JPH0819091B2 - Novel penam compound intermediate or salt thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has a general formula (2) showing a strong antibacterial action against Gram-positive and Gram-negative bacteria.

Embedded image [Wherein R ¹ represents a hydrogen atom, an amino protecting group or an acyl group; R ² represents a hydrogen atom or a lower alkyl group; R ³
Is an optionally substituted lower alkyl, lower alkenyl, cycloalkyl, aralkyl, aryl or heterocyclic group; R ⁴ is a hydrogen atom or a carboxyl protecting group; R ⁵ is a hydrogen atom, lower alkoxy, A lower alkylthio or formamide group; and n represents 0 or 1. ] The general formula (1), which is an important intermediate of the penam compound represented by

[Chemical 4] [Wherein R'is RCONH- (R represents a benzyl or phenoxymethyl group), R "is a hydrogen atom; or R'and R" are combined.

Embedded image (R represents a benzyl or phenoxymethyl group.)
R ² represents a hydrogen atom or a lower alkyl group. ] The compound or its salt represented by these.

[0002]

2. Description of the Related Art Penam compounds known in the prior art have a relatively broad antibacterial spectrum, but have a weak effect on resistant bacteria and are not always satisfactory.
The penam compound represented by the general formula (2) or a salt thereof exhibits a broad antibacterial spectrum, that is, excellent antibacterial activity against Gram-positive and Gram-negative bacteria in JP-A-62-228083. It has been shown that the compound is stable against β-lactamase, exhibits excellent antibacterial activity against resistant bacteria, and is useful as a drug for humans and animals. However, as a method for producing these compounds, there is no known method of using a novel compound represented by the general formula (1) or a salt thereof as an intermediate.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel intermediate for producing a penam compound represented by the general formula (2) or a salt thereof.

[0004]

In such a situation,
As a result of intensive studies, the present inventors have found that the compound represented by the general formula (1) or a salt thereof is useful as an intermediate for the novel compound represented by the general formula (2) or a salt thereof. Heading out, the present invention has been completed.

The present invention will be described in detail below. In the present specification, unless otherwise specified, lower alkyl is, for example, a straight chain or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. the Jo C ₁ ~ ₅ alkyl; the lower alkenyl group, for example, vinyl, allyl, isopropenyl, butenyl, C ₂ ~ ₅ alkenyl such as 2-pentenyl; the cycloalkyl group, for example, cyclopropyl, cyclobutyl, Cyclopentyl,
The C ₃ ~ ₇ cycloalkyl such as cyclohexyl; and the aralkyl group, e.g., benzyl, phenethyl, 4
-Methylbenzyl, naphthylmethyl and the like; aryl groups such as phenyl, naphthyl, indanyl and the like; heterocyclic groups such as thienyl, furyl, pyrrolyl, 1,2,4-triazolyl, oxazolyl, thiazolyl, 1 selected from oxygen, nitrogen and sulfur atoms such as 1,3,4-thiadiazolyl, tetrazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, pyrazyl, 1,2,4-triazinyl and benzo [b] thienyl. It means a 5-membered, 6-membered or fused heterocyclic group containing from 4 to 4 heteroatoms, and lower means that it has from 1 to 5 carbon atoms.

The amino protecting group for R ¹ includes, for example, commonly known amino protecting groups such as formyl, tert-butoxycarbonyl, tert-amyloxycarbonyl, trityl, trimethylsilyl, benzylidene and p-nitrobenzylidene. Further, as the acyl group,
Those commonly known in the penicillin and cephalosporin field, such as formyl, 4-aminomethylphenylacetyl, hydroxyacetyl, phenoxyacetyl, 1-tetrazolylacetyl, cyanomethylthioacetyl, carboxyethylthioacetyl, 2-thienyl. Acetyl, α-bromo-2-thienylacetyl, 5-methoxy-2-thienylacetyl, phenylacetyl, α-
Aminophenylacetyl, α-hydroxyphenylacetyl, α-carboxyphenylacetyl, α-sulfophenylacetyl, 3-bromophenylacetyl, α-
(4-Ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetyl, α- (4-ethyl-
2,3-dioxo-1-piperazinecarboxamide)-
p-hydroxyphenylacetyl, α- (4-ethyl-
2,3-dioxo-1-piperazinecarboxamide)-
3,4-Dihydroxyphenylacetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3,4-diacetoxyphenylacetyl, α-
(4-phenyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetyl, α- [4- (o, p
-Dichlorophenyl) -2,3-dioxo-1-piperazinecarboxamide] phenylacetyl, α- (4-oxo-4H-thiopyran-3-ylcarboxamide)-
Examples include α-phenylacetyl.

When the above-mentioned acyl group has an active group such as an amino group, a hydroxyl group and a carboxyl group, these groups may be protected by a commonly known protecting group. Examples of the amino-protecting group include, for example,
Examples of the protecting group for the amino group described above include, as the protecting group for the hydroxyl group, for example, tetrahydropyranyl,
Examples thereof include benzyloxycarbonyl and trimethylsilyl groups. The carboxyl protecting group may be the same as the carboxyl protecting group for R ⁴ described later.

R ² represents a hydrogen atom or a lower alkyl group.

Each group in R ³ is a halogen atom such as fluorine, chlorine, bromine or iodine; a lower alkyl group;
-A lower alkoxy group represented by a lower alkyl group; -S
-A lower alkylthio group represented by a lower alkyl group;-
Lower alkanoyloxy group represented by O-CO-lower alkyl group; lower alkoxycarbonyl group represented by -CO-O-lower alkyl group; hydroxymethyl, 2-
Hydroxy lower alkyl groups such as hydroxyethyl and 3-hydroxypropyl; amino lower alkyl groups such as aminomethyl, 2-aminoethyl and 3-aminopropyl;
Carboxy lower alkyl groups such as carboxymethyl, 2-carboxyethyl, 3-carboxypropyl; methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-
Lower alkoxycarbonyl-lower alkyl groups such as ethoxycarbonylethyl; cyanomethylaminomethyl, 2
Cyano lower alkylamino lower alkyl groups such as cyanoethylaminomethyl; N, N-dimethylaminoethyl, N such as 2- (N, N-dimethylamino) ethyl,
N-di lower alkylamino lower alkyl group; sulfamoyl lower alkyl group such as sulfamoylmethyl, 2-sulfamoylethyl; carboxyl group; nitro group; cyano group; amino group; one selected from methylenedioxy group, etc. It may be substituted with the above substituents.

As the protecting group for the carboxyl group of R ⁴ ,
Examples thereof include those conventionally known in the field of penicillin and cephalosporin compounds, for example, an ester-forming group that is eliminated by treatment with catalytic reduction, chemical reduction, or other mild conditions, or Examples thereof include ester-forming groups that are easily eliminated in the body, and ester-forming groups such as organic silyl groups, organic phosphorus groups, and organic tin groups that are easily eliminated by treatment with water or alcohol. Of these protecting groups, suitable protecting groups are specifically, for example, lower alkyl groups such as methyl, propyl and tert-butyl; benzyl, 4
-Methoxybenzyl, 4-nitrobenzyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di (tert
-Butyl) benzyl, phenethyl, benzhydryl, trityl, bis (methoxyphenyl) methyl, etc. alalkyl groups; phthalidyl groups; 2-iodoethyl, 2,2,2
Halo lower alkyl groups such as 2-trichloroethyl; acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-pivaloyl. Oxyethyl, 1-acetoxy-
Acyloxy-lower alkyl groups such as n-propyl and 1-pivaloyloxy-n-propyl; lower alkyl-2-oxo-1,3 such as 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl -Dioxole-4-
Alkyl-lower alkyl group; alkoxy-lower alkyl group such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl; methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxy Alkoxycarbonyloxy such as ethyl
Examples include lower alkyl groups.

As the lower alkoxy group and lower alkylthio group for R ^5, the same lower alkoxy and lower alkylthio groups as those described for the substituent for R ³ can be mentioned.

Examples of the salt of the compound represented by the general formula (2) include salts of a generally known basic group such as amino group or acidic group such as carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, benzenesulfonic acid, p -Toluene sulfonic acid, mesitylene sulfonic acid, naphthalene sulfonic acid, and other salts with sulfonic acids, and as the salt in the acidic group, for example, salts with alkali metals such as sodium and potassium; alkaline earth such as calcium and magnesium. Salts with group metals; ammonium salts; trimethylamine,
Triethylamine, tributylamine, pyridine, N,
N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-
β-phenethylamine, 1-ephenamine, N, N′-
Examples thereof include salts with nitrogen-containing organic bases such as dibenzylethylenediamine.

Among the compounds of the general formula (2), preferred are those of the general formula (2a)

[Chemical 6] [Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. ] The compound having a steric configuration represented by the formula or a salt thereof is mentioned. Further, in the compound of the general formula (2a), an aryl or heterocyclic group in which R ³ may be substituted is preferable.

Next, a method for producing the compound of the present invention will be described. The compound of general formula (1) or a salt thereof can be produced, for example, according to the following production route.

[0015]

[Chemical 7] [In the formula, R represents a benzyl or phenoxymethyl group, and R ² has the same meaning as described above. ]

(1) Introduction of Hydroxyalkyl Group The compound of the general formula (1a) is a compound of the general formula (3)
It can be obtained by reacting the compound of general formula (4) in the presence or absence of a base. When this reaction is carried out in a solvent, it is not particularly limited as long as it does not adversely affect the reaction. For example, methylene chloride,
Chloroform, tetrahydrofuran, ethyl acetate, N,
An aprotic polar solvent such as N-dimethylformamide is preferable, and two or more kinds of these solvents may be mixed. The base used in this reaction is 1,8
-Diazabicyclo [5.4.0] -7-undecene,
1,5-diazabicyclo [4.3.0] non-5-ene, lithium diisopropylamide, lithium bistrimethylsilylamide and the like can be mentioned. The amount of the compound of the general formula (4) and the base to be used is 1 to 2 times, preferably 1.0 to 1.1 times the mol of the compound of the general formula (3). Further, this reaction may be carried out at 0 to 50 ° C., preferably room temperature, for 30 minutes to 5 hours.

(2) Ring-opening The compound of the general formula (1b) can be obtained by reacting the compound of the general formula (1a) with an acid in the presence of water. When this reaction is carried out in a solvent, it is not particularly limited as long as it does not adversely affect the reaction, but for example, hydrophilic solvents such as methanol, ethanol, isopropyl alcohol, acetone, acetonitrile are preferable, and these solvents are You may mix 2 or more types. As the acid used in this reaction, inorganic acids such as hydrochloric acid, hydrobromic acid and perchloric acid; p-toluenesulfonic acid,
Examples thereof include organic acids such as methanesulfonic acid. The amount of the acid used is 0.1 to 1 times mol, preferably 0.2 to 0.5 times mol, of the compound of the general formula (1a). The reaction may be carried out at 0 to 50 ° C, preferably 20 to 30 ° C for 30 minutes to 5 hours.

Next, a method for producing the compound of the general formula (2) will be described. The compound of general formula (2) or a salt thereof can be produced, for example, according to the following production route.

[0019]

Embedded image [Wherein, X and Y are the same or different and each represents a halogen atom such as chlorine, bromine or iodine; R ^1a represents an acyl group of R ¹ ; R ^3a represents a substituent of R ³ ; A lower alkyl or aralkyl group; R ^4a represents a carboxyl protecting group for R ⁴ , R, R ² , R ³ , R ⁴ and R ⁴ ;
⁵ has the same meaning as described above. ]

(1)

[Chemical 9] (Introduction of the group represented by R ³ and R ^4a has the same meaning as described above) The compound of the general formula (6) is the compound of the general formula (1b),
It can be obtained by reacting the compound of general formula (5) in the presence or absence of a base. When this reaction is carried out in a solvent, it is not particularly limited as long as it does not adversely affect the reaction. For example, methylene chloride,
Chloroform, tetrahydrofuran, acetonitrile,
Aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide are preferable, and two or more kinds of these solvents may be mixed. Further, as the base used in this reaction, triethylamine, pyridine,
1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] non-5-
En is mentioned. The amount of the compound of the general formula (5) and the base used is 1.0 to 1.0 with respect to the compound of the general formula (1b).
The molar ratio is 1.5 times, preferably 1.05 to 1.10 times. Further, this reaction is carried out at 0 to 50 ° C., preferably 5 to 10 ° C.
It may be carried out for a minute to 2 hours.

(2) Halogenation The compound of the general formula (7) can be obtained by reacting the compound of the general formula (6) with a halogenating agent in the presence or absence of a base. This reaction is preferably carried out under anhydrous conditions, and when this reaction is carried out in a solvent, it is not particularly limited as long as it does not adversely affect the reaction, and for example, methylene chloride, chloroform,
Aprotic polar solvents such as tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like can be mentioned, and two or more kinds of these solvents may be mixed. The halogenating agent used in this reaction is, for example, thionyl chloride,
Examples thereof include thionyl bromide, and examples of the base include triethylamine, pyridine, 1,8-diazabicyclo [5.
4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] non-5-ene and the like can be mentioned. The amount of the halogenating agent and the base used is 1 to 5 times mol, preferably 1.05 to 1.20 times mol, of the compound of the general formula (6). Further, this reaction is 0 to 50 ° C., preferably 0 to 10
It may be carried out at 5 ° C. for 5 minutes to 1 hour.

(3) Ring-closing The compound of the general formula (2a) can be obtained by subjecting the compound of the general formula (7) to a ring-closing reaction in the presence of a base. When this reaction is carried out in a solvent, it is not particularly limited as long as it does not adversely affect the reaction, and for example, methylene chloride, chloroform, tetrahydrofuran, acetonitrile, N, N-dimethylformamide,
Aprotic polar solvents such as N, N-dimethylacetamide and dimethylsulfoxide may be mentioned, and two or more kinds of these solvents may be mixed. The base used in this reaction is 1,8-diazabicyclo [5.4.
0] -7-undecene, 1,5-diazabicyclo [4.
3.0] Non-5-ene, potassium tert-butoxide,
Examples thereof include diisopropylethylamine, lithium diisopropylamide, lithium bistrimethylsilylamide and the like. The amount of the base used is 1 to 2 times, preferably 1.0 to 1.2 times the mol of the compound of the general formula (7).
Also, this reaction is -50 to 30 ° C, preferably -10 to 5 ° C.
Then, it may be carried out for 5 minutes to 1 hour. The compound of the general formula (7) used in this reaction can also be used as it is without isolation in the above halogenation.

(4) Deacylation The compound of the general formula (2b) or a salt thereof has the general formula (2
It can be obtained by treating the compound of a) with phosphorus pentachloride to give an imino chloride, followed by reaction with an alcohol to give an imino ether, and then subjecting to conventional deacylation for further hydrolysis. As this deacylation, deacylation generally used in the fields of penicillin and cephalosporin can be used, and as a specific method, Lacuyé de Travo Simic de Peiba (Recl.Trav.Chim) can be used. Pays-Bas) 89, 1081 (1973
Year), Japanese Patent Publication No. 55-38954 and the like, or a method equivalent thereto.

(5) Acylation The compound of the general formula (2) is obtained by reacting the compound of the general formula (2b) or a salt thereof or a reactive derivative at the amino group thereof with a carboxylic acid of the general formula (8) or its reactivity. It can be obtained by reacting a derivative. In addition, the general formula (2
Examples of the reactive derivative at the amino group of the compound b) or a salt thereof include, for example, isocyanate and the general formula (2
Schiff bases (imino-type or enamine-type isomers) formed by the reaction of the compound b) or a salt thereof with a carbonyl compound such as an aldehyde or a ketone, the compound of the general formula (2b) or a salt thereof, and bis (trimethylsilyl). Organic silyl groups such as acetamide, trimethylsilylacetamide, trimethylsilyl chloride;

[Chemical 10] _{(CH 3 CH 2 O) 2} PCl, (CH 3 CH 2) 2 PCl, phosphorus compounds such as phosphorus trichloride or (C ₂ H _{5) 3} SnCl
Included are all those commonly used in acylation such as silyl derivatives, phosphorus derivatives or tin derivatives formed by reaction with tin compounds such as. Specific examples of the reactive derivative of the compound of the general formula (8) include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and Vilsmeier reagents of the compound of the general formula (8). And a reactive derivative thereof. Examples of the mixed acid anhydride include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and lower alkanoic acids optionally substituted with halogen such as pivalic acid and trichloroacetic acid. And mixed acid anhydrides thereof. Examples of the activated acid amide include N-acylimidazole, N-acylbenzoylamide, N, N'-dicyclohexyl-N-acylurea, and N-acylsulfonamide. Next, examples of the active ester include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, substituted thienyl ester and the like. In addition, as a reactive derivative with Vilsmeier reagent,
Acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide, phosgene, thionyl chloride,
Examples thereof include reactive derivatives with a Vilsmeier reagent obtained by acting a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl-chloroformate and oxalyl chloride. When the compound of the general formula (8) is used in the free acid state, a suitable condensing agent is used. Examples of such condensing agents include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide;carbonyldiimidazole; N-ethoxycarbonyl-2-ethoxy-
Examples thereof include dehydrating agents such as 1,2-dihydroxyquinoline, phosphorus oxychloride and alkoxyacetylene; and 2-halogenopyridinium salts such as 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide. This acylation is generally carried out in a suitable solvent in the presence or absence of a base.
Examples of the solvent include methylene chloride, chloroform, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, acetone, water and the like, and two or more kinds of these solvents may be mixed. Examples of the base used in this reaction include alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, alkali acetate, triethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, dicyclohexylamine and diethylamine. .. The amount of the compound of the general formula (8) used is 1.0 to 1.5 times the mol of the compound of the general formula (2b). Further, this reaction may be carried out at -50 to 40 ° C for 10 minutes to 48 hours.

Obtained in each step described above (2
When an isomer or the like exists in the compound of a), (2b), (2), (6) or (7) or a salt thereof, it can be isolated and purified by a usual method. Further, the compound of the general formula (2) in which R ⁴ is a carboxyl protecting group or a salt thereof is the same as the compound of the general formula (2) in which R ⁴ is a hydrogen atom or a salt thereof, in which the R ⁴ is a hydrogen atom. The compound of (2) or a salt thereof can be converted into a compound of the general formula (2) or a salt thereof in which R ⁴ is a carboxyl protecting group according to a conventional method.
The compound of the general formula (2) in which R ¹ is an amino protecting group or a salt thereof is the same as the compound of the general formula (2) in which R ¹ is a hydrogen atom or a salt thereof, in which R ¹ is a hydrogen atom. The compound of (2) or a salt thereof can be converted into a compound of the general formula (2) in which R ¹ is an amino-protecting group or a salt thereof according to a conventional method. Further, in the deacylation or acylation, when a group active in the reaction is present in the groups of R ^1a , R ³ and R ^4a , it may be protected with an ordinary protecting group during the reaction. The protecting group can be removed by a conventional method. Further, the compound of the general formula (2) or a salt thereof in which R ⁵ is an alkoxy group can be converted according to a conventional method. The compound of the general formula (2) or a salt thereof in which R ⁵ is a lower alkylthio group is obtained by protecting the amino group of the compound of the general formula (2b) with, for example, the above-mentioned amino-protecting group, and then converting the lower alkylthio group to It can be obtained by introducing, then deprotecting, and carrying out the acylation reaction described above. The compound of the general formula (2) in which R ⁵ is a formamide group or a salt thereof can be obtained by formamidating the compound of the general formula (2) in which R ⁵ is a lower alkylthio group or a salt thereof. Specific examples of the method of introducing the lower alkylthio group and the formamidation include the method described in JP-A-58-38288 or a method analogous thereto.

The compound of the general formula (5) is obtained by halogenating a corresponding optionally protected carboxylic acid or ketone, for example, organic synthesis (Organic S
ynthses) Vol. 1, p. 115 (1944) and Vol. 3, 6
Page 23 (1955) or its equivalents; oxidation, for example, Journal of Medicinal Chemistry
Volume 16, page 978 (1973) or a method analogous thereto; esterification, for example, Tetrahedron Letters, page 4475 (1978)
Or a method equivalent thereto; reduction, for example, the Journal of Chemical Society (Journ
al of Chemical Society) page 520 (1954) or a method analogous thereto or a method known per se can be combined to produce. The compound of general formula (2) or a salt thereof obtained as described above can be isolated by a conventional method.

[0027]

EXAMPLES Next, the present invention will be explained with reference to examples and reference examples, but the present invention is not limited thereto. The symbols used in the examples and reference examples have the following meanings. Me; methyl group, PNB; p-nitrobenzyl group Further, as a carrier for column chromatography, Kieselgel 60, Art. 7734 (manufactured by Merck) was used. Furthermore, the mixing ratio in the mixed solvent depends on the volume ratio.

Example 1 (1) (1R, 5R) -3-benzyl-4-thia-2,
6-diazabicyclo [3.2.0] -2-heptene-7
1.0 g of -one is suspended in 10 ml of methylene chloride, 140 mg of anhydrous paraformaldehyde and 0.14 ml of 1,8-diazabicyclo [5.4.0] -7-undecene are added successively, and the mixture is reacted at room temperature for 30 minutes. The reaction solution was diluted with 1N hydrochloric acid in 10 ml of water.
It is introduced while maintaining the pH at 3.0 to 6.0, and the pH is adjusted to 3.0 after the introduction. After separating the organic layer, the aqueous layer was washed with methylene chloride.
Extract twice with ml, combine the extract with the organic layer and dry over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was treated with diethyl ether, and the crystals were collected by filtration to give (1R, 5R) -3-benzyl-6-hydroxymethyl-4-thia-2. , 6-diazabicyclo [3.2.0] -2-hepten-7-one 1.00 g (yield 8
7.9%). Melting point: 135 to 136 ° C. (recrystallized from isopropyl alcohol) IR (KBr) cm ⁻¹ ; 3460,1735 NMR (CDCl ₃ ) δ value; 3.97 (2H, s), 4.25 to 5.10 (3H, m), 5.64 ( 1
H, d, J = 4Hz), 5.88 (1H, d, J = 4Hz), 7.27 (5H, s) (2) (1R, 5R) -3-benzyl-6-hydroxymethyl-4-thia-2, 6-diazabicyclo [3.2.
0] -2-Hepten-7-one (1.00 g) is suspended in isopropyl alcohol (7 ml), 1N hydrochloric acid (0.81 ml) is added, and the mixture is reacted at room temperature for 1.2 hours. The precipitated crystals are collected by filtration, washed with isopropyl alcohol, and dried to give (3R, 4R) -1.
880 mg (yield 82.1%) of -hydroxymethyl-4-mercapto-3-phenylacetamidoazetidin-2-one are obtained. Melting point: 137-138 ° C (decomposition) IR (KBr) cm ^-1 ; 3450,3260,2540,1750,1650 NMR (d ₆ -DMSO-D ₂ O) δ value; 3.56 (2H, s), 4.38,4.72 (2H, ABq,
J = 12Hz), 5.05-5.42 (2H, m), 7.26 (5H, s)

Reference Example 1 5.0 g of p-methylphenylacetic acid is dissolved in anhydrous benzene, 3.54 ml of thionyl chloride is added, the mixture is reacted under reflux for 2 hours, and then the solvent is distilled off under reduced pressure. The oil obtained is 30
Dissolve in 1 ml of anhydrous benzene, add 1.71 ml of bromine, and react under reflux for 6 hours. After distilling off the solvent under reduced pressure, the obtained residue is dissolved in 50 ml of methylene chloride, and under ice cooling, 3.57 g of p-nitrobenzyl alcohol and 4.18 ml of triethylamine are added and reacted for 30 minutes. 100 ml of water was added to the reaction solution, the pH was adjusted to 2.0 with 6N hydrochloric acid, and the organic layer was separated. 100 ml of water is added to the separated organic layer, the pH is adjusted to 9.0 with a 2N sodium hydroxide aqueous solution, and the organic layer is separated. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluting solvent: benzene) to give crystalline 2
3.2 g (yield 26.3%) of p-nitrobenzyl ester of -bromo-2- (p-methylphenyl) acetic acid is obtained. Melting point: 79-80 ° C (recrystallized from methanol) IR (KBr) cm ^-1 ; 1740 NMR (CDCl ₃ ) δ value; 2.35 (3H, s), 5.28 (2H, s), 5.43 (1H, s),
7.00 to 7.60 (6H, m), 8.13 (2H, d, J = 8Hz) In the same manner, the compounds in Table-1 are obtained.

[Chemical 11]

[Table 1]

Reference Example 2 (1) (3R, 4R) -1-Hydroxymethyl-4-mercapto-3-phenylacetamido azetidin-2-one 2.00 g and 2-bromo-2- (p-chlorophenyl) 3.04 g of acetic acid p-nitrobenzyl ester was added to N, N-
It is dissolved in 10 ml of dimethylformamide, and 1.05 ml of triethylamine is added dropwise over 3 minutes under ice cooling. At the same temperature
After reacting for 20 minutes, 70 ml of ethyl acetate and 70 ml of water are added and the pH is adjusted to 2.5 with 3N hydrochloric acid. After separating the organic layer, the aqueous layer is extracted with 30 ml of ethyl acetate, the extract is combined with the organic layer, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure,
The obtained residue was treated with chloroform and the crystals were collected by filtration to give (3R, 4R) -4- [p-chlorophenyl-
1.72 g (yield 40.2%) of (p-nitrobenzyloxycarbonyl) methyl] thio-1-hydroxymethyl-3-phenylacetamido azetidin-2-one (Compound A) is obtained. Melting point: 180-181 ° C IR (KBr) cm ^-1 ; 1755,1740,1645 NMR (d ₆ -DMSO-D ₂ O) δ value; 3.46 (2H, s), 4.35,4.64 (2H, ABq,
J = 12Hz), 4.90-5.40 (5H, m), 7.10-7.70 (11H, m), 8.18 (2
H, d, J = 9Hz) On the other hand, if the filtrate was concentrated under reduced pressure and the obtained residue was purified by column chromatography (elution solvent; benzene: ethyl acetate = 2: 1 to 1: 1), Amorphous (3R,
4R) -4- [p-chlorophenyl- (p-nitrobenzyloxycarbonyl) methyl] thio-1-hydroxymethyl-3-phenylacetamido azetidin-2-one (Compound B) 1.92 g (yield 44.8% ) Get. IR (KBr) cm ^-1 ; 1760, 1740, 1650 NMR (CDCl ₃ -D ₂ O) δ value; 3.57 (2H, s), 4.42,4.54 (2H, ABq, J =
12Hz), 4.75 (1H, s), 4.96 (1H, d, J = 4Hz), 5.18 (2H, s), 5.28
(1H, d, J = 4Hz), 7.00 ~ 7.48 (11H, m), 8.12 (2H, d, J = 9Hz)

(2) (3R, 4R) -4- [p-chlorophenyl- (p-nitrobenzyloxycarbonyl) methyl] thio-1-hydroxymethyl-3-phenylacetamido azetidin-2-one (compound A) 1.75 g was dissolved in anhydrous tetrahydrofuran 35 ml, thionyl chloride 0.24 ml was added under ice cooling, and triethylamine 0.47 ml was added at 0-5 ° C.
Is added dropwise over 2 minutes, and the mixture is reacted at the same temperature for 30 minutes.
Then, 10 ml of anhydrous benzene is added to the reaction solution, the insoluble portion is filtered off, and the solvent is distilled off under reduced pressure. The residue obtained is N,
Dissolve in 10 ml of N-dimethylformamide, and under ice cooling,
0.44 ml of 1,8-diazabicyclo [5.4.0] -7-undecene is added dropwise over 2 minutes. After reacting for 10 minutes at the same temperature, the reaction solution is introduced into a mixed solution of 50 ml of water and 50 ml of ethyl acetate while maintaining the pH at 2.0 to 7.0 with 3N hydrochloric acid, and the pH is adjusted to 2.0 after the introduction. After separating the organic layer,
The aqueous layer is extracted with 20 ml of ethyl acetate, the extract is combined with the organic layer, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (elution solvent; n-
If purified with hexane: ethyl acetate = 3: 2 to 2: 3), amorphous (3R, 5R, 6R) -3- (p-chlorophenyl) -3- (p-nitrobenzyloxycarbonyl) -7 is obtained. -Oxo-6-phenylacetamido-4-thia-1-azabicyclo [3.2.0] heptane 1.26 g
(Yield 75.0%) is obtained. IR (KBr) cm ^-1 ; 1770, 1725, 1660 NMR (CDCl ₃ ) δ value; 3.24 (1H, d, J = 12Hz), 3.61 (2H, s), 4.93
(1H, d, J = 12Hz), 5.05 (2H, s), 5.41 (1H, d, J = 4Hz), 5.66 (1H,
dd, J = 4Hz, J = 10Hz), 6.60 ~ 7.50 (12H, m), 8.08 (2H, d, J = 9H
z) On the other hand, the same product (yield: 71.0%) can be obtained by carrying out the same reaction using the compound B.

(3) (i) (3R, 5R, 6R) -3-
(P-Chlorophenyl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-6-phenylacetamido-4-thia-1-azabicyclo [3.2.0] heptane 300 mg was dissolved in methylene chloride 5 ml. After cooling to −70 ° C., 0.21 ml of N, N-dimethylaniline and 150 mg of phosphorus pentachloride are added. After reacting at -40 to -30 ° C for 1 hour, the temperature was raised to -20 ° C, 1.54 ml of anhydrous methanol was added,
Incubate for 30 minutes under ice cooling. Then, 3 ml of water is added to the reaction solution, the mixture is reacted for 10 minutes under ice cooling, and the pH is adjusted to 7.5 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate to give (3R, 5R, 6R) -6-amino-3- (p
-Chlorophenyl) -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane in methylene chloride is obtained.

(Ii) On the other hand, D-α- (4-ethyl-2,
3-dioxo-1-piperazinecarboxamido) phenylacetic acid (140 mg) was dissolved in methylene chloride (3 ml), and the mixture was cooled with ice.
A catalytic amount of N, N-dimethylformamide and 0.05 ml of oxalyl chloride are added, and the mixture is reacted at room temperature for 30 minutes. Then,
The reaction mixture was dried under reduced pressure to give D-α- (4-ethyl-
2,3-dioxo-1-piperazinecarboxamido) phenylacetic acid chloride is obtained. This is dissolved in 3 ml of methylene chloride and added dropwise to the solution prepared in (i) at -30 to -20 ° C. The reaction is carried out at the same temperature for 15 minutes and under ice-cooling for 20 minutes. The reaction solution is washed with water and saturated saline solution in that order, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (elution solvent; chloroform: acetone = 9: 1) to give amorphous (3R, 5R, 6R) -3. -(P-chlorophenyl) -6- [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetamide] -3- (p-nitrobenzyloxycarbonyl)-
7-oxo-4-thia-1-azabicyclo [3.2.
0] Heptane 300 mg (yield 75.0%) is obtained. IR (KBr) cm ⁻¹ ; 1775,1705,1675 NMR (CDCl ₃ ) δ value; 1.16 (3H, t, J = 7Hz), 3.10 to 4.30 (7H, m),
4.80 ~ 5.80 (4H, m), 5.14 (2H, s), 6.70 ~ 7.75 (12H, m), 8.1
0 (2H, d, J = 9Hz), 9.98 (1H, d, J = 7Hz)

(4) (3R, 5R, 6R) -3- (p-
Chlorophenyl) -6- [D-α- (4-ethyl-2,
3-dioxo-1-piperazinecarboxamide) phenylacetamide] -3- (p-nitrobenzyloxycarbonyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 300 mg and 5% palladium Carbon (200 mg) is added to a mixed solution of ethyl acetate (10 ml) and water (10 ml), and the mixture is reacted under a hydrogen atmosphere at room temperature for 1.5 hours. Then, the insoluble matter is filtered off, and the filtrate is adjusted to pH 2.0 with 1N hydrochloric acid. The organic layer is separated, 10 ml of water is added, and the pH is adjusted to 7.0 with a 2-3% aqueous sodium hydrogen carbonate solution. Separate the aqueous layer,
If freeze-dried, amorphous (3R, 5R, 6R)-
3-carboxy-3- (p-chlorophenyl) -6-
170 mg of [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenylacetamide] -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane sodium salt (Yield 67.1%) is obtained. IR (KBr) cm ⁻¹ ; 1765,1710,1670,1600 NMR (D ₂ O) δ value; 1.15 (3H, t, J = 7Hz), 3.20 to 4.10 (7H, m), 5.
17 (1H, d, J = 4Hz), 5.40 (1H, s), 5.50 (1H, d, J = 4Hz), 6.80〜
7.50 (9H, m)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Isamu Saikawa 7-52 Oizumi Nakamachi, Toyama City, Toyama Prefecture Examiner Shoei Hoshino

Claims (1)

[Claims] 1. A general formula: [Wherein R ′ is RCONH— (R represents a benzyl or phenoxymethyl group), R ″ represents a hydrogen atom; or R ′ and R ″ together form (R represents a benzyl or phenoxymethyl group.)
R ² represents a hydrogen atom or a lower alkyl group. ] The compound or its salt represented by these.