JPH0141153B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing 3-chloromethyl-3-cephem derivatives. More specifically, the present invention relates to the general formula [During the ceremony

[Formula] represents a carboxylic acid residue, R ² represents a protecting group for a carboxyl group, and R ³ represents a substituted or unsubstituted aromatic hydrocarbon group. ] This invention relates to a method for producing a 3-chloromethyl-3-cephem derivative represented by the following. 3-chloromethyl represented by the above general formula (2)
3-Cefem derivatives are important compounds as intermediates for synthesizing cephalosporin antibiotics. For example, the compound of the present invention can be converted into a cephalosporin antibiotic by the method shown in the following formula. Conventionally, the method for producing 3-chloromethyl-3-cephem is as follows. For example, it is produced by halogenating 3-acetoxymethylcephalosporin derivatives [Tetrahedron Letters 3991 (1974), 2401
(1976) etc.]. Kotzpel et al. also succeeded in converting 3-exomethylenecephalosporin directly to 3-chloromethyl-3-cepheme [see J.Am.Chem.soc., 99 , 2822 (1977)]. However, all of these methods require expensive starting materials, and 3-chloromethyl-3-cephem can only be obtained in low yield and purity. An object of the present invention is to provide a method for producing a 3-chloromethyl-3-cephem derivative represented by general formula (2) with high purity and high yield from readily available raw material compounds through simple operations. It is in. That is, the present invention is based on the general formula [During the ceremony

[Formula] represents a carboxylic acid residue, R ² represents a protecting group for a carboxyl group, and R ³ represents a substituted or unsubstituted aromatic hydrocarbon group. ] The azetidinone derivative represented by is treated with a base in an organic solvent to form the general formula [In the formula, R ¹ and R ² are the same as above. ] 3-chloromethyl- characterized by obtaining a 3-chloromethyl-3-cephem derivative represented by
3-Relates to a method for producing cefem derivatives. In the present invention, specific examples of R ¹ include benzyl group, p-hydroxybenzyl group, p-chlorobenzyl group, p-methoxybenzyl group, p-
Aryl lower alkyl groups such as nitrobenzyl groups,
Halogen-substituted lower alkyloxy groups such as 2,2,2-trichloroethyloxy group and 2-bromoethyloxy group, phenoxymethyl group, tolyloxymethyl group, xylyloxymethyl group, naphthyloxymethyl group, p-chlorophenoxy methyl group,
Examples include aryloxy lower alkyl groups such as p-methoxyphenoxymethyl group, p-nitrophenoxymethyl group, and p-hydroxyphenoxymethyl group. Specific examples of R ² include methyl group,
Lower alkyl groups that may have a halogen atom as a substituent, such as ethyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, n-propyl group, isopropyl group, tertiary butyl group, benzyl group, diphenylmethyl group, p-methoxybenzyl group, p-nitrobenzyl group, 2-phenylethyl group, 2-(p-nitrophenyl)ethyl group, 3
Examples include aryl lower alkyl groups such as -phenylpropyl group and 3-(p-nitrophenyl)propyl group. Further, specific examples of R ³ include phenyl group, p-methylphenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-chlorophenyl group, and the like. The compound of general formula (1) used as a starting material in the present invention is a new compound, for example, a compound of the known general formula [In the formula, R ¹ , R ² and R ³ are the same as above. It is easily produced by electrolytically treating an azetidinone derivative represented by ] in the presence of hydrochloric acid and/or chloride. The electrolytic treatment of the azetidinone derivative represented by the above general formula (3) is carried out by applying a necessary amount of electricity in the presence of hydrochloric acid and/or chloride. A wide variety of known chlorides can be used, including salts of alkali metals such as lithium chloride, sodium chloride, and potassium chloride, salts of alkaline earth metals such as magnesium chloride, barium chloride, and calcium chloride, ammonium chloride, and tetrachloride. Examples include ammonium salts and quaternary ammonium salts such as methylammonium, tetraethylammonium chloride, and benzyltrimethylammonium chloride. The amount of hydrochloric acid and/or chloride to be used is not particularly limited and can be appropriately selected within a wide range.
It is preferable to have it present in a molar amount of 0.5 to 10 times. When using a chloride, it is effective to coexist a mineral acid or an organic acid in the reaction system. Examples of the mineral acids that can be used include sulfuric acid, sodium hydrogen sulfate, potassium hydrogen sulfate, phosphoric acid, and boric acid.
Examples of organic acids include carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and citric acid, and sulfonic acids such as paratoluenesulfonic acid and methanesulfonic acid. The mineral acid or organic acid is preferably present in the reaction system in an amount of about 0.5 to 10 times the molar amount of the compound of general formula (3).
The reaction medium in this electrolytic treatment is usually water,
An organic solvent or a mixed solvent of water and an organic solvent is used. A wide range of organic solvents can be used as long as they are inert to the chlorination reaction, such as methyl formate,
Esters such as ethyl formate, methyl acetate, ethyl acetate, butyl acetate, ethyl propionate, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dibromoethane, chlorobenzene, diethyl ether, dibutyl ether, dioxane, Examples include ethers such as tetrahydrofuran, nitriles such as acetonitrile and butyronitrile, hydrocarbons such as pentane, hexane and cyclohexane, and carbon disulfide. The electrolytic reaction can be performed by either constant potential electrolysis or constant current electrolysis. The current density is usually in the range of 1 to 500 mA/cm ² , preferably 5 to 200 mA/cm ² . The amount of electricity required for the reaction is
The substrate concentration varies depending on the type of solvent, the shape of the electrolytic cell, etc., but is usually 2 to 50 F/mol. As the electrode, commonly used electrodes such as platinum, carbon, stainless steel, titanium, and nickel can be used. The reaction temperature is not particularly limited as long as it is below a temperature at which the raw materials and products do not decompose or denature;
It is carried out in the range of -30°C to 60°C, preferably -20°C to
It is in the range of 30℃. As the electrolytic cell, both an electrolytic cell without a diaphragm and an electrolytic cell with a diaphragm can be used. In this way, a compound represented by general formula (1) is produced. Examples of organic solvents used in the reaction of the present invention include alcohols such as methanol, ethanol, and isopropanol, nitriles such as acetonitrile and butyronitrile, ketones such as acetone and methyl ethyl ketone, and amides such as dimethylformamide and diethylformamide. Alternatively, polar solvents such as formamide, diethylformamide, and dimethylacetamide are preferably used alone or as a mixed solvent. Examples of the base include metal hydroxides such as potassium hydroxide and sodium hydroxide, carboxylic acid metal salts such as potassium acetate and sodium acetate, triethylamine, 1,8-diazabicyclo[5,4,0]7-undecene, 15 Amines such as -diazabicyclo[4,3,0]5-nonenepyridine, metal halides such as potassium iodide and sodium iodide, ammonia, ammonia water, etc. can be used, but ammonia or ammonia water is preferred. The amount of such a base to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually used in an amount of 0.1 to 10 times, preferably an equimole to 1.5 times, the amount of the compound of general formula (1). Good. The reaction temperature is usually -78°C to 40°C, preferably -50°C to
The temperature is 5°C. Although the reaction time varies depending on the reaction temperature and the type of raw material compound, the reaction is completed in 5 minutes to 10 hours, and the reaction time is usually 10 minutes to 1 hour. The compound of the present invention thus obtained can be easily isolated and purified from the reaction mixture by conventional separation means such as solvent extraction and column chromatography. According to the present invention, the target compound of general formula (2) can be produced with high purity and high yield through simple operations. Reference examples and examples are listed below. Reference example 30.5 mg of methyl 2-(3-phenoxyacetamido-4-phenylsulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate,
1.0 g of NaCl, 3 ml of water, 5 ml of methylene chloride, and 0.07 ml of concentrated sulfuric acid are placed in a container and stirred to prepare a two-layer solution. Perform electrolysis for 15 minutes using a platinum electrode. The amount of electricity corresponds to 5F/mol. After the reaction is completed, the reaction mixture is extracted with methylene chloride and washed with saturated sodium sulfite solution, saturated sodium bicarbonate solution, and saturated brine in this order. The methylene chloride layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column to give 3-chloromethyl-2-(-phenylacetamide-4-phenylsulfonylthio-2-).
Methyl azetidinone-1-yl)-3-butenoate
You get 29.9mg. Yield 92.4% IR (cm ^-1 ) 3060, 2960, 1780, 1740, 1655,
1600, 1595, 1520, 1490, 1440, 1322,
1235, 1135, 1070 NMR (CDCl ₃ δ) 3.72 (s, 3H), 4.10 (s, 2H)
4.40 (s, 2H), 4.82 (s, 1H) 5.12 (s,
1H), 5.26 (s, 1H) 5.1-5.35 (m, 1H)
5.94 (d, J = 6.6Hz) 6.7-8.0 (m, 11H) Example 1 Synthesis of 3-chloromethyl-7-phenylacetamido-3-cephem-4-carboxylic acid benzyl ester 101 mg of 3-chloromethyl-2-(3-phenylacetamido-4-phenylsulfonylthio-2-azetidinon-1-yl)-3-butenoic acid benzyl ester and 1 ml of dry DMF were mixed in a reaction vessel to form a homogeneous solvent. do. The reaction vessel is cooled to -25°C by immersing it in a dry ice-acetone bath. To this was added 15.5μ of commercially available 28% ammonia water, and the mixture was stirred for 1 hour while maintaining the reaction temperature in the range of -30°C to -20°C. After the reaction, add 5 drops of 5% hydrochloric acid, and then add about 30 ml of ethyl acetate. Transfer the reaction mixture to brine over ice and separate the organic layer. The obtained organic layer is washed twice with saturated brine, dried over anhydrous sodium sulfate, and then concentrated.
The resulting residue is purified using a silica gel column to obtain 68 mg (yield: 88%) of 3-chloromethyl-7-phenylacetamido-3-cephem-4-carboxylic acid benzyl ester. The analytical values of the obtained compound are shown below. IR (CHCl ₃ ): 1790, 1730, 1682 (cm ^-1 ) NMR (CDCl ₃ ): δ _ppn = 3.32 and 3.60 (2H,
ABq, 18Hz), 3.53 (2H, s), 4.31 and
4.45 (2H, ABq, 12Hz), 4.86, (1H, d,
5Hz), 5.20 (2H, s), 5.77 (1H, dd, 5
Hz, 9.2Hz), 6.43 (1H, d, 9.2Hz), 7.27
(5H, s), 7.33 (5H, s) Example 2 Production of 3-chloromethyl-7-phenylacetamide-3-cephem-4-carboxylic acid benzyl ester 3-chloromethyl-2-(3-phenyl Add 34 mg of acetamido-4-phenylsulfonylthio-2-azetidinon-1-yl)-3-butenoic acid benzyl ester and 0.4 ml of dry DMF to a reaction vessel to make a homogeneous solvent. The reaction vessel is then immersed in a dry ice-acetone bath and cooled to -35°C. Add 0.125 ml of DMF with an ammonia concentration of 11.4 mg/ml, which was prepared in advance by blowing ammonia gas, into the reaction container.
The reaction temperature was maintained at -40 to -35°C and stirred for 1 hour.
After the reaction, the same treatment as in Example-1 was carried out, and 18.8
mg (yield 74%). The analytical values of the obtained compound matched those of Example-1. Examples 3 to 12 The same reaction as in Example 1 was carried out to obtain 3-chloromethyl-3-cephem derivative (2) from azetidinone derivative (1). The results are shown in Table-1.

【table】 The analytical values of the obtained compound are shown in Table 2.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, [Formula] represents a carboxylic acid residue, R ² represents a protecting group for a carboxyl group, and R ³ represents a substituted or unsubstituted aromatic hydrocarbon group. ] The azetidinone derivative represented by is treated with a base in an organic solvent to form the general formula [In the formula, R ¹ and R ² are the same as above. ] 3-chloromethyl- characterized by obtaining a 3-chloromethyl-3-cephem derivative represented by
3-Method for producing cefem derivatives. 2. The method according to claim 1, wherein the organic solvent is at least one selected from the group consisting of dimethylformamide, diethylformamide, and dimethylacetamide. 3. The method according to claim 1 or 2, wherein the base is ammonia or aqueous ammonia. 4. The method according to any one of claims 1 to 3, wherein the reaction is carried out at -78 to 40°C.