CS253848B1 - Process for preparing hexahydrate trinatrium salt of phosphonofumaric acid - Google Patents

Abstract

Process for producing trisodium salt hexahydrate phosphonomenic acid, based on with 1 mole of phosphoric acid triethyl ester added dropwise to a solution of 6 mol of hydroxide sodium in 1 liter of water at 38 to 45 ° C and the reaction mixture was then boiled for 2 hours with a reflux condenser. After aspiration weaned solution at + 5 ° C and crystallization from water, the final product is obtained in high purity and yield, directly applicable to pharmaceuticals purposes.

Description

(54) A process for the preparation of phosphonium phosphate disodium hexahydrate

A process for the preparation of phosphonium phosphate disodium hexahydrate by adding dropwise 1 mol of triethyl phosphonate to a solution of 6 mol of sodium hydroxide in 1 liter of water at 38-45 ° C and then refluxing the reaction mixture for 2 h. After sucking off the solution at + 5 ° C and crystallizing from water, the final product is obtained in high purity and yield, directly usable for pharmaceutical purposes.

BACKGROUND OF THE INVENTION The present invention relates to a process for the production of phosphonate acid hexahydrate which is an antiviral drug (foscarnet), in particular against herpes virus and cytomegalovirus.

Phosphoric acid tri-sodium with a mobile crystalline water content was prepared for the first time by P. Nylén (Ber. 57, 1023-1038 (1924)) as part of a study of saponification of phosphonomic acid triethyl ester. In this analytical work, in which the author preferred to observe the stability of the free phosphonomic acid in an acidic and alkaline medium, the formation of the phosphonic sodium formate and its isolation are only mentioned marginally, without a detailed preparation procedure and without yields.

S. Warren and M.R. Williams (J. Chem. Soc. Β., 618-621 (1971)) criticized the work of P. Nylén, in particular, the unsuitability of the analytical methods used by the iodometriotic method, and these authors also report a process for preparing phosphonic acid trisodium salt hexahydrate by saponifying its triethyl ester. The saponification was carried out with a 15-minute spontaneous exothermic heating of a mixture of 0.5 moles of phosphorous formate triethyl ester with a solution of 2.5 moles of sodium hydroxide in 250 ml of water. After isolation and crystallization from water, phosphonium tartrate disodium hexahydrate was obtained only in a yield of 19% of theory.

Further preparation procedure according to E.I. du Pont de Nemours (German DOS 2,435,407) saponifies 21 parts (i.e., 0.1 mol) of triethyl phosphonate by boiling for two hours with a solution of 12 g (0.3 mol) of sodium hydroxide in 60 ml of water. After cooling and aspiration, these authors obtained only 4.7 parts of phosphonate disodium hexahydrate, i.e. 15.6% yield according to theory.

Said preparation processes are not economically advantageous and also do not guarantee obtaining a phosphonium phosphate disodium hexahydrate in a purity useful for pharmaceutical purposes.

The phosphate formate hexahydrate of the desired quality in high yield is obtained by the process according to the invention, characterized in that the saponification of the triethyl phosphate ester is carried out by dropwise adding to the solution of 6 moles of sodium hydroxide in 1 liter over 10 minutes. water at 38-45 ° C. The reaction mixture is then heated gradually to the boiling point over 50 minutes and refluxed for 2 hours. After standing at + 5 ° C, the cold reaction mixture is filtered off with suction and the crude trisodium salt is obtained which, after recrystallization from water, gives pure phosphonous acid trisodium salt hexahydrate.

In the process for preparing the phosphonium phosphate disodium hexahydrate according to the invention, the yield of the desired compound is significantly increased (from 19% and 15.6% to 72%, respectively), and thus much better utilization of the starting materials.

The process according to the invention is also optimal for the production of pure final phosphonate salt of hexashydrate in a quality for direct use for pharmaceutical purposes. The reproduction of the literature procedures (see above) confirmed not only lower yields but also poor quality of the trisodium salt hexahydrate formed, which had to be purified by repeated crystallization, leading to further yield losses. The lower yield and quality of the final product of these known processes are believed to be due to the intrinsic decomposition of phosphoric acid under less suitable saponification conditions, including relative weight ratios of the reaction components used in these processes.

The process according to the invention yields a pure product suitable for direct use for pharmaceutical purposes and in high yield.

Further details are given in the following exemplary embodiment. This example is merely illustrative, not limiting.

Example

To a solution of 240 g (6 mol) of sodium hydroxide in 1 liter of water at 38 [deg.] C., stirring and cooling, 210 g (1 mol) of triethyl phosphonate were sprayed over 10 minutes so that the temperature of the reaction mixture did not exceed 45 [deg.]. The mixture was stirred at this temperature for 20 minutes and then gradually heated to boiling over 30 minutes. The reaction mixture, from which crystallization of the trisodium salt hexahydrate began to crystallize at 52 DEG C., was further refluxed for 2 hours. After cooling to 5 [deg.] C. for 12 h, 254 g (86%) of the crude product are obtained by suction, which, after crystallization from water, yields 217 g (72%) of pure phosphonium phosphate disodium hexahydrate. The uniformity and purity of the final compound were confirmed by acidimetric determination, IR spectrometry and thin layer chromatography (Rf 0.35 in methanol-water-ammonia (6: 3: 1)).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of phosphonium phosphate trisodium salt by reaction of triethyl phosphonate with sodium hydroxide, characterized in that 1 mole of triethyl phosphorate is added dropwise to a solution of 6 moles of sodium hydroxide in 1 liter of water at 38 ° C to 45 ° C with stirring. The mixture was boiled under reflux for 2 hours and, after standing at 5 [deg.] C., the aspirated product was recrystallized from water.