CH316157A - Process for the preparation of pyrimidine derivatives - Google Patents

Description

Process <B>for</B> the preparation of <B>pyrimidine derivatives</B> The subject of the present invention is a process for the preparation of pyrimidine derivatives.

It has been found that the 2-amino-4-hydroxy-5-benzyl-pyrimidines of general formula

in which Ph represents a phenyl ring bearing at least two further substituents, at least one of which is a methoxy or ethoxy group, constitute valuable intermediate products for the preparation of the corresponding 2,4-diamino-5-benzyl-pyrimidines, which - they have an exceptionally high antibacterial activity, which makes them particularly suitable for surface application on wounds, and which also retain their activity in the presence of fluid bodies, and are therefore valuable for the treatment of infections of the organism.

The process according to the invention, for the preparation of 2-amino-4-hydroxy-5-benzyl-pyrimidines corresponding to the above formula, is characterized in that one reacts gua- nidine-with an α-formylhydrocinnamic ester whose phenyl ring is substituted as indicated above.

Said α-formylhydrocinnamic ester can be prepared from a suitable hydrocinnamic ester (formula II, in which R is a lower alcohol residue, R' is a methoxy or ethoxy residue, R2 is an ethoxy, chloro or bromo, and R3 and R4 are hydrogen or methoxy, ethoxy, chloro or bromo residues, which are formylated (formula III). On reaction with guanidine, the ester thus obtained gives a 2-amino-4-hydroxy-5-benzyl-pyrimidine corresponding to formula IV.

Further conversion to the diamino compound can be effected by chlorination and amination; an can also proceed by thiation and amination, in a manner analogous to that described in British patents No. 671926 and 671927 in combination with the method of American patent No. 2415793.

The following examples serve to illustrate the invention. In these examples, all temperatures are given in degrees Centigrade. Example <I>1</I> 2-Amino-4-hydroxy-5-(3,4-dimethoxy-5-bromo-benzyl)-pyrimidine. The starting formylhydrocinnamic ester was prepared as follows: 162 g of 3,4-dimethoxy-5-bromocinnamic acid was esterified (F. B. Wittmer and L. C. Racford, Journal of Organic Chemistry, Volume 10, page 527, 1945) by heating under reflux with 1.5 liters of ethanol and 3 ml of sulfuric acid for about fifteen hours. The ester was separated in the usual way by ether extraction from an alkaline solution. The yield was 6t6 of 150 g of crude ester.

The above ester was reduced at room temperature, with Raney nickel catalyst, without ethanol as solvent, using a ratio of about 40 g of the compound to 150 ml of ethanol and 10 g of catalyst. The reduced ester was filtered off from the catalyst, the solvent was evaporated in vacuo, and the ester was distilled at 205-2100/10 mm.

In a round-bottomed flask fitted with a reflux condenser, to 30 g of sodium thread in one liter of dried sodium ether was added a mixture of 150 g of y-(3,4-dim6- thoxy- ethyl 5-bromophenyl)-propionate obtained as described above, and 150 ml of ethyl formate. The mixture was allowed to stand for about forty-eight hours (while destroying the sodium clumps if necessary), after which most of the metallic sodium had disappeared.

Guanidine (prepared from 62.5 g of guanidine hydrochloride in about 300 ml of ethanol and 15 g of sodium dissolved in about 300 ml of ethanol) is introduced into the mixture containing a-formylhydrocinnamic ester. . The ether is evaporated on a steam bath and the remaining ethanol mixture is heated at reflux for six hours, stirring occasionally to remove any adhering precipitate from the bottom of the flask. The mixture is then poured into 3 liters of water and neutralized with glacial acetic acid. It is advantageous, at this time, to bring the pH <I>ä</I> to about 8 with an ammonia solution. The mixture is allowed to stand for about 12 hours, scraping the bottom occasionally. RTI ID="0002.0270" WI="4" HE="4" LX="1122" LY="834"> The precipitate is filtered, washed with water, pulsed several times with ether. The purified compound melts at 238-240, after recrystallization from a large volume of ethanol. Example <I>2</I> <I>2-</I> amino-4-hydroxy-5-(2-methoxy-5-chlorobenzyl)-pyrimidine.

From 26 g of ethyl 2-methoxy-5-chlorohydrocinnamate, 9 g of ethyl formate and 2.45 g of sodium in dry ether, the formy16 derivative was prepared by operating from the manner described in Example 1.

This derivative is condensed with guanidine (obtained from 10 g of guanidine hydrochloride and 2.45 g of sodium, in ethanol) and 2-amino-4-hydroxy- is obtained. pyrimidine, melting at 278-284o.

This product can be transformed into the corresponding 2,4-diarnino compound as follows: an treats 6 g of the above pyrimidine with phosphoryl chloride and phosphorus pentachloride, pulsed with alcoholic ammonia at 1550; an obtains the White crystalline pyrimidine, which melts at 169-1710 after recrystallization from ethanol. Example <I>3</I> 2-Amino-4-hydroxy-5-(3-ethoxy-4-methoxy-benzyl)-pyrimidine.

90 g of ethyl 3-ethoxy-4-methoxyhydrocinnamate in solution in ether were formed by adding 90 g of ethyl formate in the presence of 8.5 g of sodium thread, according to the fapn of opfer described in Example 1.

The crude formyld compound thus obtained is condensed with guanidine (obtained starting from 35 g of guanidine hydrochloride and 8.5 g of sodium in ethanol) and 2-amino-4-hydroxypyrimidine is obtained. looking for.

From the crude pyrimidine thus prepared, one can obtain 2,4-diaminopyrimidine, which melts at 197-1980 after recrystallization from ethanol. Example <I>4</I> <I>2-</I> amino <I>-4-</I> hydroxy-5-(3-ethoxy-4-methoxy-5-bromobenzyl)-pyrimidine.

The initial α-formylhydrocinnamic ester was prepared from 105 g of ethyl 3-ethoxy-4-methoxy-5-bromohydrocinnamate, 30 g of ethyl formate and 7.2 g of sodium fil in 1 'other.

The crude formyl ester is condensed with guanidine (prepared with 30 g of guanidine hydrochloride and 7.2 g of sodium in ethanol), according to the indications given in Example 1.

The crude amino-hydroxy-pyrimidine obtained can be transformed into a diamino derivative by chlorination and amination. After recrystallization from ethanol, colorless plaques are obtained, melting at 193-2030. Example <I>5</I> <I>2 -</I> amino <I>- 4</I> -hydroxy-5-(3-ethoxy-4-methoxy-5-bromo-x-chlorobenzyl) -pyrimidine. The starting α-formylhydrocinnamic ester was prepared, according to the method described in example 1, by formylation of 50 g of ethyl 3-ethoxy-4-methoxy-5-bromo-x-chlorohydrocinnamate, with 15 g of ethyl formate in the presence of 4.1 g of sodium thread, in ether.

The crude formyl ester obtained is condensed with guanidine (from 13.2 g of guanidine hydrochloride and 4.1 g of sodium in ethanol). Example <I>6</I> 2-Amino-4-hydroxy-5-(3,4-dimethoxy-5-chloro-benzyl)-pyrimidine.

The starting ester was obtained by formylation of ethyl 3,4-dimethoxy-5-chlorobenzylhydrocinnamate (81 g) with 81 g of ethyl formate in the presence of 6.9 g of sodium in 500 ml of dry ether.

The crude formylhydrocinnamate thus prepared is treated with guanidine (from 30 g of gaanidine hydrochloride and 6.9 g of sodium in 500 ml of ethanol), as in Example 1, and gives the compound 2-amino-4-hydroxy brat.

Claims (5)

CLAIM Process for the preparation of 2-amino-4-hydroxy-5-benzyl-pyrimidines corresponding to the general formula wherein Ph represents a phenyl ring further bearing at least two substituents, one at least of which is a methoxy or ethoxy group, characterized in that guanidine is reacted with an α-formylhydrocinnamic ester which has the phenyl ring substituted as indicated above. SUB-CLAIMS 1. The method of claim wherein said phenyl ring bears a methoxy or Ahoxy substituent and a halogen substituent of atomic weight 35 to 80. 2. ProcM6 according to the RTI ID="0003.0254" WI="21" HE="4" LX="1409" LY="1988"> claim, in which said phenyl ring bears more than two substituents, two of which at least are methoxy or Ahoxy groups. 3. Process according to claim, in which said phenyl ring bears more than two substituents, at least one of which is a methoxy or ethoxy group and of which at least another is a halogen of atomic weight 35 to 80. 4. Process according to claim, wherein said phenyl ring bears two methoxy or ethoxy substituents. 5. Process according to sub-claims 3 and 4, in which said phenyl ring bears two methoxy or ethoxy substituents, and a halogen substituent of atomic weight 35 to 80.