at position 3 are on opposite sides of the double bond.
In cis isomers, they have identical double bonds.
It's on the side. Trans and cis isomers in this type of compound
The above-mentioned relationships of isomers are expressed in the following examples.
The same is true. Example 55 2-(3-amino-2-oxo-1-azetidi
methyl)-3,3-bis(5-methyl-1,3,4
-Thiadiazol-2-ylthiomethyl)acrylate
Methyl chlorate. IR νcm^-1(film) 3400, 1780, 1760, 1720. Example 56 2-(3-amino-2-oxo-1-azetidi
3-(4-hydroxyphenyl)propylene
Methyl onate. IR νcm^-1(film) 3200, 1750, 1720. Example 57 2-(3-amino-2-oxo-1-azetidi
3-(4-benzyloxyphenyl)-3-(4-benzyloxyphenyl)
Methyl ropionate. IR νcm^-1(Nujiyor) 3300, 1750, 1740, 1720. Example 58 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl)-2-(4-benzyl)
xyphenyl) methyl acetate [3-position of azetidine ring
and a mixture of two trans isomers at position 4]. IR νcm^-1(film) 3400, 1770, 1740. Example 59 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetic acid methyl
[Two torsions at positions 3 and 4 of the azetidine ring]
mixture of lance isomers]. IR νcm^-1(film) 3380, 1770, 1740. Example 60 2-[3-amino-4-(5-methyl-1,
3,4-thiodiazol-2-ylthio)-2-
Oxo-1-azetidinyl]-2-phenylacetic acid
Methyl [two at the 3rd and 4th positions of the azetidine ring
mixture of trans isomers]. IR νcm^-1(film) 3280, 1770, 1640. Example 61 2-[3-amino-4-(5-methyl-1,
3,4-thiadiazol-2-ylthio)-2-
Oxo-1-azetidinyl]-2-phenylacetic acid
Methyl [two at the 3rd and 4th positions of the azetidine ring
mixture of trans isomers]. IR νcm^-1(film) 3350, 1765, 1740. Example 62 2-(3-amino-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetate ben
Zyl [two at positions 3 and 4 of the azetidine ring
mixture of trans isomers]. IR νcm^-1(film) 3400〜3300, 1770, 1740, 1680. Example 63 2-(3-amino-2-oxo-1-azetidi
)-3-(2-benzothiazolylthiomethy)
Methyl)-3-methylacrylate [cis isomer
and a mixture of trans isomers]. IR νcm^-1(film) 1790, 1770, 1730, 1710. Example 64 2-(4-
trans-styryl-2-oxo-3-phthalyl
Mido-1-azetidinyl)-2-phenylacetic acid
Reacting chill with hydrazide monohydrate as amine
By reacting, 2-(3-amino-4-to
lance-styryl-2-oxo-1-azetidine
methyl)-2-phenylacetate was obtained. IR νcm^-1(film) 3350, 1770, 1740, 1660. NMR (TMS) δppm (CDCl₃) 1.78 (2H, broads), 3.68, 3.74 (3H, each
s), 4.13, 4.78 (1H, m, q, J = 5Hz, 6
Hz), 4.33, 4.46 (1H, each d, J = 5Hz), 5.52,
5.60 (1H, each s), 6.24~6.54 (2H, m), 7.02~
7.56 (10H, m). Example 65 3-methyl-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-2-
(2-oxo-3-phthalimido-1-azetidi
Cis and trans isomers of methyl acrylate
Dissolve 0.300 g of the mixture with isomers in 15 ml of ethanol.
Dissolve 30mg of methylamine in 0.1ml of ethanol.
The dissolved solution was added to the above solution. reaction mixture
The mixture was stirred at room temperature for 15 minutes. Reaction mixture under reduced pressure
Evaporate to dryness, dissolve the residue in ethyl acetate and wash with water.
Dry with magnesium sulfate. Evaporate the solution under reduced pressure.
The mixture was evaporated to obtain an oily residue, which was poured into a solution of 5 g of silica gel.
It was developed on a ram chromatograph. with chloroform
When eluted, 2-[3-{2-(N-methylcarba)
Moyl) benzamide}-2-oxo-1-aze
Tidinyl]-3-methyl-3-(5-methyl-
1,3,4-thiadiazol-2-ylthiomethy
) The trans isomer of methyl acrylate dissolves first.
Then, 70 mg of the cis isomer of the target substance was dissolved.
I put it out. Yield of trans isomer is 95 mg and is isomer
The body yield was 70 mg. trans isomer IR νcm^-1(film) 1780, 1760, 1730, 1660. NMR (TMS) δppm (CD₃O.D.) 2.29 (3H, s), 2.70 (3H, s), 2.88 (3H, s),
3.82 (3H, s), 3.84~4.00 (2H, m), 4.24,
4.50 (2H, AB-q, J=14Hz), 5.08, 5.12
(1H, d, d, J=4Hz), 7.50~7.72 (4H,
s). cis isomer; IR νcm^-1(film) 1970, 1770, 1730, 1660. NMR (TMS) δppm (CD₃O.D.) 2.18 (3H, s), 2.74 (3H, s), 2.90 (3H, s),
3.82 (3H, s), 3.72-3.88 (2H, m), 4.52
(2H, s), 5.06, 5.10 (1H, d, d, J=5
Hz), 7.60 (4H, s) Example 66 3-methyl-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-2-
(2-oxo-3-phthalimido-1-azetidi
Cis and trans isomers of methyl acrylate
Dissolve 0.470 g of the mixture of isomers in 10 ml of methanol.
Add 10ml of 0.1N sodium hydroxide aqueous solution to this.
was added at a temperature of 0-5°C. Then the reaction mixture
Stir at the same temperature for 10 minutes, and add methanol after the reaction is complete.
was distilled off under reduced pressure to obtain an aqueous solution, and the pH was adjusted to 2~ with dilute hydrochloric acid.
Adjusted to 3. Extract the aqueous solution with ethyl acetate and
After washing, it was dried with magnesium sulfate. Solution under reduced pressure
Evaporate to dryness and transfer the residue to a column of 10 g of silica gel.
It was developed into a romatograph. chloroform and methano
When eluted with a mixture of 100:2 (volume ratio 100:2),
2-[3-(2-carboxybenzamide)-2
-oxo-1-azetidinyl]-3-methyl-3
-(5-methyl-1,3,4-thiadiazole-
2-ylthiomethyl) methyl acrylate tolan
105 mg of the isomer elutes first, then the target product
140mg of a mixture of quality trans and cis isomers
was eluted, and finally 97 mg of the cis isomer was eluted. trans isomer IR νcm^-1(film) 1780, 1760, 1720, 1660. NMR (TMS) δppm (CD₃O.D.) 2.30 (3H, s), 2.72 (3H, s), 3.82 (3H, s),
3.84-4.00 (2H, m), 4.24-4.48 (2H, AB-
q, J = 12Hz), 5.07, 5.12 (1H, d, d, J =
5Hz), 7.50-8.08 (4H, m). cis isomer IR νcm^-1(film) 1780, 1760, 1710, 1660. NMR (TMS) δppm (CD₃O.D.) 2.17 (3H, s), 2.71 (3H, s), 3.78 (3H, s),
3.88 (2H, d, J=4Hz), 4.48 (2H, s),
5.03 (1H, t), 7.46~8.06 (4H, m), Example 67 2-(3-amino-2-oxo-1-azetidi
380mg of dichloromethane)-2-(2-thienyl)acetic acid
Suspend in 15 ml of lolomethane and add bis(trichloride) to this suspension.
0.60g of (limethylsilyl)acetamide and N,N-di
0.25 ml of methylformamide was added. this mixture
The mixture was stirred at room temperature for 6 hours, and insoluble matter was filtered off. filtrate
Add 0.20g of bis(trimethylsilyl)acetamide to
Add the dichloromethane solution and stir the mixture for 30 min.
adjusted. On the other hand, 4-(3-tertiary butoxylic
Bonylamino-3-methoxycarbonylpropoxy
c) 0.440g of phenylglyoxylic acid in dichloromethane
Suspend in 10ml of methane and add triethylamine to this.
0.120g and 2 drops of N,N-dimethylbenzylamine
added. Mix this mixture for a while to form a solution.
and dichloromethane containing 0.125g of ethyl chloroformate.
Add 5 ml of the solution to the above solution at -60°C.
The mixture was added dropwise over a period of 3 minutes. This mixture at the same temperature
Stir for 5 minutes at -20 to -15℃ and then stir for 20 minutes at -20 to -15℃.
was subsequently dissolved. Add the diluted solution obtained earlier to this solution.
Add chloromethane solution dropwise over 20 minutes at -60℃
did. The mixture was then stirred at the same temperature for 30 minutes and further
The mixture was stirred at -15°C for 30 minutes. Stir for an additional hour at 0°C.
The mixture was continued to be stirred for an additional 1.5 hours at 20-25°C. reaction
The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in sodium bicarbonate.
Dissolved in thorium aqueous solution. Distill the resulting solution.
Wash with chill ether and adjust the pH to 5.5 with dilute hydrochloric acid.
After washing with ethyl acetate. Add this aqueous solution to dilute hydrochloric acid.
The pH was adjusted to 4.5 and extracted with ethyl acetate. extract liquid
is evaporated to dryness under reduced pressure to give 2-[3-{4-(3
-Tertiary butoxycarbonylamino-3-methoxy
(cycarbonylpropoxy) phenylglyoxylo
ylamino}-2-oxo-1-azetidinyl]
0.100 g of -2-(2-thienyl)acetic acid was obtained. IR νcm^-1(film) 3450-3300, 1760, 1730, 1710, 1680-1660. NMR (TMS) δppm (CDCl₃) 1.41 (9H, s), 2.12~2.34 (2H, m), 8.30~
4.18 (4H, m), 3.72 (3H, s), 4.36-4.51
(1H, m), 5.86 (1H, broad s), 7.92 (1H,
d, J=8Hz), 6.80-8.28 (7H, m). In substantially the same manner as in Example 67, the amino group was
The corresponding compound with the corresponding acylating agent is reacted with
The following compounds (Examples 68-
77). Example 68 2-[3-[4-{tertiary butoxycarbonyl
Amino-3-(4-methoxybenzyloxycal)
(bonyl)carboxy}phenylglyoxyloyl
Amino]-2-oxo-1-azetidinyl)-2
-(2-thienyl)methyl acetate. IR νcm^-1(film) 3450〜3350, 1760, 1740, 1710, 1690, 1660. NMR (TMS) δppm (CDCl₃) 1.40 (9H, s), 2.18~2.38 (2H, m), 3.34~
4.20 (4H, m), 3.78, 3.80 (3H, s), 4.40~
4.60 (1H, m), 5.12 (2H, s), 5.36-5.43
(1H, m), 5.94 (1H, s), 7.91, 8.03 (1H,
d, J=8Hz), 6.78-8.40 (11H, m). Example 69 2-[L-3-(DN-benzyloxycal
Bonyl-2-phenylglycinamide)-2-o
xo-1-azetidinyl]-2-(2-thienyl
) Acetic acid [mixture of L-form and D-form at the 2-position of acetic acid]
thing〕. Develop this compound on a column chromatograph,
The L-form and D-form were separated. L body; IR νcm^-1(film) 3300, 2550, 1740, 1715, 1670 NMR (TMS) δppm (CD₃O.D.) 3.48 (2H, m), 4.92 (1H, d, d, J = 2.5Hz,
5Hz), 5.04 (2H, s), 5.27 (1H, s), 5.81
(1H, s), 6.92~7.56 (13H, m), D body; mp 159~163℃ IR νcm^-1(Nujiyor) 3320, 3250, 2600, 1740, 1705, 1665. NMR (TMS) δppm (CD₃O.D.) 3.14 (1H, d, d, J = 2.5Hz, 5Hz), 3.75
(1H, t, J = 5Hz), 4.90 (1H, d, d, J
=2.5Hz, 5Hz), 5.02 (2H, s), 5.28 (1H,
s), 5.80 (1H, s), 6.84-7.56 (13H, m) Example 70 3,3-bis(5-methyl-1,3,4-thia
diazol-2-ylthiomethyl)-2-[2-
Oxo-3-(2-phenoxyacetamide)-1
-azetidinyl] methyl acrylate. IR νcm^-1(film) 3350, 1770, 1720, 1670. NMR (TMS) δppm (CDCl₃) 2.60 (3H, s), 2.70 (3H, s), 3.80 (3H, s),
3.64, 3.66 (1H, d, d, J = 2Hz, 5Hz),
3.86 (1H, t, J=5Hz), 4.54 (2H, s),
4.30, 4.66 (2H, AB-q, J=8Hz), 5.24~
5.42 (1H, m), 7.36-7.82 (5H, m), 7.96
(1H, d, J=8Hz) Example 71 3,3-bis(5-methyl-1,3,4-thia
diazol-2-ylthiomethyl)-2-[2-
Oxo-3-{2-(2-thienyl)acetami
Methyl do}-1-azetidinyl acrylate. IR νcm^-1(Nujiyor) 3400, 1760, 1720, 1680 NMR (TMS) δppm (CDCl₃) 3.73 (6H, s), 3.85 (3H, s), 3.23~4.00
(2H, m), 4.62 (2H, s), 4.27, 4.73 (2H,
AB―q, J=14Hz), 5.13~5.40 (1H, m),
6.93~7.33 (3H, m), 7.85 (1H, d, J=8
Hz). Example 72 2-[4-methylthio-2-oxo-3-(2
-phenylacetamide)-1-(azetidinyl)
-2-(4-benzyloxyphenyl)methylacetate
[Two torsions at positions 3 and 4 of the azetidine ring]
mixture of lance isomers]. IR νcm^-1(film) 3300, 1770, 1750, 1670. NMR (TMS) δppm (CDCl₃) 1.82, 2.05 (3H, each s), 3.60 (2H, s), 3.78
(3H, s), 4.40-4.98 (2H, m), 5.12 (2H,
s), 5.30, 5.35 (1H, each s), 6.50 (1H, d,
J=8Hz), 6.85-7.62 (14H, m). Example 73 2-(4-methylthio-2-oxo-3-{2
-(2-thienyl)acetamide}-1-azetidi
methyl]-2-phenylacetate [azetidine ring
two trans isomers (a) at positions 3 and 4 of
(b) mixture]. IR νcm^-1(Nujiyor) 3250, 1770, 1750, 1660. NMR (TMS) δppm (CDCl₃) Isomer (a); 2.04 (3H, s) 3.76 (5H, s) 4.44 (1H, d, J=2Hz) 4.87 (1H, d, J = 2Hz, 7Hz) 5.30 (1H, s) 6.63 (1H, d, J=7Hz) 6.80~7.69 (8H, m) Isomer (b); 1.78 (3H, s) 3.76 (5H, s) 4.53~4.84 (2H, m) 5.35 (1H, s) 6.63 (1H, d, J=7Hz) 6.80~7.69 (8H, m) Example 74 2-[4-(5-methyl-1,3,4-thiazi
Azol-2-ylthio)-2-oxo-3-
{2-(2-thienyl)acetamide}-1-aze
Tidinyl]-2-phenylacetate methyl
Mixture of two cis isomers at positions 3 and 4 of the ring
Compound]. IR νcm^-1(film) 3300, 1780, 1745, 1680. NMR (TMS) δppm (CDCl₃) 2.60, 2.63 (3H, each s), 3.65 (2H, s), 3.72
(3H, s), 5.05~5.90 (3H, m), 6.40~7.75
(9H, m). Example 75 2-[4-(5-methyl-1,3,4-thiazi
Azol-2-ylthio)-2-oxo-3-
{2-(2-thienyl)acetamide}-1-aze
Tidinyl]-2-phenylmethyl acetate (azetidyl)
Two trans isomers at positions 3 and 4 of the ring
mixture]. IR νcm^-1(film) 1785, 1750, 1670. NMR (TMS) δppm (CDCl₃) 2.65 (3H, s), 3.74 (3H, s), 3.78 (2H, s),
4.68-5.72 (2H, m), 5.34, 5.54 (1H, each s),
6.64~7.40 (8H, m) Example 76 2-[4-methylthio-2-oxo-3-(2
-phenylacetamide)-1-azetidinyl]-
Methyl 2-phenylacetate [3-position of azetidine ring and
Mixture of two trans isomers (a) and (b) at position 4
thing〕. IR νcm^-1(Nujiyor) 3290, 1785, 1770 (shoulder), 1760, 1665. NMR (TMS) δppm (CDCl₃) Isomer (a); 1.93 (3H, s) 3.50 (2H, s) 3.71 (3H, s) 4.46 (1H, d, = 2Hz) 4.90 (1H, q, J = 2Hz, 6Hz) 5.33 (1H, s) 6.90 (1H, d, J=6Hz) 7.04~7.50 (10H, m) Isomer (b); 1.76 (3H, s) 3.51 (2H, s) 3.71 (3H, s) 4.73~4.88 (2H, m) 5.39 (1H, s) 6.90 (1H, d, J=6Hz) 7.04~7.50 (10H, m) Example 77 2-[4-methylthio-2-oxo-3-(2
-phenylacetamide)-1-azetidinyl]-
Benzyl 2-phenylacetate [3-position of azetidine ring]
and a mixture of the two trans isomers (a) and (b) at position 4.
Compound]. IR νcm^-1(film) 3300, 1770, 1740, 1670 NMR (TMS) δppm (CDCl₃) Isomer (a); 1.72 (3H, s) 3.53 (2H, s) 4.42 (1H, d, J=2Hz) 4.82 (1H, d, J=2Hz) 5.16 (2H, s) 5.33 (1H, s) 7.23~7.33 (15H, m) Isomer (b); 1.93 (3H, s) 3.50 (2H, s) 4.41 (1H, d, J = 2Hz) 4.85 (1H, d, J=2Hz) 5.18 (2H, s) 5.23 (1H, s) 7.23~7.33 (15H, m) Example 78 2-(3-
Amino-2-oxo-1-azetidinyl)-2-
(3-Mesylaminophenyl) Methyl acetate and Fe
Reacting nylglyoxyloyl chloride
Accordingly, 2-[3-(N-mesil-N-feni
(glyoxyroylamino)phenyl]-2-
(2-oxo-3-phenylglyoxyloylua
Methyl mino-1-azetidinyl) acetate was obtained. IR νcm^-1(film) 3380, 1750, 1670. NMR (TMS) δppm (CDCl₃) 3.34, 3.40 (3H, each s), 3.71, 3.75 (3H, each
s), 3.22-3.90 (3H, m), 5.07 (1H, m),
5.65, 5.75 (1H, s), 7.3~8.3 (9H, m). Example 79 2-(2,2-dichloroacetoxyimino)-
660 mg of 2-phenylacetic acid to 5 ml of dichloromethane
Add 950 mg of phosphorus pentachloride to this suspension and bring it to room temperature.
Stir at room temperature for 40 minutes. Evaporate the reaction mixture to dryness under reduced pressure.
Once solidified, benzene was added to the residue. Then under reduced pressure
Benzene was distilled off to obtain the chloride of the acid, and di
Dissolved in 5 ml of chloromethane. On the other hand, 2-(3-A
mino-2-oxo-1-azetidinyl)-3-
Methyl (phenylthio)propionate 450mg and Pis
(trimethylsilyl)acetamide 3.25g in dichloromethane
Dissolve in 10ml of lomethane and stir at -27 to -20℃.
Add the above solution to this solution for 5 minutes while stirring.
I got it. Then, stir for an additional 50 minutes at −38 to −25°C.
I did it. Pour 50ml of water into the reaction mixture and pour the resulting mixture into
Adjust the pH to 8 with a saturated aqueous solution of sodium hydrogen carbonate.
Ta. separating the dichloromethane layer from the mixture;
4 times with dilute hydrochloric acid, then with aqueous sodium bicarbonate
After washing with liquid and water in that order, dry with magnesium sulfate.
It was dry. The solvent was distilled off under reduced pressure and the residue was filtered onto silica gel.
The mixture was developed on a 15g column chromatograph. Elution
is chloroform, methanol and chloroform
Contain the target substance by using a mixed solution (volume ratio 1:100).
The fractions with were combined. Distill the solvent under reduced pressure
and 2-[3-(2-hydroxy) at mp163-169℃.
Shiimino-2-phenylacetamide)-2-oxy
So-1-azetidinyl]-3-(phenylthio)
230 g of methyl propionate was obtained. IR νcm^-1(Nujiyor) 3480, 1760, 1730, 1670. NMR (TMS) δppm [(CD₃)₂CO〕 3.36-3.90 (4H, m), 3.66 (3H, s), 4.50
(1H, m), 5.12 (1H, m), 7.2~7.7 (10H,
m). In substantially the same manner as in Example 79, an amino group-containing
corresponding compound and 2-(2,2-dichloroacetic acid)
Toxiimino)-2-phenylacetic acid chloride
By reacting, the following compound (Example 80
~89) was obtained. Example 80 2-[3-(2-hydroxyimino-2-fe
Nilacetamide-2-oxo-1-azetidini
]-3-(phenylthio)methyl acrylate. IR νcm^-1(Nujiyor) 1750, 1710, 1660. NMR (TMS) δppm [(CD₃)₂CO〕 3.76 (3H, s), 3.9~4.2 (2H, m), 5.40 (1H,
m), 7.3-7.7 (10H, m), 8.49 (1H, d, J=
8Hz) Example 81 Erythro-2-[3-(2-hydroxyimino
-2-phenylacetamide)-2-oxo-1-
azetidinyl]-3-methoxy-3-phenylp
Methyl ropionate, mp173-176℃. IR νcm^-1(Nujiyor) 3300, 1725, 1665. NMR (TMS) δppm [(CD₃)₂CO〕 3.27 (3H, s), 3.73 (3H, s), 3.6~3.7 (1H,
m), 4.09 (1H, t, J=6Hz), 4.61 (1H, d,
J=5Hz), 4.89 (1H, d, J=5Hz), 5.24
(1H, d, d, d, J = 3Hz, 6Hz, 7Hz),
7.2~7.7 (12H, m), 8.25 (1H, d, J=7
Hz), 10.73 (1H, s). Example 82 2-[3-(2-hydroxyimino-2-feu
nyl acetamide)-2-oxo-1-azetidine
2-(2-thienyl)methyl acetate, mp174
~178℃ (decomposition). IR νcm^-1(Nujiyor) 3300, 1755, 1730, 1665. NMR (TMS) δppm [(CD₃)₂CO〕 3.48 (1H, d, d, J = 2.5Hz, 6Hz), 3.98
(1H, t, J=6Hz), 5.12 (1H, m), 5.88
(1H, s), 6.93-7.83 (8H, m). Example 83 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(1-naphthyl)methyl acetate. IR νcm^-1(film) 3250, 1740, 1660. mass spectrometry m/e431 (M⁺) Example 84 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-methyl-3-(5-methyl-1,3,
4-thiadiazol-2-ylthiomethylacrylic
Methyl phosphate [mixture of trans and cis isomers]
thing〕. Develop this compound on a column chromatograph,
The cis and trans isomers were separated. trans isomer; IR νcm^-1(film) 3300, 1760, 1730, 1670. NMR (TMS) δppm (CDCl₃) 2.22 (3H, s), 2.52 (3H, s), 3.70 (3H, s),
3.62~3.92 (2H, m), 4.08~4.40 (2H, m),
4.08~4.40 (2H, AB-q, J=14Hz), 5.15~
5.32 (1H, m), 7.04-7.56 (5H, m), 8.04
(1H, d, J=8Hz). cis isomer; IR νcm^-1(film) 3300, 1770, 1730, 1670. NMR (TMS) δppm (CDCl₃) 2.08 (3H, s), 2.66 (3H, s), 3.70 (3H, s),
3.72~3.92 (2H, m), 4.36 (2H, s), 4.92~
5.06 (1H, m), 7.24-7.52 (5H, m), 7.82
(1H, d, J=6Hz). Example 85 3-(2-benzothiazolylthiomethyl)-2
-[3-(2-hydroxyimino-2-phenyl
acetamido)-2-oxo-1-azetidinyl]
-3-Methyl acrylate [trans isomer
and a mixture of cis isomers]. IR νcm^-1(film) 3250, 1760, 1720, 1670. NMR (TMS) δppm (CDCl₃) 2.10, 2.24 (3H, each s), 3.66, 3.68 (3H, each
s), 5.04-5.20, 4.92-5.08 (1H, each m), 7.22
~7.80 (9H, m). Example 86 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(2-furyl)acetic acid. IR νcm^-1(Nujiyor) 3300, 1755, 1735, 1710, 1660. NMR (TMS) δppm [(CD₃)₂CO〕 3.41 (1H, d, d, J = 3Hz, 6Hz), 3.99
(1H, t, J=5Hz), 5.25 (1H, m), 5.71
(1H, s), 6.46 (1H, m), 6.58 (1H, d, J
= 3Hz), 7.3-7.7 (6H, m), 8.20 (1H, m). Example 87 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
Methyl]-2-phenylacetate. IR νcm^-1(Nujiyor) 3230, 1750, 1725, 1642. Example 88 D-2-[4-trans-styryl-3-(2
-Hydroxyamino-2-phenylacetamide)
-2-oxo-1-azetidinyl]-2-pheni
Methyl acetate [at the 3- and 4-positions of the azetidine ring]
mixture of two cis isomers]. IR νcm^-1(film) 3350, 1770-1740, 1670. Example 89 D-2-[3-(2-hydroxyimino-2-
(phenylacetamide)-4-hydroxymethyl-
2-oxo-1-azetidinyl]-2-phenyl
Methyl acetate [at the 3rd and 4th positions of the azetidine ring]
mixture of two cis isomers]. Develop this compound on a column chromatograph and
The gender bodies (a) and (b) were separated. Isomer (a); mp179~181.5℃ Isomer (b); mp196-198℃. Example 90 3-methyl-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-2-
(2-oxo-3-phthalimido-1-azetidi
Cis and trans isomers of methyl acrylate
Dissolve 0.350 g of the mixture of isomers in 20 ml of ethanol.
Then, add 0.050 g of hydrazine monohydrate to this solution.
After cooling, the mixture was stirred at room temperature for 19 hours. Vacuum the reaction mixture
The mixture was evaporated to dryness and the residue was dissolved in dilute hydrochloric acid. water soluble
Wash the solution with ethyl acetate and remove sodium bicarbonate.
In addition, the pH was adjusted to 8.5. Extract this with ethyl acetate
After washing with water, it was dried with magnesium sulfate. This melt
The liquid was evaporated to dryness under reduced pressure and the residue was dissolved in dichloromethane 10
Dissolved in ml. Add 2-phenoxyacetic acid to this solution.
5 ml of dichloromethane containing 0.612 g of chloride
The solution was added dropwise at -5 to -10℃, and the mixture was heated at the same temperature.
Stirred for 2 hours. The reaction mixture was mixed with dilute hydrochloric acid, water, 5%
Wash with sodium bicarbonate aqueous solution and water, then sulfur
Dry with magnesium acid. This solution is placed under reduced pressure.
Evaporate to dryness and add 0.120 g of the resulting oily residue to silica.
It was developed on a column chromatograph using 4 g of gel. nine
Elute with loloform and collect the fraction containing the target substance.
Obtained. 3-methyl-3-(5-methyl-1,3,
4thiadiazol-2-ylthiomethyl)-2-
[2-oxo-3-(2-phenoxyacetamide)
-1-azetidinyl] methyl acrylate tolan
The first fraction containing the isomer is evaporated to dryness under reduced pressure.
It solidified, yielding 0.023 g of the above material. Similarly, the above
mixture of cis and trans isomers of a substance
0.020 g and 0.027 g of the cis isomer were obtained. trans isomer IR νcm^-1(CHCl₃) 3450, 1760, 1730, 1685. NMR (TMS) δppm (CDCl₃) 2.27 (3H, s), 2.63 (3H, s), 3.76 (3H, s),
3.64, 3.68 (1H, d, d, J = 2Hz, 5Hz),
3.96 (1H, t, J=5Hz) 4.06, 4.44 (2H, AB
-q, J=14Hz), 4.56 (2H, s), 5.22~5.38
(1H, m), 6.86-7.40 (5H, m), 7.86 (1H,
d, J=8Hz) cis isomer; IR νcm^-1(CHCl₃) 3450, 1765, 1725, 1690. NMR (TMS) δppm (CDCl₃) 2.06 (3H, s), 2.62 (3H, s), 3.81 (3H, s),
3.69, 3.73 (1H, d, d, J = 2Hz, 5Hz),
3.90 (1H, t, J=5Hz), 4.32 (2H, s),
4.36 (2H, s), 5.00~5.08 (1H, m), 6.84~
7.48 (5H, m). Example 91 2-[3-{4-(3-amino-3-carboxy
cypropoxy) phenylglyoxyloylamide
No}-2-oxo-1-azetidinyl]-2-
(2-thienyl)acetic acid 400mg and hydroxylamine
Suspend 130mg in 7ml of water and add with sodium bicarbonate.
This was dissolved by adjusting the pH to 7.0. this mixture
Stir at 35-38 °C for 1.5 h and treat with charcoal. filter
Adjust the pH of the liquid to 3.2 to 3.0 with dilute hydrochloric acid and reduce to 35 to 38 under reduced pressure.
It was heated to ℃ and concentrated to 15 ml. Resin adsorbs concentrated liquid
Amberlight XAD-4 (Trademark: Rohm Anne
De Haas Company) 80ml Column Chroma
It was developed into a tograph. Dissolved in water and then methanol.
The target substance fractions were combined. Remove the solvent under reduced pressure.
Distill, add acetonitrile to the residue and grind.
and 2-[3-[2-{4-(3-amino-3-ka)
ruboxypropoxy) phenyl}-2-hydroxy
Shiiminoacetamide]-2-oxo-1-azethi
230 mg of [dinyl]-2-(2-thienyl)acetic acid was obtained.
It was done. IR νcm^-1(Nujiyor) 3400 (broad), 1740, 1660-1640, 1610. NMR (TMSP) δppm(D₂O) 2.38~2.48 (2H, m), 3.36~4.00 (3H, m),
4.08~4.28 (2H, m), 5.00~5.10 (1H, m),
5.60, 5.68 (1H, s), 6.98-7.59 (7H, m) phenyl glycol in substantially the same manner as Example 91.
The corresponding compound containing an oxyloyl group can be hydroxylated.
By reacting with silamine hydrochloride, the following can be obtained.
Compounds (Examples 92-102) were obtained. Example 92 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
Methyl]-3-(phenylthio)propionate
Le. IR νcm^-1(Nujiyor) 3480, 1760, 1730, 1670. Example 93 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-(phenylthio)methyl acrylate. IR νcm^-1(Nujiyor) 1750, 1710, 1660. Example 94 Erythro-2-[3-(2-hydroxyimino
-2-phenylacetamide)-2-oxo-1-
azetidinyl]-3-methoxy-3-phenylp
Methyl ropionate. IR νcm^-1(Nujiyor) 3300, 1725, 1665. Example 95 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(2-thienyl)methyl acetate. IR νcm^-1(Nujiyor) 3300, 1755, 1730, 1665. Example 96 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(1-naphthyl)methyl acetate. IR νcm^-1(film) 3250, 1740, 1660. Example 97 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-methyl-3-(5-methyl-1,3,
4-thiadiazol-2-ylthiomethyl)ac
Methyl lylate [mixture of trans and cis isomers]
Compound]. Develop this compound on a column chromatograph
Trans and cis isomers were separated. IR νcm^-1(film) Trans isomer; Cis isomer; 3300 3300 1760 1770 1730 1730 1670 1670 Example 98 3-(2-benzothiazolylthiomethyl)-2
-[3-(2-hydroxyimino-2-phenyl
acetamido)-2-oxo-1-azetidinyl]
-3-(2-hydroxyimino-2-phenyla
Cetamide-2-oxo-1-azetidinyl]-3
- Methyl acrylate [trans isomer and trans isomer]
mixture of isomers]. IR νcm^-1(film) 3250, 1760, 1720, 1670. Example 99 3-[3-(2-hydroxyimino-2-feu
nyl acetamide)-2-oxo-1-azetidine
]-2-(2-furyl)acetic acid. IR νcm^-1(Nujiyor) 3300, 1755, 1735, 1710, 1660. Example 100 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-(4-hydroxyphenyl)propio
Methyl acid. IR νcm^-1(Nujiyor) 3230, 1750, 1725, 1642. Example 101 D-2-[4-trans-styryl-3-(2
-Hydroxyimino-2-phenylacetamide)
-2-oxo-1-azetidinyl]-2-pheni
Methyl acetate [at the 3- and 4-positions of the azetidine ring]
mixture of two cis isomers]. IR νcm^-1(film) 3350, 1770-1740, 1670. Example 102 D-2-[3-(2-hydroxyimino-2-
(phenylacetamide)-4-hydroxymethyl-
2-oxo-1-azetidinyl]-2-phenyl
Methyl acetate [at the 3rd and 4th positions of the azetidine ring]
mixture of two cis isomers]. This compound is developed on a chromatograph, and each
The cis isomers were separated. One isomer: mp179-181.5℃ Other isomers: mp196-198℃ Example 103 0.39g of triphenylphosphine in anhydrous acetoni
Dissolve in 10 ml of tolyl and add 0.24 g of bromine to this solution.
A solution of 5 ml of anhydrous acetonitrile containing
The mixture was added dropwise over a period of 5 minutes, and then the mixture was allowed to stand at the same temperature.
Stir for 25 minutes. On the other hand, 2-azido-3-(α-method)
Toxicarbonylbenzylamino)propionic acid
Free of chloride 0.32g and triethylamine 0.4g
Dissolved in 5 ml of water and acetonitrile and heated to 15°C at 5°C.
This solution was added dropwise to the above mixture over a period of minutes.
The mixture was stirred at the same temperature for 30 minutes and further at room temperature.
Stirring was continued for 4 hours. acetonitrile under reduced pressure
was distilled off, and ether was added to the residue. Filter out insoluble matter
The solvent was distilled off under reduced pressure. Silica gel 20 to remove residue
Developed on a column chromatograph of g, and added chloroform.
It was eluted in the sample. Combine fractions containing the target product and reduce pressure
When the solvent is distilled off, 1-(3-azido-2-
Oxo-1-azetidinyl)-2-phenylacetic acid
Obtain 90 mg of a mixture of the two isomers of methyl (a) and (b).
Ta. IR νcm^-1(film) 2080, 1760, 1730. NMR (TMS) δppm (CDCl₃) Isomer (a); 2.93 (1H, q, J=2Hz, J=6Hz) 3.73 (3H, s) 3.86 (1H, t, J=6Hz) 4.63 (1H, q, J=2Hz, J=6Hz) 5.56 (1H, s) 7.28 (5H, s) Isomer (b); 3.26-3.76 (2H, m) 3.80 (3H, s) 4.50 (1H, q, J=2Hz, J=5Hz) 5.60 (1H, s) 7.33 (5H, s) Condensation of the following in substantially the same manner as Example 103
By using agents or bases (a) to (b),
The same target substance as in Example 103 was obtained. (a) N,N'-dicyclohexycarbodiimide (b) N,N'-diisopropylcarbodiimide (c) N,N′-dimethylaniline, [2-azido-
3-(α-methoxycarbonylbenzylamide
c) Propionic acid chloride hydrochloride as raw material
]. (d) Ethylmagnesium bromide [2-azide
-3-(α-methoxycarbonylbenzylamide
c) Methyl propionate was used as the raw material]. Corresponding in substantially the same way as Example 103
2,3-disubstituted propionic acid with N as a condensing agent,
React with N′-dicyclohexycarbodiimide
The following compounds (Examples 104 to 106) were prepared by
Obtained. Example 104 D-2-(3-azido-2-oxo-1-aze
Tidinyl)-2-phenylacetic acid [azetidine ring
mixture of two isomers at position 3]. IR νcm^-1(film) 2100, 1750 (broad) NMR (TMS) δppm (CDCl₃) 3.2-3.8 (2H, m), 4.48 (1H, m) 5.54 (1H, broad s), 7.35 (5H, s) Example 105 D-2-(3-bromo-2-oxo-1-aze
Tidinyl)-2-phenylacetic acid [azetidine ring
mixture of two isomers (a) and (b) at position 3]. This compound was analyzed by column chromatography.
was separated into isomers (a) and (b). NMR (TMS) δppm (CDCl₃) Isomer (a); 3.20 (1H, d, d, J = 2Hz, 6Hz) 4.17 (1H, d, d, J=5Hz, J=6Hz) 4.83 (1H, d, d, J=2Hz, J=6Hz) 5.68 (1H, s) 7.28~7.50 (5H, m) Isomer (b); 3.54~3.88 (2H, m) 4.62~4.76 (1H, m) 5.6 (1H, s) 7.17~7.45 (5H, m) Example 106 2-(4-hydroxyphenyl)-2-(2-
Oxo-3-tritylamino-1-azetidini
) Acetic acid, mp135-139°C (decomposition). IR νcm^-1(Nujiyor) 3320, 1740, 1720. NMR (TMS) δppm [(CD₃)₂SO〕 2.68 (1H, m), 3.60 (1H, t, J=6Hz),
3.92 (1H, m), 5.24 (1H, s), 6.60-7.72
(19H, m) Example 107 2-[3-{4-(3-tertiary butoxycarbo
Nylamino-3-methoxycarbonyl propoxy
c) Phenylglyoxyroylamino}-2-o
xo-1-azetidinyl]-2-(2-thienyl
) Dissolve acetic acid in 3 ml of methanol and add to this solution.
Add 2 ml of 1N aqueous sodium hydroxide solution under ice cooling.
Ta. The mixture was stirred at the same temperature for 7 hours and the
Adjust the pH to 9.0 to 9.5 with 1N sodium hydroxide.
Ta. After the reaction is complete, adjust the pH of the reaction solution with dilute hydrochloric acid.
7.0 and evaporated to dryness under reduced pressure on a water bath.
Dissolve the residue in a small amount of water and add dilute hydrochloric acid to this aqueous solution.
In addition, after adjusting the pH to 5.5, extract with ethyl acetate.
Ta. Add dilute hydrochloric acid to the aqueous solution and add vinegar again at pH 4.0 to 4.5.
Extracted with ethyl acid. Dry the extract under reduced pressure,
2-[3-{4-(3-tertiary butoxycarbony
Ruamino-3-carboxypropoxy)phenyl
glyoxyroylamino}-2-oxo-1-a
Zetidinyl]-2-(2-thienyl)acetic acid 0.350
I got g. IR νcm^-1(film) 3400-3300, 1750, 1730, 1710, 1680-1660. Example 108 2-[3-{4-(3-tertiary poxycarbo
Nylamino-3-carboxypropoxy)-fe
Nylglyoxyroylamino}-2-oxo-1
-azetidinyl]-2-(2-thienyl)acetic acid
Mix 0.830g with 4ml of benzene and 1ml of anisole.
In addition, 2,2,2-trifle was added to this mixture under ice cooling.
2 ml of fluoroacetic acid was added. The resulting mixture is heated to the same temperature.
Stir for 2.5 hours at
I got it. Then, stir for another 30 minutes under ice cooling to remove insoluble matter.
It was collected by filtration and suspended in 30 ml of ethyl acetate. suspension
The mixture was stirred for 1 hour, and insoluble materials were collected by filtration. This is true
After washing with ether and drying, 2-[3-{4
-(3-amino-3-carboxypropoxy) fluoride
enylglyoxyroylamino}-2-oxo-
1-Azetidinyl]-2-(2-thienyl)acetic acid
0.49g was obtained. IR νcm^-1(Nujiyor) 3450〜3300, 1740, 1680, 1660, 1600. NMR (TMS) δppm(D₂O＋NaHCO₃) 2.28~2.54 (2H, m), 3.32~4.10 (3H, m),
4.20~4.38 (2H, m), 5.00~5.12 (2H, m),
5.61, 5.67 (1H, each s), 7.00~8.08 (7H, m) Example 109 2-[3-(N-benzyloxycarbonyl-
2-phenylglycinamide)-2-oxo-1
-azetidinyl]-2-(2-thienyl)acetic acid
Dissolve 0.19g in 20ml of methanol and touch this solution.
0.15 g of 10% palladium-carbon was added as a medium.
This mixture is subjected to a reduction reaction in a hydrogen stream at room temperature and pressure.
Attached. After absorbing the calculated amount of hydrogen in 6.5 hours
The catalyst was filtered off and the filtrate was dried under reduced pressure to form an oil.
I got it. This was solidified with ethyl acetate and the resulting powder
Add 0.09g of powder to a mixture of acetonylyl and water (volume ratio 20:
When treated with 1), 2-[3-(2-phenyl group)
lysinamide)-2-oxo-1-azetidine
0.02g of [ru]-2-(2-thienyl)acetic acid was obtained.
Ta. mp199~215℃ (decomposition). IR νcm^-1(Nujiyor) 3300, 1730, 1690. NMR (TMS) δppm (CD₃O.D.) 3.10 (1H, d, d, J = 2.5Hz, 5Hz), 3, 86
(1H, t, J = 5Hz), 4.90 (1H, d, d, J
=2.5Hz, 5Hz), 5.56 (1H, s), 4.92 (1H,
s), 6.94-7.60 (8H, m) Example 110 Erythro-2-[3-(2-hydroxyimino
-2-phenylacetamide)-2-oxo-1-
azetidinyl]-3-methoxy-3-phenylp
Dissolve 810 mg of methyl lopionate in 4 ml of acetone,
Add 0.1 N sodium hydroxide to this solution while stirring on ice.
3.8 ml of aqueous solution was added dropwise. Stir for another 5 minutes at the same temperature.
After continued stirring, acetone was distilled off under reduced pressure. Residue
Add 5 ml of water to the ivy solution and wash with ethyl acetate.
The pH was adjusted to 2 with 3N hydrochloric acid. Add this solution to acetic acid.
Extract twice each with 10 ml of chill, and dilute the extract with sodium chloride.
After washing with a saturated aqueous solution of magnesium, dry with magnesium sulfate.
It was dry. When the solvent is distilled off under reduced pressure, 2-[3-
(2-hydroxyimino-2-phenylacetami
d)-2-oxo-1-azetidinyl]-3-meth
65 mg of toxy-3-phenylpropionic acid was obtained.
Ta. mp81-85℃ (decomposition). IR νcm^-1(film) 3300 (broad), 1750 (shoulder), 1720 (broad),
1650. NMR (TMS) δppm [(CD₃)₂CO〕 3.27 (3H, s), 3.70 (1H, m), 4.10 (1H, t,
J=6Hz), 4.56 (1H, d, J=5Hz), 4.93
(1H, d, J=5Hz), 5.20 (1H, m), 7.2~
7.8 (m), 8.18 (1H, m) Methyl ester in substantially the same manner as Example 110
By hydrolyzing the corresponding compound having a tel bond,
The following compounds (Examples 111 to 126) were obtained. Example 111 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-phenylthiopropionic acid. IR νcm^-1(film) 3250 (broad), 2900~2700, 1730 (broad)
), 1670 (Broad). NMR (TMS) δppm [(CD₃)₂CO〕 3.24-3.92 (4H, m), 4.53 (1H, m), 5.14
(1H, m), 7.15-7.80 (10H, m), 8.39 (1H,
m) Example 112 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(2-thienyl)acetic acid. IR νcm^-1(Nujiyor) 3350, 1755, 1700, 1650. NMR (TMS) δppm (CD₃O.D.) 3.43 (1H, d, d, J = 2.5Hz, 6Hz), 3.95
(1H, t, J=6Hz), 5.08 (1H, m), 5.84
(1H, s), 6.90~7.73 (8H, m) Example 113 2-[3-[4-{3-tertiary butoxycarbo
Nylamino-3-(4-methoxybenzyloxy)
carbonyl)propoxy}phenylglyoxylo
ylamino〕-2-oxo-1-azetidinyl〕
-2-(2-thienyl)acetic acid. IR νcm^-1(film) 3450-3300, 1760, 1730, 1710, 1680-1660. Example 114 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-2-(1-naphthyl)acetic acid. IR νcm^-1(film) 3250 (broad), 2900~2700, 1730 (broad)
), 1670 (Broad). Example 115 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-phenylacrylic acid, 78-83℃ (min.
solution). IR νcm^-1(Nujiyor) 1740, 1710, 1680 (broad) NMR (TMS) δppm [(CD₃)₂CO〕 3.90~4.2 (2H, m), 5.40 (1H, m), 7.2~7.8
(11H, m), 8.53 (1H, d, J=8Hz) Example 116 3-methyl-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-2-
[2-oxo-3-(2-phenoxyacetamide)
-1-azetidinyl]acrylic acid. IR νcm^-1(Nujiyor) 3250, 1740, 1720, 1650. NMR (TMS) δppm (CD₃O.D.) 2.28 (3H, s), 2.68 (3H, s), 3.72, 3.76
(1H, d, d, J = 2Hz, 5Hz), 3.90 (1H,
t, J = 5Hz), 4.16, 4.46 (2H, AB-q, J
= 14Hz), 4.56 (2H, s), 5.08, 5.12 (1H, d,
d, J=2Hz, 5Hz), 6.96-6.39 (5H, m). Example 117 2-[3-2-hydroxyimino-2-pheni
ruacetamide)-2-oxo-1-azetidine
]-3-methyl-3-(5-methyl-1,3,
4-thiadiazol-2-ylthiomethyl)ac
Lylic acid. IR νcm^-1(Nujiyor) 3300, 1740, 1720, 1660. Example 118 3-2-benzothiazolylthiomethyl)-2-
[3-(2-hydroxyimino-2-phenyla
cetamide)-2-oxo-1-azetidinyl]-
3-Methyl acrylic acid. IR νcm^-1(Nujiyor) 3250, 1740, 1720, 1660. Example 119 3,3-bis(5-methyl-1,3,4-thia
diazol-2-ylthiomethyl)-2-[2-
Oxo-3-{2-(2-thienyl)acetami
{do}-1-azetidinyl dicycloacrylate
Xylamine salt. IR νcm^-1(Nujiyor) 3300, 1760, 1675, 1640-1620. NMR (TMS) δppm (CD₃O.D.) 1.28~2.18 (10H, m), 2.68 (6H, s), 3.08~
3.28 (2H, m), 3.52, 3.56 (1H, d, d, J=
2Hz, 5Hz), 3.75 (1H, t, J=5Hz), 3.76
(2H, s), 4.34 (2H, s), 4.56 (2H, s),
4.98, 5.02 (1H, d, d, J = 4Hz), 6.92~
7.26 (3H, m). Example 120 2-[3-(2-hydroxyimino-2-fe
nyl acetamide)-2-oxo-1-azetidine
]-3-(4-hydroxyphenyl)propio
acid. IR νcm^-1(film) 3400, 1735, 1720, 1660. Example 121 2-(4-benzyloxyphenyl)-2-
[4-Methylthio-2-oxo-3-(2-phene
nylacetamide)-1-azetidinyl]acetic acid [a
Two trans at positions 3 and 4 of the zetidine ring
mixture of isomers]. IR νcm^-1(film) 3300, 1760, 1740, 1670. NMR (TMS) δppm [(CD₃)₂CO〕 1.22, 1.89 (3H, each s), 3.57 (2H, s), 4.51~
5.03 (2H, m), 5.15 (2H, s), 5.30 (1H, s)
6.95-7.69 (14H, m), 8.10 (1H, d, J=8
Hz) Example 122 2-[4-(5-methyl-1,3,4-thiazi
Azol-2-ylthio)-2-oxo-3-
{2-(2-thienyl)acetamide}-1-aze
Tidinyl]-2-phenylacetic acid [azetidine ring
mixture of two cis isomers at the 3 and 4 positions]. IR νcm^-1(Nujiyor) 1775, 1740, 1660. NMR (TMS) δppm (CD₃O.D.) 2.60 (3H, s), 3.72 (2H, s), 5.48 (1H, s),
5.66 (1H, d, J = 4Hz), 6.14 (1H, d, J =
4Hz), 6.68-7.60 (8H, m) Example 123 2-[4-(5-methyl-1,3,4-thiazi
Azol-2-ylthio)-2-oxo-3-
{2-(2-thienyl)acetamide}-1-aze
Tidinyl]-2-phenylacetic acid [azetidine ring
Mixing of two trans isomers at positions 3 and 4
thing〕. IR νcm^-1(Nujiyor) 1775, 1750, 1640. NMR (TMS) δppm (CD₃O.D.) 2.60 (3H, s), 3.72 (2H, s), 5.10 (1H, d,
J = 2Hz), 5.42 (1H, s), 5.66 (1H, d, J
= 2Hz), 6.60~7.36 (8H, m) Example 124 2-[4-methylthio-2-oxo-3-{2
-(2-thienyl)acetamide}-1-acetidi
[3-position of azetidine ring]-2-phenylacetic acid [3-position of azetidine ring]
and a mixture of two trans isomers at position 4]. IR νcm^-1(film) 3300, 1770, 1750, 1670. NMR (TMS) δppm〔(CDCl₃) 1.82, 2.05 (3H, each s), 3.60 (2H, s), 3.78
(3H, s), 4.40~4.98 (2H, m) 5.12 (2H,
s), 5.30, 5.35 (1H, each s), 6.50 (1H, d,
J=8Hz), 6.85-7.62 (14H, m) Example 125 2-[4-trans-styryl-3-(2-hi
Droxyimino-2-phenylacetamide)-2
-oxo-1-azetidinyl]-2-phenyl vinegar
acid. νcm^-1(Nujiyor) 3250, 2600-2500, 1760, 1740, 1690 Example 126 2-[3-(2-hydroxyimino-2-fe
Nilacetamide)-4-hydroxymethyl-2-
Oxo-1-azetidinyl]-2-phenyl vinegar
acid. IR νcm^-1(Nujiyor) 3380, 3200, 1750, 1720, 1700 (shoulder), 1650 Example 127 2-(2-oxo-3-phthalimido-1-a
Zetidinyl)-2-(2-thienyl)methyl acetate
3.0g and 3.4g of lithium iodide in 40ml of dry pyridine
and the mixture was heated to reflux for 2 hours. Mixing after reaction
into a mixture of 250 ml of ice water and 300 ml of ethyl acetate.
The mixture was poured and the pH was adjusted to 2 with 10% hydrochloric acid while cooling on ice. precipitation
When the crystals are collected by filtration, 2-(2-oxo-3-fluoride) is obtained.
Thalimido-1-azetidinyl)-2-(2-thi
0.20 g of enyl)acetic acid was obtained. Ethyl acetate layer
The aqueous layer was further extracted with ethyl acetate.
Combined, washed with dilute hydrochloric acid and water, and then washed with sulfuric acid mug.
dried with nesium. When the solvent is distilled off under reduced pressure
2.26 g of the same material as above was obtained. Also from mother liquor
0.17 g of the same material was obtained. Total yield 2.64g,
mp199~201℃ IR νcm^-1(Nujiyor) 2750～2500, 1770, 1740, 1720 NMR (TMSP) δppm(D₂O＋NaHCO₃) 3.36 (1H, q, J = 3Hz, 5Hz), 3.91 (1H,
t, J = 5Hz), 5.38 (1H, q, J = 3Hz, 5
Hz), 5.74 (1H, s), 7.00~7.80 (7H, m) In substantially the same manner as Example 127, methyl ether
The corresponding compound with a stellate group in pyridine
By reacting with anhydrous lithium iodide, the following can be obtained.
Compounds (Examples 128 and 129) were obtained. Example 128 2-(3-azido-2-oxo-1-azetidi
(3-position of azetidine ring)-2-phenylacetic acid
mixture of two isomers (a) and (b)]. IR νcm^-1(film) 2570, 2100, 1740, 1720 NMR (TMS) δppm (CD₃O.D.) Isomer (a); 2.95 (1H, q, J = 2Hz, 5Hz) 3.90 (1H, t, J=5Hz) 4.77 (1H, q, J = 2H, 5Hz) 5.56 (1H, s) 7.36 (5H, s) Isomer (b); 3.39 (1H, t, J=5Hz) 3.56 (1H, q, J = 2Hz, 5Hz) 4.59 (1H, q, J = 2Hz, 5Hz) 5.54 (1H, s) 7.36 (5H, s) Example 129 D-2-(2-oxo-3-phenoxy-1-
azetidinyl)-2-phenylacetic acid [azetidine
A mixture of two isomers (a) and (b) at the 3-position of the ring]. IR νcm^-1(film) 1740 (broad) NMR (TMS) δppm [(CD₃)₂CO〕 Isomer (a); 3.18 (1H, d, d, J = 2Hz, 6Hz) 4.02 (1H, t, J=6Hz) 5.27 (1H, m) 5.72 (1H, s) 6.8~7.5 (10H, m) Isomer (b); 3.56 (1H, m) 3.77 (1H, m) 5.13 (1H, m) 5.69 (1H, s) 6.8~7.5 (10H, m) Example 130 D-2- in substantially the same manner as Example 127
(3-benzyloxy-2-oxo-1-azethi
benzyl (dinyl)-2-phenylacetate and anhydrous iodination
By reacting lithium in pyridine,
D-2-(3-benzyloxy-2-oxo-1
-Azetidinyl)-2-phenylacetic acid
Mixture of two isomers (a) and (b) at the 3-position of the ring
object] was obtained. IR νcm^-1(film) 1730 (broad) NMR (TMS) δppm [(CD₃)₂CO〕 Isomer (a); 3.14 (1H, d, d, J = 3Hz, 6Hz 4.00 (1H, t, J=6Hz) 5.41 (1H, d, d, J = 3Hz, 6Hz) 5.65 (1H, s) 6.8~7.5 (10H, m) Isomer (b); 3.5~3.8 (1H, m) 5.30 (1H, d, d, J = 3Hz, 6Hz) 5.63 (1H, s) 6.8~7.5 (10H, m) Example 131 2-(3-amino-2-oxo-1-azetidi
Nyl)-3-methyl-3-(5-methyl-1,
3,4-thiadiazol-2-ylthiomethyl)
Dissolve 656 mg of methyl acrylate in 15 ml of acetone,
Furthermore, 0.1N aqueous sodium hydroxide solution was added under ice-cooling and stirring.
Added 20ml. Stir the mixture for 5 hours at 10-15℃
Then, 200 mg of sodium hydrogen carbonate was added. This mixture
N-(2,2,2-trichloroethoxy
carbonyl)-2-phenylglycyl chloride
A solution of 5 ml of acetone containing 830 mg of
It was added dropwise with stirring at the same temperature and stirred for another 2 hours.
Ta. Acetone was distilled off under reduced pressure, and the aqueous layer was dissolved in ethyl acetate.
Extracted with . Add the extract to dilute hydrochloric acid, water, and 5% carbonated water.
Wash sequentially with a sodium aqueous solution and remove magnesium sulfate.
dried in a vacuum. The solution was evaporated to dryness under reduced pressure to form an oil.
Obtain the residue and perform column chromatography on 12 g of silica gel.
It expanded to a great extent. Purpose of elution with chloroform
Combine the fractions containing the substance and add chloroform under reduced pressure.
When distilled off, 2-[3-{N-(2,2,2-t)
(lichloroethoxycarbonyl)-2-phenylg
lysinamide}-2-oxo-1-azetidine
]-3-methyl-3-(5-methyl-1,3,
4-thiadiazol-2-ylthiomethyl)ac
130 mg of lylic acid was obtained. IR νcm^-1(film) 3250, 1760, 1720, 1700, 1670 NMR (TMS) δppm (CDCl₃) 2.24 (3H, s), 2.66 (3H, s), 3.56, 3.60
(1H, d, d, J = 2Hz, 5Hz), 3.84 (1H,
t), 3.98, 4.52 (2H, AB-q, J=14Hz),
4.71 (2H, s), 4.88, 4.92 (1H, d, d, J=
2Hz, 5Hz), 7.28-7.48 (5H, m) Example 132 3-(4-benzyloxyphenyl)-2-
(2-oxo-3-phthalimido-1-azetidi
1.5 g of methyl propionate (20 g of ethanol)
ml and 10% ethyl acetate.
1.5 g of dium-carbon was added. Always use a pressurizing device.
The reduction reaction was carried out in a hydrogen stream for 3 days at room temperature, and the calculation was carried out.
amount of hydrogen was absorbed into the reaction mixture. Post-reaction catalyst
was filtered off, and the filtrate was evaporated to dryness under reduced pressure, leaving a residue of 1.01
Crystallize g from a mixture of diethyl ether and ethyl acetate.
3-(4-hydroxyphenyl)-2
-(2-oxo-3-phthalimide-1-azethi
0.33 g of methyl (dinyl)propionate was obtained.
The same substance was also recovered from the mother liquor, with a total yield of 0.38
It was hot at g. IR νcm^-1(Nujiyor) 3250, 1780, 1762, 1735, 1690 Example 133 2-(3-azido-4-methylthio-2-ox
So-1-azetidinyl)-2-phenylacetic acid
0.60 g of chill (mixture of two trans isomers)
Dissolved in 10 ml of methylene chloride, in this solution,
Dissolve 77 mg of chlorine in 5 ml of methylene chloride.
The solution was added dropwise over a period of 10 minutes at -65 to -70°C. Mixed
The mixture was stirred at the same temperature for 1 hour and then diluted with sodium thiosulfate.
Magnesium sulfate after washing with aqueous solution and water, respectively.
dried in a vacuum. The solvent was distilled off under reduced pressure, leaving a residue of 0.64
g on a column chromatograph using 15 g of silica gel.
It opened. Elutes with chloroform and contains target substance
The fractions were combined. When the solvent is distilled off under reduced pressure, 2-
(3-azido-4-chloro-2-oxo-1-a
Zetidinyl)-2-phenylacetate methyl
isomers (two trans isomers and two cis isomers)
0.44 g of an oily mixture was obtained. IR A mixture of two cis isomers. νcm^-1(liquid film) 2120, 1780, 1745 mixture of two trans isomers νcm^-1(liquid film) 2120, 1790, 1750 NMR (TMS) of two cis isomers δppm (CDCl₃) one of the cis isomers 3.76 (3H, s) 4.74 (1H, d, J=5Hz) 5.34 (1H, s) 5.68 (1H, d, J=5Hz) 7.40 (5H, s) the other cis isomer 3.76 (3H, s) 4.86 (1H, d, J=5Hz) 5.48 (1H, s) 6.07 (1H, d, J=5Hz) 7.40 (5H, s) Example 134 In substantially the same manner as Example 133, 2-[3
-Azide-4-(5-methyl-1,3,4-thia
Diazol-2-ylthio)-2-oxo-1-
Azetidinyl]-2-phenylacetate methyl
0.37 g of a mixture of trans isomers of is mixed with 0.1 g of chlorine.
By reacting, 2-(3-azido-4-
Chloro-2-oxo-1-azetidinyl)-2-
Methyl phenyl acetate [3- and 4-positions of azetidine ring
two trans and two cis isomers in
240 mg of body mixture] was obtained. mixture of two trans isomers νcm^-1(film) 2120, 1790, 1750 mixture of two cis isomers νcm^-1(film) 2120, 1785, 1745 Example 135 2-(3-azido-4-chloro-2-oxo-
Methyl 1-azetidinyl)-2-phenylacetate
Mixture of two trans and two cis isomers
Dissolve 4.0g of the substance in 50ml of dry methylene chloride,
Add 1.13 g of anhydrous calcium carbonate and 5-methyl
Ru-1,3,4-thiadiazole-2-thiol
Added 2.10g. Stir this mixture at room temperature for 8 hours.
The mixture was poured into ice water and extracted with ether. extraction
Wash the liquid with 1% potassium carbonate aqueous solution and water in that order.
and dried with magnesium sulfate. Solvent under reduced pressure
was distilled off, and 4.05 g of the residue was washed with 160 g of silica gel.
It was developed into a matograph. Elute with chloroform
The fractions containing the target substance are combined and the solvent is distilled off under reduced pressure.
Then, 2-[3-azido-4-(5-methyl-
1,3,4-thiadiazol-2-ylthio)-
2-oxo-1-azetidinyl]-2-phenyl
Methyl acetate (two trans and cis isomers each)
2.81 g of body mixture) was obtained. two trans isomers mp81~84℃ IR νcm^-1(Nujiyor) 2130, 1790, 1780 (shoulder), 1745 two cis isomers IR νcm^-1(film) 2120, 1780, 1745 Example 136 3,3-dimethyl-2-(2-oxo-3-ph)
thalimido-1-azetidinyl) methacrylate
Ru 0.334g, N-bromosuccinimide 0.360g and
0.020g of benzoic acid peroxide to carbon tetrachloride 30
ml and then heated under reflux for 1 hour. reaction
After that, the precipitated substances were filtered off, and the filtrate was placed under reduced pressure.
Evaporation to dryness gave an oil. In this, carbon tetrachloride
When crushed with the addition of
lomomethyl)-2-(2-oxo-3-phthaloyl)
(mid-1-azetidinyl) methyl acrylate,
mp127.5-131°C was obtained. IR νcm^-1(Nujiyor) 1790, 1770, 1730,
1720 NMR (TMS) δppm [(CD₃)₂CO〕 3.75 (3H, s), 4.37 (2H, d, J=5Hz)
4.55, 4.75 (2H, AB-q, J=10Hz), 4.60,
4.87 (2H, AB-q, J=10Hz). 5.65 (1H, t,
J = 5Hz), 7.93 (4H, s) Example 137 In substantially the same manner as Example 136, 3,3-
Dimethyl-2-(2-oxo-3-phthalimide
-1-azetidinyl) methyl acrylate 0.344g
was reacted with 0.178 g of N-promosuccinimide.
Then, 3-bromomethyl-3-methyl-2-(2
-Oxo-3-phthalimide-1-azetidine
) Cis and trans isomers of methyl acrylate
331.5 mg of a mixture of sex isomers was obtained. IR νcm^-1(film) 1780, 1765, 1710 NMR (TMS) δppm (CDCl₃) 2.31, 2.37 (3H, s), 3.84, 3.88 (3H, s),
3.88-4.12 (2H, m), 4.12, 4.76, 4.38, 4.70
(2H, each AB-q, J=10Hz), 5.52~5.64 (1H,
m), 7.72-7.96 (4H, m) Example 138 3-bromomethyl-3-methyl-2-(2-o
xo-3-phthalimido-1-azetidinyl)a
107mg of methyl acrylate in N,N-dimethylform
Dissolve in 2 ml of amide and add 5-methyl-1,3,
Add 41mg of 4-thiadiazole-2-thiol
Ta. Add 31% of triethylamine to this solution while stirring on ice.
mg was added dropwise, and then stirred at room temperature for 1 hour. reaction
The mixture was poured into ice diluted hydrochloric acid and extracted with ethyl acetate.
Ta. The extract was mixed with dilute hydrochloric acid, water, and 5% sodium bicarbonate.
Wash with magnesium sulfate in aqueous solution and then water.
It was dried. The solution was evaporated to dryness under reduced pressure and the residue
Developed on a column chromatograph using 4g of silica gel.
Ta. Fraction containing target substance eluted with chloroform
combined. 3-methyl-3-(5-methyl-1,
3,4-thiadiazol-2-ylthiomethyl)
-2-(2-oxo-3-phthalimido-1-a
zetidinyl) trans isomer of methyl acrylate
The eluate containing the same substance is evaporated to dryness under reduced pressure.
18 mg of quality was obtained. Cis isomers and torsion of the above compounds
Similarly, the eluate containing a mixture with the lance isomer
treatment, the cis and trans isomers of the compound
30 mg of a mixture with isomers was obtained. Do the same thing again
28 mg of the cis isomer was obtained. trans isomer IR νcm^-1(film) 1790, 1770, 1730, 1720 NMR (TMS) δppm (CDCl₃) 2, 38 (3H, s), 2.73 (3H, s), 3.85 (3H,
s), 4.10 (2H, d, J=5Hz), 4.28, 4.78
(2H, AB-q, J = 10Hz), 5.64 (1H, t, J
=5Hz), 8.00~7.76 (4H, m) cis isomer νcm^-1(Nujiyor) 1780, 1760, 1730, 1720 NMR (TMS) δppm (CDCl₃) 2.33 (3H, s), 2.74 (3H, s), 3.86 (3H, s),
3.92-4.08 (2H, m), 4.85, 4.72 (2H, AB-
q, J = 10Hz), 5.56, 5.60 (1H, d, d, J =
5Hz), 7.76-7.98 (4H, m) Example 139 In substantially the same manner as Example 138, 3,3-
Bis(bromomethyl)-2-(2-oxo-3-
Phthalimido-1-azetidinyl) acrylic acid
Chill 500mg and 5-methyl-1,3,4-thiadia
To react with 310 mg of sol-2-thiol
3,3-bis(5-methyl-1,3,4-thi)
adiazol-2-ylthiomethyl)-2-(2
-Oxo-3-phthalimide-1-azetidine
) 590 mg of methyl acrylate was obtained. IR νcm^-1(film) 1790, 1770, 1730, 1720 NMR (TMS) δppm (CDCl₃) 2.75 (3H, s), 2.77 (3H, s), 3.90 (3H, s),
4.13 (2H, d, J = 4Hz), 4.47, 4.80 (2H,
AB―q, J=14Hz), 4.77 (2H, s), 5.62
(1H, t, J=4Hz), 7.40~7.90 (4H, m) Example 140 In substantially the same manner as Example 138, 3-bro
Momethyl-3-methyl-2-(2-oxo-3-
Phthalimido-1-azetidinyl) acrylic acid
chill and 3,3-bis(bromomethyl)-2-(2
-Oxo-3-phthalimide-1-azetidine
) Add 2.54 g of a mixture of methyl acrylate to benzothi
React with 0.870g of azole-2-thiol.
3-(2-benzothiazolylthiomethythyl)
)-3-methyl-2-(2-oxo-3-phthalate)
limido-1-azetidinyl) methyl acrylate
and 3,3-bis(2-benzothiazolylthiomethy)
)-2-(2-oxo-3-phthalimide-1
-Azetidinyl) methyl acrylate mixture2.53
g was obtained. IR νcm^-1(film) 1780, 1760, 1720 Example 141 2-(3-amino-2-oxo-1-azetidi
2-(4-hydroxyphenyl)acetic acid
Suspend 0.236g in 10ml of dry chloroform, and
Bis(trimethylsilyl)acetamide 0.406g
added. Thereafter, it was stirred overnight at room temperature, and 1-(1,
1-dimethoxymethyl) perhydroazepine
Add 0.200g to the mixture and stir for another 2 hours at room temperature.
did. Add 3 ml of water to the reaction mixture and continue stirring gradually.
Ta. The mixture was evaporated to dryness under reduced pressure, leaving a small amount of residue.
of acetone. Bring the suspension to room temperature for 20 minutes.
Stir for minutes and collect the powder by decanting.
Ta. Repeat this operation three times and apply the resulting powder.
When washed with setone, 2-(4-hydroxyphenylene)
)-2-[2-oxo-3-(perhydro-1
-Azevinylmethyleneamino-1-azetidine
0.330 g of acetic acid was obtained. IR νcm^-1(Nujiyor) 3500～3400, 1740, 1690, 1600 Example 142 2-(2-oxo-3-phthalimido-1-a
zetidinyl)-3-phenylthiopropionate
5.1 g of chill and 4.0 g of pyridine in 100 g of dichloromethane
ml, and in this solution, add 2.0 g of sulfuryl chloride.
A solution of 20 ml of dichloromethane containing
It was added dropwise over 70 minutes with stirring, and then added at the same temperature for 1 hour.
Stirring was continued for an hour. After the reaction is completed, evaporate to dryness under reduced pressure.
Then add 100ml of ethyl acetate and 50ml of water and stir gradually.
did. Separate the ethyl acetate layer and add the remaining aqueous layer to acetic acid.
Extracted with ethyl. Add this extract to ethyl acetate.
Combine the layers and dilute with dilute hydrochloric acid 3 times to saturate with sodium bicarbonate.
After washing three times with hydrochloric acid solution and twice with water, wash with sulfuric acid solution.
Dried with gnesium. The solvent was distilled off under reduced pressure,
Column chromatography of the oily residue using 30 g of silica gel
It expanded to a great extent. Elute with chloroform and target substance
The fractions containing were combined. When the solvent is distilled off under reduced pressure
2-(2-oxo-3-phthalimido-1-aze
Tidinyl)-3-phenylthioacetate (methyl
4.23 g (mixture of nce and cis isomers) was obtained.
It was. Recrystallize this compound with crushed ethanol
Then, 0.84g of one of the cis and trans isomers
was gotten. mp170~171℃. IR νcm^-1(Nujiyor) 1780, 1760, 1720 (shoulder), 1710, 1610 NMR (TMS) δppm (CDCl₃) 3.80 (3H, s), 4.13 (1H, t, J=6Hz),
4.29 (1H, d, d, J = 6Hz, 3Hz), 5.63
(1H, d, d, J=6Hz, 3Hz), 7.3~8.0
(10H, m) Example 143 D-2-(3-bromo-2-oxo-1-aze
Tidinyl)-2-phenylacetic acid 120mg and sodium
Muazide 114mg in N,N-dimethylformamide
The mixture was added to 1.2 ml and stirred at 70°C for 3 hours.
After evaporating the solvent under reduced pressure, the residue was added to 5 ml of ethyl acetate.
Then, it was washed with 3% hydrochloric acid and water. Ethyl acetate layer
Extract twice with 3 ml each of saturated sodium bicarbonate aqueous solution
did. The aqueous layers were combined and adjusted to pH 2 with 10% hydrochloric acid.
Afterwards, the mixture was extracted three times with 3 ml each of ethyl acetate. extract liquid
The mixture was dried with magnesium sulfate and then evaporated under reduced pressure.
It started drying. First remove the oily residue with a thin layer of silica gel.
Benzene, ethyl acetate and vinegar
Develop with a mixture of acids (volume ratio 6:2:1) to obtain the desired
After collecting the fractions, D-2-(3-azido-2-o
xo-1-azetidinyl)-2-phenylacetic acid
Obtained. This product is based on the similar product obtained in Example 103 and IR.
I identified it. Example 144 2-[4-trans-styryl-2-oxo-
3-phthalimido-1-azetidinyl]-2-ph
enyl acetic acid (at positions 3 and 4 of the azetidine ring)
Mixture of two cis isomers) 13.0g with dichloromethane
Dissolved in 300ml of tan. Add ozone gas to this solution
Absorb it and the color of ozone appears at -78℃
Absorption continued until (45 minutes). Then at the same temperature for 30
Blow nitrogen gas for a minute and dimethyl sulfide.
6.4 ml was added and left for a while. reaction mixture
Evaporate to dryness under reduced pressure and dissolve the residue in dichloromethane.
did. Add this solution to 100ml of water and sodium chloride water.
The solution was washed twice and dried over magnesium sulfate.
The solution was evaporated to dryness under reduced pressure and the residue was washed with alumina 200
The mixture was developed on a column chromatograph of g. Elution is based
containing the target substance.
The fractions were combined and the solvent was distilled off under reduced pressure to obtain 2-
(4-formyl-2-oxo-3-phthalimide
-1-Azetidinyl)-2-phenylacetate methyl
(Two cis at positions 3 and 4 of the azetidine ring)
9.14 g of mixture of isomers) was obtained. IR νcm^-1(film) 1785, 1740 (shoulder), 1730, 1710 (shoulder) NMR (TMS) δppm (CDCl₃) 3.80 (3H, s), 4.27, 4.78 (1H, each d, d, J
=4Hz, 6Hz), 5.51, 5.79 (1H, each d, J = 6
Hz), 5.88, 5.93 (1H, each s), 7.43 (5H, s),
7.64-7.94 (4H, m), 8.79, 9.98 (1H, each d,
J=4Hz) Example 145 2-(4-formyl-2-oxo-3-phthal
imido-1-azetidinyl)-2-phenylacetic acid
Methyl 390mg and o-benzylhydroxylamine
Dissolve 170mg in 10ml of dry benzene and add this solution to
Stir at room temperature for 4 hours, then at 50-60℃ for 1 hour
Heated. The reaction mixture was mixed with 10 ml of 1% hydrochloric acid, water and salt.
Wash with sodium chloride aqueous solution and then with magnesium sulfate.
Dry. This solution was evaporated to dryness under reduced pressure to obtain
Column chroma using 15g of silica gel was applied to 560mg of the residue.
It was developed into a tograph. Elute with chloroform and
Fractions containing target substances were combined. Distill the solvent under reduced pressure
Then, 2-(4-benzyloxyimino-2-
oxo-3-phthalimido-1-azetidinyl)
530 mg of -2-phenylacetic acid was obtained. IR νcm^-1(film) 1790, 1780, 1750 (shoulder), 1730 Example 146 2-(3-azido-4-formyl-2-oxo
-1-azetidinyl)-2-phenylacetic acid 2.30
g, sodium borohydride 310mg, ethanol
A mixture of 40 ml and 5 ml of water was heated at -10 to 0°C.
Stir for hours. Add 10% hydrochloric acid to the reaction mixture at the same temperature.
In addition, the pH was adjusted to 4-5. Then distill the ethanol
and sodium chloride was added to the aqueous residue. profit
The resulting aqueous solution was extracted twice with chloroform.
The liquid was washed with an aqueous sodium chloride solution. sulfuric acid mug
After drying with a paper towel, evaporate to dryness under reduced pressure to obtain a residue.
2.02g to column chromatograph with 20g of alumina
Expanded. It is eluted with chloroform and contains the target substance.
The fractions were combined. When the solvent is distilled off under reduced pressure, 2
-(3-azido-4-hydroxymethyl-2-o
xo-1-azetidinyl)-2-phenylacetic acid
0.95 g of chill was obtained. IR νcm^-1(film) 3450, 2130, 1780 (shoulder), 1770, 1740 Example 147 2-(4-formyl-2-oxo-3-phthal
imido-1-azetidinyl)-2-phenylacetic acid
Methyl 0.38g, silver oxide 0.92g, tetrahydrofura
A mixture of 9 ml of water and 1 ml of water was stirred at room temperature for 40 hours.
did. Filter out insoluble matter and reduce tetrahydrofuran.
It was distilled off under pressure. Add to the residue and adjust the pH to 2 with 10% hydrochloric acid.
After that, the mixture was extracted with ethyl acetate. 1% charcoal extract
Wash with sodium oxyhydrogen aqueous solution, and reduce the washing solution to 10%
The pH was adjusted to 2 with hydrochloric acid. This aqueous solution was extracted with ethyl acetate.
Combine this extract with the previous one, wash with water, and sulfurize.
Dry with magnesium acid. Distill the solvent under reduced pressure
Then, 2-(4-carboxy-2-oxo-3
-phthalimido-1-azetidinyl)-2-hue
Methyl nylacetate (at the 3rd and 4th positions of the azetidine ring)
200 mg of a mixture of the two cis isomers (a) and (b)
Obtained. IR νcm^-1(film) 2600~2500, 1770, 1760, 1740~1720 NMR (TMS) δppm [(CD₃)₂CO〕 Isomer (a); 3.66 (3H, s) 4.89 (1H, d, J=5Hz) 5.59 (1H, s) 5.89 (1H, d, J=5Hz) 7.28~7.70 (5H, m) 7.80~8.54 (4H, m) Isomer (b); 3.69 (3H, s) 4.78 (1H, d, J=5Hz) 5.56 (1H, s) 5.79 (1H, d, J=5Hz) 7.28~7.70 (5H, m) 7.80～8,54 (4H, m) By substantially the same method as Example 30, the following compound was prepared.
Compounds (Examples 148-150) were obtained. Example 148 D-2-(3-amino-2-oxo-4-fe
Nyl-1-azetidinyl)-2-(4-hydroxy
Cyphenyl) Methyl acetate [3-α of azetidine ring
-4-α-coordination]. IR νcm^-1(Nujiyor) 3250, 1745, 1735 (shoulder) NMR (TMS) δppm (CDCl₃) 3.73 (3H, s), 4.52 (1H, d, J=6Hz),
5.13 (1H, d, J=6Hz), 5.37 (1H, s).
6.47~7.34 (9H, m) Example 149 D-2-(3-amino-2-oxo-4-fe
Nyl-1-azetidinyl)-2-(4-hydroxy
Cyphenyl) Methyl acetate [3-β of azetidine ring
-4-β-coordination]. IR νcm^-1(film) 3300, 1750, 1730 NMR (TMS) δppm (CDCl₃) 3.48 (2H, broad s), 3.58 (3H, s), 4.21
(1H, d, J = 6 Hz), 4.78 (1H, d, J = 6
Hz), 5.20 (1H, s), 6.70 (2H, d, J=10
Hz), 7.16-7.52 (5H, m), 7.08 (2H, d, J
=10Hz) Example 150 D-2-(3-amino-4-hydroxymethyl
-2-oxo-1-azetidinyl)-2-pheni
Methyl acetate [at the 3- and 4-positions of the azetidine ring]
mixture of two cis isomers]. IR νcm^-1(film) 3400, 1760, 1740 3-Amino- in substantially the same manner as Example 79
2-azetidinone compound and 2-(2,2-dichloro
Reacts with (roacetoxyimino)-2-phenylacetic acid
The following compounds (Example 150 and
and 152). Example 151 D-2-[3-(2-hydroxyimino-2-
phenylacetamide)-2-oxo-4-phenylated
ru-1-azetidinyl]-2-(4-hydroxy
phenyl) methyl acetate [3-α- of azetidine ring
4α-coordination]. mp209~211℃. IR νcm^-1(Nujiyor) 3270, 1765, 1735, 1645 Example 152 D-2-[3-(2-hydroxyimino-2-
phenylacetamide)-2-oxo-4-phenylated
ru-1-azetidinyl]-2-(4-hydroxy
Methyl phenyl acetate [3-β-4 of azetidine ring
-β-coordination]. mp191~192.5℃. IR νcm^-1(Nujiyor) 3350, 3280, 1740, 1710, 1670 NMR (TMS) δppm [(CD₃)₂SO〕 3.56 (3H, s), 4.95 (1H, d, J=6Hz),
5.28 (1H, s), 5.38 (1H, d, d, J = 6.8
Hz), 6.48-7.56 (14H, m), 9.40 (1H, d, J
=8Hz), 9.54 (1H, s) Methyl ester in substantially the same manner as Example 110
Hydrolyzing the corresponding compound with a tel group
The following compound (Example 153) was obtained. Example 153 2-[3-(2-hydroxyimino-2-fe
nylacetamide)-2-oxo-4-phenyl]
-2-(4-hydroxyphenyl)acetic acid [azethi
cis isomer at the 3- and 4-positions of the gin ring]. IR νcm^-1(Nujiyor) 3260, 1735 (shoulder), 1710, 1650 Example 154 2-(3-azido-2-oxo-1-azetidi
0.52g of phenyl)-2-phenylacetic acid and hydrogen carbonate
0.18g of sodium in 3ml of water and 5ml of methanol
After dissolving in water, add 0.26g of 10% palladium on carbon.
The catalytic ring element is carried out at room temperature in a stream of bare air. about 2 hours
After absorbing the calculated amount of hydrogen gas, the catalyst is
leave Methanol is distilled off from the liquid under reduced pressure,
The remaining aqueous solution is washed with ethyl acetate. this water
When the solution is lyophilized, 2-(3-amino-2-o
xo-1-azetidinyl)-2-phenylacetic acid
Sodium salt [2 at the 3-position of the azetidinone ring]
0.41 g of mixture of species isomers (a) and (b) was obtained.
Ta. IR νcm^-1(film) 1740, 1600 NMR (TMSP) δppm(D₂O) Isomer (a): 2.91 (1H, d, d, J = 2.5Hz, 5Hz) 3.78 (1H, t, J=5Hz) 4.72 (1H, d, d, J = 2.5Hz, 5Hz) 5.32 (1H, s) 7.40 (5H, m) Isomer (b); 4.04 (1H, t, J=5Hz) 4.20 (1H, d, d, J = 2.5Hz, 5Hz) 4.72 (1H, d, d, J = 2.5Hz, 5Hz) 5.30 (1H, s) 7.40 (5H, m) Example 155 3-(3-azido-2-oxo-1-azetidi
Example 154
When fused and reduced in substantially the same way as 3-(3
-Amino-2-oxo-1-azetidinyl)-3
-Phenylpropionate methyl ester is obtained.
Ta. IR νcm^-1(film) 3400, 1755, 1740, 1715.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is amino, azide, phthalimide,
Phenoxy or acylamino of the formula: or R ^d -CONH- [wherein R ^b and R ^c are oxo or hydroxyimino, R ^d
is phenyl (lower) alkyl, thienyl (lower)
alkyl or phenyl (lower) alkoxy, respectively], R ² is hydroxymethyl,
Phenyl (lower) alkoxyiminomethyl, phenyl, phenyl (lower) alkenyl, formyl,
thiadiazolethio substituted with carboxy, halogen atom, lower alkylthio or lower alkyl, and R ³ is a group [formula] (in the group, R ⁴ is phenyl which may be substituted with hydroxy or benzyloxy, R ⁵ is It means a carboxyl group, phenyl (lower) alkoxycarbonyl or lower alkoxycarbonyl, respectively.