FI66852C - 2,4-DIAMINOPYRIMIDINE INFOERING TO ANALYZING SOME MELLAN PRODUCTS WITHOUT FRAMSTAELLNING AV 2,4-DIAMINO-5-BENZYLPYRIMIDINE - Google Patents

Description

I- M ANNOUNCEMENT

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(32) (33) (31) yyy <«« r «woMmw tt * H prior ** 12.io.71 10.12.71 England-England (GB) A7A92 / 71 57512/71 (71) The Wellcome Foundation Limited, 183-193 Euston Road, London NW1 2BP, England-Engl and (GB) (72) Alexander Stuart, Bromley, Kent,

Thomas Paterson, Gravesend, Kent, England-England (GB) (7A) Oy Kolster Ab (5A) 2, 2-A-diaminopyrimidine compound used as an intermediate in the preparation of A-diamino-5-benzylpyrimidines - 2, A-diaminopyrimidine formation account the product obtained from the preparation of 2, A-diamino-5-benzylpyrimidines (62) Divided by application 2797/72 (patent 56176) -Avdelad frän ansökan 2797/72 (patent 56176)

The present invention relates to a novel 2,4-diaminopyrimidine compound of the formula NH2 «2N-'CHJ-r7 (III> wherein R is an alkanoyloxy group having 1 to 4 carbon atoms) used as an intermediate in the preparation of 2,4-diamino-5-benzylpyrimidines / which is optionally substituted by a phenyl group, or a benzenesulfonyloxy group optionally substituted by an alkyl group having 1 to 4 carbon atoms, or an alkylsulfonyloxy group in which the alkyl group contains 1 to 4 carbon atoms, and which is optionally substituted by a phenyl group.

The remarkable antimicrobial properties of 2,4-diamino-5-benzylpyrimidines are already well known (see, for example, Falco, E. A. et al., J. Am. Chem. Soc., 1951, 73, 3758). It has recently been found that certain derivatives of this class having dialkyl and alkoxy substituents on the phenyl ring, e.g.

The 3,5-diethyl-4-methoxy-substituted derivative has particularly good anti-malarial and antibacterial properties.

One of the major problems associated with the study of the therapeutic potential of the novel compounds of the 2,4-diamino-5-benzylpyrimidine series has been the great difficulty in obtaining suitably substituted starting materials for classical syntheses, as described, for example, in English Patents Nos. 957,797 and 1,142. 654.

Useful methods for preparing 2,4-diamino-5-benzylpyrimidines are not known.

UK Patent 1,132,082 (corresponding to SE Patent 311,160) relates to a process for the preparation of 2,4-diamino-5-benzylpyrimidines from acetylthymine and a substituted benzene derivative.

This method is multi-step and cannot produce the final products in good yield.

According to the invention, 2,4-diamino-5-benzylpyrimidines can be easily prepared from the starting material in good yield. It should be noted that some of the end products thus prepared are those which cannot be prepared by the methods known from English patents 957,797, 1,132,082 and 1,142,654. In particular, (3,5-dialkyl-4-alkoxybenzyl) -pyrimidines have been very difficult to prepare in the past.

There has long been a need to find a synthetic route that is relatively fast and provides a number of compounds relatively easily, without the need for costly and time-consuming development to apply known methods so that sufficient quantities of these substances can be obtained in good quality and in a relatively short time. for biological testing, field trials and subsequent marketing.

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The cowardly novel 2,4-diamino-5-substituted methylpyririridines of the invention react well even with very high molecular weight substituted phenols, although in some cases the low solubility of such compounds may necessitate the use of special media.

F1 Patent 56,176 relates to a process for the preparation of 2,4-diamino-5-benzylpyrimidine of the formula R 2 R 3 Q 1 - ° r 6 (I) R 1 Q 2 1 2 wherein one of Q and Q is 2,4-diamino- the pyrimidin-5-yl-gra-12 3 -styl group, R, R, R and the other Q group are each a hydrogen or halogen atom, or an alkyl or alkoxy group having 1 to 4, preferably 1 to 3 carbon atom, provided that Q is said pyrimidin-16-ylmethyl group only when Q is not a hydrogen atom and R is either a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, in which process a compound of formula NH2 -ch9-r7 'is obtained ( V) nh2 7 'wherein R represents a hydroxyl group, a halogen atom or an acyloxy or sulfonyloxy group, to react with a substituted phenol of the formula -—- - · Γ "__ 4 66852 R \ / r3 R5- \ 0 / -OH (II )

R1 'V

12 3 where R, R and R have the same meaning as above and at least the other 4 5

one of R 3a R is a hydrogen atom 3a is a hydrogen or halogen atom or an alkyl or alkoxy group having 1 to 4 carbon atoms, as defined for Q, in a polar non-phenolic solvent capable of dissolving both reactants, and when it is desired to prepare such a a compound of formula (I) wherein R 1 is an alkyl group, alkylating the resulting compound with an alkylating agent R 2 wherein Z 1 is

is a reactive atom or group, and R 1 is an alkyl group.

R 12 and / or R and R may be hydrogen atoms, the reaction giving compounds of particular pharmacological interest.

3. 4

It is particularly preferred that R and R are alkyl groups, so that the final products of the reaction are 3,5-dialkyl-4-alkoxy-substituted benzyl derivatives, e.g. 3,5-diethyl-substituted.

In order to obtain the highest yields and the best results, it is preferable to add a concentrated acid catalyst to the reaction medium. The acid catalyst may be a concentrated mineral acid, such as hydrochloric acid, either in water or in a carboxylic acid, such as a fatty acid having 1 to 4 carbon atoms, for example acetic acid, or in a sulfonic acid, for example toluene-4-sulfonic acid. The concentration of the acid catalyst can vary within wide limits, but 0.2 to 4 mol / l, suitably about 0.3 mol / l in aqueous or acetic acid medium or 3-n p-toluenesulfonic acid are completely sufficient for this purpose. The use of said organic solvents is particularly desirable with phenols having heavy substituents, since these media provide higher concentrations for the reaction without precipitating the reactive pyrimidine substance.

The ether activity of the groups ortho to the hydroxy group of the skeletal compounds of formula (II) is an important factor in the above reaction. The larger these groups, the greater the tendency to force the hydroxy group out of the plane of the phenyl ring, resulting in a reduction in its activating effect on the ring. Therefore, as might be expected, the yields of a compound of formula (II) having t-butyl groups in the ortho positions with respect to the hydroxy group are substantially lower than with other less massive substituents due to the high ether activity of these groups.

When a condensation reaction takes place between the pyrimidine and phenol starting materials in a carboxylic or organic sulfonic acid medium, using 2,4-diamino-5-hydroxymethylpyrimidine as starting material, a new intermediate of formula (III) according to the invention is formed. The intermediate of the invention can also be prepared from 2,4-diamino-5-bromomethylpyrimidine by reacting it with a suitable sodium salt, e.g. sodium acetate.

The compounds 2,4-diamino-5- (3,5-dimethyl-4-methoxybenzyl) -pyrimidine, 2,4-diamino-5- (2,3,5,6-tetramethyl-4-methoxybenzyl) pyrimidine , 2,4-diamino-5- (2-methoxy-3,5-demethylbenzyl) pyrimidine and 2,4-diamino-5- (2,3,5,6-tetramethyl-4-ethoxybenzyl) pyrimidine are new and have antibacterial and / or antimalarial activity.

The invention is further illustrated by the following examples.

Example 1 2,4-Diamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine 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 (100 ml) containing concentrated hydrochloric acid (3 ml) was heated on a steam bath. Initially, the precipitated precipitate slowly dissolved. After 5 hours, the reaction mixture was cooled and evaporated to dryness on a rotary evaporator. The residue was treated with acetone (50 ml) and triturated to a fine granule, filtered and recrystallized from water to give the hydrochloride, m.p. 277-279 ° C.

Alternatively, the crude solid or hydrochloride was dissolved in hot water and neutralized with sodium hydrogen carbonate solution to give the free base. Recrystallization from aqueous ethanol gave 2,4-diamino * -5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine as colorless needles, m.p. 204-205 ° C. Yield 66% of theory.

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Example 2 2,4-Diamino-5-hydroxymethylpyrimidine (1.4 g) and 2,6-diethylphenol (1.6 g) in toluene-4-sulfonic acid (10 g) containing concentrated hydrochloric acid (3 ml) were heated on a steam bath. 6 hours. The solution was cooled, diluted with ether and the ether was decanted. The residue was treated with sodium bicarbonate solution and the solid was filtered off. Recrystallization from aqueous ethanol gave 2,4-diamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine as colorless needles, m.p. 200-202 ° C.

Example 3

The procedure of Example 3 was repeated using 2,6-diisopropylphenol as the reactant. 2,4-Diamino-5- (3,5-diisopropyl-4-hydroxybenzyl) pyrimidine was obtained, yield 40% (m.p. 244-246 ° C).

Example 4 To 2,4-diamino-5-bromomethylpyrimidine hydrobromide (3 g) in acetic acid (50 ml) was added anhydrous sodium acetate (3.2 g). The mixture was heated on a steam bath for 15 minutes, filtered and cooled.

The white solid was filtered off and recrystallized from acetic acid. Yield 2.3 g, m.p. 292-295 ° C (decomposes).

Thin layer chromatography (T.L.C.) showed a single spot for the product and had the same Rf value as for the intermediate formed in situ from 2,4-diamino-5-hydroxymethylpyrimidine. This compound was shown to be 2,4-diamino-5- (acetoxymethyl) pyrimidine. Using the experimental conditions described in Example 1, the acetoxymethyl derivative was converted to 2,4-diamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine (m.p. 204-205 ° C).

Example 5 2,4-Diamino-5-hydroxymethylpyrimidine (1.4 g) was dissolved in 4-toluenesulfonic acid (10 g) at 120 ° C and concentrated hydrochloric acid (3 ml) was added. The initially formed precipitate was dissolved with stirring back at 120 ° C. The reaction mixture was stirred for 2 hours and then poured into 50 ml of acetone. Colorless plates of 2,4-diamino-5- (4-toluenesulfonyloxymethyl) pyrimidine were filtered off; mp. 176-178 ° C.

This compound was then reacted with 2,6-diethylphenol as described in Example 1 to give 2,4-diamino-5- (3,5-diethyl-4-hydroxybenzyl) pyrimidine, m.p. 204-205 ° C. Example 6 2,4-Dlamino-5- (4-hydroxy-2,6-dimethylbenzyl) pyrimidine 2,4-Diamino-5- (hydroxymethyl) pyrimidine (2.80 g), 2,6-dimethylphenol (2.45 g) and methanesulfonic acid (30 ml) was heated on a steam bath (100 ° C) with vigorous stirring. The resulting orange-red solution was kept on a steam bath for 6 hours, after which it was cooled. Ether (150 mL) was added and the mixture was triturated until a pink precipitate formed. The precipitate was filtered off, followed by chromatographic purification on a silica gel column, eluting with a mixture of CHCl 3, ethanol and ammonia (0.88) (9: 1: 0.1). The starting strip was separated and crystallized from water to give the title compound (2.62 g). ; 47.2%).

Sp. 203-205 ° C; 1 H NMR (DMSODg) δ 2.05 (s, 6H, CH 3>, 3.45 (s, 2H, CP 2), 6.70 (s, 2H, Ar-H), 7.50 (s, 1H , pyrimidine-H), 5.0-7.0 (b, s, 4H, NH 2); analysis (C 13 H 6 N 4 OH 2 O):

Calculated: C 59.54 H 6.55 N 21.35

Found: C 59.75 H 6.45 N 21.27

Example 7 2,4-Diamino-5-methanesulfonyloxypyrimidine 2,4-Diamino-5- (hydroxymethyl) pyrimidine was dissolved.

excess methanesulfonic acid and a catalytic amount of concentrated hydrochloric acid was added. Heated on a steam bath for 3 hours. The mixture was cooled and triturated in dry ether to give a precipitate (title product with a small amount of starting material). TLC analysis was performed on a silica gel column; a mixture of ethanol, CHCl 3 and ammonia (0.88) as eluent (28: 70: 2); = 0.6; NMR

(D..DMSO) 2.6 (CH_, s) 4.2 (CH_, s, starting material), 4.7 (CH_, s), 8.0 O ό Δ Δ (s, aryl-H).

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The 2,4-diamino-5-hydroxymethylpyrimidine used as a starting material in Examples 1 to 3 and 5 to 7 can be prepared as follows: 2,4-diamino-5-formylpyrimidine 2,4-diamino-5-cyanopyrimidine (1 g) prepared as described by Huber, W. described in the Journal of the American Chemical Society, 1943, 65, 2223, was dissolved in 75% formic acid (15 mL) and a 50:50 Ni-Al alloy (1 g) was added. The suspension was refluxed for 1 hour, filtered hot and then evaporated to dryness on a rotary evaporator. The residue was diluted with water and basified with sodium hydroxide solution. The precipitate was filtered off and purified by recrystallization from water (100 ml) or by dissolving in 50% acetic acid and neutralizing with a base (i.e. sodium hydroxide or ammonium hydroxide solutions). Melting point 273-275 ° C (decomposes), colorless needles from water. Yield 66% of theory.

Elemental analysis, ultraviolet and infrared spectra, nuclear magnetic resonance spectra and mass spectra, and thin layer chromatogram showed the product to be 2,4-diamino-5-formylpyrimidine.

2,4-Diamino-5-hydroxymethylpyrimidine This was prepared from 2,4-diamino-5-formylpyrimidine prepared above by reduction under the conditions described in the Journal of Medicinal Chemistry, 1968, 11, 1238.

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