FORM 2
THE PATENTS ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See Section 10)
AN IMPROVED PROCESS FOR THE SYNTHESIS OF SILDENAFIL CITRATE.

M/s Cipla Ltd., an Indian Company incorporated under the Companies Act, 1956, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
The following specification particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed.


The present invention provides an improved process for the preparation of sildenafil citrate more efficiently and in a cost effective manner.
Sildenafil was originally disclosed in EP-A-0463756, and was found to be useful in curing male erectile dysfunction. According to one embodiment of the process disclosed in EP-A-0463756 of sildenafil citrate comprises reacting a compound of the formula:

with N-methyl piperazine.
OH M

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 (c AMP 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,
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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 EP0812845 A disclosed obtaining sildenafil citrate by cyclisation of the compound of formula:
£DA NOc^
in the presence if a base and peroxide.
The present invention provides a novel commercially useful process for the preparation of sildenafil and its precursor in good yields and purity in a more efficient and cost effective manner as compared to the processes disclosed in EP 0463756A and EP 0812845 A.
The present invention provides a process for. obtaining sildenafil by reductive methylation of a compound of the formula:

wherein Rl & R2 are either both H or one is H and the other is methyl.
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According to the present invention, there is provided a process for the preparation of
sildenafil citrate of the formula: 0 + Q



Which process comprises reacting a compound of the formula:
Wherein Rl and R2 are either both H or one is H and the other is methyl with one or more methylating agents.
The invention also includes a pharmaceutical composition comprising sildenafil when made according to the process of the invention.
We prefer to methylate Rl using a mixture of formic acid and formaldehyde. This mixture can, if desired, also be used to methylate R2, although we prefer to methylate R2 using a different methylating agent such as, for example, dimethyl sulphate or methyl iodide. Thus, in a preferred aspect, Rl is methylated using a mixture of formic acid and formaldehyde followed by methylation of R2 with either dimethyl sulphate or methyl iodide.
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According to a preferred embodiment of the invention, the compound of the formula:

Where Rl is methyl and R2 is H converted to a compound of the formula:

by reacting with dimethyl sulphate or methyl iodide, which reaction may be carried out 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 to obtain the intermediate 4-[2-ethoxy-5-(piperazine-1-yl-sulfonyl) benzamido]-3-n-propylpyrazole-5-carboxamide which is cyclised using a base selected from sodium hydroxide, potassium hydroxide or alkoxides of alkali metals or a mixture of any of the above mentioned bases 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 cyclised and then treated successively with chlorosulphonic acid followed by anhydrous piperazine.

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


where both Rl & R2 are H, or where Rl 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 Rl is methyl and R2 is H can be conveniently converted to the compound of the formula:

SV H
either by means of formic acid and formaldehyde or by subjecting it to methylation using a methylating agent, such as, for example, dimethyl sulphate or methyl iodide. Other suitable methylating agents can also be used, if desired.
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 more efficient and cost effective manner than that of the prior art.
The compound of the formula: A

is, for example, synthesized by one of the methods shown in schemes 1 & 2 below:
SCHEME 1


SCHEME 2

Hjt
\Ht>C

-S>

H^NOC



m NR
< =5—


so- O/
where Rl and R2 are both H or Rl is H and R.2 is methyl and vice versa.
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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-(piperazinbe-1-yl-sulfonyl) benzamido]-3-n-propylpyrazole-5-carboxamide which is cyclised using a base selected from sodium hydroxide, potassium hydroxide oralkoxides 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-propylpyrazole 5-carboxamide with 2-ethoxy benzoyl chloride to obtain 4-(2-ethoxy benzamido) 3-n-propyl pyrazole-5-carboxamide. This is cyclised and then treated successively with chlorosulphonic acid followed by anhydrous piperazine.
The process envisaged according to the present invention is more particularly illustrated in the following examples:
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Example 1
To a stirred mixture of formic acid 9.2g (0.2 mole) and formaldehyde 37%, 16.2g (0.2 mole) was added slowly 5-(ethoxy-5(piperazine-l-yl-sulfonyl) phenyl]-3-n-propyl-l, 6-dihydro-7H-pyrazolo(4,3d)-pyrimidine-7-one,4.5g (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,3.6g.
Example 2
To a stirred mixture of formic acid 9.2g (0.2 mole) and formaldehyde 37%, 16.2g (0.2 mole) was added slowly 5-(2-ethoxy-5(piperazine-l-yl-sulfonyl) phenyl]-l-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazole(4,3d)-pyrimidine-7-one, 4.6g (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-l-ylsulfonyl) phenyl)-3-n-propyl-l, 6-dihydro-7H-pyrazolo(4,3d)-pyrimidine-7-one,4.6g (0.01 mole) in acetone 50 ml was added slowly dimethyl sulphate 1.5g (0.012 mole) at room temperature. The mass was heated to 50*C and maintained for 2 hours. The solvent was distilled off and the residue was quenched in water and filtered to obtain sildenafil 3.9g.
Claims:

50-N NOL
which process comprises reacting a compound of the formula:
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1. A process for preparing sildenafil citrate of the formula:

wherein Rl & R2 are either both H or one is H and the other is methyl with one or more methylating agents.
2. A process according to claim 1 wherein the methylating agent is a mixture of formic acid and formaldehyde.
3. A process according to claim 2 in which Rl is H and R2 is methyl.
4. A process according to claim 1 in which R1=R2=H wherein Rl is methylated using a mixture of ormic acid and formaldehyde and R2 is methylated using either dimethyl sulphate or methyl iodide.
5. A process according to claim 1 in which Rl is methyl and R2 is H wherein the methylating agent is either dimethyl sulphate or methyl iodide.
6. A process according to claim 4 or 5 wherein the methylation of R2 is done in the presence of a base.
7. A process according to claim 6 wherein the said base is sodium hydroxide, potassium hydroxide or potassium carbonate.
8. A pharmaceutical composition comprising sildenafil when made according to the process of any preceding claim.
Dated this 14th day of September, 2000.

To,
The Controller of Patents,
The Patent Office at Mumbai.
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ABSTRACT OF TH E INVENTION
Sildenafil citrate of the formula:

50^- IQCH,

is obtained by reacting a compound of the formula:

UN
^O
N
SO- iQw,

wherein Rl and R2 are either both H or one is H and the other is methyl with a methylating agent.
Dated this 14"' day of September, 2000.

To,
The Controller of Patents,
The Patent Office at Mumbai.