JPH0240070B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel synthetic intermediate of 1-dethia-1-oxacephalosporin. More details: General formula: [However, A is amino or protected amino; E is hydrogen or methoxy; Y is the formula

【formula】

【formula】

[expression] or

[Formula] (where COB is carboxy or protected carboxy; X is hydrogen or a nucleophilic group; Z is a leaving group;
represents. ) The wavy lines represent α or β bonds, respectively. ] The present invention relates to a 1-dethia-1-oxacefam compound represented by the following and a method for producing the same. 1-Dethia-1-oxacephalosporins have been synthesized by Christensen (Journal American Chemical Society, 96 , 7582 (1974)), and also by the synthesis method shown in the reaction process diagram below. has also been done. ●Japanese Patent Publication No. 51-149295 ●Japanese Patent Publication No. 51-41385 ●Unexamined Japanese Patent Publication 1973-133594 (However, A is amino or substituted amino; COB is carboxy or protected carboxy; X is hydrogen or a nucleophilic group; ph is phenyl; and R' is aryl or alkyl;) However, in the above process, Since a carbonium ion is generated at the 4-position of azetidinone, the epimer isomer ratio is 1:1 depending on the direction of introduction of the oxygen functional group.
occurs at a rate of The epimer mixture has approximately 1/2 the activity of the 6-epimer form of 1-dethia-1-oxacephalosporins. The present inventors have completed the present invention as a result of intensive research aimed at finding an economical synthesis method to improve the above-mentioned disadvantages. In the above definition, a protected amino group is
For example, it means an amino group protected with the groups shown below. ( ₁ ) C1- _C10 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropylacetyl, trimethylacetyl, valeryl, t
-Butylacetyl, caproyl, octanoyl, cyclohexylacetyl, dicanoyl, 2
(2) _C1 - _C7 haloalkanoyl (e.g., chloroacetyl, chloropropionyl, chloroisovaleryl, dichloroacetyl,
(3) Azidoacetyl, cyanoacetyl, trifluoromethylthioacetyl, cyanomethylthioacetyl, (4-pyridon-1-yl)acetyl; (4) Formula: Ar―CO― (However, Ar is aryl, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, Pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophenyl,
Tetrahydrophenyl, tetrahydropyrimidyl, naphthyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl, benzopyrimidyl, cinnolinyl, pyridopyrimidyl, indanyl, etc.; methyl, ethyl, propyl,
Hydroxymethyl, chloromethyl, trifluoromethyl, cyano, carboxy, carboxymethyl, aminomethyl, phenyl, chlorophenyl, fluorophenyl, amino, formylamino, acetamide, propionamide, butyrylamino, valeramide, isovaleramide,
imino, nitro, hydroxy, methoxy, ethoxy, propoxy, methylenedioxy, ethylenedioxy, formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy, phenylacetoxy, benzoyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy , bromobenzenesulfonyloxy, methoxycarbonyloxy, ethoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, carbamoyloxy, methylcarbamoyloxy, oxo, chloro, bromo,
It may be appropriately substituted with iodine or the like. ); (5) Acyl represented by the formula: Ar-CQQ'-CO- (However, Ar has the same meaning as above; Q and Q' each represent hydrogen or methyl); (6) Acyl represented by the formula :Ar―G―CQQ′―CO― (However, Ar, Q, and Q′ have the same meanings as above;
(G represents oxygen, sulfur, or imino): (7) Formula:

[Formula] (However, Ar has the same meaning as above; T ¹ is hydrogen or C ₁ - _{C 6} alkyl, for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
These include pentyl, isoamyl, t-pentyl, neopentyl, isopropylethyl, and cyclopentyl. ); Formula (8):

[Formula] (However, Ar has the same meaning as above; T ² represents any of the following (i) to (iv). (i) Hydroxy or C ₁ to C ₁₀ acyloxy (e.g., formyloxy, Acetoxy, propionyloxy, butyryloxy, valeryloxy, cyclopropylacetoxy, cyclopentylpropionyloxy, phenylacetoxy, thienylacetoxy, phenoxyacetoxy, glycoloyloxy, glyoxyloyloxy, glycyloxy, chloroacetoxy, bromoacetoxy, trifluoroacetoxy, Benzoyloxy, methylbenzoyloxy, dimethylbenzoyloxy,
Nitrobenzoyloxy, methoxybenzoyloxy, cyanobenzoyloxy, methanesulfonylbenzyloxy, carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy, methoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, methoxybenzyloxy carbonyloxy, nitrobenzyloxycarbonyloxy, etc.): (ii) Carboxy or protected carboxy as shown in the COB column below; (iii) Sulfo or _C1 - _C5 alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl) , propoxysulfonyl, butoxysulfonyl, cyclopropylmethoxysulfonyl, pentyloxysulfonyl, or cyclopropylethoxysulfonyl; or (iv) formula:

The group represented by [Formula] [W ¹ and W ² are each hydrogen or a C ₁ to _{C 10} amino substituent, specifically, a C ₂ to _{C 7} alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, or methylhexylcarbonyl), _C3 - _C10 cycloalkyl- _C2 - _C3
-Alkoxycarbonyl (e.g. cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexylethoxycarbonyl, cycloheptylmethoxycarbonyl), _C5 - _C8 cycloalkoxycarbonyl (e.g. cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl) , cyclopropylcarbonyl), C ₁ ~
C ₄ alkylsulfonyl - C ₁ - C ₄ alkoxycarbonyl (eg methanesulfonyl ethoxycarbonyl, ethanesulfonyl ethoxycarbonyl, methanesulfonyl butoxycarbonyl, butanesulfonyl butoxycarbonyl),
Halo _C1 - _C3 alkoxycarbonyl (e.g. chloromethoxycarbonyl, chloroethoxycarbonyl, bromoethoxycarbonyl, iodoethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl, trichloropropoxycarbonyl),
Aralkoxycarbonyl (e.g., benzyloxycarbonyl, methylbenzyloxycarbonyl, dimethylbenzyloxycarbonyl, aminobenzyloxycarbonyl, acetamidobenzyloxycarbonyl, nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl, chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl) , diphenylmethoxycarbonyl, diphenylethoxycarbonyl, thiazolylmethoxycarbonyl, pyridylmethoxycarbonyl, and other Ar-CH ₂ O-CO- (However, Ar
(same meaning as above)), _C1 - _C10 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, t-valeryl, hexanoyl,
heptanoyl, cyclohexanecarbonyl,
octanoyl, cyclopentanepropionyl, decanoyl), an acyl group represented by Ar—CO— (where Ar has the same meaning as above), or other acyl groups (e.g., pyronecarbonyl, thiopyronecarbonyl, pyridonecarbonyl, carbamoyl, anidylcarbonyl, ureidocarbonyl, methylimidazolidonecarbonyl, methanesulfonylimidazolidonecarbonyl, methyldioxopiperazin-1-ylcarbonyl, ethyldioxopiperazin-1-ylcarbonyl, butyldioxopiperazin-1-ylcarbonyl);

[Formula] is taken together to form a carbonyl compound that can be enolized with amino (e.g.
_C5 to _C10 acetoacetate (e.g. methyl, ethyl, propyl, butyl, isobutyl, or pentyl ester of acetoacetate), _C5 to C10
Groups constituting Schiff bases or enamines derived from _C10 acetoacetamide (e.g. amide, methylamide, anilide, or methylanilide of acetoacetate), acetylacetone, acetoacetonitrile, α-acetylbutyrolactone, 1,3-cyclopentanedione, etc.) ,or

( ₉ ) 5- _Aminoadipoyl , C ₁ ~C ₁₀ alkanoyl, aroyl, aralkanoyl, haloalkanoyl, or 5-aminoadipoyl, alkyl with amino group protected with alkoxycarbonyl,
5-aminoadipoyl with carboxy protected with aryl, aralkyl, or alkylsilyl; (10) Formula: L-O-CO- (where L is appropriately substituted and easily removable)
C ₁ -C ₁₀ hydrocarbon groups (e.g. t-butyl, 1,
1-dimethylpropyl, cyclopropylmethyl, cyclopropylethyl, 1-methylcyclohexyl, isobornyl, 2-methoxy-t-
(11) Derived from C ₄ to C ₁₀ polybasic carboxylic acids diacyl (e.g., succinyl, maleoyl, phthaloyl, pyridine-2,3-dicarbonyl, etc.); (12) optionally substituted C ₁ -C ₂₀ hydrocarbon group (e.g., methyl, ethyl, t -butyl,
Trityl, methylidene, benzylidene, hydroxybenzylidene, α-halobenzylidene, α
(13) C ₃ to C ₁₀ organic Silyl (e.g. trimethylsilyl, dimethylmethoxysilyl, chlorodimethylsilyl, methyldimethoxysilyl, methylethylenedioxysilyl); (14) _C3 - _C10 organostannyl (e.g. trimethylstannyl, dimethylmethoxystannyl, chlorodimethylstannyl); and (15) _C1 - _C10 sulfenyl (e.g., methylthio, phenylthio, o-nitrophenylthio, etc.). fluoro, chloro, bromo, etc.), nitrogen functional groups (e.g. amino, hydrazinyl, azide, alkylamino, arylamino, acylamino, alkylidene amino, acylimino, imino, nitro, etc.),
Oxygen functional groups (e.g. hydroxy, alkoxy,
aralkoxy, aryloxy, acyloxy,
oxo), sulfur functional groups (e.g. mercapto,
Alkylthio, aralkylthio, arylthio,
Acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl, aryloxysulfinyl, carbon functional groups (e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl, cyano, etc.) , phosphorus functional groups (e.g. phospho,
phosphoroyl, etc.) may be substituted as appropriate. Among the above amino-protecting groups, the acyl group constituting the side chain in penicillin and cephalosporin is particularly important, but since it can be removed or introduced by conventional methods at any stage after the reaction, its composition varies between raw materials and final products. A wide range of changes are possible regardless of the structure, and the main focus is on stability against reactions. Also, groups that can be converted to amino or amide (e.g. enamino, amide, azide, isocyanato,
isocyano) and cyclic groups (e.g. 4-phenyl-2,2-dimethyl-5-oxoimidazolidin-1-yl, 4-p-hydroxyphenyl-2,
2-dimethyl-3-nitroso-5-oxoimidazolidin-1-yl, 4-p-hydroxyphenyl-2-phenyl-5-oxoimidazolidine-
1-yl, 4-thienyl-5-oxoimidazolidin-1-yl, etc.) are also included within the scope of A. The protected carboxy group represented by COB is
It is commonly used in the chemistry of β-raftam and can withstand the reaction conditions of this reaction.
Protecting groups B include (1) ester-forming groups [e.g. C ₁ -C ₁₀ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, monohydroxy-t-butoxy, methoxy-t-butoxy, cyclo Propylmethoxy, pentyloxy, isopentyloxy, cyclopropylethoxy, cyclopentyloxy, hexyloxy, cyclohexyloxy, octyloxy,
decyloxy, etc.), _C1 - _C6 haloalkoxy (e.g. chloromethoxy, chloroethoxy, bromoethoxy, iodoethoxy, dichloropropoxy, trichloroethoxy, trichlorobutoxy, dibromocyclohexyloxy, etc.),
_C3 - _C10 acylalkoxy (e.g. acetonyloxy, acetyl ethoxy, propionylmethoxy, phenacyloxy, chlorophenacyloxy, bromophenacyloxy, nitrophenacyloxy, methylphenacyloxy, etc.),
_C3 to _C10 alkoxyalkoxy (e.g. methoxymethoxy, ethoxymethoxy, chloroethoxymethoxy, propoxyethoxy, butoxyethoxy, cyclohexyloxyethoxy, methoxyethoxymethoxy, butoxyethoxymethoxy, octyloxyethoxy, etc.), _C2 to _C10
Aminoalkoxy (e.g. aminomethoxy, aminoethoxy, dimethylaminoethoxy, ethylaminomethoxy, etc.), aryloxy (e.g. phenoxy, chlorophenoxy, nitrophenoxy, naphthyloxy, pyridyloxy,
indolyloxy, indanyloxy, pentachlorophenoxy), aralkoxy (e.g. benzyloxy, methylbenzyloxy, xylylmethoxy, chlorobenzyloxy, bromobenzyloxy, methoxybenzyloxy,
Ethoxybenzyloxy, nitrobenzyloxy, dibromobenzyloxy, phenethyloxy, phthalidyloxy, p-hydroxy-di-
t-butylbenzyloxy, diphenylmethoxy, trityloxy, etc.), _C1 - _C10 alkylsilyloxy (e.g. trimethylsilyloxy,
( ₂ ) _Anhydride -forming groups _[ e.g. C ₁₀ organic acyloxy (e.g. acetoxy, propionyloxy, sulfonyloxy, etc.), inorganic acyloxy (e.g. acyloxy such as sulfuric acid, perchlorate, etc.); (3) Salt-forming groups [e.g. metals of the periodic table or groups of metals; oxy (e.g. lithium oxy, sodium oxy _, potassium oxy, magnesium oxy, etc.), C ₁ -C ₁₅ hydrocarbylammonium oxy (e.g. triethylammonium oxy, dicyclohexylammonium oxy, etc.); (5) Amide-forming groups [e.g. C _{1 -C 5} alkylamino (e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino, etc.), di-C ₁ -C ₅ Alkylamino (e.g. dimethylamino, diethylamino, piperidyl, morpholin-1-yl, methylmorpholine-1-
and (6) a hydrazide or azide forming group. Since these protecting groups are usually removed after the reaction, changes in their structure often have no important meaning for this invention. The nucleophilic group represented by X includes all groups that are substituted with an acetoxy group at the 3-position in the chemistry of cephalosporin. For example, halogen (chloro, bromo, etc.), hydroxy, optionally substituted C1 _{- C4} alkanoyloxy (formyloxy, acetoxy, propionyloxy, butyryloxy, malonyloxy, succinoyloxy, cyanoacetoxy, glycyloxy, alanyloxy, glycoloyloxy, glyoxyloyloxy, phenoxyacetoxy, sulfopropionyloxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, etc.), aroyloxy (benzoyloxy, naphthoyloxy, etc.), which may be substituted as appropriate Acyloxy of carbonic acid (chloroformyloxy, methoxyformyloxy, trichloroethoxyformyloxy, cyclopropylmethoxyformyloxy, methanesulfonylethoxyformyloxy, etc.), C ₁ - _{C 6} alkoxy (methoxy,
ethoxy, propoxy, butoxy, s-butoxy, cyclopropylmethoxy, cyclohexyloxy, etc.), aralkoxy (benzyloxy, furfuryloxy, naphthylmethoxy, etc.), aryloxy (phenoxy, naphthyloxy, indanyloxy, etc.), mercapto, C ₁ ~ _C5 alkanoylthio (acetylthio, propionylthio,
butyrylthio, etc.), aroylthio (benzoylthio, naphthoylthio, etc.), thiocarbamoylthio, methylthiocarbamoylthio, _C1 - _C6 alkylthio (methylthio, ethylthio, propylthio, butylthio, cyclopropylmethylthio,
cyclopropylethylthio, etc.), aralkylthio (benzylthio, picolylthio, phenethylthio, etc.), and arylthio (phenylthio, triazolylthio, thiadiazolylthio, oxadiazolylthio, tetrazolylthio, etc.).
All of these groups include optionally substituted alkyl (methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, sulfoethyl, dimethylaminoethyl, dimethylaminopentyl, morpholinoethyl, etc.), nitrogen functional groups (amino, azide, hydrazinyl, acetylamino, methylamino, pyridinium, picolinium, 4-carboxypyridinium, carbamoylpyridinium, hydroxymethylpyridinium, carboxymethylpyridinium, chloropyridinium, etc.). The leaving group represented by Z is the anionic part of the nucleophile, such as halogen (chloro, bromo, iodo, etc.), hydroxy, acyloxy of C ₁ to C ₈ carboxylic acids (acetoxy, trifluoroacetoxy, etc.). ), acyloxy sulfonic acids (methanesulfonyloxy, ethanesulfonyloxy, toluenesulfonyloxy, bromobenzenesulfonyloxy, etc.), arylthio (phenylthio), arylsulfenyl (phenylsulfenyl, etc.), arylselenyl, arylsulfinyloxy Nyl, alkylsulfinyl, etc.
Since these leaving groups are eliminated during the reaction, their structure can vary widely and are often of no significance to the invention. The compound () of the present invention means a compound as shown below.

【formula】

【formula】

[expression] or

[Formula] (However, A, E, COB,
b), (c), or (d) can be easily produced by carrying out the following ring-closing reaction, methoxylation, addition reaction of XZ, etc. sequentially or in an appropriate combination. (1) Ring-closing reaction (The numbers inside the brackets indicate the position numbers of the bone nucleus.) (2) Methoxylation (3) XZ addition reaction (4) Other conversion reactions (in the above process formula, A, E, COB, X, and Z have the same meanings as above; Y ¹ is Y or

[Formula] R means a group obtained by removing carbonyl from acyl. ) In the above definition, the group represented by R, obtained by removing carbonyl from acyl, specifically means a group obtained by removing carbonyl from acyl, which is exemplified as an amino protecting group in the section A above. That is, R.C.O.
is included within the definition of A. According to the method of the present invention, by using the compound ( ) as a starting material, the oxygen atom of the hydroxyl group bonds from the opposite side of the ring bond during the ring-closing reaction, so that only the preferred stereoisomer (6β form) at the 6-position is present. can be obtained in high yield.
Therefore, the method of the present invention is an excellent method that improves the drawback of the conventional synthetic method that a 6-position isomer is produced. Each step will be explained in detail below. (1) Ring-closing reaction When oxazolinoazetidines () are treated with acid, the ring is closed to obtain compound (). Examples of acids include mineral acids (hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, bromobenzenesulfonic acid, trifluoromethanesulfonic acid) acids, naphthalenesulfonic acid, etc.), strongly acidic carboxylic acids (trichloroacetic acid, trifluoroacetic acid, etc.),
Lewis acids (boron trifluoride, zinc chloride, stannous chloride, stannic chloride, stannous bromide, antimony trichloride, antimony pentachloride, titanium trichloride, etc.) can be used. The reaction is usually carried out in an inert solvent. Examples of inert solvents include hydrocarbon solvents (hexane, cyclohexane, benzene, toluene, etc.), halohydrocarbons (methylene chloride, chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, etc.), ethers (diethyl ether, diisobutyl ether, dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), sulfoxides (dimethyl sulfoxide, etc.), nitriles (acetonitrile, benzonitrile, etc.) These can be used alone or in combination. Solvents with hydroxyl groups, such as water, alcohols (methanol, ethanol, t-butanol, benzyl alcohol), acids (formic acid, acetic acid, propionic acid, etc.), are preferred because they react with the raw material () to produce by-products. However, it can be used by adjusting the reaction conditions. The reaction is usually carried out at -30°C to 50°C, preferably 15°C.
It is achieved at ~30°C and can be completed in 5 minutes to 10 hours, usually 15 minutes to 3 hours, to obtain the desired product () in high yield. If necessary, the reaction can be carried out under stirring or
Alternatively, it may be carried out in an inert gas (eg nitrogen, argon, carbon dioxide, etc.). The terminal hydroxy group connected to Y ¹ of oxazolinoazetidine ( ) may be protected in advance with an easily removable hydroxy protecting group such as formyl, tetrahydropyranyl, etc. In this step, for example, oxazolinoazetidine () is mixed with a 5 to 10 times amount of a hydrocarbon solvent (chloroform, methylene chloride, etc.) and a 0 to 10 times amount of an ether solvent (ether, dioxane, etc.). After melting and adding 0.001 to 1 molar equivalent of acid (boron trifluoride etherate, toluene sulfonic acid, copper sulfate, zinc chloride, tin chloride, etc.), the solution is kept at 10 to 60℃ for 0.5 to 10 hours. Compound () can be obtained in yields of about 50-90%. Raw material () is 6-epipenicillin-1-
It can be produced from oxide according to the following reaction scheme, for example. (R, COB, and
After forming = (exo form at position 7),
This can be achieved by adding methanol. When A is amino or amide, when compound (a) is treated with an N-halogenating agent, a base is added to eliminate the hydrogen halide, and the resulting imino compound is treated with methanol, E becomes α
- Obtain the target substance () which is methoxy. N-
When a halogenating agent is added, other parts within the molecule may be halogenated to form a perhalogen, but excess halogen can be removed by reduction. This step is achieved by any of the following methods (i) to (iv). (i) The amine or amide is treated with an N-halogenating agent (e.g., molecular halogen, t-butyl hypochlorite) and then with an alkali metal methoxide (LiOCH ₃ , NaOCH ₃ ,
KOCH ₃ ) or alkaline earth metal methoxides (Mg( _OCH3 ) ₂ , Ca( _OCH3 ) ₂ , Ba
(OCH ₃ ) ₂ , etc.). (ii) in the presence of a base and phenyllithium, optionally in a solvent (such as tetrahydrofuran);
Use t-butyl hypohalite and methanol. (iii) Bromine-DBU, phosphorus pentachloride-pyridine, base, methanolic base, and trialkylsilyl chloride or tetraalkylammonium chloride are reacted sequentially. or (iv) Treat t-butylhypohalite in methanol in the presence of sodium borate, and if a perhalogenated product is partially generated, reduce with zinc, phosphite, etc. Also, compound (a) (E=H, A=NH ₂ )
is a suitable aldehyde (benzaldehyde, p
-Hydroxybenzaldehyde, 3,5-di-t-butyl-4-hydroxybenzaldehyde) to form Schiff's base, oxidize to imino form, treat with methanol, and then hydrolyze to form the target compound ().
(E=OCH ₃ , A=NH ₂ ) is obtained. To describe this process specifically, amide (a)
with 10 to 50 times the volume of an inert solvent (dichloromethane,
dioxane, ether, dibropylether,
1 to 5 molar equivalents of an N-halogenating agent (molecular halogen/
carbon tetrachloride, t-butyl hypocrite, etc.) and stir at -70 to -10°C for 2 to 10 minutes, and then
4 equivalents of metal methoxide (LiOCH ₃ , Mg
Add a methanol solution of ( _OCH3 ) ₂ , etc.) and bring to -50
Stir for 5-70 minutes at ~0°C. When the reaction mixture is neutralized with acetic acid or mineral acid and extracted with an organic solvent, a compound () in which E is methoxy is obtained.
With such operations, yields are usually up to 95%. (3) Addition reaction Compounds with exomethylene at the 3rd position (
c) is an inert solvent (hydrocarbon, halohydrocarbon,
Addition reagent XZ [molecular halogen, peracid, peroxide, hypohalite salt, hypohalite ester, heavy metal peroxide (osmium tetroxide, etc.), sulfenyl halide, etc. ], Y becomes the formula:

[Formula] (However, COB, X and Z have the same meanings as above)
A compound (a) having a divalent group represented by is obtained. The addition reaction proceeds smoothly in an inert solvent, especially a halohydrocarbon or ether solvent, with low salt, ie at -70 to 0°C, and is completed in 5 minutes to 10 hours. Also, due to the high reactivity of the exomethylene double bond at the 3-position, the yield is 90%.
reach up to. When the reagent is a molecular halogen, light irradiation or catalysts (Cu, Cu ₂ S, Cu ₂ Cl ₂ ,
ph ₃ PO, etc.), the halogenation can proceed and the yield can be increased. (4) Other conversion reactions Compound () can be processed by conventional conversion reactions in β-lactam chemistry (for example, transfer of double bonds with bases, protection of carboxy represented by COB or deprotection of protected carboxy), protection of the indicated amino or deprotection of the protected amino, introduction or conversion of the X or Z group with a nucleophile, conversion of X or Z by conversion reactions such as acylation, hydrolysis, oxidation, reduction, etc.) can be converted into another compound (). These reactions involve hydrocarbon solvents (hexane, toluene, etc.), halohydrocarbon solvents (dichloromethane, chlorobenzene, etc.), ether solvents (diethyl ether, dioxane, etc.), ketone solvents (acetone, cyclohexanone, benzophenone, etc.), Ester solvents (ethyl acetate, methyl benzoate, etc.), alcohol solvents (ethanol, t-butanol, benzyl alcohol, etc.),
It is carried out in a solvent commonly used for organic reactions such as amides and carboxylic acids. The compound () produced as described above is isolated from the solvent, unreacted substances, by-products, etc. by concentration, extraction, washing, drying, or other conventional methods, and then subjected to reprecipitation, chromatography, crystallization, adsorption, etc. Can be purified. Stereoisomers at the 3- or 7-position can be separated by chromatography, fractional recrystallization, and the like. The mixture of stereoisomers may be used in the next step or synthetic reaction without separation. During the above steps, double bond transfer, introduction of nucleophilic group,
Although side reactions such as elimination may occur during the reaction, these side reactions can also be effectively utilized and are within the scope of the present invention. The compound () of the present invention can be used as a raw material for the synthesis of known antibacterial agents, such as 1-oxacephalosporins (Japanese Patent Application Laid-Open Nos. 49-133594 and 51-
149295). That is, operations such as transfer of the double bond to Δ ³ , conversion of the A group to a side chain suitable for exhibiting antibacterial activity, and/or deprotection of the protected carboxy represented by COB are performed on the compound (). It can be synthesized by applying For example, as shown in the process diagram below, (a) when HZ is eliminated from compound (a), 1-dethia-1-oxacephalosporin () is obtained. (b) When compound (d) is treated with a base (such as trimethylamine) at 0 to 70°C for 5 hours to 3 days, the double bond is rearranged to obtain 1-dethia-1-oxacephalosporin (). (c) Compound (a) is treated with a Lewis acid (eg, boron trifluoride) at 0°C to 50°C for 0.1 to 1 hour to cause ring closure and yield 1-dethia-1-oxacephalosporin (). Compound of the present invention () (A=7β-amide, COB
=COOH) or a pharmaceutically acceptable salt thereof is
It itself has a mild antibacterial effect and can be used with diluents to treat diseases caused by susceptible Gram-positive bacteria (e.g. (Streptococcus pyogenes)) or Gram-negative bacteria (e.g. Escherichia coli) for one day. It is sufficient to inject 0.1 to 10 g.The embodiments of the present invention will be clarified by giving examples below.The names and position numbers of the compounds in the examples are as follows. 1βH, 5βH- or (1R,5S)-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0]
hept-2-en 1-Dethia-1-oxacepham The configuration of carbons at the 7- and 6-positions of oxacefam is the same as the configuration of the 1- and 5-positions of oxabicycloheptene. The stereochemistry at carbon 6 of the 1-dethia-1-oxacepham ring is consistent with the stereochemistry at carbon 6 of cephalosporin. Preferably, the stereochemistry of COB is the same as penicillin, ie the R configuration, but this need not be the case. The measurement error in the following examples is ±10 IR
cm ^-1 , NMR is within ±0.2 ppm, melting point is not accurate. Anhydrous sodium sulfate is used to dry the solution. The physical constants of the products are listed in the table. Ring Closing Reaction Examples -1 to 32 When oxazolinoazetidine is dissolved in a solvent and an acid is added, a 1-dethia-1-oxacefam compound is obtained. The reaction conditions are shown in the table. Taking No. 14 as an example, it will be shown in detail below. (1) 2-[(1R,5S)-3-phenyl-7-oxa-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-2-
Diphenylmethyl isopropenylacetate 12.0g,
Osmium tetroxide 1.0g and potassium chlorate
Dissolve 12.0g in a mixture of 400ml of tetrahydrofuran and 200ml of water, and stir at 58°C for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract was sequentially washed with brine, 10% sodium thiosulfate aqueous solution and sodium bicarbonate aqueous solution, dried, and the solvent was distilled off, resulting in 2-
[(1R,5S)-3-phenyl-7-oxo-4
-Oxa-2,6-diazabicyclo [3.2.0]
12.88 g of diphenylmethyl hept-2-en-6-yl]-3,4-dihydroxybutyrate are obtained. IR: ν ^CHCl3 _nax 3500br, 1770br, 1742, 1636cm ^-1 (2) Add 10.88g of the above product to 300ml of diethyl ether.
Boron trifluoride etherate 75μ dissolved in
and stirred at room temperature for 3.5 hours in a nitrogen stream.
Pour into a cooled aqueous sodium bicarbonate solution,
Extract with ethyl acetate. The extract is washed with brine and concentrated. Treatment of the residue with a concentrated solution of methylene chloride and ether gives 15 g of a mixture of isomers in the 3-position of diphenylmethyl 7α-benzamide-3ξ-methyl-3ξ-hydroxy-1-dethia-1-oxacefam-4α-carboxylate. IR:ν ^CHC13 _nax 3560, 3445, 1774, 1739, 1670cm
^{The -1} isomer mixture was subjected to column chromatography on 10% hydrous silica gel and eluted with benzene-ethyl acetate (4:1). The stereoisomers can be separated by crystallizing the eluate with acetone-ether and acetone-methylene chloride, respectively. Example -33 (a) 2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)]-3
-Dissolve 54 mg of benzyl formyloxymethyl-2-butenoate in 2 ml of methanol, add 19μ of boron trifluoride etherate while cooling at -20°C, and heat the mixture at -20°C to 0°C for 40 minutes and at 0°C for 2 hours. , then stirred for 1 hour at room temperature. A 5% aqueous sodium hydrogen carbonate solution is added to this, and the mixture is extracted with methylene chloride. The extract is washed with water, dried, and then the solvent is distilled off. When the residue is crystallized from methanol, 7α-benzamide-3-methyl-1
10 mg (yield 20%) of benzyl -dethia-1-oxa-3-cefem-4-carboxylate is obtained.
mp.208-212℃ (b) Add 5μ of trifluoromethanesulfonic acid while cooling with water instead of boron trifluoride and stir for 130 minutes, or add 0.38N hydrochloric acid-methanol.
Add 0.5 ml, stir for 3 hours, and otherwise perform the same procedure as above to obtain the same substance (14 mg; 5 mg) (yield 27.5%; 7%). mp・208～212℃ Methoxylation Example -1～24 7β-Unsaturated-7α-Amido-1-Dethia-1-
When an oxacefam compound is dissolved in a solvent and an N-halogenating agent and a base are reacted in methanol,
A 7α-methoxy-7β-amide compound is obtained. The reaction conditions are shown in the table. (No. 5) 7α-benzamide-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4α-
Dissolve 486 mg of diphenylmethyl carboxylate in 20 ml of anhydrous methylene chloride and add t-butyl hypochlorite.
Add 0.15 ml and 1.1 ml of 2N lithium methoxide in methanol at −50° C. and stir for 15 minutes.
Add 1.2 ml of acetic acid to this, stir for 5 minutes, dilute with ice-cooled aqueous sodium bicarbonate solution, and extract with methylene chloride. After washing the extract with an aqueous sodium hydrogen carbonate solution and then with water, the solvent was distilled off. The resulting colorless foamy residue was purified by silica gel chromatography to yield 7β-benzamide.
7α-methoxy-3α-hydroxy-3β-methyl-
250 mg (yield 48%) of diphenylmethyl 1-dethia-1-oxacefam-4α-carboxylate is obtained. (No.9) 7α-benzamide-3ξ-bromo-3ξ-bromoethyl-1-dethia-1-oxacefam-4α
-Dissolve 187 mg of diphenylmethyl carboxylate in 1 ml of anhydrous methylene chloride, add 46μ of t-butyl hypochlorite and 0.17 ml of a methanol solution of 2M lithium methoxide at -30°C, and stir at the same temperature for 1 hour. To this, 1-methyltetrazole-5
- Add a solution of 100 mg of sodium ilmercaptide in 1 ml of acetone and stir at room temperature for 1.5 hours. The reaction mixture is diluted with methylene chloride, washed with aqueous sodium bicarbonate and brine, dried, and the solvent is evaporated. 180 mg of the residue was subjected to silica gel column chromatography and eluted with benzene-ethyl acetate (1:1), resulting in 7β-benzamide-7α.
-methoxy-3-(1-methyltetrazole-5
-yl)thiomethyl-1-dethia-1-oxa-
Diphenylmethyl 3-cephem-4-carboxylate
Get 108mg. Addition reaction examples -1 to 16 Dissolve 3,3-methylene-1-dethia-1-oxacefam compound in a solvent and add addition reagent XZ. The reaction conditions are shown in the table. (No.3) 7α-benzamide-3-exomethylene-1
Dissolve 519 mg of diphenylmethyl -dethia-1-oxacefam-4α-carboxylate in 5 ml of methylene chloride, add 1.6 ml of 0.76N chlorine/carbon tetrachloride solution, and stir at -20 to -30°C for 40 minutes while irradiating with a tungsten lamp. . Add this to 0.14ml of cyclopentene
Add and stir for an additional 5 minutes. 1,5 to the reaction mixture
-Diazabicyclo[3.4.0]nonene-50.14ml was added, stirred at -20°C for 10 minutes, washed with dilute hydrochloric acid and then water, dried, and the solvent was distilled off. Recrystallization of the crystalline residue from methanol yields 7α-benzamide-3-chloromethyl-1-dethia-1-oxa-
Diphenylmethyl 3-cephem-4-carboxylate
Obtain 484 mg (86% yield). mp.120-128℃ (No. 4) Dissolve 103 mg of diphenylmethyl 7α-benzamide-3-methylene-1-dethia-1-oxacefam-4α-carboxylate in 1 ml of methylene chloride,
Add 0.3 ml of 0.75N chlorine in carbon tetrachloride solution, -20 ~
After reacting under irradiation with a tungsten lamp for 30 minutes at −30°C, the solvent was distilled off under reduced pressure to produce 7α-benzamide-3ξ-chloro-3ξ-chloromethyl-1-
120 mg of diphenylmethyl dethia-1-oxacefam-4α-carboxylate is obtained. (No. 5) In the same manner, 141 mg of benzyl 7α-benzamide-3-methylene-1-dethia-1-oxacefam-4α-carboxylate and 1.4 equivalents of chlorine were reacted in 3 ml of methylene chloride at -50°C under light irradiation. If 7α
170 mg of benzyl -benzamide-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacefam-4α-carboxylate (yield 102%) is obtained. (No. 15) In the same manner as above, 1.77 equivalents of chlorine was added to 705 mg of diphenylmethyl 7α-phenylacetamide-3-methylene-1-dethia-1-oxacefam-4α-carboxylate in 7 ml of methylene chloride at -25°C or below. If allowed to act, 7α-phenylacetamide-
3ξ-chloro-3ξ-chloromethyl-1-dethia-
Diphenylmethyl 1-oxacefam-4α-carboxylate is obtained. If 0.16 ml of pyridine is treated with this at 15°C for 40 minutes, 586 mg of diphenylmethyl 7α-phenylacetamide-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate (yield
78.4%). mp.179-182℃ (decomposition). Example -17 1.405 g (3 mmol) of diphenylmethyl 7α-benzamide-3-methylene-1-dethia-1-oxacepham-4α-carboxylate was dissolved in anhydrous methylene chloride cooled to -26°C, and 141 mg of copper powder was added under stirring in a nitrogen stream. In addition, 6.3 ml (2.5 equivalents) of 1.2M chlorine-chloroform solution was added dropwise over 10 minutes, and the mixture was stirred at -22 to -30°C for 3 hours. To this, sodium thiosulfonate pentahydrate (2.98 g; 4
Add an aqueous solution of the same amount) and extract twice with methylene chloride. The extract is washed with brine, dried over magnesium sulfate, and then the solvent is distilled off. Silica gel residue
190g of benzene-
If eluted with ethyl acetate (3:1), 7α
-Benzamide-3α-chloro-3β-chloromethyl-1-dethia-1-oxacefam-4α-diphenylmethyl carboxylate 1.541g (yield 95.2%)
is obtained as a white foam. Other Conversion Reactions A Elimination Reaction Examples A-1 to 20 If the 1-dethia-1-oxacefam compound is dissolved in a solution and a eliminating agent is used, 1-dethia-1-
Oxacefam compound is obtained. Table A shows the reaction conditions. (No.12) Add 15.0 g of diphenylmethyl 7α-benzamide-3ξ-hydroxy-3ξ-methyl-1-oxadethiacefam-4α-carboxylate to 100 g of methylene chloride.
ml, add 6.8 ml of pyridine and 3 ml of thionyl chloride while stirring on ice, stir at the same temperature for 7.25 hours and at room temperature for 2.25 hours, and then pour into ice water. The organic layer is separated, washed with water, dried, and the solvent is distilled off. The residue was chromatographed on 350 g of 10% hydrated silica gel, and benzene-ethyl acetate (9:
1), 7α-benzamide-3-methyl-1-dethia-1-oxa-3-cephem-
2.65 g of diphenylmethyl 4-carboxylate (yield:
25.2%) and 7α-benzamide-3-methyl-
1-Decia-1-Oxa-2-Cefem-4α-
Diphenylmethyl carboxylate 1.05g (yield: 10.8
%). (IR: ν ^CHC13 _nax 3440, 1782, 1745, 1676, 1663Sh
cm ^-1 ) B Double bond transfer example B-1 Dissolve 100 mg of 7β-benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cefem-carboxylic acid in 10 ml of acetone, and dissolve 0.1 triethylamine. ml and leave at room temperature for 6 days.
When the reaction solution is subjected to thin layer chromatography,
7β-benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-3-cephem-4-
Carboxylic acid and raw material spots are shown. Example B-2 7α-benzamide-3,3-methylene-1-
Dissolve 5.0 g of diphenylmethyl dethia-1-oxacefam-4α-carboxylate in 25 ml of methylene chloride and add 0.5 ml of triethylamine. at room temperature
Stir for 80 minutes, add a small amount of benzene, and then concentrate. Crystallization of the residue from ether gives 4.5 g (90% yield) of diphenylmethyl 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate. After the mixture was left at room temperature for 15 hours, chromatographic separation revealed that 50.8% of Δ ² isomers and 38.3% of Δ ³ isomers were obtained.
% and their mixture yields 4.1%. Example B-3 7α-benzamide-3,3-methylene-1-
Dethia-1-oxacefam-4α-carboxylic acid
Dissolve 100 mg in 10 ml of acetone, add 0.1 ml of triethylamine, and leave for 5 days. When the reaction mixture is subjected to thin-layer chromatography, 7α-benzamide-3-methyl-1-dethia-1-oxa-2
-Cefem-4-carboxylic acid, 7α-benzamide-3-methyl-1-dethia-1-oxa-3-
The spots of Cefm-4-carboxylic acid and raw materials are shown. C Removal example of carboxy protecting group C-1 7β-benzamide-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacefam-4α-carboxylic acid diphenylmethyl 960
mg in 4 ml of anisole, 10 ml of trifluoroacetic acid was added at 0°C, stirred for 15 minutes, and the solvent was distilled off under reduced pressure. When the residue is solidified from ether-n-hexane, 7β-benzamide-7α-methoxy-
3α-methyl-3β-acetoxy-1-dethia-1
-Oxacefam-4α-carboxylic acid 470 mg (yield: 70%) is obtained as a colorless powder. mp.203~208
℃ (Decomposition) The following carboxylic acids can be produced from the corresponding diphenyl methyl esters in a similar manner. 7β-Benzamide-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylic acid, mp.100-105℃ (decomposition) 7α-Benzamide-7α-methoxy-3α-trifluoro Acetoxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylic acid,
mp.108～113℃ 7β-benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4
-Carboxylic acid, mp.195-198℃ IR: ν ^KBr _nax 3250, 1766, 1742, 1642cm ^-1 7α-benzamide-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacefam-4α
-Carboxylic acid, mp.118-122℃ (decomposition) Example C-2 7α-benzamide-3-exomethylene-1
1.125 g of diphenylmethyl dethia-1-oxacefam-4α-carboxylate and 15 ml of methylene chloride
A solution of aluminum trichloride (625 mg) in nitromethane (20 ml) was added to the solution of aluminum trichloride (625 mg) in nitromethane (20 ml) while stirring at -20°C, and the solution was heated to -10° C. in a nitrogen stream.
Stir for 30 min at ~-20°C. This is poured into an aqueous solution of hydrochloric acid and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium carbonate solution, the washings are acidified with concentrated hydrochloric acid, and extracted again with ethyl acetate. The organic layers were combined, washed with water, dried, and the solvent was distilled off to give 7α-benzamide-3-exomethylene-1-dethia-
623 mg of 1-oxacefam-4α-carboxylic acid is obtained. Similarly, 7α-benzamide-3-methyl-1
-diphenylmethyl dethia-1-oxa-2-cephem-4α-carboxylate (1.8 g) in methylene chloride
7α-benzamide-3-methyl-1-dethia-1-oxa-
2-Cefem-4α-carboxylic acid 935 mg (yield 72.6
%). D Example of protection of amino group and removal of amino protecting group D-1 7α-amino-3-methylene-4-dethia-1
Dissolve 25 mg of diphenylmethyl oxacefam-4α-carboxylate in 0.5 ml of methylene chloride, add 7μ of pyridine and 10μ of benzoyl chloride at -20°C in a nitrogen stream, and stir for 1 hour. This is poured into ice water, stirred for 5 minutes, and then extracted with methylene chloride. The organic layer was separated, washed with water, an aqueous sodium bicarbonate solution, then water, dried, and the solvent was distilled off to give 7α-benzamide-3-methylene-1-
28 mg (yield 86%) of diphenylmethyl dethia-1-oxacefam-4α-carboxylate is obtained. This product was identified by thin layer chromatography and NMR. Example D-2 7α-benzamide-3-methylene-dethia-
Dissolve 94 mg of diphenylmethyl 1-oxacefam-4α-carboxylate in 4 ml of methylene chloride, add 32μ of pyridine and 1.08 ml of a 0.37M phosphorus pentachloride solution in methylene chloride at -40°C in a nitrogen stream, warm to room temperature, and stir for 1 hour. . Cool again to -40℃,
Add 8 ml of methanol, warm to 0℃, and add 0.8 ml of water.
was added and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate, washed with water, extracted with an aqueous sodium bicarbonate solution and then with water. Combine the extract and washing liquid, cover with ethyl acetate, adjust the pH to 7.0, and extract with ethyl acetate. Separate the organic layer, wash with water,
After drying and distilling off the solvent, 7α-amino-3-
Methylene-1-dethia-1-oxacefam-
Diphenylmethyl 4α-carboxylate 29 mg (yield:
40%). IR: ν ^CHC13 _nax 3000, 1770sh, 1760, 1740cm ^-1 E Example of conversion reaction of X and Z E-1 (1) 7α-benzamide-3ξ-hydroxy-3ξ-
Diphenylmethyl bromomethyl-1-dethia-1-oxacefam-4α-carboxylate 108mg
Potassium carbonate dissolved in 5 ml of 10% aqueous acetone
After adding 50 mg and stirring at room temperature for 1.5 hours, dilute with brine and extract with methylene chloride.
The extract is dried over magnesium sulfate and the solvent is distilled off. When 90 mg of the residue was purified by silica gel thin layer chromatography (developing solvent: benzene-ethyl acetate (2:1)), 7α-benzamide was obtained.
3,3-epoxymethanol-1-dethia-1
40 mg of diphenylmethyl -oxacefam-4α-carboxylate (isomer A) is obtained. Furthermore, from 140 mg of the stereoisomer of the raw material, 56 mg of the stereoisomer B at the 3-position is obtained. (2) 1-methyltetrazol-5-ylthiol
Dissolve 20mg in 2ml of tetrahydrofuran,
1.5Mn-butyllithium hexane solution 0.05ml
Add and stir for 30 minutes. I got this above
Add 56 mg of diphenylmethyl 7α-benzamide-3,3-epoxymethano-1-dethia-1-oxacepham-4α-carboxylate (isomer B) dissolved in 1 ml of tetrahydrofuran, stir for 1 hour, and add aqueous sodium bicarbonate solution. Extract with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was subjected to column chromatography using 1 g of 10% hydrous silica gel and eluted with benzene-ethyl acetate (9:1) to give 7α-benzamide-3-(1-methyltetrazol-5-yl).
Thiomethyl-3-hydroxy-1-dethia-1
43 mg of diphenylmethyl -oxacefam-4α-carboxylate (isomer B) is obtained. Example E-2 (1) 7α-benzamide-3α-hydroxy-3β-
Methyl-1-dethia-1-oxacefam-4
-Dissolve 100 mg of diphenylmethyl carboxylate in 5 ml of isopropenyl vinegar solution, add 6 mg of p-toluenesulfonic acid hydrate, and heat at 60°C for 75 minutes. After cooling, the reaction mixture is poured into an ice-cooled aqueous sodium bicarbonate solution and extracted with methylene chloride. After separating the organic layer, washing with water and drying,
When the solvent was distilled off, diphenylmethyl 7α-benzamide-3α-acetoxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylate (yield: 30.5%) was obtained. (2) 7α-benzamide-3α-hydroxy-3β-
Methyl-1-dethia-1-oxacefam-4
- Diphenylmethyl carboxylate was added to a mixture of 1.1 equivalents of lithium diisopropylamide, 1.2 equivalents of acetyl chloride, and 20 times the volume of tetrahydrofuran, heated at -40°C for 45 minutes, at -20°C for 15 minutes, and then heated to 0.
C. or treatment with a solution of 1 equivalent of pyridine and 1.2 equivalents of acetyl chloride in methylene chloride gives the same product as (1). (3) Dissolve 52 mg of diphenylmethyl 7β-benzamide-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylate in 1 ml of dioxane, and add trifluoroacetic anhydride under ice cooling in a nitrogen stream. Add 0.1 ml of the solution and stir at room temperature for 2 hours. Add 0.3 ml of water to this, stir for 30 minutes, dilute with ice water, and extract with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off, resulting in 7β-benzamide-7α-methoxy-3α-trifluoroacetoxy-3β-methyl-1-dethia-1-oxacefam-4α-
64 mg of diphenylmethyl carboxylate are obtained as an oil. (4) 7α-benzamide-3ξ-hydroxy-3ξ-
Diphenylmethyl hydroxymethyl-1-dethia-1-oxacefam-4α-carboxylate 112
mg is dissolved in a mixture of 0.5 ml of pyridine and 0.3 ml of acetic anhydride, left overnight at 0°C, and then concentrated under reduced pressure. Pour the residue into water and extract with ethyl acetate. The extract was washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, dried, and the solvent was distilled off to give 7α-benzamide-3ξ-hydroxy-3ξ-acetoxymethyl-1-dethia-
54 mg of diphenylmethyl 1-oxacefam-4α-carboxylate is obtained as crystals. mp・118〜
120℃ (5) 7α-Benzamide-3ξ-Hydroxy-3ξ-
Hydroxymethyl-1-dethia-1-oxacefam-4α-carboxylic acid diphenylmethyl 350
Dissolve mg in 3 ml of methylene chloride, and dissolve 78μ of pyridine.
and 75μ of methanesulfonyl chloride, and stirred at 0°C for 1 hour and then at room temperature for 3 hours. Pour this into ice water and extract with ethyl acetate. The extract is washed with water, an aqueous sodium bicarbonate solution and then with water, dried, and the solvent is distilled off.
When 370 mg of the obtained residue was subjected to silica gel chromatography, 7α-benzamide-3ξ-
Hydroxy-3ξ-methanesulfonyloxymethyl-1-dethia-1-oxacefam-4α
- Obtain 145 mg of diphenylmethyl carboxylate. Continuous Process Examples -1 to 8 7α-amino-7β-unsubstituted-3-exomethylene-1-dethia-1-oxacefam-4-carboxylic acid ester was dissolved in methylene chloride and treated with a halogenating agent and a base in methanol. Then, 3
-Halo-3-halomethyl-7α-methoxy-7β-
Amino-1-dethia-1-oxa-3-cefem-4-carboxylic acid ester is obtained. The reaction conditions are shown in the table. 3-Halomethyl may be substituted with other nucleophilic groups. (No.6) 7α-p-cyanobenzamide-3-exomethylene-1-dethia-1-oxacefam-4α
-Dissolve 246mg of diphenylmethyl carboxylate in 8ml of methylene chloride cooled to -50℃, add 1.47ml of 1.2M chlorine in carbon tetrachloride solution, and stir for 7 minutes while irradiating with a 300W tungsten lamp to obtain 7α-
(N-chloro-p-cyanobenzamide)-3-
Diphenylmethyl exomethylene-1-dethia-1-oxacefam-4α-carboxylate is obtained.
Add 1.57 ml of a 2M lithium methoxide methanol solution to this, and stir at -50°C to -60°C for 10 minutes. After adding 0.2ml of acetic acid to this, pour it into ice water.
Extract with methylene chloride. The extract is washed with a dilute aqueous sodium bicarbonate solution and then with water, dried, and the solvent is distilled off. The residue (diphenylmethyl 7α-cyanobenzamide-7α-methoxy-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate) was dissolved in 6 ml of methylene chloride, and 1-methyltetrazole-5 was dissolved in this. -Dissolve 100 mg of mercabutide and 20 mg of tetrabutylammonium bromide in 3 ml of water and stir at room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with methylene chloride, washed with water, dried, and the solvent is distilled off. When 335 mg of the obtained residue was subjected to silica gel column chromatography, 7β-p-cyanobenzamide-7α-methoxy-3-(1-methyltetrazol-5-ylthio)methyl-1-dethia-1-
251 mg of diphenylmethyl oxa-3-cephem-4-carboxylate is obtained. Usage example Add 15.0 g of diphenylmethyl 7α-benzamide-3ξ-hydroxy-3ξ-methyl-1-oxadethiacefam-4α-carboxylate to 100 g of methylene chloride.
ml, add 6.8 ml of pyridine and 3 ml of thionyl chloride while stirring on ice, stir at the same temperature for 75 minutes, then at room temperature for 2.25 hours, and pour into ice water. The organic layer is separated, washed with water, dried and the solvent is distilled off. The residue was chromatographed on 350 g of 10% hydrous silica gel and eluted with benzene-ethyl acetate (9:1) to give 7α-benzamide-3-methyl-
2.65 g of diphenylmethyl 1-dethia-1-oxa-3-cephem-4-carboxylate (yield: 25.2
%, mp・144-146℃) and diphenylmethyl 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylate 1.05 g
(Yield: 10.8%, IR: ν ^CHC13 _nax 3440, 1782, 1745, 1676, 1663shcm
^-1 ). Raw material manufacturing example 1 Dissolve 512 mg of compound (a) in a mixture of 10 ml of benzene and 1 ml of methanol, and add triphenylphosphine.
Add 0.4g and stir at 65°C for 1.5 hours. This is 10
The product was subjected to column chromatography using 30 g of hydrated silica gel and eluted with benzene containing 20-30% ethyl acetate to obtain 202 mg of compound (b). IR: ν ^CHC13 _nax 3370, 1782, 1755, 1635cm ^-1 NMR: δ ^CHC13 2.50~3.35m 1H, 4.18S 2H,
5.08S1H, 5.25SIN, 5.28d (3Hz) 1H, 5.50SIH,
6.08d (3Hz) 1H, 6.93S1H, 7.20~8.00m15H. Raw material manufacturing agent 2 (1) 2-(3-benzyl-7-oxo-2,6-
Diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoic acid diphenylmethyl 4.6g Ethyl acetate 70ml
Add 2.74M hydrochloric acid-ethyl acetate 3.8ml and 1.47M hydrochloric acid-carbon tetrachloride 12ml, and stir at room temperature.
Stir for 15 minutes. To this were added 80 ml of 5% sodium thiosulfate, 3.4 g of sodium bicarbonate and 240 g of acetone, stirred at room temperature for 2.5 hours, and then extracted with ethyl acetate. The extract was dried with sodium sulfate, and 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-
Diphenylmethyl chloromethyl-3-butenoate
Obtain 3.33g. mp.82-83°C (2) Dissolve the above product in 25 ml of acetone, add 3.3 g of sodium iodide, and let stand at room temperature for 2 hours, then evaporate the solvent. The residue is extracted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and then with water, dried over sodium sulfate, and the solvent is distilled off to give 3.0 g of the corresponding iodide. (3) Add 1.59 g of the above product to dimethyl sulfoxide 13
ml of cuprous oxide and 3 ml of water.
Add 0.77 g, stir at 39°C for 1 hour, and then filter. The filtrate was extracted with ethyl acetate, washed with water, dried and the solvent was distilled off to give 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2- 0.35 g of diphenylmethyl en-6-yl)-3-hydroxymethyl-3-butenoate is obtained. mp・40～55℃ Explanation of abbreviations ―ph=phenyl ―STert=1-methyl-1,2,3,4-tetrazol-5-yl ―C ₆ H ₄ NO ₂ ―p=p-nitrophenyl ―C ₆ H ₄ CH ₃ -p=p-tolyl -C ₆ H ₄ CN-P=p-cyanophenyl -C ₆ H ₄ C1-p=p-chlorophenyl -Bu-t=tertiary butyl -OAc=acetoxy Between X and Z ==CH ₂ X and Z together represent methylene. -O-=X and Z between X and Z represent epoxy. = CH ₂ = Weight of raw material 3-epoxymethylene compound EtOAC = Ethyl acetate THF = Tetrahydrofuran DMF = N,N-dimethylformamide c-H ₂ SO ₄ = Concentrated H ₂ SO ₄ Et ₂ O = Diethyl ether t-BuOC1 = Tertiary butylhypochlorite eq = equivalent DBN = 1,5-diazabicyclo[3.4.0]nonene-5 (CH ₂ ) ₅ NH = piperidine hν = photoirradiation Δ ² or Δ ³ at Z = elimination at 3-position It means that a double bond is present at the 2(3) or 3(4) position in place of the group.

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[Table] Among the reagents, methoxide is used as a methanol solution.

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Claims (1)

[Claims] 1. General formula By reacting acid with the compound represented by the general formula A method for producing a compound represented by [However, RCO is an acyl residue derived from a carboxylic acid;
COB is carboxy or protected carboxy; Each represents a divalent group as shown. ]