FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one of formula I.

BACKGROUND OF THE INVENTION:

5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-1 -methyl-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one is generically known as Sildenafil. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phophodiesterase type 5 (PDE5). Sildenafil enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil is used for the treatment of erectile dysfunction in male and it is also used for hypertension and which is marketed under the brand names Viagra® & Revatio®.

Sildenafil and its pharmaceutically acceptable salts are disclosed in US 5,250,534.
According to the process disclosed in US '534, Sildenafil is prepared by reacting 5-(2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-d]pyrimidin-7-one of formula (II) with chlorosulfonic acid to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-d]pyrimidin-7-one of formula (III), which is further converted to Sildenafil (I) by reacting with N-methylpiperazine in ethanol, followed by crystallisation using methanol and dimethylformamide(DMF).

The Drocess is as shown in Scheme-I below:

Scheme I

It has now been found that, during the chlorosulfonation of 5-(2-ethoxyphenyl)-l-
methyl-3-propyl-li/-pyrazolo[4,3-d]pyrimidin-7-one (II) with chlorosulfonic acid to
produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-
d]pyrimidin-7-one (III), about 8 to 10% of 5-(2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-d]pyrimidin-7-one (II) is remained un-reacted in the reaction mass. It is difficult to separate the compound (II) through crystallization from Sildenafil, which typically required repeated crystallizations to achieve desired Sildenafil purity. The repeated crystallization adds time to the manufacturing process and thus negatively impacts product throughput.

Hence, there is a need to develop a process, which completes chlorosulfonation of 5-(2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-d]pyrimidin-7-one (II) to produce compound (III).

In the instant invention, it has been found that if the reaction of 5-(2-ethoxyphenyl)-l-methyl-3-propyl-l//-pyrazolo[4,3-d]pyrimidin-7-one (II) with chlorosulfonic acid is carried out in presence of thionyl chloride, results in compound (III) with high purity and reduces the un-reacted compound (II) to below 1%.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Sildenafil citrate (la) of high purity on commercial scale.

SUMMARY OF THE INVENTION

The present application provides an improved process for the preparation 5-(2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil citrate) of Formula la,

which comprises:

(i) reacting 5-(2-ethoxyphenyl)-1 -methyl-3-n-propyl-1,6-dihydro-7#-
pyrazolo[4,3-d]pyramidin-7-one of formula (II),
Formula II


with chlorosulfonic acid in the presense of thionyl chloride to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1 -methy-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one of formula (III),

Formula III

(ii) reacting compound (III) of step (i) with N-methylpiperazine of formula (IV),

Formula IV
to produce 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)-phenyl]-1 -methyl-3-n-propyl-l ,6-dihydro-7i/-pyrazolo[4,3-d]pyrimidin-7-one of formula (I),

(iii) treating Sildenafil (I) with citric acid to produce Sildenafil citrate (la).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Sildenafil citrate of formula (la).

The process comprises, reacting 5-(2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyramidin-7-one (II) with chlorosulfonic acid (CISO3H) in the presence of thionyl chloride (SOCI2), optionally in the presence of a solvent to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methy-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one (III).

The solvent used in the reaction is selected from ethyl acetate, butyl acetate, methyl acetate, methylene chloride, ethylene chloride or mixtures there of, preferably methylene chloride. The reaction is carried out at a temperature of about 0 to 50°C for a period of about 1 to 10 hrs, preferably 3 to 4 hrs. The reaction is carried out by adding compound (II) in portion wise to the mixture of CISO3H and SOCI2 and raise temperature of the reaction after addition of the compound (II). The reaction is optionally carried out by adding compound (II) to the chlorosulfonic acid in a portion wise, followed by addition of thionyl chloride.

After completion of the reaction, as ascertained by the known techniques such as HPLC, the reaction mass is treated with ice, followed by extraction with a solvent selected from methylene chloride, ethyl acetate, mixture of methylene chloride and methanol, preferably methylene chloride. Separated the layers and the organic layer containing 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1 -methy-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one (III) is used as such in the next step. Optionally compound (III) is isolated as a solid by known methods such as evaporating the solvent, followed by crystallization using same or another solvent selected from acetone, acetonitrile.
5-(5-Chlorosulfonyl-2-ethoxyphenyl)-l-methy-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one (III) is reacted with N-methylpiperazine (IV). The reaction is optionally carried out in the presence of a solvent selected from methylene chloride, ethyl acetate, toluene, ethanol or mixtures thereof. Preferably the solvent used is methylene chloride. The reaction is carried out at a temperature of about 0 to 50°C, preferably at about 20 to 30°C for a period of about 1 to 10 hrs, preferably 4 hrs. The reaction is optionally carried out in the presence of a base selected from inorganic base such as such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, organic base such as an amine, more preferably, triethylamine, diisopropylethylamine, pyridine more preferably triethylamine.

After completion of reaction, the reaction mass is washed with aqueous base followed by washing with DM water. The organic layer containing Sildenafil free base is concentrated under reduced pressure until no more solvent distills out.

Sildenafil free base obtained by the above process is purified by known methods, for example recrystallization by dissolving in a solvent selected from methanol, ethanol, isopropanol, methylene chloride, tetrahydrofuran, acetone, acetonitrile, ethyl acetate or mixtures thereof; and precipitating pure Sildenafil free base by cooling the solution to about 0-30°C, or by adding an anti solvent selected from cyclohexane, n-hexane, heptane, diisopropyl ether etc.

Sildenafil free base is converted to Sildenafil citrate by treating with citric acid in a solvent selected from water, methanol, ethanol, isopropanol, acetonitrile, acetone. Optionally Sildenafil citrate is purified by recrystallization by dissolving in a solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile or mixtures thereof; and precipitating pure Sildenafil citrate (la) by cooling the solution to about 0-30°C, or by adding an anti solvent selected from cyclohexane, n-hexane, heptane, diisopropyl ether etc.

5-(2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]- pyramidin-7-one (II) used in the present invention is prepared by reacting 4-amino-l-methyl-3-n-propylpyrazole-5-carboxamide (V) with 2-ethoxybenzoyl chloride (VI) in the presence of base selected from inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or mixtures thereof; in a solvent selected from methylene chloride, ethylene chloride, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof; to produce 4-(2-ethoxyphenyl)carbonylamino-l-methyl-3-n- propylpyrazole-5-carboxamide (VII). The reaction is optionally carried out in the presence of sodium chloride. Compound (VII) is further cyclised in the presence of base selected from inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide in a solvent selected from alcohols such as alcohols such as methanol, ethanol, isopropanol, butanol; toluene, xylenes, methylene chloride, ethylene chloride, ethyl acetate, butyl acetate, methyl acetate, or mixtures thereof; to produce 5-(2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo[4,3-d]pyramidin-7-one (II), which is further isolated by crystallization or triturating using a solvent selected from alcohols such as methanol, ethanol, isopropanol, butanol; toluene, xylenes or mixtures thereof.

The process is as shown in Scheme-II below:

Scheme II

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE

Step-I:

Preparation of 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methyI-3-n-propyl-l,6-
dihydro-7/J-pyrazolo[4,3-d]pyrimidiii-7oiie(III)

Method A:

5-(2-ethoxyphenyl) 1 -methyl-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyramidin-7-one (II) (25 gms, 0.08 mol) was added to a mixture of chlorosulfonic acid (50ml, 0.75 mol) and thionyl chloride (9.53 gms, 0.08 mol) portion wise at 0-10°C. The reaction mass temperature was raised to 20-30°C and the resulting reaction mass was stirred for ~4 h to complete the reaction. Thereafter, reaction mass was poured into ice (-500 g) slowly and the product was extracted into methylene chloride (250 ml). Methylene chloride layer was separated and washed with 5% w/w aqueous sodium bicarbonate (100 ml). Methylene layer containing 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo- [4,3-d]pyrimidin-7one (III) is used as such in the step-II.

Method B:

5-(2-ethoxyphenyl) 1 -methyl-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyramidin-7-one (II) (25 gms, 0.08 mol) was added to chlorosulfonic acid (50 ml, 0.75 mol) portion wise at 0-10°C. Thereafter thionyl chloride (9.53 g, 0.08 mol) was added to reaction mixture at 0-10°C. The temperature of the reaction mass was raised to 20-30°C and stirred for ~4 h to complete the reaction. The reaction mass was poured into ice (-500 g) slowly and the product was extracted into methylene chloride (250 ml). Methylene chloride layer was separated and washed with 5% w/w aqueous sodium bicarbonate
(100 ml). Methylene layer containing 5-(5-chlorosulfonyl-2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-pyrazolo- [4,3-d]pyrimidin-7one (III) is used as such in the step-II.

Step-II:

Preparation of 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)-phenyI]-l-niethyl-3-n-
propyl-l,6-dihydro-7iy-pyrazolo[4,3-d]pyrimidin-7-one (Sildenafil)
N-methylpiperazine (12 g, 1.5 m.eq) was added to the methylene chloride layer, containing Sildenafil sulfonyl chloride (obtained from Step-I), at 20-25°C. The reaction mass was stirred for ~4 h at 20-30°C to complete the reaction. The reaction mass was washed with 5% w/w aqueous sodium bicarbonate (100 ml) followed by DM water (100 ml). Thereafter methylene chloride layer was concentrated at 20-40°C under reduced pressure till no more solvent distils out to obtain Sildenafil crude. The crude Sildenafil is further recrystallised from methanol.

Step-Ill:

Preparation of 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)-phenyl]-l-methyl-3-n-
propyl-l,6-dihydro-7Jyr-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil citrate):
Citric acid monohydrate (11.615 g, 0.055 mol) was added to a solution of Sildenafil base (25 g, 0.052 mol) in DM water (700 ml) at 80-85°C and the reaction mass was stirred to obtain a clear solution. Reaction mass was treated with carbon at 80-85°C and filtered. The filtrate was seeded with Sildenafil citrate reference sample and cooled to 10-15° to isolate the product. The product collected by filtration and dried to obtain 30 g of anhydrous Sildenafil citrate.

WE CLAIM;

1. A process for the preparation of Sildenafil citrate of Formula la,
Formula la

which comprises:

(i) reacting 5-(2-ethoxyphenyl)-l-methyl-3-n-propyl-l,6-dihydro-7//-
pyrazolo[4,3-d]pyramidin-7-one of formula (II);
Formula II

with chlorosulfonic acid in the presense of thionyl chloride to produce 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1 -methy-3-n-propyl-1,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one of formula (III);

Formula III

(ii) reacting compound (III) of step (i) with N-methylpiperazine of formula (IV);
Formula IV

to produce 5-[2-ethoxy-5-(4-methylpiperazinylsulfonyl)-phenyl]-l-methyl-3-n-propyl-l ,6-dihydro-7//-pyrazolo[4,3-d]pyrimidin-7-one of formula (I);

(iii) treating Sildenafil (I) with citric acid to produce Sildenafil citrate (la).

2. The process according to claim 1, wherein the compound of formula (II) is added in portion wise to the mixture of CISO3H and SOCI2.

3. The process according to claim 1, wherein the step (i) is carried out in the presence of a solvent selected from ethyl acetate, butyl acetate, methyl acetate, methylene chloride, ethylene chloride or mixtures thereof.

4. The process according to claim 1, wherein step (ii) is carried out in the presence of a solvent.

5. The process according to claim 4, wherein the solvent is selected from
methylene chloride, ethyl acetate, toluene, ethanol or mixtures thereof.

6. The process according to claim 1, step (ii) is carried out in the presence of a base.

7. The process according to claim 6, wherein the base is selected from inorganic base such as such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; organic base such as an amine, more preferably, triethylamine, diisopropylethylamine, pyridine.