WO2007141805A2

WO2007141805A2 - Novel process for the preparation of sildenafil citrate

Info

Publication number: WO2007141805A2
Application number: PCT/IN2007/000219
Authority: WO
Inventors: Seeta Ramanjaneyulu Gorantla; Mohan Bhandari; Venkata Sunil Kumar Indukuri; Srinivas Simhadri
Original assignee: Matrix Laboratories Limited
Priority date: 2006-06-05
Filing date: 2007-06-01
Publication date: 2007-12-13
Also published as: EP2024369A2; WO2007141805A3; EP2024369A4

Abstract

Disclosed herein the process for producing 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl- sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof employing novel intermediate.

Description

1. Title of the invention.

"NOVEL PROCESS FOR THE PREPARATION OF SILDENAFIL CITRATE"

The Following specification describes the nature of this invention (and the manner in which it is to be performed).

FIELD OF THE INVENTION

This invention in general relates to a process for producing 5-[2-ethoxy-5-(4- methyl)piperazine- 1 -yl-sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof. More particularly, the present invention provides a process for producing pure 5-[2-ethoxy-5-(4-methyl)piperazine-l- yl-sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- one or its salt thereof employing novel intermediate.

BACKGROUND OF THE INVENTION

Sildenafil is the active ingredient in Viagra ™ and it is chemically designated as 5-[2- ethoxy-5 -(4-methyl)piperazine- 1 -yl-sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, and the following chemical structure V:

V

Sildenafil is originally disclosed in US Patent No. 5,250,534 and it has been found to be particularly useful in the treatment of inter-alia male erectile dysfunction. Multi step syntheses for the production of Sildenafil are disclosed in US'534 with a yield of 27%.

An improved process for its preparation is described in a later application i.e. US Patent No. 5,955,611 which consisting the preparation of 5-chlorosulfonyl-2-ethoxybenzoic acid and converting it into 2-ethoxy-5-(4-methylpiperazin-l-ylsulfonayl)benzoic acid. The acid is then condensed with 4-amino-l-methyl-3-n-propylpyrazole-5-carboxyamide in the presence of N,N'-carbonyldiimidazole, and the resulting 4-[2-ethoxy-5-(4- methylpiperzin-l-ylsulfonyl)benzamido]-l-methyl-3-n-propylpyrazolo-5-carboxyamide is cyclized in an alkaline, neutral or acid solution to yield Sildenafil with about 47% yield.

Patent application number WO 2001/22918 describes the process for the preparation of Sildenafil wherein the process involves the reaction step between 2-ethoxy-5-(4-methyl- piperazine- 1 -sulfonyl)benzaldehyde and 4-amino- 1 -methyl-S-n-propyl-pyrazole-S- carboxamide to form an intermediate which is further cyclised to form Sildenafil.

Patents/ patent applications US6204383, US20030069422, US20030144530, US 20040106796, US 20040110948, EP 0812845, EP 1002798, EP 1077214, WO 01/19827, WO 04/31134 also discloses several processes for the preparation of Sildenafil citrate.

There is a need of the industry to provide a novel and an alternate process which is commercially useful for the preparation of Sildenafil citrate and has advantages over the processes mentioned in the prior art.

It has now been found that Sildenafil can be prepared with the higher yield while employing smaller number of steps than that of methods known in the art, using novel starting compounds, not yet described in the literature and utilizing a new intermediate compound, the said compound is also constituting the essential of the invention.

SUMMARY OF THE INVENTION

It is, therefore, a principal aspect of the present invention to provide a novel way for producing 5 - [2 -ethoxy- 5 -(4-methyl)piperazine- 1 -y l-sulfonyl)phenyl] - 1 -methyl-3 -n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one of formula (V) or its salt thereof over limitations in the prior art. These and other objects are attained in accordance with the present invention wherein there is provided several embodiments of the process for producing 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl-sulfonyl)phenyl]-l-methyl-3-n- propyl- l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof employing novel intermediate.

Accordance with one preferred embodiment of the present invention, there is provided a novel process for producing 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl-sulfonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof employing a novel intermediate 2-Hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid in a way to improve the yield and purity and obviates the formation of byproduct.

Accordance with another preferred embodiment of the present invention, there is provided a process for the preparation of 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl- sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof, which comprises the condensation of 2-hydroxy-5-(4-methyl-l- piperazinylsulfonyl)benzoic. acid with amino pyrazole derivative to form an amide derivative and then followed by cyclization of the amide derivative and the hydroxy group of cyclized product is protected which on decarboxylation give 5-[2-ethoxy-5-(4- methyl)piperazine- 1 -yl-sulfonyl)phenyl] - 1 -methy 1-3 -n-propyl- 1 ,6-dihydro- 7H-pyrazolo [4,3-d]pyrimidin-7-one (Sildenafil base) followed by salification to get 5-[2-ethoxy-5-(4- methyl)piperazine-l-yl-sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one or its salt thereof.

Accordance with another preferred embodiment of the present invention, there is provided a process for producing of an novel intermediate 2-hydroxy-5-(4-methyl-l- piperazinylsulphonyl)benzoic acid used in the production of 5-[2-ethoxy-5-(4- methyl)piperazine- 1 -yl-sulfonyl)phenyl]-l -methyl-3-n-propyl- 1 ,6-dihydro- 7H-pyrazolo [4,3-d]pyrimidin-7-one or its salt thereof. The process comprises the reaction of salicylic acid with chlorosulfonic acid and then condensation with N-methyl piperazine or its salt thereof. Accordance with still another embodiment of the present invention, there is provided a novel intermediate 2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The disclosed embodiment of the present invention deals with a process for producing 5- [2-ethoxy-5-(4-methyl)piperazine- 1 -yl-sulfonyl)phenyl]- 1 -methyl-3 -n-propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one of formula (V) or its salt thereof by using novel intermediate.

Scheme 1

V Sildenafil Base Sildenafil Citrate The present invention in its aspect is a new, improved, economical and industrial feasible method for preparing Sildenafil (V) or its salt thereof. The process for the preparation of Sildenafil or its salt thereof is outlined in scheme 1 and comprises:

a) condensing the 2-hydroxy-5-(4-methyl-l-piperazinylsulfonyl)benzoic acid (I) with amino pyrazole derivative (VII), coupling agent and a solvent optionally in presence of reagent forming actives esters to form an amide derivative (II); b) cyclizing the amide derivative (II) in presence of base and solvent to get compound of formula III; c) protecting the hydroxy group of the amide derivative (III) with halo ester in presence of base and solvent; d) decarboxylating the compound IV to form Sildenafil base in presence of decarboxylating agent and solvent and; e) treating the Sildenafil base with citric acid in presence of organic solvent to get Sildenafil citrate. ^; .

The present invention is also related to a process for the preparation of 2-hydroxy-5-(4 methyl)- l-piperazinylsulphonyl)benzoic acid (I) as given in scheme 2, which comprises:

a) treating the salicylic acid (VIII) with chlorosulphonic acid optionally in the presence of thionyl chloride to get 5-chlorosulfonyl-2-hydroxy benzoic acid (IX); b) condensing the N-methyl piperazine or its salt thereof with 5-chlorosulfonyl-2- hydroxybenzoic acid (IX) to get the compound of formula (I) or its salt thereof.

Scheme 2

I According to the present invention, the preparation of Sildenafil citrate as given in the scheme 1, involves the preparation of Compound of formula II i.e. 4-[2-hydroxy-5-(4- methyl- 1 -piperazinylsulfonyl)benzamido)- 1 -methyl-3 -n-propyl- 1 H-pyrazolo-5 - carboxamide which is obtained by condensing the 2-hydroxy-5-(4-methyl-l- piperazinylsulfonyl)benzoic acid with 4-amino-l -methyl-3 -n-propyl pyrazolo-5- carboxamide. The reaction is carried out by Condensing 2-hydroxy-5-(4-methyl-l- piperazinylsulfonyl)benzoic acid (I) with coupling agent in a solvent and 4-amino-l- methyl-3 -n-propyl pyrazolo-5-carboxamide (VII) optionally in presence of reagent forming reactive esters selected from the group consisting of but not limited to 1 -hydroxy benzotriazole, N-hydroxy succinimide and N-hydroxy phthalimide. The coupling agent used is selected from the group consisting of but not limited to l-(3-dimethylaminoρropyl)- 3-ethylcarbodiimide hydrochloride, 1,1-carbonyldiimidazole, 1,3- dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide and like, preferably 1,3- dicyclohexylcarbodiimide (DCC). The reaction is carried out in a solvent selected from the group consisting of halogenated hydrocarbons such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; aliphatic or aromatic hydrocarbons such as C_5-8 aliphatic hydrocarbon, cyclohexane, cycloheptane, xylene, toluene; aliphatic or cyclic ethers such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; esters such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketones such as methyl ethyl ketone, acetone, methyl isobutyl ketone; nitriles such as acetonitrile; alkanols such as C_1-4 alcohol; dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl pyrrolidinone and mixture thereof over a period of 1-10 hours, preferably 3-4 hours and at a temperature from O⁰C to boiling point of the solvent, preferably room temperature to boiling point of the solvent.

Compound of formula II is then cyclized to get compound of formula III. In general cyclization may be done in the presence of a base and a solvent. The base used for the cyclization is selected from the group consisting of but not limited to alkali or alkaline earth metal salts Of Cj-C₅ alkanol, a C₃-C₇ cycloalkanol; an alkali metal salt of ammonia, N-(sec- or tert- C₃-C₆ alkyl)-N-(primary, sec- or tert- C₃-C₆ alkyl)amine; an alkali or alkaline earth metal hydride, hydroxide, oxide, carbonate and a bicarbonate preferably sodium hydroxide, potassium hydroxide and lithium hydroxide in the molar ratio of 2 to 8 mole equivalents preferably 3-4 mole equivalents. The cyclization reaction is carried out in a solvent selected from the group consisting of but not limited to alkanol such as C i-₄ alcohol; ether such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; ester such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone such as methyl ethyl ketone, acetone, methyl isobutyl ketone; nitrile such as acetonitrile; water, dimethylsulfoxide, dimethylformamide, dimethylacetamide, ethylene glycol, diethylene glycol, dioxane, diglyme, toluene, xylene and mixures thereof at a temperature from about room temperature to reflux temperature of the solvent preferably 110-140⁰C over a period of 2-15 hours preferably 4-6 hours.

The compound of formula III is then reacted with halo ester in presence of a base and solvent to give compound of formula IV i.e. 5-[2-ethαxy carbonyloxy-5-(4-methyl piperazine- 1 -yl-sulfonyl)phenyl] - 1 -methyl-3 -n-propyl- 1 ,6-dihydro-7H-pyrazolo- [4,3 -d] pyrimidin-7-one. The halo ester used for the reaction is selected from the group consisting of but not limited to ethyl chloroformate, benzyl chloroformate,' phenyl chloroformate preferably ethyl chloroformate, in a molar ratio of 1-5 equivalents and most preferably 1-3 equivalents, whereas the base used for the reaction is selected from the group consisting of but not limited to alkyl amines such as triethyl amine, n-propyl amine, tri n-butyl amine, diisopropyl ethyl amine. The reaction is carried out in a solvent selected from the group consisting of but not limited to halogenated hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; aromatic hydrocarbon such as toluene and xylene; ester such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone such as methyl ethyl ketone, acetone, methyl isobutyl ketone; nitrile such as acetonitrile and ether such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether and mixture thereof at a temperature of about -1O⁰C to reflux temperature preferably 0-50⁰C over a period of 1-36 hours preferably 18-26 hours. Compound of formula IV is then decarboxylated to get Sildenafil base in presence of decarboxylating agent and solvent. The decarboxylating agent used for decarboxylation reaction is selected from the group consisting of but not limited to dicyclohexylcarbodiimide (DCC) and 1,3-diisopropylcarbodiimide (DIC). The reaction is carried out in a closed vessel and a solvent selected from the group consisting of but not limited to alcohol preferably ethanol at a temperature of about 25 to 18O⁰C preferably 100-120⁰C, over a period of about 1 to 48 hours preferably 4-10 hours. The product Sildenafil base is isolated and purified by conventional purification procedures known for the person skilled in the art like crystallization, precipitation and column chromatographic techniques. Preferably the obtained sildenafil base is isolated through crystallization using the solvent, which is selected from the group consisting of but not limited to halogenated hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; aromatic or aliphatic hydrocarbon such as toluene, xylene, C_5-8 hydrocarbons; ester such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone such as methyl ethyl ketone, acetone, methyl isobutyl ketone; and ether such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; alkanols such as CM alcohol and mixtures thereof. The isolated Sildenafil base can be recrystallized or purified from alkanol such as Ci_-4 alcohol, ether such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether, ester such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; nitrile such as acetonitrile; halogenated hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene, aromatic or aliphatic hydrocarbon such as toluene, xylene, C_5-8 hydrocarbon; ketone such as methyl ethyl ketone, acetone, methyl isobutyl ketone and mixtures thereof.

Sildenafil base is then converted to the Sildenafil citrate by treating the Sildenafil base with citric acid in presence of organic solvent selected from group consisting of but not limited to alkanol such as Ci_-4 alcohol; ketone such as methyl ethyl ketone, acetone, methyl isobutyl ketone; ester such as ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; aromatic or aliphatic hydrocarbon such as toluene, xylene, C₅-₈ hydrocarbon; ether such as tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; halogenated hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; nitrile such as acetonitrile and mixtures thereof. The reaction is carried out at a temperature range of about room temperature to reflux temperature preferably 40-60⁰C, for a period of about 30 min to 6 hours. The Sildenafil citrate salt obtained is purified by conventional purification procedures.

According to the invention compound of formula I is a novel and characterized by ¹H- NMR, ¹³C-NMR and IR. The process for the preparation of compound I as depicted in scheme 2, which involves the reaction of salicylic acid (VIII) with chlorosulfonic acid optionally in presence of thionyl chloride to get the compound of formula (IX), which is then further treated with N-methyl piperazine or its salt thereof. The reaction of N-methyl piperazine with a compound of formula IX is carried out in a solvent selected from the group consisting of but not limited, to C_1-6 alkanol, halogenated hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; ester such as. ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; nitrile such as acetonitrile; aromatic or aliphatic hydrocarbon such as chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; water and mixture thereof at a temperature range of -1O⁰C to reflux temperature preferably 0^:15°C, over a period of 1-5 hours preferably 1-3 hours.

In the present invention purification steps are conventional processes which are well known for the person skilled in the art. In conclusion, this is a novel, economical and a high yielding process for the industrial production of Sildenafil citrate using cheaply available raw materials. The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of the present invention in any way.

Example 1

Preparation of 2- hydroxy-5-(4 methyl)-l-piperazinyl sulphonyl) benzoic acid Step-1: Preparation of 5-Chlorosulfonyl-2-hydroxy benzoic acid

To the chilled chlorosulfonic acid (1012 g), salicylic acid (200 g) was added at 0-5⁰C over a period of 1 hour 40 min. The temperature of the reaction mixture was maintained at 20-25⁰C for 2 hrs. Then thionyl chloride (172.4 g) was added over a period of 15 min and maintained for 12 hrs. The product formed was poured onto ice and maintained for lhr. The product was filtered and washed with DM water to get 5-Chlorosulfonyl-2- hydroxy benzoic acid.

Step-2: Preparation of 2-hydroxy-5-(4-methyI)-l-piperazinylsulphonyl)benzoic acid

5-Chlorosulfonyl-2-hydroxy benzoic acid (40Og) obtained in step 1 was dissolved in acetone (1200 ml) and cooled to 5-10⁰C. To this clear solution N-methyl piperazine (254 g) was added and maintained for 2 hrs. The product formed was filtered, washed with water and purified in methanol to get 308 g of the titled compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 2.78 (3H, s), 3.17 (8H, brs), 6.85(1H, d, J = 8.7),

7.52 - 7.56 (IH, dd, J=8.7, 2.7), 7.95 (IH, d, J = 2.7)

¹³C-NMR (75 MHz in DMSO-d₆): δ 41.98, 43.36, 51.60, 117.58, 118.33, 119.46,

130.28, 132.01, 167.63, 170.35.

Melting point: 268-272⁰C

Purity by HPLC: 99.4% Example 2

Preparation of 4-[2-hydroxy-5-(4-methyI-l-piperazinyIsulphonyl)benzamido]-l- methyl-3-n-propyl-lH-pyrazole-5-carboxamide

2-Hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid (10Og) was dissolved in dichloromethane (500 ml) and triethylamine (50 ml) followed by distillation to get residual mass. The residual mass was dissolved in dichloromethane (1500ml) followed by the addition of 1,3-dicyclohexylcarbodiimide (75.6 g) and 1-hydroxybenzotriazole (45g). The reaction mixture was stirred at 27-28⁰C and then 4-amino-l-methyl-3-n-propyl- pyrazole-5-carboxamide (60.6 g) was added. The reaction mixture was heated to reflux temperature and maintained for 3 hours. Filtered the undissolved material at hot and washed the cake with dichloromethane (200ml). The filtrate was distilled out completely to get residue. Dissloved the residue in methanol (300ml) at 4O⁰C and then cooled the mass to 27-28⁰C and stirred overnight. Further, cooled the mass to 5-7⁰C and stirred for lhr. Filtered the product and washed the cake with chilled methanol (100ml) and dried to get 130 g of title compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.87 (3H, t, J = 7.5), 1.53-1.60 (2H, m), 2.39- 2.46(5H, m), 2.72 (4H, brs), 2.96 (4H, brs), 3.17 (3H, s), 3.91 (3H, s), 6.93 (H, d, J = 8.7), 7.57-7.61 (H, dd, J=8.7 & 2.1), NH2-(2H, brs, J =7.69 & 7.72), 8.15 (IH, d, J=2.1) 11.5 (OH, br).

¹³C-NMR (75 MHz in DMSO-(I₆): 613.80, 21.37, 27.45, 44.05, 44.75, 48.60, 52.87, 116.37, 118.06, 119.67, 120.03, 130.64, 132.17, 132.38, 146.16, 160.83, 166.33, 166.89.

Purity by HPLC: 97.5%

Example 3

Preparation of 5-[2-hydroxy-5-(4-methylpiperazinyl-l-yl-sulphonyl)phenyl]-l- methyl -3-n- propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one Sodium hydroxide (34 g) was added into diethylene glycol (780ml) and then heated to 110-115⁰C. 4-[2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzamido)-l-methyl-3-n- propyl-lH-pyrazole-5-carboxamide (130 g) obtained from example 2 was added to the above reaction mixture. The reaction mixture was maintained at 125-13O⁰C for 4-6 hrs. The reaction mixture was cooled to room temperature and then DM water (1300ml) was added slowly over 20min at 25⁰C and maintained at this temperature for 1 hour. Filtered the mass and filtrate pH was adjusted to 6.5-7.5 with dilute hydrochloric acid at room temperature and stirred at room temperature for 2-3hrs. Product was filtered and slurried the cake with excess DM Water followed by purification in methanol to get 91 g of titled compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.96 (3H, t, J=7.2), 1.71-1.83 (2H, m), 2.41 (3H, s), 2.78-2.83 (6H, m), 2.99 (4H, brs), 4.15 (3H₃ s), 6.93 (IH, d, J=8.7), 7.54-7.57 (IH, dd, J=8.7, 2.1), 8.47 (lH, d, J=2.1).

¹³C-NMR (75MHz in DMSO-d₆): 513.84, 21.52, 27.20, 37.80, 43.94, 44.72,- 52.80, 115.97, 119.82, 120.19, 124.48, 128.71, 131.13, 136.46, 143.82, 151.26, 154.05, 167.24.

Purity by HPLC: 97.8%

Example 4

Preparation of 5-[2-ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyI)phenyl]- l-methyI-3n-propyI-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one

5-[2-hydroxy-5-(4-methylpiperazinyl-l -yl-sulphonyl)phenyl]- 1 -methyl-3 -n- propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (90 g) obtained from example 3 was dissolved in dichloromethane (360 ml) and added triethyl amine (41 ml) at room temperature and stirred for 10 min. The reaction mixture was cooled to 0-5⁰C and followed by the addition of ethyl chloro formate (24ml) over 30 min under nitrogen atmosphere. The temperature of the reaction was raised slowly to 28-3O⁰C and maintained for 24 hrs. The reaction mixture was cooled to 0-5⁰C and kept it for 1 hr. The product formed was filtered, washed with dichloromethane, dried and purified from methanol (270ml) to obtain 81 g of the title compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.92 (3H, t, J=7.2), 1.17 (3H, t, J=7.2), 1.68-1.75 (2H, m), 2.16 (3H, s), 3.99 (4H, br), 2.73 (2H, t, J=7.0), 4.12-4.19 (2H, t, J=6.9), 4.15 (3H, s), 7.71 (IH, d, J = 8.7), 7.93-7.97 (IH, dd, J=8.7 & 2.1), 8.01 (IH, d, J=2.0)

¹³C-NMR (75 MHz in DMSO-d₆): 513.47, 13.80, 21.57, 27.03, 37.90, 45.72, 53.49, 65.12, 124.51, 127.65, 130.14, 130.61, 132.82, 137.30, 144.96, 146.51, 151.38, 151.66, 154.36.

Purity by HPLC: 98.6%

Example 5

Preparation of 5-[2-ethoxy-5-(4-methyl piperazine-l-ylsulfonyl)phenyl]-l-methyl-3- n-propyl-1 ,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (Sildenafil base)

5-[2-Ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyl)phenyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (50g) was dissolved in ethanol (750ml) in an autoclave and then added dicyclohexylcarbodimide (29.8g). The reaction temperature was raised to HO⁰C with internal pressure of 1.8-4.0 kg/cm and maintained for 6 hours followed by cooling to room temperature. The solvent was distilled off to get the crude Sildenafil base. The base thus obtained was dissolved in dichloromethane (380ml), filtered and filtrate was distilled out completely to get solid material, which is again dissolved in a mixture dichloromethane and isopropyl ether. The crude obtained was recrystallized from ethanol (260ml) to obtain 17.4gm of pure Sildenafil base.

Purity by HPLC: 99.77% Example 6

Preparation of 5-[2-Ethoxy-5-(4-methylpiperazine-l-yI-sulfonyl)phenyl]-l-methyl- 3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil Citrate)

Sildenafil base (50 g) was dissolved in acetone (850 ml) at 55⁰C and then slowly added citric acid solution (20 g in 100 ml acetone) over 45 min and maintain the reaction mixture for about 30 min. The reaction mixture was cooled, filtered and dried to get 65 g of Sildenafil citrate.

Purity by HPLC: 99.85%

¹H-NMR spectra and !³C-NMR spectra were recorded at 300 MHz NMR spectrometer. Certain modifications and improvements of the disclosed invention will cover to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:

1. A process for the producing the 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl- sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one of formula (V) or its salt thereof employing a novel intermediate, the process comprises: a) condensing the 2-hydroxy-5-(4-methyl-l-piperazinylsulfonyl)benzoic acid (I) with amino pyrazole derivative (VII), coupling agent and a solvent optionally in presence of reagent forming actives esters to form an amide derivative (II); b) cyclizing the amide derivative (II) in presence of base and solvent to get compound of formula III; c) protecting the hydroxy group of the amide derivative (III) with halo ester in presence of base and solvent; d) decarboxylating the compound IV to form Sildenafil base in presence of decarboxylating agent and solvent and; e) treating the Sildenafil base with citric acid in presence of organic solvent to get Sildenafil citrate.

2. The process according to claim 1, wherein said coupling agent used is selected from the group such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1,1-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1,3- diisopropylcarbodiimide and like.

3. The process according to claim 2, wherein coupling agent used is 1,3- dicyclohexylcarbodiimide.

4. The process according to step a of claim 1, wherein said solvent used is selected from the group consisting of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, aliphatic or cyclic ether, ester, ketone, nitrile, alkanol, dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl pyrrolidinone and mixture thereof.

5. The process according to claim 4, wherein halogenated hydrocarbon is chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; aliphatic or aromatic hydrocarbon is C_5-8 aliphatic hydrocarbon, cyclohexane, cycloheptane, xylene, toluene; aliphatic or cyclic ether is tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; ester is ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone is methyl ethyl ketone, acetone, methyl isobutyl ketone; nitrile is acetonitrile; alkanol is C_1-4 alcohol.

6. The process according to claim 1, wherein reagent forming active esters used is 1- hydroxy benzotriazole, N-hydroxy succinimide and N-hydroxy phthalimide.

7. The process according to step b of claim 1, wherein said base used is alkali or alkaline earth metal salts of C₁-C₅ alkanol, a C₃-C₇ cycloalkanol; an alkali metal salt of ammonia, a N-(secondary or tertiary C₃-C₆ alkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine; an alkali or alkaline earth metal hydride, hydroxide, oxide, carbonate and a bicarbonate.

8. The process according to step b of claim 1, wherein said solvent used is selected from alkanol; ether; ester; ketone; nitrile; water, dimethylsulfoxide, dimethylformamide, dimethylacetamide, ethylene glycol, diethylene glycol, dioxane, diglyme, toluene, xylene and mixture thereof.

9. The process according to claim 8, wherein alkanol is C_M alcohol; ether is tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; ester is ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone is methyl ethyl ketone, acetone, methyl isobutyl ketone; nitrile is acetonitrile.

10. The process according to step c of claim 1, wherein said solvent used is selected from halogenated hydrocarbon; aromatic hydrocarbon; ester; ketone; nitrile and ether and mixture thereof.

11. The process according to claim 10, wherein halogenated hydrocarbon is chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; aromatic hydrocarbon is toluene and xylene; ester is ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; ketone is methyl ethyl ketone, acetone, methyl isobutyl ketone; nitrile is acetonitrile and ether is tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether.

12. The process according to step c of claim 1, wherein said base used is alkyl amines such as triethyl amine, n-propyl amine, tri n-butyl amine, diisopropyl ethyl amine.

13. The process according to claim 1, wherein said halo ester used is ethyl chloroformate, benzyl chlαrofoπήate and phenyl chloroformate.

14. The process according to step d of claim 1, wherein said reagent used is dicyclohexylcarbodiimide (DCC) and 1,3-diisopropylcarbodiimide (DIC).

15. The process according to step d of claim 1, wherein said solvent used is alcohol preferably ethanol.

16. The process according to step e of claim 1, wherein said organic solvent used is alkanol; ketone; ester; aromatic or aliphatic hydrocarbon; ether; halogenated hydrocarbon; nitrile and mixture thereof.

17. The process according to claim 16, wherein alkanol is CM alcohol; ketone is methyl ethyl ketone, acetone, methyl isobutyl ketone; ester is ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate; aromatic or aliphatic hydrocarbon is toluene, xylene, C_5-S hydrocarbon; ether is tetrahydrofuran, dioxane, diethyl ether, isopropyl ether and methyl t-butyl ether; halogenated hydrocarbon is chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene; nitrile is acetonitrile.

18. A novel intermediate 2-hydroxy-5-(4-methyl)-l-piperazinylsulphonyl)benzoic acid (I) or its salt thereof.

19. A process for the preparation of 2-hydroxy-5-(4-methyl)-l- piperazinylsulphonyl)benzoic acid (I) or its salt thereof comprises:

a) treating the salicylic acid (VIII) with chlorosulphonic acid optionally in the presence of thionyl chloride to get 5-chlorόsulfonyl-2-hydroxy benzoic acid

(IX); b) condensing the N-methyl piperazine or its salt thereof with 5-chlorosulfonyl-2- hydroxybenzoic acid (IX) in presence of solvent to get the compound of- formula (I) or its salt thereof.

20. The process according to claim 19, wherein solvent used is selected from C_1-6 alkanol, halogenated hydrocarbon; ester; nitrile; aromatic or aliphatic hydrocarbon; water and mixture thereof.

21. The process according to claim 20, wherein solvent is chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, methyl acetate, acetonitrile, chloroform, dichloromethane, dichloromethane, carbon tetrachloride, tetrachloroethane, chlorobenzene, dichlorobenzene and watfC~