DD243501A5 - PROCESS FOR PREPARING 11-AZA-10-DEOXO-10-DIHYDROERYTHRAMYCIN A - Google Patents

Abstract

The invention relates to a novel process for the preparation of 11-aza-10-deoxo-10-dihydroerythromycin A by the electrochemical reduction of 7,16-dioxa-2-aza-10-O-cladinosyl-12-O-desoasaminyl-4, 5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicyclo / 11.2.1/ hexadeca-1 (2) -en-8-one in an electrolytic cell with a synthetic diaphragm, in one acid-acidic catholyte in a nitrogen stream, with a mercury cathode and with a lead anode and 1 N sodium acetate as anolyte at a constant current density of 1-2 A / dm2 and subsequent isolation of the product. The product is a semi-synthetic macrolide antibiotic from the erythromycin A series.

Description

in an electrolytic cell with a synthetic diaphragm, in an aqueous-acidic catholyte, in a stream of nitrogen, with addition of a suitable electrolyte, such as tetraalkylammonium salts, preferably tetrabutylammonium iodide, with a mercury cathode and a lead anode, and with an appropriate anolyte, such as 1N sodium acetate, electrolytically reduced at a constant current density such as 1-2 A / dm ² and the resulting product of formula (1) is isolated.

Field of application of the invention

The present invention relates to a novel process for the preparation of 11-aza-IO-deoxo-IO-dihydroerythromycin A, which is a semisynthetic macrolide antibiotic of the erythromycin A series and the formula

(D

GH

having.

Characteristic of the known technical solutions

Erythromycin A is a macrolide antibiotic with a very broad clinical utility (US Pat. No. 2,653,899). Its structure is characterized by a 14-membered macrolactone ring with a keto group in position C-9 and two sugars, L-cladinose and D-desosamine, which are glycosidically bound to the aglicone part of the molecule, erythronolide A. For the purpose of modifying its biological and / or pharmacological properties, numerous derivatives have been obtained by chemical transformation, including the erythromycin A oxime (Antibiotics Annual, 1953-1954, Proc. Symposium Antibiotics / Washington DC /, 500-514, GB-PS 1100504, U.S. Patent 3,417,077 and U.S. Patent 3,925,352). It is known that by Beckmann rearrangement of erythromycin A oxime or its mono- or dihydrochlorides by means of sulfochlorides in the presence of acid acceptors, in a mixture of acetone and water or other inert solvent, and the subsequent isolation of the product by the pH gradient extraction using halogenated hydrocarbons or other non-polar solvent containing 7,16-dioxa-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5, 9,11,13,15-hexamethylbicyclo / 11.2.1 / hexadeca-1 (2) -en-8-one (US-PS 4328334 and EP-AA-32038.7).

It is also known that the 11-aza-IO-deoxo by catalytic hydrogenation of the above imino ether by means of noble metals or their oxides in inert solvents, such as glacial acetic acid, or by reduction with complex metal hydrides, such as NaBH ₄ , in methanol. IO-dihydroerythromycin A, a new semisynthetic antibiotic from the erythromycin A series, with a 15-membered azalactone ring (U.S. Patent 4,328,334). This product is a very important intermediate for the synthesis of N-methyl-11-aza-IO-deoxo-IO-dihydroerythromycin A, an effective antibacterial agent in the treatment of Gram-positive and Gram-negative microorganisms (BE-PS 892357), which also in preliminary in vivo tests had a significant activity (EP-AO 101186 A1).

Object of the invention

The aim of the invention is to provide an improved process for the preparation of 11-aza-IO-deoxo-IO-dihydroerythromycin A.

Explanation of the essence of the invention

, The invention has for its object to produce 1 i-aza-10-deoxo-IO-dihydroerythromycin A by electrochemical means.

According to the invention, the production of 1 i-aza-10-deoxo-IO-dihydroerythromycin A by the electrochemical reduction of 7,16-dioxa-2-aza-10-O-cladinosyl-12-0-desosaminyl-3,5,9 , 11,13,15-hexamethylbicyclo / 11.2.1 / hexadeca-1 (2) -en-8-one of the Fomel

CH

(2)

in particular, the electrochemical reduction of TJo-Dioxa ^ -aza-IO-O-cladinosyl - ^ - O-desosamiriyl- ^ S-dihydroxy-e-ethyl-3,5,9,11,13,15-hexamethylbicyclo / H.2.1 / hexadeca-1 (2) -en-8-one to the 11-aza-IO-deoxo-IO-dihydro-erythromycin A. It has now been found that the electrochemical reduction of 7,16-dioxa-2-aza -10-0-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicyclo / ii.2.1 / hexadeca-1 (2) -en- 8-on easily and in good yield in an electrolytic cell with a mercury cathode and a lead anode, at room or elevated temperature, using a synthetic diaphragm, at a constant current density of 1-2 A / dm ² , in an aqueous acidic catholyte, in a nitrogen atmosphere, with the addition of a suitable electrolyte, such. As of tetraalkylammonium salts, preferably of tetrabutylammonium iodide, and a suitable anolyte, such as. B. 1 N sodium acetate, can perform. The recovered product of formula (1) is purified by evaporation of the solvent and by the usual method of pH gradient extraction (pHs of 5,0,6,5 and 7,5) by means of halogenated hydrocarbons or other suitable solvents, or alternatively the precipitation of the product from the mixture of an organic solvent and water, such. B lower alcohols or ketones and water, and gradual alkalization of Rea.ktionsgemisches with inorganic bases such. B. 10% sodium hydroxide solution, to a pH of 8.5 to 11.0, preferably pH 10.2 isolated. Because of the potential for regulating the required electrochemical potential during the actual reduction process, the electrochemical process will more readily facilitate optimal recovery of 11-aza-IO-deoxo-IO-dihydroerythromycin A in comparison with catalytic or chemical reduction at the same time of sufficient quality for further use in the synthesis of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A.

embodiment

The process is illustrated by the following examples:

example 1

11-aza-IO-deoxo-IO-dihydroerythromycin A (Method A)

In 50 ml of a 0.05 N solution of tetrabutylammonium iodide in 20% (v / v) acetic acid, 0.5 g (0.000684 mol) of 7.1 e-dioxa ^ -aza-IO-O-cladinosyl - ^ - O-desosaminyl ^ S -dihydroxy-e-ethyl-S ^ AH, 13,15-hexamethylbicyclo / H. 2.1 / hexadeca-1 (2) -en-8-one dissolved and in a 100ml cell while flowing nitrogen through the catholyte at a constant current density of 1.5 A / dm ² with a mercury cathode at the bottom of the cell and with a centrally located lead anode (the anolyte is a 1N sodium acetate solution) electrolytically reduced at room temperature.

The catholyte and the anolyte are separated by a synthetic diaphragm. Additional stirring of the catholyte is achieved by means of a magnetic stirrer. The course of the reaction is monitored by thin-layer chromatography (benzene: chloroform: ammonia 40: 55: 5, NH ₃ atmosphere).

After completion of the reaction, the catholyte is evaporated, the precipitate suspended in water, 5 ml chloroform added (to pH 4.6) and the pH of the reaction mixture adjusted to 5.0 with 10% NaOH. The layers are separated and the aqueous layer is extracted twice more with 5 ml of chloroform each time. The extraction of the aqueous solution with chloroform is repeated at a pH of 6.5 (3 × 5 ml) and a pH of 7.5 (3 × 10 ml), the combined organic extracts are dissolved over K ₂ CO ₃ dried and evaporated to dryness. At pH 7.5, 0.41 g (81.55%) of 11-aza-IO-deoxo-IO-dihydroerythromycin A, m.p. 121-125 ° C is obtained. ¹³ C NMR (CDCl ₃ ): 57.3 (t, C-10) and 56.7 (d, C-12).

Example 2 H-aza-IO-deoxo-IO-dihydroerythromycin A (method B)

0.5 g (0,000684Mol) 7,16-dioxa-2-aza-10-0-cladinosyl-12-0-desosaininyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13, 15-hexamethylbicyclo / 11.2.1 / hexadeca-1 (2) -en-8-one are reduced electrolytically according to the procedure described in Example 1.

After completion of the reaction, the catholyte is evaporated, the precipitate suspended in water (12 ml), 5 ml chloroform added (pH 4.5) and the pH of the reaction mixture adjusted to 5.0 with a 10% NaOH solution , The layers are separated and the aqueous layer is extracted twice more with 5 ml of chloroform. To the aqueous solution is added an acetone-water mixture 1: 1 (12 ml) and then the pH is adjusted to 10.2 by gradually analyzing the reaction mixture with 10% NaOH solution. The reaction suspension is stirred for two hours at room temperature, filtered, the filter precipitate with an acetone-water mixture 1: 3 (5ml) and dried in a ventilation dryer (50 ⁰ C), 0.38g (73.5%) of the 11 -aza-IO-deoxo-IO-dihydroerytromycin A with the same physicochemical constants as described in Example 1.

Claims (2)

Invention claim: 1. A process for the preparation of 11-aza-IO-deoxo-IO-dihydro-erythromycin A of the formula CD characterized by reacting 7,16-dioxa-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicyclo /11.2.1/hexadeca-1(2)-en-8-on the formula (2)