DE2620959A1 - PROCESS FOR THE PREPARATION OF 7- (D-2-AMINO-3-PHENYLACETMIDO) -3-METHYL-3-CEPHEM-4-CARBONIC ACID - Google Patents

Description

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3IEBERTSTR.4 TEL (089) 471079. 2620959

KRKA - farmacevtika, kemija, zdravilisca E 1199

NOVO MESTO, Yugoslavia

Process for the preparation of 7- (D-2-amino-3-phenylacetamido) -

3-methyl-3-cephem-4-carboxylic acid

The present invention relates to methods for Preparation of 7- (D-2-Amino-3-p & eriylaeetaniido) -3-methyl-3-cephem-4-carboxylic acid the formula

COOH I.

The compound of the formula I is according to the invention Process by the cyclization of D-phenylglycine of the formula

CH-COOH

II with thiophosgene of the formula

Cl

C = S

Cl III

at a temperature of 80 ° to 120 ⁰ C for 4 £ henyl-2,5-thiazolidinedione of formula

CH-C = O

ΗΪΓ p

Il

0 IV

7 0.9 Β 7 * / 0 9 B 8

and condensing it with 7-aminodeacetylcephalosporanic acid the formula

obtained at a temperature of 5 ° to 25 ° C.

The reaction of the condensation of 4-phenyl-2 _t 5-thiazolidinedioa with 7-aminodesacetylcephalosporanic acid is carried out in aqueous solutions or aqueous suspensions depending on the pH of the media. 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 inert solvents, preferably in dioxane. All starting materials are generally known and commercially available chemicals.

The compound of the formula I has a broad spectrum of activity having, semisynthetic cephalosporin antibiotic, which similar to the other broad spectrum antibiotics used. It is specifically used in chemotherapy by by ampicillin-resistant microorganisms E. coli and Pr. mirabilis applied to infections. · The compound is known and described in the specialist literature (J.S. Welles, R.O. Froman, W.R. Gibson, 3Sf.V. Owen and CR. Anderson, Antimicrob. Ag. Chemother., 489, 1968).

The 7- (D-2-amino-3-phenylacetamido) -3-methyl-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 on the phenylglycine.

The advantage of the method according to the invention is that that after the condensation of 7-aminodesacetylcephalosporanic acid with 4-phenyl-2,5-thiazolidinedione the pure

709823/0 968

End product without the usual "with" previously known processes inevitable chemical aftertreatments is gained.

There is a further advantage of the method according to the invention in that the intermediate 4-phenyl-2,5-thiazolidinedione through a simpler and more economical chemical synthesis consisting in the direct heterocyclization of D-phenylglycine with thiophosgene, is obtained

The only previously known method for the synthesis of 4-phenyl-2,5-thiazolidinedione ran according to an elaborate three-phase proceed from. This synthesis is described in I. Z. Siemion, W. Steglich and L. Wilschowith, Roczniki Ghemii, 46, 21 (1972).

The process is intended to be explained in more detail by the following examples, but in no way restricted.

example 1

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 to reflux (SO ⁰ G) with stirring and stirred at this temperature for 4 hours. After the reaction has ended, the dioxane is distilled off to an oily consistency at 60 ° G and $ Q mm Hg and then chromatographed on a silica gel column (50 g, particle size 0.05 Ms 0.2 mm) and 150 ml of chloroform. The elution is carried out using 350 nil chloroform / methanol (20: 1). After the solvent has evaporated at 40 ^° C. and 50 mm Hg, 2.85 S (4 * 5 % of theory) white crystalline 4-phenyl-2, 5 ~ thiazolidinedione, mp. to 143 ⁰ C, obtained 140 °.

The structure of the compound was determined by IR and HMR spectroscopy secured.

Analysis for C ₉ H ₇ NO ₂ S: CHN Calc .: 55.94 % 3.65 % 7.25 % Found: 56.23 % 3.92% 7.22 %

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Example 2

2.14 g (0.01 mol) of 7-aminodesacetylcephalosporanic acid are suspended in 100 ml of water and sodium hydroxide solution (1 N) is added to a pH of 5 * 6. The suspension is cooled to 5 ° C., 2.9 g (0.015 Hol) of 4-phenyl-2,5-thiazolidinedione are added while stirring, and the mixture is stirred for 2 hours at 5 ° C. and then for 4 hours at low temperature. Then the reaction mixture is poured over a DICALITE layer
(DICALITE-Europe, Mdlano, Italy) filtered, the filtrate
acidified with HGl (1 U) to pH 5> O and at
4-0 ⁰ C and 50 mm Hg concentrated to a volume of 20 ml. After cooling to room temperature, the 7-aminodesacetylcephalosporanic acid (0.2 g) is deposited, 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. There are 2.5 g (79 % of theory)
pure 7- (D-2-amino-3-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid, mp. 181 ° C to ⁰ 184- recovered.

709823/0968

Claims (3)

PATENT CLAIMS Process for the preparation of 7- (D-2-amino-3-phenylacetamido) -3-methyl-3-cephem-4 ~ -carboxylic acid the formula COOH I, characterized in that one D-phenylglycine of the formula CH-COOH II with thiophosgene of the formula Cl C = S Cl III at a temperature of 80 ° "to 120 G cyoliaiaris ua & das obtained 4-phenyl-2,5-thiazolidinedione of the formula rrr r r Oil V ₁ dd 0 IV with 7-aminodesacetylcephalosporanic acid of the formula COOH condensed at a temperature of 5 ° to 25 ⁰ C. 709823/0968 2. Procedure according to. Claim 1, characterized marked, that the cyclization is carried out in anhydrous, inert solvents, preferably in dioxane. 3. The method according to claim 1, characterized marked, that condensation in an aqueous solution "at a pH is running from 5 to 5 ^ 7 0 SS 2 3 i 0 9 b 8