SU445283A1 - Method of preparing 6-aminomethylpyrimido-/4,5-b/ /1,4/thiazines - Google Patents

Description

The invention relates to a process for the preparation of novel pyrimido derivatives 4,5-b. 1,4 thiazine, which have biological activity and can be used in the pharmaceutical industry. The method of obtaining these derivatives is not known, only the reaction of 5-amino-6-mercaptopyrimidines with C3-halogenonitriles has been described, which results in other derivatives - 6-aminopyrimido 4, 4 thiazines. In addition, the known methods of introducing hetero. the aromatic compounds of the CHjCl, CH, OH, CH2N (A1K) 2 and CHO groups by chloromethylation, hydroxymethylation, .Mannika, Wilsmeier and others are not acceptable for 6-aminomethylpyrimide-4, 4 thiazines, since pyrimidothiazines do not enter into an electrofile reaction. substitutions. gd nc de ao in mi I 9 D, cn NC V K. k. D J e R - hydrogen or amino group; R is lower alkyl, amino, or dialkylamino; Rj is hydrogen, alkyl, or and RJ jointly with the adjacent nitrogen atom form, an unsubstituted or substituted five or six hexane ring, which can sorce the second heteroatom, for example, from, oxygen or sulfur. The proposed method for the preparation of the compound of formula 1 is concluded that 5-amino-6-mercaptopyridine of the general formula P A ™ VII base and the resulting 6-chloromethyl pyrimido 4, 4 thiazine of the general formula III where R and R have the indicated meanings, are treated with an amine of the general formula IV where K has the indicated meanings, followed by isolation of the target compound by known techniques. In the interaction of 5-amino-b-mercaptopyrimidines of the formula I with 1,3-dihaloacetone, alcoholic alkali is preferably used as a base. The intermediate 6-chloromethylpyrimido 4,, 4 thiazines of formula 111 are prepared by conventional methods after the reaction and after purification are used in the next stage. Compounds of formula 1 are prepared as follows. The reaction product, obtained from compound I and diahalogenacetone, is washed with water. it is sewn, dissolved in dioxane and treated with the corresponding amine of formula IV. Example 1. Preparation of 4-amine-6-chloromethylpyrimido 4 ,, zina .. Korastrom 1 g (0; 007 mol) of 4,5-diamino-6-mercaptopyrimidine in a 10 4% solution (0.007 mol) of KOH in methanol added A solution of 0.9 g (0.007 mol) of 1,3-dichloroacetone in 10 ml of methanol. After 1.5 h of stirring at le-ZO C, the precipitated precipitate of KCl is filtered off, the filtrate is evaporated to dryness, the residue is washed with water and dried. 0.9 g (60.0%) of a light brown crystalline substance is obtained with a decomposition temperature of 1 ° C (from methanol). IR spectrum: 3310 cm, 3430 cm (NHj). Found,%: C 39.3b; n 3.26; Ы 26,27; S 14.81; CI 16.43. : StNtK48S1. Calculated,%: 39,16; H 3.29; And 26.10; S 14.94; CI 16.51. Example 2, Preparation of 4-dig methylamino-6-chloromethylpyrimido 4,5-1,4 thiazine. To a solution of 1 g (0.004 mol) of 4-dimethylamino-5-amino-6-mercaptypyrimidine. In 6 ml of 4% solution (0.004 mol) KOH in methanol and labyrinth solution. O, f g (0.004 mol) 1, -dichloroacetone in 10 ml of methanol. After 2 hours of stirring at 18-20 ° C, the precipitate of KCl is filtered off, the filtrate is evaporated to dryness, the residue is washed with water and dried. Obtain 1.06 g (74.5%) of a yellow crystalline substance with so pl. 150 C (from methanol). Found,%: C 44.69; H 4.56; N 22.94. SdN N4,301. Calculated,%: .C 44,53; H 4.57; N 23.09. Example 3. Preparation of 2-amino-4-methyl-6-chloromethyl pyrimido 4, 5-b 1.4 thiazine. To a solution of 2 g (0.0128 mol) of 2,5-diamino-4-methyl-6-mercaptopyrimidine in 30 ml of water containing 0.81 g (0.0124 mol) of KOH, was added at 18-20 ° C. 1.6 g (0.0126 mol) of 1,3-dichloroacetone in 20 ml of chloroform. The reaction mixture is stirred vigorously for 1 hour at this temperature, the precipitate formed is filtered off, washed with water and dried in air. , Obtain 2 g (68%) of yellow. Crystals with so pl. 300 ° 0 (from ethanol). Found,%: O 41.85- H 3, 9; 01 14.74; N 24.37; S 13.77. CgH,. Calculated,%: O 42.02; H 3.98; 01.5.5; N 24.48; S 14.02. Example 4. Obtaining 4-amino-6-morpholinomethyl 4 4, 4 thiazine. To a solution of 0.5 g (0.0023 mol) of 4-amino-6-chloromethyl-pyrimido 4,5-b 1,4 thiazine in 50 ml of dioxane was added with stirring a solution of 0.6 g (0.0069 mol) of morpholine in 5 ml of dioxane and left for a day at 18-20 ° C. The precipitated morpholine hydrochloride is filtered off, the filtrate is evaporated to dryness, the residue is washed with water and dried. Obtain 0.27 g (43.9%) of light brown crystals with so pl. 140142 ° 0 (from cyclohexane. IR spectrum: 3320 cm. 3440 cm (NHj). Found,%: O 49.72; H 5.66; N 26.53; S 1.2.23. C H yNjSO. Calculated,%: O 49.78; H, 5.70; N, 26.40; S, 12.09. Example 5. Preparation of 4-amino-6-piperidinomethylpyrimido 4, 5-b 1.4 thiazine. To a solution of 0.5 g (0.0023 mol) of 4-amino-6-chloromethylpyrimido 4,5-b If 4 thiazine in 50 ml of dioxane was added a solution of 0.6 g (0.007 mol) of piperidine in 5 ml of dioxane with stirring and left for 24 hours at 18-20 o. From 1hillow is a precipitate of piperidine hydrochloride.

the filtrate is evaporated to dryness, the residue is washed with water and dried.

Obtain 0.32 g (52.4%) of a yellow crystalline BeiiiecTBa with so pl. (from cyclohexane.

IR spectrum: 3290 cm, 3420 cm -NH

Found,%: C 54.35; H 6.49; .N 26.84; S 12.15.

C12 17% Calculated,%: from 54.72; H 6.51;

N 26.60; S 12,18.

Example 6, Preparation of 4-dimethylamino-6-morpholinomethylpyrimido 4,5-b 1,4 thiazine.

To a solution of 0.5 g (0.002 mol) of 4-dimethylamino-6-chloromethylpyrimido 4, 4 thiazine in 50 ml of dioxane, a solution of 0.6 g (0.0069 mol) of morpholine in 5 ml of dioxane is added with stirring and left on day at 18-20 ° C. Filtration of the precipitated morpholine hydrochloride, 4ltrate evaporated to dryness, the residue is washed with water and dried.

Obtain 0.50 g (78.1%) of light yellow crystals with so pl. 146-147 ° C (from cyclohexane).

Found,%: C 53, -34; H 6.48; N 23.82; S 11,10.

With „NjSO.

Calculated,%: C 53.21; H 6.53; N 23.88; S 10.93.

Example. Getting 4-dimethylamino-6-piperidinomethylpyrimido 4, 4 thiazine ..

A. To a solution of 0.5 g (0.002 mol) of 4-dimethylamino-6-chloromethylpyrimido

, 4, 4 thiazine in 50 ml of dioxane add a solution of 0.6 g (0.007 mol of piperidine with stirring and leave for a day at 18–20 ° C, the precipitated hydrochloride of piperidine is filtered off, the filtrate is evaporated to dryness, the residue is washed with water and dried.

Obtain 0.54 g (90.4%) of a light yellow crystalline substance with so pl. 180-l8lc (from cyclohexane).

B, To a solution of 1 g (0.0011 mol) of 4-dimethylamino-5-amino-6-mercaptopyrimidine 3 6 ml of a 4% solution (0.004 mol) of IEN in methanol was added a solution of 0.6 g (0.004 mol) 1 , 3-dichloroacetone in 10 ml of methanol. After 2 hours of stirring at 18-20 ° C, the solution is evaporated to dryness, the residue is washed with water, dried, dissolved in 100 ml of dioxane, 1.2 g (0.014 mol) of pyridine is added to the resulting solution with stirring and left for 18 days at 1820 ° s It is evaporated to dryness, the residue is washed with water and dried.

2.35 g (98.6%) of a light yellow crystalline substance are obtained. from m.p. 180-l8l-C (from cyclohexane).

Found,%: C 57.50; H 7.29; N 24.11; S 10.99.

.Hi,% S.

Calculated,%: C 57.69; H 7.26; N 24.04; S 11.01.

5 Example 8. Preparation of 2-amino-4-methyl-6-piperidinomethylpyrimido 4 ,, 4 thiazine.

To a solution of 0.5 g (0.002 mol) of 2-amino-4-methyl-6-chloromethylpyri0, 4 thiazines in 30 ml of dioxane, at 30-40 ° C, 0.38 g (0.004 mol) of piperidine is added. The reaction mixture is cooled to 18-20 ° C and left to stand at this temperature for 3 days. Distinguished

piperidine hydrochloride is filtered off, the filtrate is evaporated to dryness, the residue is treated with 20 ml of water, the undissolved substance is filtered, washed with water and dried.

0

Obtain 0.4 (65%) of the product yellow crystals with so pl. 144-146 C (from ethanol).

Found,%: With 56,43; H 7.16; N 24.89; S 11.33. C.H.gKVS.

Calculated,%: C 56.08; H 7.24; about N 25,16; S 11.52.

Example 9. Preparation of 2-amino4-methyl-6-morpholinomethylpyrimido 4, 4 thiazine.

Prepared according to example 8 of 0.5 g (0.002 mol) of 2-amino-4-methyl-6-hlirmethylpyrimido 4 ,, 4 thiazine and 0.39 g (0.004 mol) of morpholine. Yield 0.5 g (82%).

Yellow crystals with so pl. 152154с (from benzene).

Found,%: C51.68; H6.21; N 25.19; S 11.25. C ,,.

Calculated,%: C, 51.59; H 6.13, N 25.07; S 11.48.

Example 10. Preparation of 2-amino-4-methyl-6-pyrrolidinomethylpyrimido 4 ,, 4 thiazine.

Prepared according to example 9 of 0.5 g (0.002 mol) of 2-amino-4-methyl-6-chloromethylpyrimido 4 ,, 4 thiazine and 0.32 g (0.004 mol) of pyrrolidine ..

Yield 0.4 g (69%).

Yellow crystals with so pl. 147-148 ° C (from toluene).

Found,% :. C, 54.73; H 6.74; S 12.26.

C, H ,,,.

Calculated,%: C 54.72; H 6.50; S 12.17.

Example 11. Obtaining 2-amino-4-methyl-6-dipropylaminomethylpyrim ,,, 4 thiazine.

Prepared according to examples 8 and 9 with the difference that the dry residue after evaporation is extracted with boiling benzene, the extract is passed through

Claims (2)

65 column with А12Оз, the eluate is evaporated to dryness, the material obtained is recrystallized from methanol. Yield 40%, mp. 118-120s (from methanol). Found,%: C 57.25; H 8.12; N 23.64; S 10, 69.. Calculated,%: C 57.30; H 7.90; N 23.87; S 10.93. Claims 1. Method for the preparation of pyrimido 6-aminometi 4, 4 thiazines of the general formula Lch ™. where R g is hydrogen or an amino group; R is a low alkyl, amino, or a lakylamino group; R hydrogen, alkyl, or Rj and R 5 together with the adjacent nitrogen atom form an unsubstituted or substituted five or six membered which may contain a second heteroatom, for example nitrogen, oxygen or sulfur, which is 5-amino-6-mercaptopyrimyl Formula RI wherein Ne and R have the indicated meanings, are reacted with 1,3-dihaloacetone, for example with 1,3-dichloroacetone, in a solvent medium, for example an alcohol, in the presence of a base and the resulting b-chloromethylpyrimido 4 ,, 4 thiazine of the general formula, A f TVT $ where R and R have the indicated values, bathe with an amine of the general formula H-1T where R 3 has the indicated meanings, followed by isolation of the target compound by known methods. 2. A process according to claim 1, characterized in that alkali metal hydroxides, such as caustic potassium, are used as the base.