CS268286B1 - Dialkyl esters of 2-chloroethoxymethanephosphonic acid and method of their preparation - Google Patents

Abstract

This innovation applies to the area of intermediate products of the production of substances with an antiviral effect. It deals with a technical issue of obtaining a new, economically more beneficial intermediate product for the preparation of antiviral substances and the method of its production. The fundamental issue of this innovation is the new substances, dialkyl esters of 2- chloroethoxy-methanephosphonic acid. Part of the solution is a method of production of the substances in question, the essence of which rests in the fact that the 2-chloroethoxy-methyl-chloride is reacted with trialkyl (methyl-, ethyl-) phosphite, and by the distillation of such a mix the dialkylester of 2-chlorethoxy-methanphosphone acid is obtained which complies with the aforesaid requirements and the method of their preparation.

Description

The present invention provides 2-chloroethoxyraethanephosphonic acid dialkyl esters of formula I and a process for their preparation.

N- (2-Dialkoxyphosphonylmethoxyethyl) heterocyclic base derivatives of the general formula. b-ch ₂ ch ₂ and ₂ p (o) (OR) ₂ , where V is purin-9-yl or pyrimidin-1-yl, are important intermediates in the production of N- (2-phosphonylmethoxyethyl) derivatives of purine and pyrlmidine bases, These compounds have so far been prepared by reacting sodium salts of the affinity heterocyclic base with diethyl 2-bromoethoxymethanephosphonate, obtained in situ by reacting 2-hydroxyethoxymethanephosphonic acid diester with triphenylfoapane and carbon tetrabromide or bromine, respectively. diethyl p-toluenesulfonyloxyethoxymethanephosphonate, prepared by reaction of p-toluenesulfochloride 8 with the same diethyl 2-hydroxyethoxymethanephosphonate. Both of these processes utilize 2-hydroxyethoxymethanephosphonic acid diester, which must be prepared from 1,3-dioxolane sequentially by reaction with acetyl chloride, triethylphosphite and subsequent acid hydrolysis. Moreover, the two synthons cannot be effectively obtained in a pure state by a simple purification operation, such as crystallization or distillation, but they need to be purified by chromatography, e.g. on silica gel. This significantly reduces the scale of synthesis of these key syntons, as well as the scale of possible production of said virostatics.

These disadvantages are eliminated by the present invention dlalkylesterů 2-chlorethoxymethanfosfonové formula and smell ₂ CH ₂ OCH ₂ P (O) (OR) _2, wherein R is methyl or ethylakupina, and a process for their preparation, characterized in that it is 2-chlorethoxymethylchlorid the formula IIZ ♦ of smell ₂ CH ₂ OCH ₂ CIII reacted в trialkyl phosphorous acid of the formula III ^{P (0R} BIII, wherein R is methyl or ethyl, the mixture is heated to 100 ° C and the compound of general formula I is isolated by fractional distillation in vacuo.

The starting material of formula II is readily accessible by reaction of 2-chloroethanol in 1,3,5-trioxane and hydrogen chloride gas in high yield (JW Farren, HR Pife, FE Clark, E. Garland, J. Amer. Chem. 1, 2419 (1925) »is vacuum distillable and stable enough to be prepared in large quantities.

The principle of the present invention for the preparation of the compounds of formula (I) is a marked difference in the reactivity of the two C-Cl bonds in the compound of formula (II) to trialkylphaefites in the Arbuzov reaction. Under reaction conditions, the exothermic reaction with triethyl or trimethylphosphite The reaction liberates the alkyl (methyl-, ethyl) chloride in the gaseous state, which can be collected in a deep-cooled receiver. Upon completion of the initial exothermic phase of the reaction, accompanied by the vigorous development of the alkyl chloride, the reaction is completed by heating to 100-130 ° C (depending on the boiling point of the trialkylphosphite of formula III used) and finally fractionated, most preferably under oil pump vacuum. In principle, other thirty-phosphorous acids which are subjected to the Arbuzov reaction may also be used in the reaction, provided that their reactivity is not reduced too much (in order to avoid a partial side reaction with the 2-chloroethoxy group of the compound of formula II). However, the diethyl ester of formula I (R ^with ethyl) seems optimal for use in the synthesis of said virostatics.

A similar reaction could be carried out with 2-bromoethoxymethyl chloride instead of the compound of formula II, but in this case there is also a risk of a competitive reaction of the trialkyl phosphite with the 2-bromoethyl group. Since the reactivity of the sodium salts of the heterocyclic bases in the diethylformamide with the 2-chloro derivative of the formula I and its 2-bromo analog is practically the same, the compounds of the formula I according to the invention are an optimal solution to the technical problem of producing 2-phosphonylmethoxyethyl derivatives of heterocyclic bases.

In the following, the invention is illustrated by way of non-limiting examples of the preparation of the compounds of formula (I) and their use.

Example 1

A mixture of 376 g (4.66 mol) of 2-chloroethanol and 140 g (4.66 mol) of 1,3,5-trioxane is saturated at -10 ° C with gaseous hydrogen chloride for 10 hours. The aqueous phase is separated and the residue is judged finely divided calcium chloride with stirring and bubbling dry hydrogen. After 2 h, the mixture was filtered and the filtrate rectified in vacuo. 432 g of compound of formula II are obtained, m.p. 50-155 ° C / 2 kPa (74%).

To 129 g (1 mol) of the compound of formula (II), 162.6 g (1.1 mol) of triethylphosphite were added dropwise at 90 ° C with stirring to release methyl chloride vigorously (total 90 min). The mixture was then heated at 125 ° C for 4 hours and rectified in vacuo. There were obtained 209 g (90%} of diethyl 2-chlorethoxymethanfoslonové TV 110 ° C / 5 mm Hg, according to GLC content higher than 98%. For _C? H ₁₆ O ₄ C1P (236.5) calculated 36.45 * C. 6 99% H, 15.37% Cl, 13.43% P Found: 36.75% C, 7.70% H, 15.44% Cl, 13.43% P.

Example 2

X 35.6 g (0.276 mol) of the 2-chloroethoxymethyl chloride of formula II prepared according to example 1 was added dropwise at 90 ° C over a period of 40 mih of stirring and stirring with 33 ml (0.28 mol) of trimethylphosphite. The reaction was carried out as in Example 1. 33.4 g (69%) of 2-chloroethoxymethanphosphonic acid dimethyleater were obtained, b.p. 100 ° C / 5 Pa. H, 5.97; H, 17.50; P, 15.29; Found: C, 30.23; H, 6.91; Cl, 17.48;

Example 3. .

4.8 g (0.2 mol) of sodium hydride are added to a suspension of 27 g (0.2 mol) of adenine vil dimethylformamide and the mixture is stirred at 90 ° C for 1 hour, excluding moisture. 50.7 g (0.22 mol) of 2-chloroethoxymethanephosphonic acid diethyl ester are then added at this temperature and the resulting clear solution is heated at 100 ° C for 7 hours. After cooling, it is filtered through a pad of diatomaceous earth and the filtrate is evaporated at 50 ° C / 2 kPa. The residue was extracted with boiling ethyl acetate (3 x 500 mL) and decanted from the residual oil. The extract is concentrated to a final volume of about 300 µl at 40 ° C / 2 kPa and 500 ml of ether and 200 ml of petroleum ether are gradually added under stirring. The resulting oily product crystallizes by stirring, decanted off, washed with petroleum ether and dried. 39 g (65%) of practically pure 9- (2-phosphonylmethoxyethyl) adenine diethyl ester, mp 137 [deg.] C. are obtained. (Ry 0.55 in chloroform-methanol, 4: 1 over silica gel). The filtrate was evaporated in vacuo, combined and the residue undissolved in ethyl acetate extraction and evaporated at 40 ° C / 2 kPa. The residue in 200 ml of 0.5 mol m ^"1 sodium hydroxide solution heated for 8 hours at 60 ° C, neutralized with a cation exchanger in the H + -cycle (e.g. Dowex-50), the suspension was poured on a 300 ml column of the same ion exchanger, and the column elutes with water. The course ae is monitored by continuous measurement of conductivity and UV-absorption. After removal of the non-absorbing salts, the 9- (2-phosphonylmethoxyethyl) -adenine ethyl ester fraction is eluted successively, which is evaporated at 40 ° C / 2 kPa and crystallized from aqueous ethanol (ether to turbidity). 5.5 g (10%) of 9- (2-phosphonylmethoxyethyl) adenine free ethyl ester, chromium, pure in B: 2-propanol-ammonia-water 7: 1: 2 (R _y »0.48) and on paper electrophoresis (E > 0.47, relative to uridine-3-phosphate, at 20 V / cm in 0.05 mol of 1'-tri-ethylamine hydrogen carbonate).

Claims (1)

SUBJECT OF THE INVENTION A dialkyl ether of 2-chloroethoxynethanephenoic acid of the general formula I cic ₂ ch ₂ and ₂ p (o) (OR) ₂ I, wherein R is methyl or ethyl, 2. Preparation of compounds of formula I according to claim 1, characterized ee TiN, ie ee chlorethoxyoethylchlorid 2-II of smell _{2 CH2 OCH2} or II is reacted and trialkyleaterem foeforité kyaeliny formula III P (OR) _3> wherein R is methyl or ethylakupina, ee mixture heated to 100, and £ 130 ° C and the compound of general formula I ee isolated by fractional distillation in vacuo.