RU2239637C1 - Improved method for preparing 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-n-propyl-1, 6-dihydro-7h-pyrazil[4,3-d]pyrimidine-7-one - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing 5-[2-(ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol[4,3-d]pyrimidine-7-one of the formula (I)

and its pharmaceutically acceptable salts. Method involves interaction of compound of the formula (II)

wherein R₁ and R₂ means hydrogen atom, or R₁ means hydrogen atom and R₂ means methyl group with a mixture of formic acid and formaldehyde in the presence of tetrabulyl ammonium bromide in the ratio tetrabutyl ammonium bromide to the parent compound from 1:60 to 1:130 but preferably 1:100. Also, invention proposes a method for preparing 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol[4,3-d]pyrimidine-7-one of the formula (I) and its pharmaceutically acceptable salts by interaction of compound of the formula (II) wherein R₁ means methyl group; R₂ means hydrogen atom with formic acid and formaldehyde or dimethylsulfate in the presence of tetrabutyl ammonium bromide in the ratio tetrabutyl ammonium bromide to the parent compound from 1:60 to 1:130 but preferably 1:10 and if necessary in the presence of a base, such as sodium hydroxide, potassium hydroxide and potassium carbonate. Invention provides enhancing purity of the end compound.

EFFECT: improved preparing method.

6 cl, 7 ex

Description

The present invention relates to an improved and economical process for preparing 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one and its pharmaceutically acceptable salts.

5- [2-Ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidine- 7-one is disclosed in US Pat. No. 5,250,534. The process described in this patent involves several steps and the final product is obtained in very low yield and low purity.

5- [2-Ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidine- 7-one and related compounds are described in European patent application EP 0 443 756 A1. The application discloses the use of these compounds in the treatment of cardiovascular diseases. This activity is attributed to the selective inhibition of cyclic guanosine-3 ', 5'-monophosphate phosphodiesterase (cGMP PDE), rather than cyclic adenosine-3', 5'-monophosphate phosphodiesterase (cAMP PDE), which leads to an increase in cGMP concentrations. Thus, these compounds are used in the treatment of a number of diseases, including stable, unstable and variant (Prinzmetal) angina pectoris, hypertension, congestive heart failure, atherosclerosis, conditions with reduced blood vessel diameters, for example, after percutaneous intraluminal coronary angioplasty (post-FVCA), diseases peripheral vessels, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by intestinal motility disorders ika, for example, irritable bowel syndrome.

The method of obtaining 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidine -7-she, disclosed in European patent application EP-A-0463756, consists in the interaction of the compounds of the formula:

with N-methylpiperazine.

EP 0 443 756 A1 discloses the preparation of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H- Pyrazole [4,3-d] pyrimidin-7-one by O-alkylation of a compound of the formula:

A later European patent application EP 08128454 A2 discloses the preparation of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro 7H-pyrazole [4,3-d] pyrimidin-7-one by cyclization of a compound of the formula:

in the presence of a base and peroxide.

The present invention relates to an improved process for the preparation of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4 , 3-d] pyrimidin-7-one and its precursor. The process of the present invention is an economical and commercially suitable process for the preparation of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro -7H-pyrazole [4,3-d] pyrimidin-7-one of high purity and high yield.

The present invention relates to a method for producing 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4, 3-d] pyrimidin-7-one by catalytic methylation of a compound of the formula:

where R ₁ and R ₂ mean hydrogen or R ₁ means hydrogen and R ₂ means methyl, using a mixture of formic acid and formaldehyde in the presence of a catalyst, such as tetrabutylammonium bromide, to obtain a compound of the formula:

The use of tetrabutylammonium bromide in appropriate quantities ensures a high yield of the finished product at the highest speed. According to the present invention, the ratio of tetrabutylammonium bromide to the starting compound is from 1:60 to 1: 130.

In a preferred embodiment, the ratio of catalyst to starting compound is 1: 100.

In accordance with another embodiment of the present invention, the compound of the formula:

where R ₁ means methyl, a R ₂ means hydrogen, converted into a compound of the formula:

by reaction with dimethyl sulfate, which can be carried out in the presence of a base and a catalytic amount of tetrabutylammonium bromide.

The compound of the formula:

prepared by reacting 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxy-5- (piperazin-1-ylsulfonyl) benzoyl chloride to give the intermediate 4- [2-ethoxy-5- (piperazin-1-ylsulfonyl ) -benzamido] -3-n-propylpyrazole-5-carboxamide, which is cyclized using a base selected from the group consisting of sodium hydroxide, potassium hydroxide or alkali metal alkoxides or a mixture of any of the above bases with hydrogen peroxide.

Alternatively, it can be prepared by reacting 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxybenzoyl chloride to give 4- (2-ethoxybenzamido) -3-n-propylpyrazole-5-carboxamide, which is cyclized and then treated with chlorosulfonic acid and then anhydrous piperazine.

Therefore, by choosing the appropriate pyrazole and piperazine, you can get a compound of the formula:

The compound of the following formula:

where R ₁ and R _{2 are} hydrogen or R ₁ is hydrogen and R ₂ is methyl, can be converted to 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3- n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one, i.e. to the compound of the formula:

reacting with a mixture of formic acid and formaldehyde in the presence of a catalyst such as tetrabutylammonium bromide.

The compound of the formula:

where R ₁ means methyl, and R ₂ means H, can easily be converted to 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1 , 6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one, i.e. to the compound of the following formula:

or with formic acid and formaldehyde, or by methylation using a methylating reagent such as dimethyl sulfate in the presence of a catalyst such as tetrabutylammonium bromide.

Using the present invention, it is possible to provide a commercially suitable process for the preparation of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazole [4,3-d] pyrimidin-7-one and its precursor with a high yield and high purity are more cost-effective than in the prior art.

The compound of the formula:

synthesized using 2 methods described in the following schemes 1 and 2:

where R ₁ and R ₂ mean hydrogen or R ₁ means H and R ₂ means methyl, and vice versa.

In accordance with a preferred embodiment of the present invention, compounds of the formula:

prepared by reacting 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxy-5- (piperazin-1-ylsulfokyl) benzoyl chloride to give an intermediate, 4- [2-ethoxy-5- (piperazin-1- ylsulfonyl) benzamido] -3-n-propylpyrazole-5-carboxamide, which is cyclized using a base selected from the group consisting of sodium hydroxide, potassium hydroxide or alkali metal alkoxides or a mixture of any of the above bases with hydrogen peroxide.

In accordance with a preferred embodiment of the present invention, compounds of the formula:

can be obtained by reacting a compound of the formula:

with a mixture of formic acid with formaldehyde in the presence of a catalyst such as tetrabutylammonium bromide.

The method corresponding to the present invention, without limiting its scope is described using the following examples:

Example 1

9.0 g of 5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7- it is slowly added to the mixture of 18.4 g of formic acid with 32.4 g of 37% formaldehyde. The solution is stirred for 15 hours at 40-45 ° C. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 5.76 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 96.5%.

Example 2

Interaction is carried out, as in example 1, in the presence of tetrabutylammonium bromide as a catalyst while maintaining all other process parameters. The concentration of the catalyst was, however, changed as follows.

1. 9.0 g of 5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-it is slowly added to a mixture of 18.4 g of formic acid with 32.4 g of 37% formaldehyde and 150 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours at 40-45 ° C. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 6.96 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 98.85%.

2.5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one ( 9.0 g) 18.4 g of formic acid with 32.4 g of 37% formaldehyde are slowly added to the mixture. To the resulting reaction mass, tetrabutylammonium bromide (112.5 mg) was then added and the solution was stirred at 40-45 ° C. for 5 hours. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 6.96 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 99.50%.

3. 9.0 g of the starting compound, 5- [2-ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d ] -pyrimidin-7-one, 18.4 g of formic acid with 32.4 g of 37% formaldehyde are gradually added to the mixture in the presence of 90 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours while maintaining the temperature between 40-45 ° C. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 7.2 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 99.69%.

4. 9.0 g of 5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-it is slowly added to a mixture of 18.4 g of formic acid with 32.4 g of 37% formaldehyde and 75 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours at 40-45 ° C. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 6.92 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 99.52%.

5. 9.0 g of 5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-it is slowly added to a mixture of 18.4 g of formic acid with 32.4 g of 37% formaldehyde in the presence of tetrabutylammonium bromide (64.28 mg). The solution is stirred for 5 hours at 40-45 ° C. To stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 6.90 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 99.50%.

The resulting yield was maximum when the ratio of the catalyst to the starting compound was 1: 100.

Example 3

5.5 g of 5- [2-Ethoxy-5- (piperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] with stirring, pyrimidin-7-one is added slowly to a mixture of 11.04 g of formic acid with 19.44 g of 37% formaldehyde. The reaction mass is stirred for 20 hours at 35-40 ° C. After completion of the reaction, to stop the reaction, the reaction mass was poured into about 2000 ml of water and filtered, yielding 3.94 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3- n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 96.75%.

Example 4

The reaction is carried out, as in example 4, in the presence of tetrabutylammonium bromide as a catalyst while maintaining all other process parameters. The ratio of catalyst to starting material ranged from 1:90 to 1: 150. It was found that the reaction gave an optimal yield at a ratio of 1: 100. With a decrease in the ratio from 1: 100 to 1: 130, the yield gradually decreased. It was found that below this ratio (i.e., below 1: 130) of the catalyst, no significant increase in yield occurs to the starting compound. Purity 99.54%.

Example 5

Suspension of 6.9 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-one and 75 ml of acetone are stirred at room temperature. Then 2.25 g of dimethyl sulfate is slowly added at room temperature. The reaction mass is heated to 35-40 ° C and incubated for 8 hours. After completion of the reaction, the solvent was removed by distillation, and the residue was stopped in water and filtered to give 4.68 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3- n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 96.58%.

Example 6

Suspension of 6.9 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-one, 75 ml of acetone and 69 mg of tetrabutylammonium bromide are stirred at room temperature. Then 2.25 g of dimethyl sulfate is slowly added at room temperature. The reaction mass is heated to 35-40 ° C and incubated for 2 hours. After completion of the reaction, the solvent was removed by distillation, and the residue was stopped in water and filtered to give 5.85 g of 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3- n-propyl-1,6-dihydro-7H-pyrazole [4,3-d] pyrimidin-7-one. Purity 99.56%.

Example 7

The reaction, as in example 6, was carried out at various ratios of the catalyst to the starting compound while maintaining all other process parameters. The selected ratios were - 1: 110, 1: 100, 1:80, 1:60 and 1:40. The yield of the final product was 5.75, respectively; 5.85; 5.79; 5.78 and 5.78. The average purity of the final product obtained is 99.58%.

Claims (6)

1. The method of obtaining 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3- d] pyrimidin-7-one of the formula (I)

and its pharmaceutically acceptable salts by reacting a compound of formula (II)

where R ₁ and R _{2 are} hydrogen or R ₁ is hydrogen and R ₂ is methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, wherein the ratio of tetrabutylammonium bromide to the starting compound is from 1:60 to 1: 130. 2. The method according to claim 1, in which the ratio of tetrabutylammonium bromide to the starting compound is 1: 100. 3. The method of obtaining 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3- d] pyrimidin-7-one of formula (I) and its pharmaceutically acceptable salts by reacting a compound of formula (II)

where R ₁ means methyl; R ₂ means hydrogen, with formic acid and formaldehyde or dimethyl sulfate in the presence of tetrabutylammonium bromide, the ratio of tetrabutylammonium bromide to the starting compound being from 1:60 to 1: 130. 4. The method according to claim 3, in which the ratio of tetrabutylammonium bromide to the starting compound is 1: 100. 5. The method according to claim 4, in which dimethyl sulfate is used, and the reaction is carried out in the presence of a base. 6. The method according to claim 5, wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide and potassium carbonate.