DE2165362A1 - 5-benzyl-2,4-diaminopyrimidines prepn - by 5-stage process from benzaldehydes and alkyl cyanoacetates - Google Patents

Abstract

Title cpds. of formula (I): (where each R, same or different, is H or alkoxy) which are antibacterials, antiprotozoals and sulphonamide-potentiators, are prepd. by reacting an R-substd. benzaldehyde with a lower alkyl cyanoacetate, catalytically hydrogenating the resulting R-substd. alkyl alpha-cyanocinnamate, condensing the resulting R-substd. alkyl alpha-cyano-hydrocinnamate with guanidine, substituting the OH gp. of the resulting 2,4-diamino-5-benzyl-6-hydroxypyrimidine with a halogen, and subjecting the resulting 2,4-diamino-5-benzyl-6-halopyrimidine to reductive dehalogenation. The inter. R-substd. alkyl alpha-cyano-hydrocinnamate is obtd. in good yields and is readily conferted into (I) which can readily be sepd. off and isolated, so that the process can be easily carried out on an industrial scale.

Description

"Process for the preparation of pyrimidine derivatives' The invention relates to a process for the preparation of pyrimidine derivatives of the general formula (I) wherein R is hydrogen or a methoxy group.

The process of the invention is illustrated in the following equation, wherein R is hydrogen or a methoxy group, R 'is a lower alkyl group and X is a halogen.

The condensation of a compound of the general formula (II) with a cyanoacetic acid ester gives a compound of the general formula (III), which is hydrogenated; to give a compound of the general formula (1V). That Cyanoacetic acid ester derivative (IV) is then condensed with guanidine and e s3i bt the 2,4-Dtamino-5-benzvl-hydro> ypyrimidine derivative of the general formula (V), which is halogenated and gives a compound of general formula (VI). In the last step of the process results in the hydrogenolysis of the compound (VI) Pyrimidine derivative of the general formula (I). The pyrimidine derivatives of the general Formula (I) ctie prepared by the process of the invention have antibacterial properties Activity and are effective in the treatment of bacterial and protozoa diseases caused in humans and animals.

These compounds show in combination with antibacterial sulfonamides a synergistic effect. The pyrimidine derivatives of the general formula (I) are manufactured by various processes and are in the Japanese patent specifications No. 280 554 and No. 424,983, U.S. Patents No. 2 658 897, 2 9o9 522, 3 o49 544 and in British Patent Specification No. 734 801, 875 562, 920 412 and 957 797.

The compounds of the general formula (IV) which are used to build up the Pyri midinringes are necessary can be produced in good yield. That Halogen atom of compound (VI) is easily split off reductively under mild conditions. The end product (I) can easily be separated off and isolated. For these reasons the method according to the invention can easily be carried out on an industrial scale will.

The principles of the method according to the invention are set out in the following Description portrayed.

A. Preparation of Starting Material (IV).

This synthesis was carried out by dividing the aldehyde (II) with C7yanoacetic acid ester condensation was carried out using ammonium acetate and glacial acetic acid as a catalyst. The acrylic acid derivative (III) was thereby obtained. The compound (IV) was made by reducing the product (III) with a palladium-carbon catalyst. The yield was 80-95%.

B. Preparation of 2,4-diamino-5-benzyl-6-hydro> pyrimidine (CV).

This procedure was carried out by using the compound (IV) Guanidine condensed in the presence or absence of sodium alkoxide 2,4-diamino-5-benzyl-6-hydroxypyrimidine was obtained in a 80-85% yield.

C. Preparation of 2,4-diamino-5-benzyl-6-halopyrimidine (VI).

This compound was synthesized by adding the hydroxyl group on Pyrimidine nucleus was halogenated by means of phosphorus oxychloride or phosphorus oxybromide. 2,4-Diamino-5-benzyl-6-halogenopyrimidine was obtained in a yield of 60 - 85%.

D. Preparation of Compound (I).

This compound was made by the elimination of the pyrimidine nucleus seated halogen atom by means of catalytic hydrogenation of the compound (VI) with a palladium catalyst in the presence of a base or by reducing with Zinc powder in water and alcohol.

This gave the 2,4-diamino-5-benzyl-pyrimidine derivative.

(The yield was 70-80% in the catalytic hydrogenation and 4o - 80% for dehalpgenation with zinc powder).

The pyrimidine derivatives prepared by the process of the invention are white crystals and are identical to authentic samples. This was done through -Elemental analysis, IR-Spectra, UV-Spectra and N.M.-R.-Spectra determined.

The process of the invention is illustrated by the following examples explained in detail, with all specified temperatures being given in degrees Celsius are.

Example 1 2,4-diamino-6- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine A. Production of ethyl cb-cyano- '3- (3,4,5-trimethoxyphenyl) propionate.

In a 200 ml round bottom flask attached to a modified Dean and Stark constant Water separator connected to a reflux condenser, were 12 g of ethyl cyanoacetate, 19.5 g of 3,4,5-trimethoxybenzaldehyde, 2 g of ammonium acetate, 7 ml of glacial acetic acid and 50 ml of benzene were added. The flask was placed in an oil bath 120-180 C C and the water was distilled out of the mixture, wherein the refluxing benzene was removed from the separator at intervals. It was refluxed over a period of 7 hours. After the solution has cooled down the benzene was removed by distillation under reduced pressure.

Water was added to the residue with stirring. The raw ethyl α-cyano-β- (3,4,5-trimethoxyphenyl) acrylate was collected on a filter and washed with 200 ml of water. The yield was 25.7 g (92.8%) and passed of white crystals with a melting point of 158 - 154 ° C.

A solution of 10 g of ethyl α-cyano-ß- (3,4,5-trimethoxyphenyl) acrylate in loo ml of ethyl acetate was together with 1.5 g of palladium on carbon% pd) in placed in a 300 ml flask attached to a low pressure reducing device could be. 2 ml of glacial acetic acid was added and the flask was connected to the reducing device tied together. The flask was alternately evacuated and filled with hydrogen twice. The mixture was reduced at 60 ° C by using hydrogen at 1-2 atmospheres Pressure was shaken. In two to three hours the theoretical amount was on Hydrogen was gutted and absorption ceased. The reduction mixture was filtered through a Buchner funnel and the flask was filled with 30 ml of ethyl acetate rinsed out, which were also filtered through the Buchner funnel. That The filtrate was washed twice with 30 ml portions of a 5% sodium bicarbonate solution, three times with 40 ml quantities of a 10% hydrochloric acid solution and three times with 40 ml amounts of water. The ethyl acetate layer was dried over anhydrous sodium sulfate dried. Night em the ethyl acetate had been filtered off and distilled was obtained the crude ethyl α-cyano-ß-3,4,5- (trimethoxyphenyl) propionate in the form of a colorless oil. The yield was 9.4 g (93.4%).

B. Preparation of the 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-hydroxypyrimidine.

9.5 g of Guanldinhydrohlorld, which has been dissolved in 30 ml of methanol was added to 5.4 g of sodium methoxide dissolved in 20 ml of methanol had been. This mixture was filtered off and washed with 30 ml of methanol. That The filtrate and the wash liquor became a solution of 9.0 g of ethyl α-cyano-β- (3,4-5-trimethoxyphenyl) propionate in 30 ml of methanol was added and the solution was refluxed for 20 hours heated. The slurry was quenched in an ice bath and the white product was filtered off and washed with cold methanol. After drying, one obtained 8.4g of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-hydroxypyrimidine with a melting point from 266 - 268 ° C. The yield was 89.1%.

C. Preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-chloropyrimidine.

A mixture of 3g of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-hydroxypyrimidine and 30 ml of phosphorus oxychloride was refluxed for 4 hours. After cooling down the excess phosphorus oxychloride was removed under reduced pressure and the syrupy mixture was poured over 10 g of ice. This product was 15 ml of a concentrated hydrochloric acid was added and for 30 minutes under Stirring heated. After cooling, the solution was made by adding dilute ammonium hydroxide made alkaline. The alkali sieving was checked with litmus paper.

It was cooled, the precipitate filtered off and washed with cold water washed and dried. 2.3 g of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-chloropyrimidine were obtained. The yield was thus 72.0%.

D. Preparation of 2,4-diamino-5- (3'4 ', 5'-trimethoxybenzyl) pyriamidine.

(a) In a 100 ml pressure flask of a device for catalytic 1.2 g of 2,4-diamino-5- (3 ', 4'5-trimethoxybenzyl) -6-chloropyrimidine, 1, above-mentioned powdered anhydrous sodium acetate and 30 ml of ice vinegar are added. Then 1.0 g of pallidium on carbon (10% Pd) were added. The flask was attached to a shaker, flushed with hydrogen and an initial pressure employed from about 1.5-2.0 atmospheres. With the shaking of the flask was at Room temperature started. The theoretical amount of hydrogen was in 4-5 hours absorbed. The solution was separated off by means of filtration upstream of the catalyst. The filtrate was diluted with 50 ml of water and treated with 2B% ammonium hydroxide Made basic using litmus paper. Extraction was then carried out with 150 ml of chloroform. The chloroform was removed under reduced pressure by means of distilled water. The residue was crystallized by dissolving it in 20 ml of 10% acetic acid and then 28% ammonium hydroxide was added (using litmus paper), to make the solution alkaline. The white precipitate was collected by filtration separated, washed well with cold water and dried.

The product obtained was recrystallized from 20 ml of hot 80% alcohol and there was obtained 0.89 2,4-diamino-5- (3'4 ', 5'-trimethoxybenzyl) pyrimidine in the Form of wide crystals and with one Melting point of 198 - 199 ° C. The yield was thus 74.8%.

(b). 1.0 g of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) -6-chloropyrimidine, 1.0g zinc powder and 25ml glacial acetic acid were used, the mixture was under for 24 hours Heated to reflux, cooled and filtered through a sintered glass funnel to remove the zinc powder. The flask and solid were mixed with 10 ml of acetic acid washed. After cooling, the clear filtrate was cooled further in an ice bath and by adding concentrated ammonium hydroxide and using litmus paper made alkaline. The precipitate of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine was collected and dried. This product was made from 15 ml of an 80% alcohol recrystallized and obtained 0.5 9 (55.9%) of pure 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine with a melting point of 198-200 ° C.

Example 2 2,4-diamino-5- (3 ', 4', 5'-dimethoxybenzyl) pyrimidine.

A. Production of ethyl-α-cyano-R- (3, 4-dimethoxyphenyte) - propionate.

16> 5 g 3,4-dimethoxybenzaldehyde, 12 g ethyl cyanoacetate, 2 g ammonium acetate and 7 ml of glacial acetic acid were treated as described in Example 1 -A. One received thereby 25.7 g (98.8%) of crude ethyl-α-cyano-ß- (3,4-dimethoxyphenyl) acrylate, with a melting point of 153-154 ° C.

13 g of the ethyl-α-cyanoacrylate became the ethyl-α-cyanopropionate converted by catalytic hydrogenation as described above. The yield was 11.8 9 (90.2%) of ethyl α-cyano-propionate.

B. Preparation of 2,4-diamino-5- (3 ', 4'-dimethoxy) -6-hydroxypyrimidine.

This connection was made in the same manner as in Example 1-B, in the 2.69 ethyl αcyano-P - (3,4-dimethocyphenyl) propionate condensed with 0.6 g of guanidine in 0.54 g of sodium methoxide in alcohol.

2.2 g (83.3%) of the diaminohydroxy compound having a melting point were obtained from 270 - 272 ° C.

C. Preparation of 2,4-diamino-5- (3 '4' -dimethoxybenzyl) - chloropyrimidine, The above compound 2, above, was converted into phosphorus oxychloride by treatment with 20 ml as in Example 1-C 1.7 g (79.6%) of the diaminochloropyrimidine compound with a Melting point of 226-228 ° C.

D. Preparation of 2,4-diamino-5- (3 ', 4'-dimethoxybenzyl) pyrimidine.

This compound was prepared in the same manner as in Example 1-D (method A) produced. One gram of the diamino-chloro compound was dehalogenated by catalytic reduction by means of pallidium-carbon. 2,4-diamino-5- (3 ', 4' -dimethoxybenzyl) -pyrimidine.

The yield was 0.67 g (76.5%) of a white crystalline product with a melting point of 226 - 228 ° C.

Example 3 2,4-Diamino-5- (2 ', 3'-dimethoxybenzyl) -pyrimidine A. Preparation of methyl α-cyano-β- (2 ', 3'-dimethoxyphenyl) propionate.

18.5 9 2,3-dimethoxybenzaldehyde and 12 g methyl cyanoacetate with 2 g Ammonium acetate and 7 ml of glacial acetic acid were treated as in Example 1-A.

23.4 g (95.3% yield) of a crude methyl A-cyano (2,3-dimethoxyphenyl) acrylate were obtained. 18g of the methyl α-cyano-acrylate were reduced by means of palladium-carbon in methyl α-cyano-ß- (2,3-dimethoxyphenyl) propionate converted. 12.1 g (92.2% yield) of this product were obtained.

B. Preparation of 2,4-diamino-5- (2 ', 3'-dimethoxybenzyl) -6-hydroxypyrimidine.

From 6.4 g of methyl α-cyano-β (C 2, 3-dimethoxyphenyl) propionate and guanidine were 5.5 g (83.3% yield) of the diamino-hydroxy-pyrimidine in the usual procedure.

C. Preparation of 2,4-diamino-5- (2 ', 3'-dimethoxybenzyl) -6-bromopyrimidine.

2.8 g of the above compound were treated with 15 ml Phosphorus oxybromide as in Example 1-C 2.9 g of the diamino-bromopyrimidine (83.7% Yield).

D. Preparation of 2,4-diamino-5- (2 ', 3'-dimethoxybenzyl) pyrimidine.

The preparation of the 2,4-diamino compound from the above compound was carried out in the manner described as in Example 1 - D (method B.), From 2.4 g of the diamino-bromo compound 1.3 g (71.4%) of the desired 2,4 "diamino-5- (2 ' , 3'-dimethoxybenzyl) -o pyrimidins with a melting point of 191-193 ° C.

Claims (1)

Claim: 1. Process for the preparation of an erimidine derivative of the general formula wherein R can be the same or different and represents a hydrogen atom or an alkoxy group, characterized in that an aromatic aldehyde of the general formula: wherein R has the same meaning as defined above, with a cyanoacetate of the general formula: wherein R 'represents a lower alkyl group, is condensed to produce a compound of the general formula wherein R and R> have the same meaning as defined above, the compound III is reduced in the presence of a palladium catalyst to give a compound of the following general formula wherein R and R 'have the same meaning as defined above, the compound IV is condensed with guanidine to produce a compound of the following general formula wherein R has the same meaning as defined above, the compound (V) is subjected to halogen substitution to produce a compound represented by the following general formula wherein R has the same meaning as defined above and X represents a halogen atom, and the compound (VI) is subjected to reductive dehalogenation.