KR790001071B1 - Process for preparing deacetoxy cephalosporins via penicillin sulfoxide rearrangement - Google Patents

Abstract

Title process gave better high-purity yields which are intermediates esp. for the prepn. of the antibiotic cephalexin by heating a 6-acylamido penicillanic acid ester sulfoxide in 1,1,2-trichlo-roethane in the presense of an amino salt which is formed with an amine selected from the group consisting of pyridine, quinoline, isoquinoline and the methyl-substd. deriv. with dichloromethane phosphoic acid.

Description

Method for preparing the acetoxy cephalosporin by inverting penicillin sulfoxide

The present invention relates to a process for the preparation of deacetoxy cephalosporin. The process of the invention makes it possible to prepare intermediates, especially for the synthesis of the commercial antibiotic cephalexin, in high yields.

The present invention relates to an improved process for preparing 7-acylamido-3-methyl-3-cepem-4-carboxylic acid by heating 6-acylamido penicillanoic acid sulfoxide ester in the presence of an acidic catalyst in an inert solvent. will be. The method is prepared by heating the penicillin sulfoxide ester in the presence of a salt of dichloromethanephosphonic acid with pyridine, quinoline, isoquinoline or its methyl substituent in 1, 1, 2-trichloroethane.

In US Pat. No. 3,275,626, Maureen and Jackson describe penicillin sulfoxide rearrangement. Here the chiazolidining of penicillin sulfoxide extends to the dihydrochiazine of desacetoxy cephalosporin. This method was the first practical method for the preparation of desacetoxy cephalosporin, or 3-methyl-3-cefem compound, and was also the first to prepare cephalosporin compound without using cephalosporin C as starting material. .

In US Pat. No. 3,647,787, Cooper converted penicillin sulfoxide esters to deacetoxycephalosporins by heating in tertiary carboxamides, urea derivatives and / or sulfonamides under acidic conditions. Further refined methods are described in US Pat. No. 3,591,585 (July 6, 1971).

The use of sulfonic acid catalysts in tertiary carboxamide solvents is described herein.

More recently, US Pat. Nos. 3,725,397 and 3,725,399 describe acid catalysts used in ring expansion reactions. In the above patents, it is indicated that nitrogen base complexes made with lower alkyl, phenyl lower alkyl or phenyldihydrogen phosphate are useful acid catalysts for potential reactions. The latter patent describes the use of certain amine salts of sulfonic acid, phosphoric acid or trifluoroacetic acid in ring expansion.

The conversion of penicillin sulfoxide esters to deacetoxy cephalosporins is the commercial method of choice for the preparation of deacetoxy cephaloscillin. For example, the well-known antibiotic cephalexin can be prepared with 7-acylamido deacetoxy cephalosporin made by ring expansion of penicillin sulfoxide ester. For example, 6-acylamido penicillanoic acid ester sulfoxides, such as 6-phenoxy acetamido penicillinic acid sulfoxide ester, are reacted under ring expansion conditions to produce the corresponding 7-phenoxyacetamido deacetoxycene. Palosporanoic acid ester (7-phenoxyacetamido-3-methyl-3-cefe-4-carboxylic acid ester) is prepared. The 7-phenoxyacetyl side chain of the ring expanding cephalosporin product was removed by applying known side chain leaving reaction conditions to prepare an ester of 7-amino-3-methyl-3-cefe-4-carboxylic acid with cephalosporin nucleus ester. do. For example, the intermediate ring expanded esters are reacted with phosphorus pentaoxide in an inert solvent to produce iminochloride, and to react with lower alkanols to produce unstable imino ethers. Iminoethers decompose to N-deacetylate the 7-phenoxyacetyl side chain to form a 7-amino nucleus ester. Next, the nucleates are acylated with an appropriately protected phenylglycine derivative to prepare 7-phenylglyciamido-3-methyl-3-cepem-4-carboxylic acid ester having an amino group protected by a 7-position side chain. The ester group of the amino protecting group and the C ₄ carboxyl group is then removed to produce the antibiotic cephalexin.

In view of the commercial importance of the antibiotic cephalexin, it is necessary to increase the yield in its preparation. One important thing in the preparation of this antibiotic is the penicillin sulfoxide ring expansion reaction. Thus, the improved yield of deacetoxy cephalosporin, an intermediate prepared by the ring expansion reaction, increases the yield in antibiotic preparation.

According to this reaction, a 1,1,2-trichloroethane solvent in the presence of a dichloromethane phosphonic acid salt prepared from 6-acylamido penicillanoic acid ester sulfoxide represented by the following structural formula (I) with a cyclic tertiary amine: It heated to the inside, and 7-acyl amido deacetoxy cephalosporanic acid ester (7-acyl amido-3-methyl-3- cefe-4- carboxylic acid ester) represented by following formula (II) was produced.

Where

R represents an acyl group derived from carboxylic acid,

R 'is a carboxylic acid protecting group.

Cyclic tertiary amines that can be used in the preparation of the dichloromethylphosphonate salts include pyridine, quinoline, isoquinoline and 4-methylpyridine, 3-ethylquinoline, methylated quinoline, lower alkyl substituted derivatives such as methylated isoquinoline, and the like. . A salt of choice in the reaction of the present invention is pyridinium dichloromethanephosphonate made from dichloromethane phosphonic acid and pyridine. Dichloromethane phosphonate is prepared by the method described in US Pat. No. 3,725,397, filed April 3, 1973. This amine salt acts as an acidic catalyst for the potential reactions described by Maureen and Jackson in US Pat. No. 3,275,626.

The solvents used in combination with the amine salts described above have properties that are very suitable for commercial scale penicillin sulfoxide potentials. For example, the boiling point of 1, 1, 2-trichloroethane is about 114 ° C. This boiling point causes the potential reaction to occur within 3-5 hours, which is a reasonably short time at the reflux temperature. Another advantage of this solvent is that it forms an azeotrope (boiling point 86 ° C.) with water. The azeotrope contains 16.4% of the drug. Therefore, the water during the reaction is rapidly removed from the reaction mixture to prevent the formation of by-products. The solvent can also be easily recovered and reused in a yield of about 85-90%. 1, 1, 2-trichloroethane is a solvent having the stability required for use in commercial ring expansion reactions. The starting material 6 acylamidophenicylanate ester sulfoxide and the potential product desaceoxycephalosporin ester are dissolved in this solvent. Also, the potential product can be easily recovered from the reaction mixture.

In carrying out this reaction, the concentrations of penicillin sulfoxide and amine salts in the reaction solvents 1, 1 and 2-trichloroethane can be changed, respectively. However, there are concentrations to choose from. For example, the best yields can be obtained when using a penicillin sulfoxide concentration of about 0.05-0.5 mol (about 0.11 mol is preferred) and an amine concentration of about 0.005 and 0.05 mol.

When the reaction is performed within the range of the above-described conditions, a ring expansion cephalosporin potential product can be obtained in an improved yield. In general, the process of the present invention is 5-10% better than the yields of past methods obtained using other acid catalysts and other solvents. This enhanced percentage has a significant economic significance compared to past commercial methods.

The present invention not only improves the yield of deacetoxycephalosporin but also partially removes by-products that are typically formed in past ring expansion reactions. For example, in US Pat. No. 3, 275, 626 to Maureen and Jackson, 7-acylamido-3-exomethylenecepam-4-carboxylic acid esters were present in the cephalosporin material produced in the desired potential reaction. A by-product 7-acylamido-3-hydroxy-3-methylcepem-4-carboxylic acid ester is also formed. These two by-products form a significant amount in known ring expansion reactions.

Table 1 below lists the yields obtained by conducting a dislocation reaction using pyridinium dichloromethanephosphonate, a selectable salt, among the solvents described in US Pat. No. 3,725,397. In the table, the reported yield data transposes P-nitrobenzyl 6-phenoxyacetamidophenicylinic acid sulfoxide to P-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-cepem-4-carboxyl. The rate is obtained.

The salts formed of dichloromethanephosphonic acid and pyridine in the reaction in the listed solvents used the above selectable concentration ranges.

[table]

P ¹ -nitrobenzyl7-phenoxymethyl-3-methyl-3cepem-4-carboxylate The penicillin sulfoxide rearrangement reaction herein is also applicable to the penicillin rearrangement reaction of the past literature. For example, the present invention can also be applied to the aforementioned U.S. Patent Nos. 3,275,626, 3,275,397 and 3,591,585. Prepared by the process of the present invention, and usable in the process of the present invention are those compounds of formula (I) wherein R is lower alkyl such as methyl, ethyl or chloromethyl, and penicillin G wherein R is benzyl Benzylphenicillin), phenoxyphenicillin (penicillin V), phenylmercapto penicillin, wherein R is a phenylthiomethyl group, or 6-benzamidophenicillin, or 6- (2, 6-dimethoxy benzamid, wherein R is phenyl or substituted phenyl; Or penicillin) or R is a heterocyclic methyl group such as 2-chienylmethyl, 2-furfurylmethyl, 3-chienylmethyl, or the like, or penicillin, wherein R is an α-substituted benzyl group of the following structure.

Wherein Z is an amino group substituted with a protecting group such as a urethane protecting group such as t-butoxycarbonyl group, trichloroethoxycarbonyl group, cyclohexyloxycarbonyl group and urethane group, or a trityl group or a haloacetyl group such as chloroacetyl group Either the same aminoprotecting group or Z represents a carboxyl group or sulfo group (-SO ₃ H), which is protected by esterification. Or Z represents an ester formed from a formyl group or a lower alkyl carboxylic acid such as acetyl or propionyl, or a halogenated ester obtained from halogenated lower alkanophosphoric acid or the like. Penicillins such as hetacillin and N-nitrozohetercillin, already known in the literature, can also be used.

In the past literature, in ring expansion of penicillin sulfoxide to desacetoxy cephalosporin, the starting material penicillin is used in the ester form. Known in many penicillin esters and can be used in this reaction. The ester function is to protect the carboxyl group during the heat catalyzed rearrangement reaction, and thus the ester group is selected that can be easily formed and readily degraded in the cephalosporin potential product. Examples that can be used as penicillin sulfoxide esters and which can be easily decomposed are halogenated hydrocarbon ester groups such as 2, 2, 2-trichloroethyl, benzyl, P-nitrobenzyl, 3, 5-dimethoxy benzyl Type, diaryl methyl type such as diphenylmethyl (benzhydryl), 3, 5-dimethoxybenzhydryl, 4, 4-dimethoxybenzhydryl, and the like, and R 'in the formula (I) Imidomethylesters such as methyl or succinimido methyl, C ₄ -C ₆ alethylesters such as t-butyl and t-pentyl and 1, 1-dimethyl-2-propenyl, 1, 1-dimethyl-2-butenyl Branched alkyls such as C ₅ -C ₇ -t-alkenyl and C ₅ -C ₇ -t-alkynyl groups such as 1, 1-dimethyl-2-propynyl, 1, 1-dimethyl-2-pentynyl and the like , Alkenyl and alkynyl.

The penicillin nucleus, 6-aminophenicylanic acid (6-APA), is also a starting material that can be used in the present invention. However, when used as starting material, the 6-amino group and C ₃ -carboxyl group should be protected like other penicillins with free amino groups. As the protecting group for the 6-amino group of 6-APA, various groups used in this aspect can be used. For example, urethane t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, and the like. As the arylmethylamino protecting group, a trityl group can be used. A more convenient protecting group for the 6-amino group of 6-APA is the formyl group represented by formula (I) when R is hydrogen.

In carrying out this reaction, one skilled in the art knows that the 6-acylamido group of the starting material becomes the 7-acylamido side chain of the cephalosporin transposition product. If the 6-acylamido group of penicillin is the desired side chain of cephalosporin, the ester group is removed to give the desired product as the free acid. The 6-acylamido side chain of the starting material penicillin may also be selected for convenience or as a reason for ease of use. In the latter case, the 6-acylamido side chain of penicillin in the translocation reaction is the 7-acylamido side chain of desacetoxy cephalosporin, such as phosphorus pentaoxide as described by Schubert in US Pat. No. 3,549,628. The halides can be used to remove them by known decomposition reactions. After the side chains are removed, the 7-aminodesacetoxy cephalosporanic acid ester is acylated at the 7-position with the selected carboxylic acid to prepare the desired 7-acylamido desacetoxy cephalosporin ester. Next, the ester group is removed to prepare an antibiotic compound.

Likewise, the sulfoxide is used in the rearrangement reaction of the present invention by oxidizing the 6-protecting group-aminophenicylanate ester formed by protecting the 6-amino group of 6-APA ester. The protecting group can be removed from the 7-protected-aminodesacetoxy cephalosporanic acid ester product, and acylated with the desired carboxylic acid and de-esterified to produce the desired antibiotic.

In carrying out the present invention, the penicillin starting material, if it is 6-amino-protected-penicilanic acid or 6-acylamido-penicylanic acid, is first esterified to a C ₃ protective carboxylic acid functional group, Is oxidized to sulfoxide. As known techniques, penicillin compounds are prepared by oxidizing in an inert solvent with an inorganic oxidic acid such as m-periodic acid or an organic phosphoric acid such as peracetic acid, perbenzoic acid or substituted benzoic acid such as m-chloroperbenzoic acid.

6-acylamido penicillanoic acid ester sulfoxide is dissolved or partially dissolved in 1, 1, 2-trichloroethane in an amount sufficient to be 0.05-0.5 mol in concentration. The amine salt of dichloromethane phosphonic acid is then added to a concentration of about 0.005-0.05 moles. The reaction mixture is then heated at reflux for 3-5 hours. During the reflux period, the azeotrope formed with the solvent and water collects a solvent heavier than water in a water trap designed to return back to the reaction vessel. After the reaction, the mixture is cooled to room temperature and concentrated in vacuo. Upon cooling or the addition of an organic liquid (eg methanol or ethanol), the reaction product is precipitated because it is basically insoluble. The reaction product is filtered off and, if necessary, recrystallized and purified.

The reaction was carried out at the reflux temperature of the reaction mixture, but can be carried out at a temperature of about 90-125 ° C. The reaction is continued for a time sufficient to complete and obtain maximum yield. The reaction temperature above the reflux temperature of 1,1,2-trichloroethane can be achieved by performing above atmospheric pressure.

Optionally, P-nitrobenzyl 6-phenoxyacetoamido penicilanate sulfoxide was dissolved in 1, 1, 2-trichloroethane to a concentration of about 0.11 moles, and the reaction mixture was then heated at reflux for 4 hours. do. In the reflux period, the water produced in the reaction is distilled into an azeotrope with the solvent and collected in the water trap by the reflux cooler. After the reaction the mixture is cooled to room temperature and concentrated on a rotary evaporator. Ethanol is added to the concentrated reaction mixture to obtain crystalline precipitation of P-nitrobenzyl 7-phenoxyacetamido deacetoxy cephalosporanate. The product is collected by filtration or other suitable method, washed with ethanol and dried in vacuo.

In the present invention, it is also possible to select 2, 2, 2-trichloroethyl 6-phenylacetamidopheniclanate sulfoxide by dissolving in 1, 1, 2-trichloroethane to a concentration of about 0, 1 mole. Pyridinium dichloromethane phosphonate is then added at a concentration of about 0, 01 molar. The reaction mixture is then heated to reflux for three hours, at which time the water in the reaction is distilled off to an azeotrope and collected in a water trap. The reaction mixture is then cooled to room temperature and the solvent is evaporated to give a concentrated reaction product. The reaction mixture is then evaporated to obtain a reaction mixture residue. The potential product, 2, 2, 2-chloroethyl 7-phenylacetamido deacetoxycephalo sporanate, may be purified by washing with a suitable solvent such as methanol or ethanol, and further recrystallized.

As described above, the deacetoxy cephalosporanic acid ester, which is a translocation product, can be deesterified to obtain deacetoxy cephalosporanic acid. When the translocation product does not have the desired 7-acylamido side chain, the transposition product first deacylates the side chain by a known method to obtain 7-amino deacetoxycephalosporanoic acid ester and then the 7-acyl amido derivative as the desired carboxylic acid derivative. Acylate the position to obtain the desired cephalosporins. The acylation product is then deacylated to give the desired antibiotic.

The yield of deacetoxy cephalosporanic acid esters is improved by the process of the present invention consisting of a specific bond of 1, 1, 2-trichloroethane, a solvent, and an acid salt of t-cyclic amine and dichloromethanephosphonic acid. As shown in Table 1, the yield of the reaction product reacted using the selected acid catalyst of the present invention and the past solvent is much lower than that obtained in the present invention using 1, 1, 2-trichloroethane as a solvent. . In addition, the yields obtained in the present invention are much higher than those obtained using the amine salts of the acid catalysts described in US Pat. No. 3,725,397.

The method of the present invention is particularly valuable for the preparation of commercial cephalexin antibiotics. Cephalexin can be prepared in a multistage reaction including the translocation reaction of penicillin V sulfoxide esters. The transesterified 7-phenoxyacetamido-3-methyl-3-cepem-4-carboxylic acid was then removed from the side chain to obtain the 7-amino-3-methyl-3-cepem-4-carboxylic acid ester nucleus. This was acylated with an amino group-protected p-phenylglycine derivative to prepare an amino group-protected cephalexin ester. The cephalexin is prepared by removing the amino protecting group and the ester group. In the commercial scale multistage reaction of the antibiotic cephalexin, the yield is significantly improved by using the ring expansion method of the present invention.

Next, an Example is given.

Preparation Example 1

Preparation of Pyridinium Dichloromethanephosphonate

A mixture of 17.6 ml (0.2 M) of phosphorus trichloride, 53.6 g (0.4 M) of aluminum chloride and 32 ml (0.4 M) of chloroform is refluxed for 2 hours with good stirring and then cooled to room temperature. The reaction mixture is poured into 140 ml of methylene chloride and the solution is cooled to -30 ° C.

While stirring vigorously, 52 ml (2.88 M) of water is added dropwise, and the temperature is maintained at 5 ° C or lower. After all the water was added dropwise, the reaction mixture was warmed to about 20 ° C. and stirred for 30 minutes. The aluminum chloride 6H ₂ O formed by precipitation is filtered and the filtrate is washed three times with 100 ml of methylene chloride and the washings are combined with the filtrate. 8 ml (0.44 M) of water are added to the mixture, refluxed for 1 hour and allowed to stand overnight. The reaction mixture is evaporated in a rotary evaporator to remove methylene chloride. The solid residue is dissolved in 100 ml of acetone and the acetone is evaporated off. The remaining pale yellow syrup is dissolved again in 100 ml of acetone and evaporated on a rotary evaporator. The syrup is dissolved again in 100 ml of acetone and the solution is cooled to 0 ° C. Then, about 16 ml of pyridine is added dropwise to the solution until the precipitation is completed. Pyridinium dichloromethanephosphonate, heavy granular white crystals, is filtered and washed with acetone. The salt was dried in vacuo to yield 40.54 g of white granular crystals, yield 83, 1%. The salt indicates that nitrate is free of chlorine ions in the experiment.

Example 1

Ring expansion of penicillin with pyridinium dichloromethane phosphonate in 1, 1, 2-trichloroethane

100 ml of 1,1,2-trichloroethane, P-nitrobenzyl 6-phenoxyacetamido penicilanate sulfoxide 5.0 (with a thermometer, a reflux condenser and a Dean-Stark trap in a round-bottom 3-Plasco (300 ml) 10 mM) and 0.25 g (1 mM) of pyridinium dichloromethane phosphonate are added and the mixture is heated at reflux (114 ° C.) for 4 hours. About 0.2 ml of water collects in the water trap during reflux. After the reaction was completed, the mixture was cooled to room temperature and warmed with a water bath at 40-50 ° C. to obtain about 10-15 g of residue. 1, 1, 2-trichloroethane is collected and reused. About 90% of the solvent is recovered.

50 ml of 3A alcohol is added to the residue, which is a reaction product, and crystallized by vigorous stirring. The crystal product, P-nitrobenzyl-7-phenoxy-acetamido deacetoxycephalosporanenit, is filtered and washed with 50 ml of 3A alcohol. The wash product is dried in vacuo to 50-60 ° C. until content is obtained. The yield of the obtained product is 4.09 g (yield 84.5%), and melting | fusing point is about 188-189 degreeC.

Example 2

To a solution of 10.0 g of P-nitrobenzyl 6-phenylacetamidophenicilanate sulfoxide in 175 ml of 1, 1, 2-trichloroethane, 0.5 g of pyridinium dichloromethane phosphonate (2 mM) was added, and the mixture was mixed. It is heated at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure to give about 28 g of product, to which 100 ml of methanol is added. The distilled concentrate is cooled to 0 ° C. The precipitated product is corrected by filtration. The precipitated product is washed with 60 ml of cold meras and air dried. The yield of this product, P-nitrobenzyl 7-phenylacetamido deacetoxy cephalosporanate, was 7.87 (81.7%), and the white solid had a melting point of 226-226.5 占 폚.

TLC of the diluted reaction mixture filtrate shows that the filtrate contains more than 5% of adduct.

Claims (1)

6-acylamido penicillanoic acid sulfoxide ester is heated in 1, 1, 2-trichloroethane in the presence of a salt of dichloromethanephosphonic acid with pyridine, quinoline, isoquinoline or a methyl-substituted derivative thereof to 7-acylami Process for preparing Fig. 3-Methyl-3-cepem-4-carboxylic acid ester.