PROCESS FOR THE PREPARATIONOF 2-SUBSTITUTED CEPHEM DERIVATIVES

Abstract: 2-Substituted cephem derivatives represented by the general formula (I), (wherein R¹ represents substituted or unsubstituted phenyl, substituted or unsubstituted phenyl­ methyl, or substituted or unsubstituted phenoxymethyl, R² represents hydrogen or a carboxylic acid-protecting group, Y represents allyloxy, benzyloxy, alkythio, carboxyalkylthio, or a group represented by the general formula of (II), R⁴ represents hydrogen or lower alkyl, X represents -O-, -S- or N-CH₃, R⁵ represents hydrogen, lower alkyl or phenyl, and R⁶ represents hydrogen or lower alkyl), and a process for their preparation.

Description: This invention relates to a process for preparing 2-substituted cephem derivatives represented by the formula wherein R¹ represents phenyl, p-methoxyphenyl, p-methylphenyl, phenyl substituted with halogen or nitro on the benzene nucleus, benzyl, p-methylbenzyl, benzyl substituted with halogen or nitro on the benzene nucleus, phenoxymethyl or p-chlorophenoxymethyl; R² represents hydrogen atom or a protective group for carboxylic acid; and Y represents a C₁-C₄-alkoxy group, an allyloxy group, a benzyloxy group, a C₁-C₄-alkylthio group, a C₂-C₄-carboxyalkylthio group or a group of the formula wherein R⁴ represents a hydrogen atom or a methyl group, X represents -O-, -S- or N-CH₃, R⁵ represents a hydrogen atom, a methyl group or a phenyl group and R⁶ represents a hydrogen atom or a methyl group, the process comprising reacting a cephem derivative of the general formula wherein R¹ and R² are as defined above and R³ represents an acetyl group with a necleophilic reagent of the general formula Y - H wherein Y is a defined above, in the presence of iodine or an acid selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochlorid acid, aluminum chloride, tin chloride, titanium chloride and boron trifluoride at a temperature of -60 to 50° C wherein the iodine or acid is used in an amount of 0,01 to 10 mole% per mole of the cephem derivative of the formula (I). In the case wherein R³ is methyl Y represents the possibilities indicated above except C₁-C₄-alkoxy. From the DE-A-2 455 358, the JP-A-4948690, the US-A-3 852 282, the US-A-4 098 999, the "Biology of β-Lactam Antibiotics", Vol. 2, 1982, pages 143-151 and page 154, and the "Cephalosporins and Penicillins" (1972), pages 569, 570 it is known that a wide range of cephalosporins having a substituent in C₂ has an antibacterial acitivity. However, all the prior known cephalosporins are different in structure from the compounds according to the present invention. The above mentioned documents also describe processes for the preparation of the said compounds. The known processes comprise an intramolecular rearrangement (DE-A-2 455 358) or a substitution of 2-position halogen (JP-A-4948690, US-A-3 852 282 and US-A-4 098 999). The 2-substituted cephem derivatives of the formula (II) are novel compounds undisclosed in literature and can be converted into useful compounds having an antibacterial activity by, for example, the saponification of the carboxylic acid-protecting group or acyl exchange at the amido site in the 7-position. For example, the compound (II) can be converted into a compound of the formula (X) which is useful as an antibacterial agent, according to the following reaction equation. In the above reaction equation, R¹, R² and Y are as defined above, M represents hydrogen atom or alkali metal and R represents a group such as that of Examples of phenyl substituted with halogen or nitro on the benzene nucleus represented by R¹ in the formula (II) are e.g. p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-nitrophenyl. Examples of benzyl substituted with halogen or nitro on the benzene nucleus are e.g. p-chlorobenzyl, p-nitrobenzyl. Examples of the carboxylic acid-protecting groups represented by R² are alkyl, halogenated alkyl, methyl substituted with phenyl optionally substituted and like protective groups commonly used. Preferred examples of the alkyl groups are those having 1 to about 4 carbon atoms such as methyl or tert-butyl. Preferable halogenated alkyl groups are lower alkyl groups having 1 to about 4 carbon atoms and substituted with at least one halogen group such as 2,2,2-trichloroethyl. Preferred methyl groups substituted with phenyl optionally substituted are benzyl, p-nitrophenylmethyl or diphenylmethyl. Examples of the C₁-C₄-alkoxy groups represented by Y are methoxy or ethoxy. Representatives of the C₁-C₄-alkylthio groups are methylthio, ethylthio, butylthio or isobutylthio. Illustrative of the C₂-C₄-carboxyalkylthio groups are -SCH₂COOH, -SCH₂CH₂COOH, -SCH₂CH₂CH₂COOH. Exemplary of the groups are furanyl, 2-methylfuranyl, thiophene-2-yl, 2-methylthiophene-5-yl or N-methylpyrrole-2-yl. Representative of the groups are 1,2,3,4-tetrazole-5-thio, 1-phenyl-1,2,3,4-tetrazole-5-thio or 1-methyl-1,2,3,4-tetrazole-5 thio. Illustrative of the groups are 1,3,4-thiadiazole-5-thio or 2-methyl-1,3,4-thiadiazole-5-thio. The process of preparing the compound (II) comprises reacting a cephem derivative of the formula wherein R¹ and R² are as defined above and R³ represents a methyl group or an acetyl group with a nucleophilic reagent of the formula Y - H wherein Y is as defined above in the presence of iodine or an acid selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochlorid acid, aluminum chloride, tin chloride, titanum chloride and boron trifluoride at a temperature of -60 to 50° C wherein the iodine or acid is used in an amount of 0,01 to 10 mole % per mole of the cephem derivative of the formula (I). (When the compound (I) wherein R³ is methyl is used as the starting material, a nucleophilic reagent wherein Y is alkoxy is not usable.) The cephem derivative (I) serving as the starting material wherein R³ is methyl can be prepared, for example, from a cephalosporin derivative of the formula wherein R¹ and R² are as defined above by the processes disclosed in Tetrahedron Letters, 1978 , 409 and 1972 , 3717 or by a similar process. The cephem derivative (I) can be also produced by the electrolytic oxidation of the compound (A) in the presence of a primary or secondary alcohol or lower carboxylic acid and a supporting electrolyte. More specifically stated, useful primary or secondary lower alcohols are e.g. methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol and useful carboxylic acids are formic acid, acetic acid or propionic acid. These compounds are used in an amount of 5 to 100 times the amount of the compound (A) serving as the starting material. Suitable supporting electrolytes include salts usable in usual electrolytic oxidation, such as ammonium formate, ammonium acetate, tetraethylammonium formate, tetraethylammonium acerate, tetrapropylammonium acetate, tetrabutylammonium acetate, tetrabutylammonium tosylate, tetraethylammonium tosylate, tetrabutylammonium perchlorate, triethylbenzylammonium chloride and like ammonium salts, salts of alkali metals or alkaline earth metals (such as salts of lithium, sodium, potassium, magnesium, calcium, barium) of formic acid, acetic acid or propionic acid lower fatty acids, salts of alkali metals of perchloric acid or like perhalogenic acid. When lower carboxylic acid is used as a solvent for the electrolytic oxidation, a metal salt of the lower carboxylic acid is preferably used. In this case, sodium hydroxide, potassium hydroxide, barium oxide, calcium oxide, magnesium oxide or the like may be incorporated in the reaction system to form a salt of the carboxylic acid. While the amount of the supporting electrolyte to be used varies with the kind of the electrode or the shape of electrolytic cell and other conditions, a preferred amount thereof is that sufficient to form a saturated solution. Usable as the electrodes is any of suitable electrodes commonly used in the art among which platinum or carbon electrode is preferably used. The electrolysis can be conducted at either controlled potential or constant voltage, for example at a constant current density in the range of 1 to 500 m A/cm², preferably 3 to 50 m A/cm². While the required quantity of electricity varies with the selection of the solvent and supporting electrolyte, electric current is passed through the electrolyte at usually 2 to 50 F, preferably 2 to 15 F, per mole of the compound (A). The temperature suitable for the electrolysis is adequately selected from the range of -10 to 60°C. Useful nucleophilic reagents of the formula Y-H wherein Y is as defined above are e.g. methyl alcohol, ethyl alcohol, allyl alcohol, benzyl alcohol; methanethiol, ethanethiol, butanethiol or isobutanethiol; furan, 2-lower alkylfuran, thiophene, 2-lower alkylthiophene or N-methylpyrrole; 5-mercapto-1,2,3,4-tetrazole, 1-methyl-5-mercapto-1,2,3,4-tetrazole or 1-phenyl-5-mercapto-1,2,3,4-tetrazole; 5-mercapto-1,3,4-thiadiazole or 2-methyl-5-mercapto-1,3,4-thiadiazole. The nucleophilic reagent is employed in an amount of usually 1 to 50 moles, preferably 1 to 10 moles, per mole of the cephem derivative (I) to be used as the starting material. The nucleophilic reagent which is a liquid having a low viscosity such as lower alcohol, furan, methylfuran or the like can be used by itself as a solvent. When a nucleophilic reagent of the other type is used, the reaction is carried out by using an organic solvent inert to the reaction. Suitable examples of the organic solvent are methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and like chlorinated hydrocarbons; ethyl acetate, ethyl formate, methyl formate and like esters of lower fatty acids; nitroethane, nitromethane and like nitro compounds; carbon disulfide; acetonitrile, butyronitril and like nitriles. These solvents can be used singly or at least two of them are usable in admixture. The amount of the organic solvent to be used is not particularly limited but is such that the amount of the compound (I) is usually 0.1 to 50% (w/v), preferably 1 to 30% (w/v), based on the solvent. In the present invention, the reaction between the cephem derivative (I) and the nucleophilic reagent is conducted in the presence of iodine or an acid selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochlorid acid, aluminum chloride, tin chloride, titanium chloride and boron trifluoride at a temperature of -60 to 50° C wherein the iodine or acid is used in an amount of 0,01 to 10 mole % per mole of the cephem derivative of the formula (I). Although variable depending on the kind of the catalyst and the nucleophilic reagent, the amount of the catalyst to be used is usually 0,01 to 10 mole %, preferably 0,1 to 10 mole %, per mole of the compound (I). The reaction is performed at a temperature of -60 to 50° C, preferably -40° C to room temperature and is completed usually in 10 minutes to 10 hours, although the reaction time varies with the reaction temperature and the kind of the catalyst and nucleophilic reagent. The 2-substituted cephem derivative (II) thus obtained is separated from the reaction mixture and purified by the usual separation method such as column chromatography or recrystallization. The present invention will be described below in more detail with reference to the following Examples in which Ph stands for phenyl group; Ac for acetyl group; Et for ethyl group; and r.t. for room temperature. Example 1 Dissolved in dry methylene chloride (2 ml) was benzyl ester of 2-acetoxy-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid (130 mg, 0.26 mmol), and the solution was cooled to -25°C. Thereto added were allylalcohol (2 ml, 29.4 mmol) and then titanium tetrachloride (15 µl, 0.14 mmol). The reaction was carried out at temperatures gradually elevated from -25°C to 3°C while stirring the reaction mixture for 4.3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the resulting reaction mixture whereupon the reaction was stopped. The reaction product was extracted with methylene chloride. The methylene chloride solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was subjected to separation and purification by silica gel column chromatography using benzene-ethyl acetate (20:1), giving 108 mg of benzyl ester of 2-allyloxy-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid in 83% yield. IR (CHCl₃): 1782, 1772, 1690 cm⁻¹ ¹HNMR (CDCl₃, δ ): 2.15 (s, 3H), 4.15 (m, 2H), 4.54 (s, 2H), 4.92 (s, 1H), 5.10 (d, 1H, 4.4Hz), 5.28 (s, 2H), 5.0-5.5 (m, 3H), 5.94 (dd, 1H, 4.4Hz, 8.8Hz), 6.8-7.5 (m, 11H) Example 2 Allyl alcohol (2 ml, 29.4 mmol) was added to benzyl ester of 2-acetoxy-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid (130 mg, 0.26 mmol) at room temperature to obtain a uniform solution. Iodine (2 mg) was added to the solution and the mixture was stirred for 4.7 hours. The reaction mixture was diluted with methylene chloride (30 ml) and the dilution was washed successively with 5% sodium thiosulfate and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled at reduced pressure. The residue was subjected to silica gel column chromatography using benzene-ethyl acetate (20:1) to separate and purify the contemplated product, giving 105 mg of benzyl ester of 2-allyloxy-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid in 80% yield. The IR and ¹HNMR spectrum data of the product were thoroughly identical with those of the product obtained in Example 1. Examples 3 to 20 The same procedure as Example 1 was repeated with the exception of using the ester of 2-acetoxy-3'-desacetoxy cephalosporanic acid, nucleophilic reagents and acid catalysts as listed in Table I below. Table II shows the IR and ¹HNMR spectrum data of the products obtained. Example 21 Dissolved in methylene chloride (5 ml) were benzyl ester of 2-methoxy-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid (203 mg, 0.43 mmol) and 2-methylfuran (0.1 ml, about 1 mmol). Aluminium chloride (74 mg, 0.56 mmol) was added to the solution at room temperature and the mixture was stirred for 40 minutes. An aqueous solution of sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography using benzene-ethyl acetate (10:1), to separate and purify the contemplated product, giving 149 mg of benzyl ester of 2-(2-methyl-5-furyl)-7-phenoxyacetamido-3'-desacetoxy cephalosporanic acid in 82% yield. The IR and ¹HNMR spectrum data of the products thus purified were totally identical with those of the product obtained in Example 6. Examples 22 to 26 The procedure of Example 21 was followed except that use was made of the ester of 2-methoxy-3'-desacetoxy cephalosporanic acid and nucleophilic reagents as indicated in Table III below. Table IV shows the IR and ¹HNMR spectrum data of the products obtained.

Claims: A process for preparing a 2-substituted cephem derivative represented by the general formula wherein R¹ represents phenyl, p-methoxyphenyl, p-methylphenyl, phenyl substituted with halogen or nitro on the benzene nucleus, benzyl, p-methylbenzyl, benzyl substituted with halogen or nitro on the benzene nucleus, phenoxymethyl or p-chlorophenoxymethyl; R² represents hydrogen atom or a protective group for carboxylic acid; and Y represents a C₁-C₄-alkoxy group, an allyloxy group, a benzyloxy group, a C₁-C₄-alkylthio group, a C₂-C₄-carboxyalkylthio group or a group of the formula wherein R⁴ represents a hydrogen atom or a methyl group, X represents -O-, -S- or N-CH₃, R⁵ represents a hydrogen atom, a methyl group or a phenyl group and R⁶ represents a hydrogen atom or a methyl group, the process comprising reacting a cephem derivative of the general formula wherein R¹ and R² are as defined above and R³ represents an acetyl group with a necleophilic reagent of the general formula Y - H wherein Y is a defined above, in the presence of iodine or an acid selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochlorid acid, aluminum chloride, tin chloride, titanium chloride and boron trifluoride at a temperature of -60 to 50° C wherein the iodine or acid is used in an amount of 0,01 to 10 mole % per mole of the cephem derivative of the formula (I). The process as defined in claim 1 wherein R³ represents a methyl group and Y represents an allyloxy group, a benzyloxy group, a C₁-C₄-alkylthio group, a C₂-C₄-carboxy-alkylthio group or a group of the formula wherein R⁴ represents a hydrogen atom or a methyl group, X represents -O-, -S- or N-CH₃, R⁵ represents a hydrogen atom, a methyl group or a phenyl group and R⁶ represents a hydrogen atom or a methyl group. The process as defined in claim 1 or 2, wherein the nucleophilic reagent is used in an amount of 1 to 10 moles per mole of the cephem derivative of the formula (I). The process as defined in any of claims 1 to 3, wherein the reaction system contains the acid or iodine in an amount of 0,1 to 10 moles per mole of the cephem derivative of the formula (I). The process as defined in any of claim 1 to 4, wherein Y represents a C₂-C₄-carboxyalkylthio group or a group of the formula wherein R⁴ represents a hydrogen atom or a methyl group, X represents -O-, -S- or N-CH₃ and R⁶ represents a hydrogen atom or a methyl group. The process as defined in claim 5, wherein R¹ is a phenyl group, a benzyl group or a phenoxy group and Y is a C₂-C₄-carboxyalkylthio group or a group of the formula wherein R⁴ represents a hydrogen atom or a methyl group, X represents -O-, -S- or N-CH₃ and R⁶ represents a hydrogen atom or a methyl group.

Inventors: NOGAMI JUNZO, SAITO NORIO, SASAOKA MICHIO, SHIROI TAKASHI, TANAKA HIDEO, TORII SHIGERU, NOGAMI, JUNZO, SAITO, NORIO, SASAOKA, MICHIO, SHIROI, TAKASHI, TANAKA, HIDEO, TORII, SHIGERU
Applicants: OTSUKA KAGAKU YAKUHIN, OTSUKA KAGAKU YAKUHIN KABUSHIKI KAISHA
Application year: 1983
Main classification: C07D501
IPC codes: A61K31, C07D501, A61P31