DE864556C - Process for the production of 2,4-diamino-5-benzylpyrimidine-Abkoemmlingen - Google Patents

Description

Process for the preparation of 2,4-diamino-5-benzylpyrimidi.nabkömmlingen The invention relates to a process for the production of 5-benzyl-2, 4-diaminopyrimidirlen, which contain substituents in the p-position of the benzene ring. It is established that these compounds are highly effective against malaria. When trying It has been found that compounds of the character mentioned above are extraordinary effective therapeutic agents against malaria pathogens such as Plasmodium berghei in; mice, Plasmodium gallinaceum in chickens and Plasmodium cyanomologi in monkeys, are.

The compounds found to have this effect can be represented by the following formula: wherein X is a chlorine or bromine atom or a nitro group and R is hydrogen or a methyl radical.

The meanings given above for X and R are essential for the Creation of antimalarial effectiveness. A replacement of R by higher molecular weight Alkyl radicals as methyl results in a marked reduction in the therapeutic effect. as well the effect against malaria is practically zero if X is hydrogen, a methoxy radical, and the like, or when X is chlorine and is in the ortho rather than the para position is located.

According to the present invention, compounds of the same general formula are obtained by the condensation of. Guanidine prepared with a compound of the general formula (II) in which: R has the meaning defined above, R1 is a low molecular weight alkyl radical and Y is the same as X or a group which can be converted into X. The starting material of the formula (II) is also an α-formylhydrocinnamic acid ester (where R = hydrogen) or an α-benzyl acetic acid ester (where R = methyl). The resulting aminooxypyrimidine derivative (III) can then be halogenated and aminated to give the desired diaminopyrimidine derivative. yield, or it may be by the method of Hitchings and Elion, as described in the American patent specification 2,451,793, be treated to the corresponding 2-amino-4-mercaptopyrimidinderivat to form, and this product is then in turn treated with ammonia to give the corresponding diaminopyrimidine derivative. At any stage that appears suitable, the group Y can, if necessary, be converted into the group X; -so z. B. where X is intended to mean the nitro group, Y can initially be hydrogen, and = the 5-benzylpyrimidine derivative obtained as the first condensation product can then be nitrated to the corresponding 5-p-nitrobenzylpyrimidine derivative. The present invention will now be illustrated in greater detail by the following examples.

Example x 2, 4-Diamino-5-p-chlorobenzylpyrimidine A. 2-Amino-4-oxy-5-p-chlorobenzylpyrimidine To I2.6 g (0.548 gram atom) of sodium wire in 150 cm3 of sodium-dried ether was slowly poured in on the reflux condenser Mixture of 116.5 g of ethyl p-ChlorhydrozÜmtsäureester (0.548 M01) and 44.6 ethyl formate (0.6 mol) was added. This reaction mixture was left to stand overnight and then a mixture of 12.6 g (Q, 548 gram atom) sodium in 500 cm 3 of absolute ethanol and 52.3 g (0.548 mol) of guanidine hydrochloride was added. The ether was evaporated and the mixture was refluxed on the steam bath for 4 hours. The mixture was then poured into 2 l of water and neutralized with glacial acetic acid. The precipitate formed in this way was filtered off and washed with 50% ethanol: the product was recrystallized by dissolving in dilute alkali and precipitating with dilute acetic acid; the crystals melt at 278 to 282 °. B. 2,4-Diamino-5-p-chlorobenzylpyrimidine 15 g of 2-amino-4-oxy-5-p -chlorobenzylpyrimide in a (0.0637 mol) were refluxed with 150 cm3 of phosphorus oxychloride for 1 to 2 hours. The excess reagent was removed in vacuo and the residue was decomposed by pouring onto zoo g of ice. The product was made alkaline to a pI # value of 9 with ammonium hydroxide and filtered. The crude 2-amino-4-chloro-5-p-chlorobenzylpyrimidine was dried and placed in a sealed tube with 200 cubic meters of ammonia at 10 ° saturated ethanol. The bomb tube was heated to 150 ° for 16 hours, then opened and the alcohol evaporated on the steam bath. The residue was taken up in dilute acetic acid and precipitated by adding sodium hydroxide at pA 10. The resulting precipitate was filtered off and recrystallized from 95% ethanol to give: white needles with a melting point of 205 to 208 °: Example 2 2, 4-diamino-5-p-chlorobenzyl-6-methylpyrimi: in Man prepared a solution of 23 g of sodium in 300 cm3 of absolute ethanol and added 130 g of ethyl acetoacetate. After cooling to 30 °, 161 g of p-chlorobenzyl chloride were added, the solution was left to stand for one hour and then refluxed on the steam bath for one hour. The sodium chloride formed was removed by filtering off, and then 108 g of the ethyl ap-chlorobenzyl acetic acid ester contained were separated off by distillation in vacuo at 15 to 20 mm of mercury.

The above ester (57 g) was dissolved in 1 liter of absolute alcohol, 22 g of guanidine carbonate was added and the mixture refluxed for 5 hours treated. The reaction mixture was poured into 2 l of water and made with acetic acid neutralized, whereupon the 2-amino-4-oxy-5-p-chlorobenzyl-6-methylpyrimidine is filtered off received. After cleaning by dissolving in aqueous alkali and precipitating with acid a yield of 40 g was obtained.

The 2-amino-4-oxy-5-p-chlorobenzyl-6-methylpyrimidine from the preceding Reaction (15 g) was refluxed for 30 minutes with phosphorus oxychloride (10o cm3). After removing the excess phosphorus oxychloride by distillation the residue was poured onto ice in vacuo and the mixture washed gently with ammonia made alkaline. The 2-amino-4-chloro-5-p-chlorobenzyl-6-methylpyrimidine was through Filter off, placed in a bomb tube and at 155 for 16 hours heated to 16o ° with 100 cm3 of an alcoholic solution, which with ammonia gas had been saturated at 0 to 5 °. The contents of the bomb tube turned to dryness evaporated, and the solid residue was with 25 cm3 of 2 N sodium hydroxide solution drained. The solid residue was obtained by dissolving in dilute aqueous hydrochloric acid and precipitates cleaned with caustic soda. After two such recrystallization stages 8.75 g of colorless needles remain, which melted at 235 to z36 °.

Example 3 2,4-Diamino-5-p-bromobenzyl-6-methylpyrimidine Following the procedure of Example i, 2,4-diamino-5-p-bromobenzyl-6-methylpyrimidine was obtained in the form of needles with a melting point of 239 to 241 ° made.

Example 2, 4-Diamino-5-nitrobenzylpyrimidine a) 2 = Amino-4-oxy-5-benzylpyrimidine was prepared in the manner described above from ethyl hydrocinnamate and was a compound which melted at 235 to 23 °. This compound was in the usual Way chlorinated and aminated to give 2,4-diamino-5-benzylpyrimidine with a melting point of 194 to igg °. analysis Theoretically found C: 66, o 11/0 66.0 i 0 _ ' 0 H: 6, o 0/0 5.720 / o N: 28, 0 0/0 27,8o0 / 0 (Literature: melting point = 145 to 146 °, reports of the German chemical society, 45, p. 3i34). b) 1.7 g @, 4-diamino-5-benzylpyrimidine were dissolved in 2o cm3 of concentrated sulfuric acid, and the solution was cooled to -5 °. 1.4 g of potassium nitrate were then added, the temperature being kept below 10 °. The mixture was then poured onto 50 g of ice and the resulting precipitate was filtered off. This was then placed in hot water and filtered into excess dilute alkali. After a further recrystallization from dilute acid and precipitation with alkali, 1.5 g of a yellow crystalline compound were obtained, which melted at 238 to 23 °.

Example 5 2,4-Diamino-5-p-nitrobenzyl-6-methylpyrimidine The ethyl p-nitrobenzyl acetic acid ester according to Burgess, Journal of the Chemical Society, (1g27), 2017 (_A 27) p-Nitrobenzyl bromide, sodium hydroxide and ethyl acetoacetate in alcohol manufactured. The crude product was obtained in 65% yield with a melting point from qo to 43 ° (literature: 43 to 45 °).

The crude ethyl p-nitrobenzylacetoacetate was as in Example e condensed with guanidine to give 2-amino-4-oxy-5-p-nitrobenzyl-6-methylpyrimidine. The latter resulted in chlorination and. Amination in the usual way 2,4-diamino-5-p-nitrobenzyl-6-methylpyrimidine with a melting point of 2q0 to 2q.2 °.

The same compound was produced by nitration of 5-benzyl-2,4-diamino-6-methylpyrimidine. 1.8 g of the latter in 20 cm3 of concentrated sulfuric acid at -5 ° were added over the course of 1 hour with stirring 1.4 g of potassium nitrate were added in small portions. The mixture was poured over 150 g of ice. After standing, the crystals were obtained by filtration; they were removed by dissolving in 50 cm3 of hot water and then adding sodium hydroxide to a pH of 10 The product melted at 2 ° to 241 °. A mixture of the substances produced by the two processes melted at 241 °.

Claims (1)

Claim: Process for the preparation of 2,4-diamino-5-benzylpyrimidine derivatives of the general composition where N is a chlorine or bromine atom or a nitro group and R is a hydrogen atom or a methyl group, characterized in that a compound of the general composition is obtained where R has the meaning given above, Ri is a low molecular weight alkyl radical and Y has the meaning given above for X or represents an atomic grouping which can be converted into X, including a hydrogen atom, condensed with guaniline, in the a-amino-q.-oxy- 5-benzylpyrimidine derivatives, the 4-position oxy group is replaced by a halogen atom or a mercapto group and the latter is then exchanged for the amino group in the usual manner, whereby in the case of using condensation partners of the general composition (I) in which Y is a hydrogen atom, the nitro group is introduced into the phenyl nucleus of the benzyl radical by conventional nitration during any further processing step of the oxy group-containing condensation product.