DE2620959C3 - Process for the preparation of 7- (D-2-amino-3-phenylacetmido) -3-methyl-3-cephem-4-carboxylic acid - Google Patents

Description

characterized in that D-phenylglycine of the formula

CH-COOH

NH ₂

reacted with thiophosgene at a temperature of 80 to 120 ⁰ C in anhydrous dioxane, the reaction mixture is concentrated, the residue is taken up in chloroform and chromatographed with a silica gel column, the elution is carried out using a chloroform / methanol mixture (20: 1), then the solvent evaporates and the resulting crystalline 4-phenyl-2,5-thiazolidinedione of the formula

CH

NH
\

C = O

in a known manner in an aqueous solution or suspension at a temperature of 5 to 25 ° C and a pH of 5 to 5.6 7-AminodesacetyIcephalosporanic acid converts.

The invention relates to the method characterized by the claim.

The reaction of 4-phenyl-2,5-thiazolidinedione with 7-aminodesacetylcephalosporanic acid is carried out in aqueous Solutions or aqueous suspensions executed. An aqueous suspension with a pH of 5 to 5.6 is preferred.

The reaction of the heterocyclization of D-phenylglycine with thiophosgene is carried out in anhydrous dioxane. All starting materials are general known and commercially available chemicals.

The compound of the formula I is a semisynthetic cephalosporin antibiotic with a broad spectrum of activity. It is specifically used in the chemotherapy of infections caused by ampicillin-resistant microorganisms E. coli and Pr. Mirabilis. The compound is known and described in the specialist literature (JS Welles, RO Froman, WR Gibson, NV Owen and CR Anderson, Antimicrob. Ag. Chemother., 489, 1968).

7- (D-2-Amino-2-phenylacetamido) -3-methy] -3-cephem-4-carboxylic acid was previously made by the condensation of a protected D-phenylglycine with 7-aminodesacetylcephalosporanic acid won. However, this condensation reaction always required the removal of the corresponding protective groups Phenylglycine.

The advantage of the process according to the invention is that after the condensation has taken place

ίο of 7-aminodesacetylcephalosporanic acid with 4-phenyl-2,5-thiazolidinedione the pure end product without the usual processes that were unavoidable with previously known processes chemical aftertreatment is obtained.

Another advantage of the process according to the invention is that the intermediate 4-phenyl-2,5-thiazolidinedione through a simple and economical chemical synthesis consisting of direct heterocyclization of D-phenyl-glycine with thiophosgene. Known methods for peptide synthesis

: o by means of Thiazoiidindionen z. B. in J. Org. Chem., VoI. 36, 1971, pp. 49 to 59, and Houben-Weyl, Methods of organic chemistry, Volume 15, Part 2, p. 289 described.

The only previously known method for the synthesis of 4-phenyl-2,5-thiazolidinedione ran according to a complex three-phase process. This synthesis is described in I. Z. Siemion, W. Steglich and L. Wilschowith, Rocszniki Chemii, 46, 21 (1972). It is particularly disadvantageous in this known method that

jo that the functional groups of phenylglycine, namely the carboxyl and the amino group, each must be protected individually. In contrast, in the first stage of the invention Process for the reaction of D-phenylglycine with thiophosgene in a single step, the 4-phenyl-2,5-thiadiazolidinedione obtained because both functional groups are protected at the same time, which is a means great economic and technical advantage.

D · · ι

example

a) 5.0 g (0.033 mol) of D-phenylglycine are suspended in 100 ml of anhydrous dioxane. 7.5 ml (0.1 mol) of thiophosgene are added to the suspension while stirring. The reaction mixture is heated with stirring to reflux (90 ⁰ C) for 4 hours at this temperature. After completion of the reaction, the dioxane at 6O ⁰ C and 50 mm Hg to an oily consistency and then distilled off with a silica gel column (50 g, particle size 0.05 to 0.2 mm) and 150 ml of chloroform chromatographies. Elution is carried out using 350 ml of chloroform / methanol (20: 1). After evaporation of the solvent at 40 ⁰ C and 50 mm Hg 2.85 (45% of theory) of white are Crystalline 4-phenyl-2,5-thiazolidinedione, F = 140 through 143 ° C, was obtained.

The structure of the compound was confirmed by IR and NMR spectroscopy

Analysis for C ₉ H ₇ NO ₂ S:

Ben: C 55.94%, A 3.65%, N 7.25%;
Found: C 56.23%, H 3.92%, N 7.22%.

b) 2.14 g (0.01 mole) 7-aminodeacetylcephalosporanic acid are suspended in 100 ml of water and with sodium hydroxide solution (1 N) to a pH of 5.6 offset. The suspension is cooled to 5 ° C., 2.9 g (0.015 mol) of 4-phenyl-2,5-

thiazolidinedione is added and the mixture is stirred for 2 hours at 5 ° C. and then for a further 4 hours at room temperature. The reaction mixture is then filtered through a filter aid layer, the filtrate is acidified to pH 5.0 with HCl (1 N) and concentrated to a volume of 20 ml ^{at 40 ° C. and 50 mm Hg.} After cooling to room temperature, the 7-aminodeacetylcephalosporanic acid (0.2 g) is separated out, which is filtered off. The filtrate is concentrated to a volume of 10 ml and the separated crude product is washed twice with 10 ml of acetone each time. 2.5 g (79% of theory) of pure 7- (D-2-amino-2-phenylacetamido) -β-methyl ^ -cephem ^ -carboxylic acid, melting point 181 to 184 ° C., are obtained.

Claims (1)

Claim: Process for the preparation of 7- (D-2-amino-2-phenylacetamidoJ-a-methyl-S-cephem-t-carboxylic acid the formula CH ₃ NH ₂