DE889151C - Process for the preparation of 2,4-diamino-5-phenyl-pyrimidine-Abkoemmlingen - Google Patents

Description

Process for the preparation of 2,4-diamino-5-phenyl-pyrimidine derivatives The invention relates to a process for the preparation of 2,4-diamino-5-phenyl-pyrimidine derivatives which have been found to be valuable for certain therapeutic applications Possess properties. The effectiveness of the new pyrimidine derivatives is similar to that of the already known 5-aryloxy- and 5-benzyl-2,4-diaminopyrimidine derivatives, but they have a considerably greater range of activity for certain areas of application and are therefore more valuable because of this property. It was z. B. in experiments with the malaria pathogen Plasmodium berghei found in mice that the new compounds have an excellent chemotherapeutic effect, which exceeds that of those now commercially available many times over. According to the present invention, the new pyrimidine derivatives correspond to the formula: wherein X represents hydrogen or halogen atoms or a nitro, amino and acylamino group and Y represents a halogen or hydrogen atom.

The compounds according to the invention can by the condensation of a a-Formyl-a-phenyl-acetic acid ester with guanidine can be prepared to the 2-amino-4-oxy-5-phenyl-pyrimidine to surrender. These the latter compound is then chlorinated and aminated, to form the desired 2,4-diamino-5-phenyl-pyrimidine derivative.

If so educated. 2-Amino-4-oxy-5-phenylpyrimidine an unsubstituted Contains phenyl radical; so this compound can be nitrided to the appropriate 2-Amino-4-oxy-5-nitrophenyl-pyrimidine .. The latter compound will give then chlorinated and aminated to give the corresponding 2,4-diamino-5-nitrophenyl-pyrimidine to give, which in turn can be reduced and, if desired, acylated can to the corresponding 2, 4-diamino-5-p-aminophenylpyrimidine or the corresponding 2,4-Diamino-5-p-acylaminophenyl-pyrimidine to give.

Optionally, the nitriding operation can also be performed after the operations of chlorination and amination take place. _ The new derivatives can also do the same through a number of optional methods which in certain cases prove advantageous have been shown to be produced, albeit the synthesis scheme given above is generally preferred.

An optional process for the preparation of the compounds according to the invention consists in converting an α-formyl-α-phenylacetonitrile by treatment with diazomethane. its enol ether and condensation of this enol ether - mt _ guanidine. The following examples serve to illustrate preferred processes in the preparation of the compounds of the invention. - Example i 2, 4-diamino-5 = phenyl-pyrimidine: To sodium wire (11.5 g = 0.5 M01) under dry (anhydrous) ether (2oo cm3) were slowly ethyl phenylacetate (82 g = 0.5 mol) and ethyl formate (37 g = 0.6 mol) was added. The reaction was slow. After standing overnight, a solution of guanidine (from 47.7 g [0.5 Moll of the hydrochloride and 11.5 g of sodium) in ethanol (250 cm3) was added and the solution was refluxed after standing for 5 hours. The reflux condenser was continued for 6 hours and the mixture was then poured into 1 liter of water. The aqueous solution was acidified with acetic acid. A white solid, 2-amino-4-oxy-5-phenylpyrimidine, crystallized out on standing. After recrystallization from ethanol, the crystals melted at 244 to 247 °.

The 2-amino-4-oxy-5-phenyl-pyrimidine (5 g) was refluxed with phosphoioxychloride for 2 hours. The excess phosphorus oxychloride was evaporated and the evaporation residue was poured onto ice (250 g). The whole was made basic with strong ammonium hydroxide and the temperature was kept between 0 ° and 10 ° by the addition of ice. After standing for 1 hour, the crude chlorine compound was filtered off. It was then heated for 16 hours in a sealed bomb tube at 130 to 1q.5 ° with zoo cm3 at 0 ° with ethanol saturated with ammonia. The bomb was then cooled and opened. Excess ammonia and ethanol were evaporated. The residue was treated with concentrated sodium hydroxide solution, and the resulting insoluble 2,4-diamino-5-phenyl-pyrimidine was filtered off and washed out with cold water. When recrystallized from water, it forms colorless needles with a melting point of 163 to 16q. °. Example 2 2, 4-diamino-5-p-chlorophenyl-pyrimidine: 39.6 g of p-chlorophenylacetic acid ethyl ester and 14.8 g formic acid ethyl ester in 50 cm3 were added to a suspension of freshly prepared dry sodium ethylate (from 4.6 g sodium) in 50 cm cm3 of dry ether. The flask was closed with a stopper and left at room temperature for 3 days. At the end of this time guanidine (from 19.2 g of the hydrochloride and 4.6 g of sodium) in zoo cm3 of alcohol was added, the flask was allowed to stand overnight, and its contents were then refluxed for 6 hours. The solution was then poured into 500 cm3 of water and the whole acidified. The solid precipitate was washed out with ether and recrystallized from aqueous ethanol; it consisted of 2-amino-4-oxy-5-p-chlorophenylgyrimidine, had a melting point of 323 ° with decomposition and softened at 287 °.

The 2-amino-4-oxy-5-p-chlorophenylpyrimidine (ig g) obtained in this way was heated in a reflux condenser with 150 cm 'of phosphorus oxychloride until the solution was complete. The excess phosphorus oxychloride was distilled off and the residue was poured onto 500 g of ice (with the aid of a little acetone). The ice was stirred and made alkaline with strong ammonia. After about 1 hour the crude chlorine compound was filtered off; it was heated for 16 hours in a sealed tube at a temperature of 15o to 16o ° with 250 cm3 of a solution of ammonia in ethanol (saturated at 0 ° to 5 °). The product was worked up as in the previous experiment to yield 2,4-diamino-5-p-chlorophenyl-pyrimidine which, after recrystallization from aqueous ethanol, had a melting point of 187 to igo °. Example 3 2, 4 - Diamino --5 - p -bromophenyl - pyrimidine: The 2-amino-4-oxy-5-p-bromophenyl = pyrimidine was, as for the 2-amino-4-oxy-5-phenyl- pyrimidine indicated, prepared from the p-bromophenylacetic acid ethyl ester (40 g), formic acid ethyl ester (12.2 g), sodium (3.8 g) and guanidine (from 16 g of the hydrochloride). The compound was recrystallized from ethanol and melted at 313 °.

The thus obtainable 2-amino-4-oxy-5-p-bromophenylpyrimidine (5 g) was chlorinated in the usual manner and the chlorine compound was treated with ammonia to give the 2,4-diamino-5-p-bromophenylpyrinlidine result that, auswäßrigemÄthanolkristallisierte as needles, melting at 205 to 2o7 °. Example 4 _ 2, 4-Diamino-5- (3 ', 4'-dichlorophenyl) -pyrimidine The 2-amino -4-oxy-5 - (3', 4'-dichlorophenyl) -pyrimidine was, as for the 5-p-chlorophenyl compound: described, prepared from the corresponding 3, 4-dichlorophenyl acetic acid ethyl ester (32 g), sodium ethylate (from 3.2 g sodium), ethyl formate and guanidine. The compound was purified by recrystallization from aqueous ethanol.

The thus obtainable 2-amino-4-oxy-5- (3 ', 4'-dichlorophenyl) -pyrimidine (4 g) was chlorinated and aminated as previously described. From aqueous alcohol the z, 4-diamino-4-oxy-5- (3 ', 4'-dichlorophenyl) -pyrimidine fell in colorless flakes which melted at 2o8 to 21o °. Example 5 2,4-diamino-5-m-chlorophenyl-pyrimidine: The 2-amino-4-oxy-5- (m-chlorophenyl) -pyrimidine was, as for the p-chloro compound described, prepared from m-chlorophenylacetic acid ethyl ester. It crystallized from aqueous alcohol as prisms melting at 255 to 258 °. This connection was, as previously described, chlorinated and aminated to give the 2,4-diamino-5-m-chlorophenyl-pyrimidine to give, which from water in the form of at 198 to 200 ° melting platelets crystallized. Example 6 2,4-Diamino-5-m-bromophenyl-pyrimidine: This compound was made in exactly the same manner as the m-chloro compound described in Example 5 produced and had a melting point of 216-2z8 °. Example 7 2,4-Diamino-5-p-nitrophenyl-pyrimidine: The 2-amino-4-oxy-5-phenylpyrimidine described above in Example i was in the nitrated in the usual way at 5o to 6o ° with a mixture of acetic and nitric acid and then gave the 2-amino-4-oxy-5-p-nitrophenyl-pyrimidine. The like in the above Examples carried out chlorination and amination of this product gave the 2, 4-diamino-5-p-nitrophenylpyrimidine, which is obtained from water in melting at 156 to 158 ° Platelets crystallized out. Example 8 2,4-Diamino-5-p-aminophenyl-pyrimidine: That in the example? mentioned 2, 4-diamino-5-p-nitrophenylpyrimidine was made at room temperature and 2 to 3 atmospheres of hydrogen pressure using a Raney nickel catalyst reduced catalytically and gave 2,4-diamino-5-p-aminophenyl-pyrimidine of melting point 233 °. Example 9 2,4-Diamino-5-acetylaminophenyl-pyrimidine: The one mentioned in Example 7 2-Amino-4-oxy-5-p-nitrophenylpyrimidine was made as in the previous example catalytically reduced to 2-amino-4-oxy-5-p-aminophenyl-pyrimidine. The latter resulted in the acetylation of the 2-amino-4-oxy-5-p-acetylamino-phenyl-pyrimidine, which was chlorinated and aminated in the usual way. The 2,4-diamino-5-p-acetylaminophenyl-pyrimidine obtained crystallized from aqueous ethanol in the form of platelets of melting point 237 °. Example ro 2,4-diamino-5-phenyl-pyrimidine: a-phenyl-a-formylacetonitrile was converted into a-methoxymethylene-a-phenylacetonitrile by treatment with the molecular equivalent amount of diazomethane in ether. r mole of the oily methoxymethylene compound was treated with z mole of guanidine in alcohol. The reaction started immediately. The mixture was left on a steam bath for 2 hours heated, the alcohol was removed, and then a concentrated caustic soda was added added. The crystalline solid component was filtered off; he was with that 2,4-diamino-5-phenylpyrimidine prepared by the method of Examples z and 9 identical.

Claims (1)

Claim: Process for the preparation of 2,4-diamino-5-phenyl-pyrimidine derivatives of the general composition wherein X is hydrogen or halogen atoms or a nitro, amino or acylamino group and Y is a halogen or hydrogen atom, characterized in that, for. an α-formyla-phenylacetic acid ester of the general formula where R denotes a phenyl radical which contains the substituents X and Y of the specified composition in the m- and or or p-position and R1 represents a low molecular weight alkyl radical condensed with guanidine into the 2-amino-4-oxy-5 formed -phenyl-pyrimidine derivatives then exchange the 4-position oxy group for a chlorine atom and this chlorine atom is then replaced by an amino group in the usual manner or that 2. an α-formyl-α-phenylacetonitrile of the general composition by the action of a methylating agent, e.g. B. diazomethane, in the corresponding enol ether of the general composition where in each case R has the meaning given above, is converted and this is condensed with guanidine and that the 2-amino-4-oxy-5-phenyl-pyrimidines which are obtained here and are unsubstituted in the 5-position phenyl group before or after the conversion of the 4-position Oxy group is nitrated into the amino group in a conventional manner, then reduced and acylated, whereupon, if necessary, the substituent in the 4-position of the pyrimidine nucleus is converted into the amino group in the manner indicated.