SU639878A1 - Method of obtaining 6-amino-4-acylamido-2-mercaptopyrimidines - Google Patents

Description

one

This invention relates to a process for the preparation of 6-amino-4-acylamido-2-mercaptopyrimidines, which can be used as intermediates in the synthesis of biologically active compounds.

There are several known methods for the preparation of acylamidomercaptopyrimidines.

Thus, 2-amino-4-methyl-6-mercaptopyrimidine with acetic anhydride at 110 ° C gives 2-acetamido-4-methyl-6-mercaptopyrimidine 1. From 2-amino-4-methyl-6-mercaptopyrimidine and benzoyl chloride in the presence of aqueous alkali, 2-amino6-benzoylthio-4-methylpyrimidine 2 was obtained, and from 4.5 - diamino - 6 - mercaptopyrimidine under the same conditions - 4-amino-5-benzamido-6mercaptopirimidine 3.

Pirpmpdins containing an amino group at the 5-position of the pyrimidine cycle are acylated primarily in this group, regardless of the number and position of the other substituents. Even with the presence of three amino groups in the 4-, 5- and 6-positions (4,5,6-triaminopyrimidine) or in the 2-, 4- and 5-positions (2,4,5-triamino-6-oxypyrimidine) moocylation by chloride benzoyl in the presence of aqueous alkali flows through the 5-amino group, and the amino groups at the 4-, 6- and 2-positions are not affected 4.

If the mercaptopyrimidine does not contain

the amino group in the 5-position, as mentioned above 2-amino-4-methyl-6-mercaptopyrimidine, the acylation with benzoyl chloride in the presence of alkali (i.e., in essence, the acylation of the sodium salt of this pyrimidine) is on the sulfur atom 2 .

In addition, it was shown that the sodium salt of 4,6-diamino-2-mercaptopyrimidine with benzoyl chloride in dimethylformamide

at a temperature of 20–25 ° C, it forms 2-bezzoylthio-4, 6-diaminopyrimidine, the structure of which is confirmed by elemental analysis data and IR spectroscopy 5. Thus, the acylation method with carboxylic acid chlorides in the presence of alkali, but which was obtained 4-amino- 5-benzamido-6-mercaptopyrnmidine, is not applicable to the synthesis and of the 6-amino-4-acylamido-2-mercaptopyrimidines in the application.

However, some 6-amino-4-acylamido 2-mercaptopyrimidium can be obtained by thermal isomerization of the corresponding 1-acyl-4,6-diamino-1,2-dihydropyrimIDINTON-2 6.

The disadvantage of this method is the necessity to use 1-acyl-4,6-diamino-1, 2-dihydropyrimidinethioiov-2, which are obtained by acylation of 4,6-diamino-2-mercaptopyrimidine, as well as obtaining in this way only such 4-acylamido derivatives wherein the acyl group is a benzoyl radical substituted in the meta and para positions with a nitro group.

The aim of the invention is to develop a simple method for the preparation of 6-amino-4-acylamido-2-mercaptopyrimidines and to expand the range of the desired products obtained.

The goal is achieved by the described method of preparing 6-amino-4-acylamido-2-mercaptopyrimidines of the general formula

H, s

where R (CH3) 2CH, C., CeHs, m- or / g-, MO2CbH4, i1-CH3SbH4, pyridyl-3, which implies that 4,6-diamino-2-mercaptopyrimidine is reacted with acid chlorides of the formula RCOC1 ,

where R is as defined above, in the presence of triethylamine with a molar ratio of 4,6-diamino-2-mercaptopyrnmidine: acid chloride: triethylamine, 1: 1: 1, in a dimethylformamide concentration of 120-150 ° C.

Distinctive features of the method are the use of 4,6-diamino-2-mercaptopyrimidine as the starting compound and the acylation of the latter with acid chlorides in the presence of triethylamine at a molar ratio of reagents of 1: 1: 1 in dimethylformamide at a temperature of 120-150 ° C.

The advantages of the proposed method in comparison with the known method for producing 6-amio-4-acylamido-2-mercaptopyrimidines by thermal isomerization of 1-acyl4, 6-diamino -1,2-dihydropyrimidinethiones-2 are the single-stage process, the greater availability of the starting compounds and the possibility of more a wide range of compounds.

The proposed method allows to obtain pure 6-amino-4-acylamido-2-mercaptopyrimidines with yields of 50-60% of theoretical.

The structure of the products obtained was confirmed by the results of elemental analysis, IR spectroscopy data, and chemical transformations.

In the IR spectra of 6-amino-4-acylamido-2mercaptopyrimidines, there is an absorption in the region of 1680-1700 cm, typical of acid amides, in the region of 3200-30000 cm-1, characteristic of Vas and Vs NH2 and NH-rpynn.

In addition, the sodium salt of 6-amino-2mercapto-4-phenylacetamide-pyrimidine is easily alkylated with iodide propyl to 6-amino-2-propylthio-4-phenylacetamido-pyrimidine.

For a better understanding of this invention, the following examples are prepared for the preparation of 6-amipo-4-acyl 1-2-mercaptopyrimidiums.

10 Example 1. Preparation of 6-amino-4-isobutyrylamido-2-mercaptopyrimidine.

To a suspension of 8.1 g of 4,6-diamino-2-mercapto-pyrimidine in a solution of 5.6 g of triethylamine in 100 ml of dimethylformamide at 120 ° С was added dropwise 6.1 g of p-butyric acid chloride. The mixture is stirred for 15 minutes at a temperature of 120-125 ° C, cooled, the precipitate is filtered, the solvent is removed in vacuo. The residue is recrystallized from methanol. The output of 6.4 g (53% of theoretical), so pl. 266 ° C (decomp.). Found,%: C 44.93; 45.16; H 5.35; 5.42; N 26.07; 26.36. Calculated for CsHigNiOS. %: C 45.26H 5.7; N 26.4.

5 EXAMPLE 2. Preparation of 6-amino-2-mercapto-4-phenyl acetamidopyrnmidine.

Under conditions similar to example 1, pz

2.5 g of 4,6-diamio-2-mercaptoiirimidine, 3 g

triethylamine and 2.7 g of phenyl 0 acetic acid chloride are obtained 6-amio-2-msrcapto-4-pheylacetamidopyrimidine. Output

2.3 g (51% of theoretical), so pl. 250 ° C

(decomp.) (from methanol). Paydeno,%: C 55.55;

55.79; H 4.20; 4.30; N 21.69; 21.84. Calculated but for Ci2Hi2N4OS,%: C 55.36; H 4.64;

N 21.52.

Example 3. Obtaining 6-amino-4-benzamido-2-mercaptopyrimidine.

From 5 g of 4,6-diamino-2-mercapto-pyrimidine, 6 g of triethylamine and 5 g of benzoyl chloride and the conditions of example 1 are obtained

6-amio-4-benzamido-2-mercaptopyrimidine.

The output of 5.2 g (61% of theoretical), so pl.

220 ° C (decomp.) (From methanol). Found%:

5 C 53.85; 54.18; P 4.35; 4.55; N 22.98; 23.04.

Calculated for SiNyuk OZ,%: C 53.64;

H 4.09; N 22.70.

Example 4. 6-Amino-4-p-nitrobenzamido-2-mercaptopyrimidine is obtained similarly from 2.5 g of 4,6-diamino-2-mercaptopyrimidine, 3.3 g of p-nitrobenzoyl chloride and 2.5 g of triethylamine. Output 4.5 g (88.2% of theoretical), so pl. 300 ° C (from methanol). Found,%: C 44.37; 44.65; H 3.65; 3.95; 5 N 26.72; 26.49. Calculated for CnHgNgOsS,%: C 45.61; H 3.44; N 26.6.

Example 5. 6-Amino-4-g-nitrobenzamido-2-mercaptopopyrimidine is prepared analogously from 2.5 g of 4,6-diamino-6-mercaptopyridine, 3.3 g. {- nitrobenzoyl chloride and 2.5 g of triethylamine. The output of 4.3 g (84.5% of theoretical), so pl. 320 ° C (from methanol). Found,%: C 45.34; 45.56; H 3.20; 3.08; N 26.48; 26.34. Calculated for CuHgNsOsS,%: C 45.61; H 3.44; N 26.6.

Example 6. 6-Amino-2-mercapto-4-nicotinoyl amidopyrimidine is prepared analogously from 2.5 g of 4,6-diamino-2-mercaptopyrimidine, 2.5 g of nicotinic acid chloride and 2.5 g of triethylamine. Yield 2 g (46.5% of theoretical), t. Il. 300 ° C (from methanol). Found,%; C 48.37; 48.52; H 3.66; 3.72; N 28.27; 28.05. Calculated for CioHgNsOS,%: C 48.56; H 3.66; N 28.32.

Example 7. 6-Amino-2-mercapto-4-l1-methoxybenzamide-pyrimidine is prepared analogously from 2.5 g of 4,6-diamino-2-mercaptopyrimidine, 3 g of lg-methoxybenzoic acid chloride and 2.5 g of triethylamine. The output of 4.0 g (83.5% of theoretical), so pl. : 300 ° С (decomp., From methanol). Found,%: C 51.90; 52.12; H 4.01; 4.13; N 20.0; 20.24. Calculated for Ci2Hi2N4O2S,%: C 52.16; H 4.37; N 20.28.

Example 8. 6-Amino-4-benzamido-2-mercaptopyrimidine.

To a suspension of 5 g of 4,6-diamino-2-mercaptopyrimidine in a solution of 5 g of benzoyl chloride in 100 ml of dimethylformamide at 150 ° C, 6 g of triethylamine are added dropwise. The mixture is stirred for 15 minutes at this temperature, cooled, the precipitate is filtered off, the solvent is removed in vacuo, the residue is recrystallized from methanol. Output 5 g (58.6% of theoretical), so pl. 220 ° C (dec., From methanol). Found,%: C 53.48; 53.26; H 3.89; 3.94; N 22.74; 22.98.

CnHioN40S,%: C 53.64;

Calculated for H 4.09; N 22.70.

Claims (6)

1. I.K. Feldman. Acylation of 2-amino-4-methyl-6-mercaptopyrimidine. “Tr. Leningrad chemical-farm Inst., 1962, No. 16, p. 25 2.S. Gabriel. Zur Kenntniss der Abkommlinge des 4-Methyl-pyrimidines. "Ber., 1899, 32, p. 2921. 3.S. C. Fy. Dehydrocye lization of 4-amino5-aryIamidopyrirnnidines. "J. Org. Chem., 1965, 30, c. 1916. 4.D. J. Broron. The pyrimidines. N. Y.- London, Intersci. Publ., 1962, c. 247, 324-329. 5. Avt. St. The USSR on the application number 2357974 / 23-04 dated 10 May 1976 6.Avt. St. The USSR according to the application number 2357975 / / 23-04 of 10 May 1976 (prototype).