FR2467853A1 - PROCESS FOR THE PRODUCTION OF ESTER OF 1,3-DIHYDRO-3-OXO-1-ISOBENZOFURANNYLE ACID (2S) -6 - ((AMINO-PHENYLACETYL) -AMINO) -3,3-DIMETHYL-7-OXO-4 -THIA-1-AZABICYCLO (3.2.0.) HEPTANE-2-CARBOXYLIQUE - Google Patents

Abstract

1,3-Dihydro-3-oxo-1-isobenzofuranyl (2S)-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyc lo[3.2.0]heptane-2-carboxylate of the formula I and its pharmaceutically acceptable salts are obtained by condensing 1,3-dihydro-3-oxo-1-isobenzofuranyl 6-aminopenicillanate with 4-phenylthiazolidine-2,5-dione and converting the resulting product, if desired, into one of its pharmaceutically acceptable salts.

Description

et de ses sels acceptables du point de vue pharmaceutique.The present invention relates to a novel process for the production of the ester of I, 3-dihydro-3-oxo-1-iso-benzofuranyl acid (2S) -6- ((aminophenylacetyl) -amino I-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo (3.2.0) heptane-2-carboxylic of formula I

and its pharmaceutically acceptable salts.

avec la 4-phénylthiazolidine-2,5-dione de formule III

The compound of formula I is prepared according to the invention by condensation of the 1,3-dihydro-3 oxo-1-isobenzofuranyl ester of 6-aminopenicillanic acid of formula II

with 4-phenylthiazolidine-2,5-dione of formula III

 The condensation is carried out in water-miscible solvents, preferably in a mixture of acetone and water in a volumetric ratio of 7: 2 to 7: 3, at a fold of value between 6.2 and 8 , 0, with cooling, preferably at a temperature of -5 to 100C. The product obtained is purified and isolated in the form of acceptable point salts. pharmaceutical view, by methods already known.

 The compound of general formula I is a known semi-synthetic antibiotic with a broad spectrum of antibacterial activity (talampicillin), which hydrolyzes into ampicillin in the body. It is taken by mouth, so it is absorbed twice as fast and reaches a concentration in the blood twice as large as an equivalent dose of ampicillin. This compound is described in J. Med. Chem. 19, 1385 (1976) and J. Antibiot. 27, 665 (1974).

In accordance with the methods already known, talampicillin is obtained by condensation of the reactive form of protected D-phenylglycine on the nitrogen atom and of the 1,3-dihydro-3-oxo-1-isobenzofurannyl ester 6-aminopenicillanic acid. These processes are time-consuming because, in the last phase of synthesis, the nitrogen protecting groups must be chemically removed before the final isolation of talampicillin. The advantage of the process of the invention lies in particular in the chemical and technological simplicity, because in the process for the synthesis of talampicillin in accordance with the present invention, 4-phenylthiazolidine-2,5-dione is used, the groups of which carboxy and functional amino are simultaneously protected and activated accordingly for the condensation reaction with the phthalidyl ester of 6-aminopenicillanic acid. When the condensation is complete, the final product, namely talampicillin, is obtained without the subsequent chemical treatments which were inevitable in the case of the processes already known.

 The process of the invention is illustrated in detail by the examples of implementation below, given without any limitation being implied.

EXAMPLE 1
0.385 g (0.001 mole) of 1,3-dihydro-3-oxo-1isobenzofuranyl ester of 6-aminopenicillanic acid is dissolved at a temperature of 2 to 30 ° C. at a temperature of 2 to 30 ° C. in a mixture of 5 ml of acetone and 2 ml of water. The solution thus obtained is added, with stirring, to a solution of 0.193 g (0.001 mole) of 4-phenylthiazolidine-2,5-dione in 2.5 ml of hydrated acetone (water content of 5%). The reaction mixture is again stirred at the same temperature for 40 minutes at a pH value of 7.2 to 7.6, the pH value is adjusted to 6.2 using 4N hydrochloric acid and stirring is continued for another 1 hour at the same temperature. When the reaction is complete, 10 ml of water are added and the mixture is acidified to a pH value of 2 by adding 4N hydrochloric acid. The aqueous solution is washed several times with ethyl acetate and added with 4 g of NaCl so as to precipitate the oil which is extracted twice with 10 ml of methylene chloride. The combined organic phases are washed with a 15% aqueous NaCl solution, dried over sodium sulfate and filtered. 8 ml of isopropanol are added, which is removed by vacuum distillation. When most of the methylene chloride has been removed, the product begins to precipitate. The precipitated product is kept for about 16 hours in the refrigerator, then filtered. After drying under vacuum (20.0 kPa), 2.33 g of the ampicillin 1,3-dihydro-3-oxo-1-benzofuranyl ester hydrochloride are obtained (45% yield).

Melting point (decomposition) = 154 to 1580 20 = +1570 (1 volume / volume, MeOH) tai
Content determined by iodometry, 96.5%
Content determined by argentometry 97%
Content determined by a microbiological method 98%
The infrared spectrum and the NMR spectrum correspond to the reference talampicillin hydrochloride.

EXAMPLE 2
0.385 g (0.001 mole) of 1,3-dihydro-3-oxo-1-isobenzofuranyl 6 aminopenicillanic acid ester hydrochloride is dissolved in 7 ml of a mixture of acetone and water 5: 2 to a temperature of OOC. The solution thus prepared is added dropwise to a solution prepared in advance of 4-phenylthiazolidine-2,5-dione in 2 ml of acetone. The solution is stirred for an hour and a half at the same temperature and at a pH of 7 to 8. It is added with 10 ml of water and the acetone is distilled off. 20 ml of ethyl acetate are then added and, with stirring, the pH is adjusted to 2 using 2N hydrochloric acid. The aqueous phase is washed twice more with 20 ml of ethyl acetate. 4 g of NaCl are added to precipitate an oil which is extracted twice with 10 ml of methylene chloride. The combined organic phases are washed with a 15% aqueous NaCl solution and dried over magnesium sulfate. The dehydrating agent is removed by filtration and 20 ml of ether are added to the filtrate. The precipitate obtained is filtered and dried under vacuum (20.0 kPa). 2.08 g of product are obtained (yield 40%).

Melting point (decomposition) = 153 to 1570C (ars120 = +1580 (1 volume / volume, MeOH)
Content determined by iodometry, 95.5%
Content determined by argentometry, 98%
Content determined by a microbiological method 95%
The infrared spectrum and the NMR spectrum correspond to the reference talampicillin hydrochloride.

Claims (4)

 1. Process for the production of 1,3-dihydro3-oxo-1-isobenzofuranyl ester of (2S) -6 - ((aminophenyl-acetyl) -amino) -3,3-dimethyl-7-oxo-4 ester -thia-1-azabicyclot3.2.O) - heptane-2-carboxylic acid of formula I

 and its pharmaceutically acceptable salts, characterized in that the 1,3-dihydro-3-oxo-1-isobenzofuranyl ester of 6-aminopenicillanic acid of formula II is condensed

 with 4-phenylthiazolidine-2,5-dione of formula III

 and in that the product obtained is optionally transformed into its pharmaceutically acceptable salts. 2. Method according to claim 1, characterized in that the condensation reaction is carried out at a pH value of 6.2 to 8.0.  3. Method according to claim 1, characterized in that an organic solvent miscible with water is used as reaction medium such as an acetone / water mixture, preferably in a ratio of 7: 2 to 7: 3.  4. Method according to claim 1, characterized in that the -reaction is carried out at a lowered temperature, for example from -5 to 700C.