CS244907B2 - Preparation method of 2,4-diamino-5-/3,4,5-trimethoxybenzyl/-pyriminine - Google Patents

Abstract

2,4-Diamino-5-/3',4',5'-trimethoxybenzyl/pyrimidine is prepared by reacting alpha-/3,4,5-trimethoxy-benzal/-beta-methoxypropionitrile with a diethylene glycol monalkyl ether of the formula HO-CH2-CH2-O-CH2-CH2-OR (wherein R is an alkyl group having 1 to 4 carbon atoms) at 60 to 90 DEG C in the presence of an alkali metal alkoxide, and reacting the obtained benzyl isomer of the formula <IMAGE> (optionally without separation) with guanidine in the presence of an alkanol having 4 to 8 carbon atoms.

Description

2,4-dian-rno-5- (3 ‘, 4‘, 5‘-trimethoxybenzyl) pyrimidine, known as Trimethoprim, is a valuable pharmaceutical product showing high antibacterial activity.

Several methods for the preparation of a compound of formula I are known, some of which are carried out via α- (3,4,5-trimethoxybenzyl) - [3- (substituted) acrylonitrile.

According to British Patent No. 957,797, 3,4,5-trimethoxybenzaldehyde is condensed with n-alkoxypropionitrile to form a condensation product. The yield of this reaction is above% and the reaction product consists of about 80 why. .alpha .- (3,4,5-trimethoxybenzyl) -1H-alkoxyacrylonitrile and about 20% .alpha. In the next step, the condensation product is cyclized with guanidine. However, only the benzyl compound is involved in the cyclization reaction with guanidine, with virtually no isomerization of the benzal compound to the benzyl compound. As a result, a yield of Trimethoprim of more than 28% and an overall yield based on

3.4.5-trirxethoxybenreldehyde is preferably at 20 to 24%.

According to British Patent No. 1,261,455, the condensation product of 3,4,5-trimethoxybenzaldehyde and N-alkoxypropionitrile is reacted with an amine to produce at (3,4,5-trimethoxybenzal) -N-aminopropionitrile, which can be isomerized to the corresponding benzylisomer in 40 to 50% yield. The latter isomer can be cyclized with guanidine to give Trimethoprim in 80% yield. However, the total yield of Trimethoprim, based on 3,4,5-trimethoxybenzaldehyde, is less than 40%.

According to British Patent No. 1,554,493, U.S. Pat

3.4.5-Trimethoxybenzyldehyde reacts with (R) - (2-alkoxy-hexyl) -piperopropene to give α- (3 ', 4 ^' , 5'-trimethoxebenzal) - β- (2-alkoxyethoxy) propionitrile in yields above 80%. After thorough separation and purification, the latter compound is isomerized to the corresponding benzylisomer in the presence of a base at 90 to 95 ^o C. The produced benzylisomer is reacted with guanidine to produce trimethoprim in a yield of about 80%. Thus, the overall yield is 64 to 72% on a laboratory scale.

Although this procedure is in fact more economical than previous procedures, it is difficult to implement it industrially. The condensation reaction of 3,4,5-trimethoxybenzaldehyde and J (2-alkoxyethoxy) propionitrile produces water, which is distilled off at a high temperature of about 120 ° C. At this high temperature, α- (3,4,5-trimethoxybenzal) - N - [2-alkoxyethoxy) propionitrile is hydrolyzed by the presence of water. In our experience, there is a competitive reaction which is the hydrolysis of the nitrile group to give the corresponding carboxylic acid.

This by-reaction causes the formation of tar-like by-products, the amount of which is greatly increased with increasing batch size. The overall yield on a laboratory scale of 64-72% decreases to about 50-55% already at a batch size of about 10 moles.

As a result, the process of British Patent No. 1,554,493 is not economically efficient enough to be carried out on an industrial scale.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an economical industrial process for the preparation of 2,4-diamino-5- {3 ‘, 4‘, 5 ‘-imimethoxybenzylpyrimidine.

It was found that when a - ^^ S-trimethoxybenzal) (4-methhxypropionitril the formula III ^CH 3 ° CH ^о сн г осн з (III) is reacted with diethylene glycol monoalkyl ethers of the formula IV

HO — CH2CH2 —O — CH2CH2 — OR (IV) wherein

R is C 1 -C 4 alkyl, the benzalisomer of Formula IIIa

where

R is as defined above, which is formed in theoretical yield, almost in theoretical yield isomerized to the corresponding benzylisomer of formula II

CN

CCiC

CCCOCH0

СП ^ Сд ^O ' ^CC 2. ^CH £ ^OR (I /) where

R is as defined above, already at a temperature as low as 60 to 90 ° C. The benzyl isomer thus obtained is of such purity that it can be used for subsequent cyclization with guanidine to Trimethoprim optionally without separation and purification.

The subject of the invention is a method of preparation

Claims (1)

2,4-diamino-5- (3 ', 4', 5 ^{<-trimethhxybenzyl)} pyrimidine of formula I by reaction of a- (3,4,5-trimethoxybenzyl) -β- (substituted) acrylonitrile with guanidine, characterized in that the α- (3,4,5-trimethoxybenzal (-3-methoxypropiononitrile III) is reacted with diethylene glycol monoalkyl ether (IV) at 60-90 ° C in the presence of an alkali metal alkoxide and the benzylisomer (II) obtained is reacted, optionally without separation, with guanidine in the presence of a C 4 -C 8 alkanol. Diethylene glycol monomethyl ether is preferably used as the compound of formula (IV). Usually this compound is used in excess, in which case the presence of another solvent is not necessary. The alkali metal alkoxide used is preferably sodium methoxide, sodium ethoxide, potassium methoxide and the like. Both the benzyl isomer of formula II and the benzalisomer of formula IIa are novel compounds. The benzalisomer does not need to be separated and is quantitatively converted to the benzylisomer in the process of the invention, usually within 1 to 2 hours. The resulting benzylisomer can be isolated but, if desired, cyclized with guanidine without separation. The benzylisomer of formula (II) is reacted with guanidine in the presence of a C 4 -C 8 alcohol. Tertiary butanol or isobutanol is preferably used for this purpose. The reaction between the benzyl isomer and the guanidine can be carried out in the presence of another organic solvent (for example another alcohol such as methanol) in addition to the alcohol containing 4 to 8 carbon atoms. When, according to a preferred embodiment of the invention, the compound of formula II is reacted with guanidine without isolation, formula IV is always present in the cyclization step, provided that it has been used in the preparation of the benzyl derivative in excess. Guanidine is preferably added to the benzyl derivative in the form of an acid addition salt, for example the hydrochloride, and is released from its acid addition salt directly in the reaction mixture using a base such as an alkali metal hydroxide. The cyclization of the benzyl isomer is preferably carried out at a temperature of 70 to 100 ° C, preferably at the boiling point of the reaction mixture. The? - (3,4,5-trimethoxybenzal) -? - methoxypropionitrile of formula III, used as starting material, is prepared from 3,4,5-trimethoxybenzaldehyde by reaction with β-methoxypropionitrile. β-methoxypropionitrile is obtained by reacting acrylonitrile with methanol in an alkaline medium. The process according to the invention allows the economical production of Trimethoprim. The overall yield, based on 3,4'-dimethoxybenzaldehyde, is about 80% and does not deteriorate as the dose is increased. According to the process of the invention, Trimethoprim can be prepared from a compound of formula III by a one-step process. The purity of the product obtained meets therapeutic requirements.