CS212733B2 - Process of preparing 2,4-diamino-5-benzylpyrimidine derivatives - Google Patents

Description

The invention relates to a process for the preparation of 2,4-diamino-5-benzylpyrimidines.

The excellent antimicrobial properties of 2,4-diamino-5-henzylpyrimidines are well known in the art (see, for example, Falco, E, A, et al., J. Am. Chem. Sec. 1951, 73, 3758). It has recently been discovered that some derivatives of this group having dialkyl and alkoxy substituents in the phenyl ring, for example a 3,5-diethyl-4-methoxysubstituted derivative, have particularly good anti-malarial and anti-bacterial properties. One of the major problems associated with investigating the therapeutic potential of the novel compounds in the 2,4-diamino-5-benzylpyrimidone series was the great difficulty in obtaining a suitably substituted starting material by classical synthesis as described, for example, in British Patent Nos. 957,797 and 1,142,654.

It was necessary to design a synthetic method that is relatively fast and which could provide a variety of compounds without the necessary expensive and time-consuming development work to adapt known methods so that adequate quantities could be available in good quality and relatively short time for bioassays , field trials and later for the market.

It has now been found that some 2,4-diamino-5-substituted methylpyrimidines can overcome even with very highly substituted phenols, although in some cases the low solubility of such compounds may make it necessary to use specific media.

Moreover, one of the starting pyrimidine derivatives, namely 2,4-diamino-5-hydroxymethylpyrimidine, which has not yet been readily available, may advantageously be prepared by an improved method which increases the industrial applicability of the entire synthetic process.

Accordingly, the present invention provides a process for the preparation of 2,4-diamino-5-benzylpyrimidine derivatives of the formula I

R ^Z _R 2>

Q ¹ -? - OR ⁶ P 5 (I) wherein one of the substituents Q ¹ and Q ² is

2,4-diaminopyrimidin-5-ylmethyl, R ¹ , R ² , R ³ and the other Q ¹ or Q ² are hydrogen, alkyl or alkoxy of 1 to 4, preferably 1 to 3 carbon atoms, with the proviso that Q ² is a pyrimidinyl group only when Q ^x has a meaning other than hydrogen, R ® denotes a hydrogen atom or a C 1 -C 4 alkyl group, characterized by reacting a compound of the formula IN

Ml of ^N OT ^CH 7 ', in which

R ⁷ 'represents a hydroxy group or a halogen atom such as a bromine or chlorine atom or · represents an anionic radical of a carboxylic or sulphonic acid with a substituted phenol of the general formula II

R R '

where

R 1, R 2 and R 3 are the same as above, and one of R ⁴ and R ⁵ is hydrogen and the other is hydrogen, C 1 -C 4 alkyl or alkoxy, and when R 1 is C 1 alkyl After reaction in a non-phenolic polar solvent capable of dissolving both reactants, the resulting product is alkylated with an alkylating agent R ⁶ Z, where Z is a halogen atom and R ⁶ is an alkyl of 1 to 4 carbon atoms.

Particularly preferred is the case where R ³ and R ⁴ are alkyl groups such that the final product of the reaction are 3,5-dialkyl-4-alkoxy substituted benzyl derivatives, for example 3,5-diethylsubstituted. In order to achieve the highest yields, it is preferred to introduce a strong acid catalyst into the reaction medium. The acid catalyst may be a strong mineral acid such as hydrochloric acid, either in water as a solvent or in a carboxylic acid such as saturated carboxylic acids of 1 to 4 carbon atoms, for example acetic or sulfonic acid, for example p-toluenesulfonic acid as an alternative polar solvent .

The amount of acid catalyst can be varied within a wide range, from 0.2 to 4 N, typically 0.3 N in aqueous medium or acetic acid, or 3 N p-toluenesulfonic acid is sufficient for this purpose. The use of these organic solvents is particularly desirable for phenols carrying larger substituents since these media allow for higher concentrations without precipitation of the pyrimidine component.

For example, reaction of 2,6-diethylphenol with 5-hydroxymethylpyrimidine results in 2,4-diamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine.

The spherical effect of the groups in the ortho position relative to the hydroxy group of the compounds of formula II is an important factor in the above reaction. The larger these groups are, the more the hydroxy group tends to be displaced from the plane of the phenyl ring, with a consequent decrease in its ring activating effect. Therefore, as expected, the yields of the process of the invention with compounds of formula II having a t-butyl group in orthoposition to the hydroxy group are substantially lower than those of the other less bulky substituents, due to the great steric effect of these groups.

When conducting the condensation reaction between a pyrimidine and a phenol derivative in an kysheliny carboxylic or sulfonic using 2,4-diamino-5-hydroxymethyl starting material produces the novel intermediate of Formula III ^ N ^ OyCK N-R ^{7 1} (III wherein R ⁷ is the anionic moiety of the corresponding carboxylic or sulfonic acid. Compounds of formula III, for example an acetylated intermediate, have been identified and isolated and have been shown to react with phenols of formula II to form compounds of formula I. Compounds of formula III can also be readily prepared from

2,4-diamino-5-bromomethylpyrimidine by reaction with a suitable sodium salt, for example sodium acetate.

If desired, the 2‘- or 4‘-hydroxy group of the compound of formula (I) may be converted to an alkoxy group by reaction with an alkylating agent of formula R 2 Z, wherein R 2 is an alkyl group and Z is a halogen atom.

The reaction of the hydroxyl groups with R 2 Z may be carried out in the presence of a base strong enough to form a phenate anipn, for example a base such as sodium hydroxide or potassium tertiary butoxide.

According to the process of the present invention, a novel compound of formula (IV), falling within formula (I) * and ¹ (V), can be prepared wherein the substituents are the same as in formula (I); wherein Q ¹ is 2,4-diaminopyrimidin-5'-ylmethyl and R ³ is an alkyl or alkoxy group, then at least one of R ¹ and R ² has a meaning different from hydrogen. In addition to Formula IV, other intermediates of Formula I may be obtained by the process of the invention, wherein R ⁸ is hydrogen and the compounds have only 3,5-dialkyl substitution at the 4-hydroxyphenyl group, each of the alkyl groups being selected from methyl, ethyl or propyl, for example

3,5-dimethyl, -diethyl or -diisopropyl-substituted compounds.

The phenols of formula II can be conveniently obtained by well-known general chemical processes such as Friedel-Crafts phenol condensation or diazotization and hydrolysis of the respective aniline derivatives.

^{2,4-diaminO'-5-l} hydroxymethylpyrimidi new starting material had been previously prepared by a two stage process which consisted of the first catalytic hydrolytic hydrogenation of 2,4-diamino-5-cyanopyrimidine to give 2,4-diamino-fOTmylpyrimidin which was reduced with sodium borohydride to form 5-hydroxymethylpyrimidine (see Journal of Medicinal Chemistry, 1968, 11, 1238). However, this method yielded unsatisfactory yields.

It has now been found that hydrolytic hydrogenation of 2,4-diamino-5-cyanopyrimidine to

The 2,4-diamino-5-formylpyrimidine can be successfully performed with Raney nickel or nickel-aluminum alloy catalysts in the presence of acid. In this context, formic acid is the acid most appropriate in view of the very high yields obtained. . An ethanolic hydrochloric acid solution can also be used. It leads to a considerable increase in yield and the product is very suitable for further processing, to obtain

2,4-diamino-5-hydroxymethylpyrimidine by further selective reduction with, for example, borohydride, as described in the literature. .

Co-pending British Patent Application No. 47491/71 also describes the application of a process for the manufacture of a compound of formula I, wherein Q is a 2,4-diamino-pyrimidin-5-ylmethyl group,

R ¹ and R ² are hydrogen and R ³ and Q ² are C 2 -C 4 alkyl groups. It should be noted that the compounds:

2,4-diamino-5- (3,5-dimethyl-4-methoxybenzyl) pyrimidine,

2,4-dlamino-5- (2,3,5,6-tetramethyl-4-methoxybenzyl) pyrimidine,

2,4-diamino-5- (2,3,4-trimethoxybenzyl) pyrimidine,

2,4-Diamino-5- (2-methoxy-3,5-dimethylbenzyl) pyrimidine a

2,4-Diamino-5- (2,3,5,6-tetramethyl-4-ethoxybenzyl) pyrimidine are novel and have antibacterial and / or antimalarial activity.

Compounds of formula V wherein R ⁷ is bromo may be prepared by bromination of the corresponding hydroxy compound of formula V.

The invention will be illustrated by the following examples.

Example 1

2,4-Diamino-5-cyanopyrimidine (1 g) prepared as described by Huber W., Journal of the American Chemical Society 1943, 65, 2223, is dissolved in 75% formic acid (15 mL) and a 50:50 nickel alloy is added. and aluminum. The suspension was heated under reflux for one hour, filtered while hot and then evaporated to dryness on a rotary evaporator. The residue was dissolved in water and basified with sodium hydroxide solution. The precipitate is removed by filtration and purified by recrystallization from water (100 ml) or by dissolution in 50% acetic acid and neutralization with base (i.e., sodium or ammonium hydroxide solutions). Melting point 273 DEG-275 DEG C. colorless needles when crystallized from water Yields 66% of theory The elemental analysis, ultraviolet spectrum, infrared spectrum, nmr spectra and mass spectra, thin-layer and column chemistry showed that the product was 2,4 ' -diamino-5-formylpyrimidine.

2,4-diamino-5-hydroxymethylpyrimidine,

Prepared from 2,4-diamino-5-formyl-pyrimidine by reduction using the conditions described in Journal of Medicinal Chemistry, 1968, 11, 1238. 2,4-Diamino-5- (3,5-diethyl) -4 ^; hydroxybenzyl] pyrimidine.

A mixture of 2,4-diamino-5-hydroxymethylpyrimidine (1.4 g, 0.01 mol) and 2,6-diethylphenol (1.6 g, 0.01 mol) in glacial acetic acid (10 ml) containing concentrated hydrochloric acid (3 ml), heated on a steam bath. The initial precipitate slowly dissolves. After five hours, the mixture was cooled and evaporated to dryness on a rotary evaporator. The residue was treated with acetone (50 mL) and granulated to a granular solid. The solid residue is filtered and recrystallized from water to give the title compound as the hydrochloride, m.p. 277-279 ° C.

Also, the crude product or hydrochloride can be dissolved in hot water and neutralized with sodium bicarbonate solution to the free base. Recrystallization from water / ethanol gave colorless needles

2,4-diamino ^: -5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine, m.p. 204-205 ° C. Yield: 66% of theory.

Example 2

1.4 g of 2,4-diamino-5-hydroxymethyl produced according to Example 1 and 1.6 g of 2,6-diethylfenolu are heated in 10 g of a ¹ Luen-4-sulfonic acid containing 3 ml of hydrochloric acid on a steam bath 6 hours. The solution was cooled, diluted with ether and the ether layer was decanted.

The residue was treated with a sodium hydrogen carbonate solution ^1, and the precipitate formed was collected by filtration. Recrystallization from a mixture of water and ethanol gave colorless needles of 2,4-dlamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine, m.p. 200-202 ° C.

Example 3

The procedure of Example 1 was repeated except that 2,6-diisopropylphenol was used as the reactant. 2,4-Diamino-5- (3,5-diisopropyl-4-hydroxybenzyl) pyrimidine is obtained in a yield of 40%, the melting point of the free compound being 244-246 ° C.

Example 4

The 4-hydroxybenzylpyrimidine derivatives prepared according to the preceding examples can be converted to the corresponding 4-methoxy derivatives as follows. 0.005 mol of the corresponding 5- (4-hydroxybenzylpyrimidine) was dissolved in 10 ml of anhydrous dimethylsulfoxide, a small excess of sodium alkoxide was added, a little more than 0.005 mol of methyl iodide was added and the stoppered reaction vessel was allowed to stand in the dark for 3-4 days.

The solution is then poured into water and the product is collected by filtration or extraction with ethyl acetate followed by evaporation. Recrystallization is carried out from a mixture of water and ethanol.

A satisfactory degree of methylation was found to occur with both hydroxybenzylpyrimidines to give 2,4-diamine-5- (3,5-diethyl-4-methoxy) pyrimidine and 2,4-diamino-5- (3,5-diisopropylamine). of polyl-4-methoxy-pyrimidine Example 5

1.4 g. Of the 2,4-diamino-5-hydroxymethylpyrimidine produced according to Example 1 and 1.1 g of 2,6-dimethylphenol are heated to reflux in 30 ml of water containing 1 ml of concentrated hydrochloric acid together with a small amount of acetone. to facilitate the solubility of the phenol. After 5 hours, the reaction mixture was cooled and the product was filtered. Recrystallization from water sel gives the title product 2,4-diamino-5- (3,5-dimethyl-4-hydroxybenzyl) pyrimidine as the hydrochloride, m.p. 280 DEG C. with slow decomposition. The free solid is obtained in a conventional manner and has a melting point of 242-244 ° C.

Example 6

The procedure of Example 2 was repeated using 2,6-dimethylphenol, 2,3,5,6-tetramethylphenol and 2,6-dimethoxyphenol to give the appropriately substituted 2,4-diamino-5-benzylpyridine derivatives of 2,4 -diamino-5- (3,6-dimethyl-4-hydroxybenzyl) pyrimidine in 50% yield, 2,4-diamino-5- (2,3,5,6-tetramethyl-4-hydroxybenzyl) pyrimidine in 45% yield and a mixture of 2,4-diamino-5- (3,5-dimethoxy-4-hydroxybenzyl) pyrimidine and 2,4-diamidine in a yield of 33%.

Example 7

The procedure of Example 1 was repeated except that 2,6-diethylphenol was used

2,6-dimethylphenol.

2,4-diamino-5- (3,6-dimethyl-4-hydroxybenzyl) pyrimidine is obtained in 58% yield, the melting point of its hydrochloride being 280 ° C with slow decomposition.

Example 8

The procedure of Example 1 was repeated using 2,4-dimethylphenol instead of 2,6-diethylphenol. 2,4-Diamino-5- (2-hydroxy-3,5-dimethylbenzyl) pyrimidine is obtained in a satisfactory yield. The melting point of its hydrochloride is 279-281 ° C with decomposition.

Example 9

The procedure of Example 1 was repeated using 2,3,5,6-tetramethylphenol instead of 2,6-diethylphenol. 2,4-Diamino-5- (2,3,5,6-tetramethyl-4-hydroxybenzyl) pyrimidine was obtained in 60% yield. The hydrochloride melting point is greater than 330 ° C.

Example 10

The procedure of Example 1 was repeated using 2,6-dimethoxyphenol instead of 2,6-diethylphenol. A mixture of 2,4-diamino-5- (3,5-dimethoxy-4-hydroxybenzyl) pyrimidine and 2,4-diamino-5- (2,4-dimethoxy-3-hydroxybenzyl) pyrimidine is obtained in good yield. The melting point of the second component in free form was 248-248 ° C.

Example 11

The procedure of the example is repeated. 1 using 2-methoxyphenol instead of 2,6-diethylphenol. 2,4-diam. No-5- (3-methoxy-4-hydroxybenzyl) pyrimidine is isolated as its hydrochloride, m.p. 263-265 ° C.

Example 12

The methylation described in Example 4 is repeated on the compounds prepared as in Examples 12 and 13 to give the corresponding 2,4-diamino-5-benzylpyrimidines with the following substituents on the benzyl ring:

2.3.4- trimethoxy with a yield of 42 ° / o,

3.4.5-Trlmethoxy in 42% yield.

Example 13

The methylation of Example 4 was repeated on the products of Examples 5, 6, 9, 11 and 12 to give the corresponding 2,4-diamino-5-benzylpyrimidine derivatives with the following substituents on the benzyl ring:

3 ‘, 5‘-dimethyl-4-methoxy in 55% yield,

3,5-dimethyl-2-methoxy in 62% yield.

2,3,5,6-tetramethyl 4-methoxy in 44% yield a

The benzylpyrimidines derivatives of the individual examples have the following melting points.

NH _Z

N- ~ (

N

2 3 4 Me OH Me Me OH About me OH □ My OH About me OH About me About me About me About me About me Me About me Me Me About me About me Me About me Me -Me OET Et OH Et About me i-Pr About me

SUBJECT V

6 m.p.

Me 280 '(decomposition) Me Me 330 About me 265-270- (decomposition) 246—248 30-3—306 22-6—227 228—229 Me 2D6—207 Me Me 311—313 198—202 Me 176—177 Me Me 276—278 Et 204—205 Et 153 i-Pr 205—207

NALEZU

Claims (7)

A process for the preparation of 2,4-diamino-5-benzylpyrimidine derivatives of the general formula I R ^Z R ^five halogen as bromine or chlorine, or represents o-ntový acid residue of a carboxylic or sulfonic with a substituted phenol of the formula II R ¹ (I) wherein one of the substituents Q ¹ and Q ² represent a 2,4-diaminopyrimidin-5-ylmethyl group, R ^1, R ^2, and R ³ and one group Q ¹ or Q ² denote in-sulphide, alkyl or alkoxy of ·-1-4, preferably 1-3 carbon atoms, provided that Q ² represents pyrimidinylov- group only if Q ¹ has a meaning different from hydrogen, R ⁶ is hydrogen or C 1 -C 4 alkyl, characterized in that the compound of formula V is reacted CH _£ R ^f (V) wherein R ⁷ 'represents a hydroxy group or an atom wherein R ¹ , R ² and R ³ are the same as above and one of the substituents R ⁴ and R ⁵ are hydrogen, and the other is hydrogen, C 1 -C 4 alkyl or alkoxy, in a non-phenolic polar solvent capable of dissolving both the reactants and the resulting product of formula I, wherein R ⁶ is hydrogen and other general the symbols having the above meaning is optionally alkylated with an alkylating agent R ⁶ Z, wherein Z represents a halogen atom and R ⁶ represents an alkyl of 1 to 4 carbon atoms. 2. The process of claim 1 wherein the compound of formula (V) wherein R < ⁷ > is a hydroxyl group with a substituted phenol of formula (II) wherein R < ¹ > to R < ⁵ > 1. 3. A process according to any one of claims 1 and 2, wherein the reaction of the compound of formula V with phenol is carried out in the presence of a strong acid catalyst. 4. The process according to claim 3, wherein the strong acid is an inorganic acid such as hydrochloric acid. Process according to any one of the preceding claims, characterized in that the reaction is carried out in a carboxylic acid solvent. 6. The process according to claim 5, wherein the carboxylic acids are lower fatty acids having from 4 to 4 carbon atoms, such as acetic acid. 7. A process according to any one of claims 1 to 4, wherein the reaction is carried out in a sulfonic acid as a solvent, such as paratoluene sulfonic acid.