FI77656B - PROCEDURE FOR FRAMSTATION OF 2,4-DIAMINO-5- / 3,5-DIMETOXY-4- (2-METHOXYETOXY) -BENYL / -PYRIMIDINE. - Google Patents

Abstract

1. A process for the preparation of 2,4-diamino-5-(3,5-dimethoxy-4-(2-methoxyethoxy)-benzyl)- pyrimidine represented by formula I see diagramm : EP0065705,P4,F1 characterized in that beta-anilino-alpha-(3,5-dimethoxy-4-(2-methoxyethyl)- benzyl)-acrylonitril represented by formula II see diagramm : EP0065705,P4,F2 is brought to reaction with guanidine as a free base in a solution containing ethanol under reflux.

Description

77656

Process for the preparation of 2,4-diamino-5- (3,5-dimethoxy-4- (2-methoxyethoxy) -benzyl) -pyrimidine - Preparation of 2,4-diamino-5- (3,5-dimethoxy-4) - (2-methoxy-ethoxy) -bensyl) -pyrimidin

The invention relates to a new process for the preparation of a substituted pyrimidine, namely 2,4-diamino-5- (3,5-dimethoxy-4- (2-methoxyethoxy) -benzyl) -pyrimidine, which is known as tetroxoprim as well as trimethoprim for a long time. with the known 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -10 pyrimidine as a chemotherapeutic agent, but which is characterized by its water solubility compared to the latter.

To date, four methods for preparing tetroxoprim are known.

One of these starts from 3,5-diraethoxy-4- (2-methoxyethoxy) benzaldehyde, which is converted by reaction with 3-alkoxy-propionitrile in the presence of a basic catalyst to the corresponding β-alkoxy-α- (3,5-dimethoxy- (2-methoxyethoxy) ) -benzyl) -acrylonitrile; the latter is then converted to tetroxoprim by a reaction leading to the pyrimidine ring closure with guanidine.

The second method differs from the above in that it uses 2- (imidazolyl-1) -propionitrile instead of 3-methoxypropionitrile.

According to a third known method, 3,5-dimethoxy-4- (2-methoxyethoxy) -hydrocinnamic acid ethyl ester is reacted with guanidine in the presence of sodium methylate 2-amino-4-hydroxy-5- (3,5-dimethoxy-4 - (2-methoxyethoxy) -benzyl) -pyrimidine, the OH group of which is then replaced by chlorine with phosphorus oxychloride. The 5-chloro derivative is then obtained by aminolysis at 160 ° C to tetroxoprim.

According to a fourth method, starting from 2,4-diamino-5- (3,5-dimethoxy-4-hydroxybenzyl) -pyrimidine, the OH group of this is etherified by reaction with p-toluenesulfonyl-77656 2 acid-2-methoxyethyl ester in the presence of a basic catalyst.

In contrast, a considerable number of methods are known for the preparation of trimethoprim, the structure of which largely corresponds to that of tetroxoprim. Much of this passes through the acrylonitrile intermediate obtained by the reaction of trimethoxybenzaldehyde in the β-position with mono- or di-substituted propionitrile, which can then be formed into a pyrimidine ring by reaction with guanidine. This method, which is already known per se, is the most interesting in terms of the availability of starting materials; however, it has the disadvantage that the reaction between benzaldehyde and propionitrile generally forms mixtures of isomers, in particular mixtures of the benzyl and benzal isomers -0 ~ CH * - <c_or or · 0- "" cNh-I 1 15 and also polymeric by-products , which naturally leads to difficulties in isolating the product and sensitive yield reductions. However, the causes and consequences of the shift in equilibrium between the two isomers have not been fully elucidated in detail; According to the literature, not only the quality of the β-substitution of the starting propionitrile but also the ring substituents of the benzaldehyde, specifically in the para-position, is decisive for the formation of such isomers. The prevailing view is that the resulting difficulties in the preparation of trimethoprim can best be avoided by starting with propionitriles substituted in the β-position by an amino group, especially a morpholino or anilino group.

li 3 77656

It seems all the more surprising that, as far as can be deduced from the published patent literature, the above-mentioned further development of the benzaldehyde / propionitrile process, which has proved to be useful in the synthesis of trimethoprim, cannot be successfully used in the synthesis of tetroxoprim. Of the prior art tetroxoprim preparation methods listed at the beginning, the second method uses the idea of using β-amino-substituted propionitriles; however, the melting point of 153 ° C given for tetroxoprim in that publication (DE-10 application 26 17 967) does not in any way indicate a high degree of purity, and its own attempts to finalize this method have yielded questionable results.

It has now been shown that the advantages of using amino-substituted propionitrile at the 3-position lead to significant advantages in the preparation of tetroxoprim in terms of yield and purity of the final product when starting from an aniline-substituted acrylonitrile intermediate at the 3-position in the pyrimidine ring closure.

The invention thus comprises a process of formula I

CH ^ O

CU, 0 - CH2CH2O ™ 2-1 olo '«ra /

for the preparation of 2,4-diamino-5- (3,5-dimethoxy- (2-methoxyethoxy) -benzyl) -pyrimidine according to . characterized in that the formula II

/ - o "

CEjO - CH2CH2O-e CE2-II

CH

77656 4 β-Anilino-α- (3,5-dimethoxy- (2-methoxyethoxy) -benzyl) -acrylonitrile to react with the free guanidine base in ethanolic solution under reflux.

The β-anilino-α- (3,5-dimethoxy-4- (2-methoxyethoxy) -benzyl) -acrylonitrile used as a starting material, which has not been disclosed so far, can be easily prepared using similar methods described in CH Patent Publication No. 574,399. To prepare β-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. After recrystallization from toluene, it has a melting point of 106 ° C.

A suitable embodiment of the method of the invention is explained in detail below by means of Example 15.

Example

Dissolve 115 g (5 moles) of sodium metal in 1725 ml of absolute ethanol, add 200 g (2 moles) of guanidine hydrochloride (95%), heat at reflux for 20 hours and filter the separated boiling salt after cooling off the liberated guanidine base solution. 368 g (1 mol) of β-anilino-α- (3,5-dimethoxy-4- (2-methoxyethoxy) -benzyl) -acrylonitrile are then added to the solution. After heating under reflux for 3 hours, the volume of the reaction mixture is reduced by distilling off the ethanol to about one-third until crystalline tetroxoprim begins to separate. Cool to 0-5 ° C, filter, wash with a small amount of acetone and dry at 60 ° C to give 314 g (94% of theory) of tetroxoprim, m.p. 158-161 ° C.

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Claims (1)

77656 Claim: Process for the preparation of 2,4-diamino-5- (3,5-dimethoxy-4- (2-methoxyethoxy) benzyl) pyrimidine of the formula CH 2 CH 3 O-CH 2 CH 2 O CB 2 ** 2 CH 2 O 2 ra 2, known from reacting β-anilino-α- (3,5-dimethoxy-4- (2-methoxyethoxy) benzyl) acrylonitrile of the formula cVv / «-« - O CH 2 O - CH 2 CH 2 O CH 2 - CH 2 CH 2 CH with guanidine base in ethanolic solution under reflux. For the preparation of 2,4-diamino-5- (3,5-10 dimethoxy-4- (2-methoxyethoxy) benzyl) pyrimidine in the form of CH 2 O 2 CH 2 O - CH 2 CH 2 O CB 2 * ^ 2 CH 3 O 2, the title compound 3-Anilino-α- (3,5-dimethoxy-4- (2-methoxyethoxy) benzyl) acrylonitrile