Sildenafil was original disclosed in European Patent Office [EPO] EP-A- 0463756, and was found to be useful in curing of male erectile dysfunction.

According to one of the embodiment of the process disclosed in EP-A-043756 of sildenafil citrate comprises of reacting a compound of the formula. with N-methyl piperazine. According to another embodiment of the process for obtaining sildenafil disclosed in EPO document EP0463756A1 comprises O-alkylation of the compound of the formula : The compounds disclosed in the EP0463756A 1 known to exhibit selectivity for inhibition of cGMP PDEs rather than cyclic adenosine 3', 5'-monophosphate phosphodiesterases (cAMP PDEs) and, as a consequence of this selective PDE inhibition. cGMP levels are elevated which in turn can give rise to beneficial platelet anti-aggregatory, anti-vasospastic and vasodilatory activity, as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF) and nitrovasodilators. Thus the compounds have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e. g. post-percutaneous transluminal coronary engioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, chronic asthama, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e. g., irritable bowel syndrome (IBS).

A subsequent EPO document EP08128454A2 disclosed obtaining of sildenafil citrate by cyclisation of the compound of formula : in the presence of a base and peroxide.

The present invention provides a novel commercially useful process for preparation of sildenafil and its precursor in good yield and purity in a cost effective manner as compared to the processes disclosed in the EP 0463756A1 and EP 0812845 A1.

The present invention provides a process for obtaining of sildenafil by reductive methylation of compound of the formula : where Ri& R2 are H or R, is H when R2 is methyl ; using a mixture of formic acid and formaldehyde to give compound of the formula.

According to the present invention. a process for preparation of sildenafil citrate of the formula : comprises steps of reacting a compound of the formula where R, & R2 are H ; or R, is H and R2 is methyl ; with a mixture of formic acid and formaldehyde, by reacting as herein described.

According to another embodiment envisaged according to the process of the invention, the compound of the formula : where R, is methyl and R2 is H is converted to a compound of the formula : by reacting with dimethyl sulphate, which may be in the presence of a base.

The compound of the formula is prepared by reacting 4-amino-3-n-propylpyrazole-5-carboxamide with 2- ethoxy-5-(piperazine-1-yl-sulfonyl) benzoyl chloride(piperazine-1-yl-sulfonyl) benzoyl chloride to obtain the intermediate 4- [2-ethoxy-5-(piperazine-1-yl-sulfonyl) benzamido]-3-n-propylpyrazole-5- carboxamide which is cyclise using a base selected from sodium hydroxide, potassium hydroxide or alkoxides of alkali metals or a mixture of any of the above mentioned base and hydrogen peroxide.

Alternatively it can be prepared by reacting 4-amino-3-n-propylpyrazole 5- carboxamide with 2-ethoxy benzoyl chloride to obtain 4- (2-ethoxy benzamido]-3- n-propyl pyrazole-5-carboxamide. This is cyclise and then treated successively with chlorosulphonic acid followed by anhydrous piperazine.

Thus, by choosing the appropriate pyrazoie and piperazine. the desired compound of the formula can be prepared.

The compound of the formula where both R, and R2 are H, or when R, is H and R2 is methyl, can be conveniently converted to the compound of the formula : by reaction with a mixture of formic acid and formaldehyde.

The compound of the formula : where R, is methyl and R2 is H can be conveniently converted to the compounds of the formula : either by means of formic acid and formaldehyde or by subjecting it to methylation using a methylating agent, like for example dimethyl sulphate.

It is thus possible by way of the present invention to provide a commercially useful process for preparation of sildenafil and its precursor in good yield and purity in a cost effective manner than that of the prior art.

The compound of the formula : is synthesized by two methods shown in schemes 1 & 2 herebelow : SCHEME 1 SCHEME 2 where R, and R2 are both H or R, is H when R2 is methyl and vice versa.

In accordance with a preferred embodiment of the invention, the compound of the formula : is prepared by reacting 4-amino-3-n-propylpyrazole-5-carboxamide with 2- ethoxy-5- (piperazine-1-yl-sulfonyl) benzoyl chloride to obtain the intermediate 4- [2-ethoxy-5-(piperazine-1-yl-sulfonyl) benzamido]-3-n-propylpyrazole-5- carboxamide which is cyclise using a base selected from sodium hydroxide, potassium hydroxide or alkoxides of alkali metals or a mixture of any of the above mentioned base and hydrogen peroxide.

In accordance with another embodiment of the process envisaged according to the invention, the compound of the formula : Is prepared by reacting 4-amino-3-n-propylpyrazole 5-carboxamide with 2-ethoxy benzoyl chloride to obtain 4- (2-ethoxy benzamido]-3-n-propyl pyrazole-5- carboxamide. This is cyclise and then treated successively with chlorosulphonic acid followed by anhydrous piperazine.

Thus, by choosing the appropriate pyrazole and piperazine, the desired compound of the formula : can be prepared, where R, and R2 are H, or when R, is H and R2 is methyl. is conveniently converted to the compound of the formula: by reaction with a mixture of formic acid and formaldehyde.

The compound of the formula : where R, is methyl and R2 is H is converted to the compounds of the formula: either by means of formic acid and formaldehyde or by subjecting it to methylation using a methylating agent, such as. dimethyl sulphate.

The process envisaged according to the present invention is more particularly illustrated in detail in the following examples : Example 1 To a stirred mixture of formic acid 9.2 g (0.2 mole) and formaldehyde 37%, 16.2 g (0.2 mole) was added slowly 5- (2-ethoxy-5 (piperazine-1-ylsulfonyl) phenyl]-3-n- propyl-1, 6-dihydro-7H-pyrazolo (4. 3d)-pyrimidine-7-one, 4.5 g (0.01 mole). The contents were stirred at 50-60°C for 12 hours. The mass was quenched in excess water, and filtered to afford Sildenafil, 3.6 g.

Example 2 To a stirred mixture of formic acid 9.2 g (0.2 mole) and formaldehyde 37%, 16.2 g (0.2 mole) was added slowly 5-(2-ethoxy-5 (piperazine-1-ylsulfonyl) phenyl]-1- methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3d)-pyrimidine-7-one, 4.6 g (0.01 mole). The contents were stirred at 45-50°C for 8 hours. The mass was quenched in excess water and filtered to afford sildenafil 4.1 g.

Example 3 To a suspension of 5- (2-ethoxy-5 (4-methylpiperazine-1-ylsulfonyl) phenyl)-3-n- propyl-1, 6-dihydro-7H-pyrazolo (4,3d)-pyrimidine-7-one, 4.6 g (0.01 mole) in acetone 50 ml was added slowly dimethyl sulphate 1.5 g (0.012 mole) at room temperature. The mass was heated to 50°C and maintained for 2 hours. The solvent was distille off and the residue was quenched in water and filtered to obtain sildenafil 3.9 g.