This application claims priority to this Indian patent application numbers 1877/CHE/2012 filed on May 11,2012.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Vardenafil hydrochloride.

BACK GROUND OF THE INVENTION:

Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Vardenafil is chemically known as 2-[2-ethoxy-5-(4-ethyl-piperazine-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one and structurally represented as below.

Vardenafil is disclosed in US 6362178 and marketed as Vardenafil monohydrochloride trihydrate under the brand name of LEViTRA®. It is indicated for the treatment of erectile dysfunction in male.

US' 178 patent disclosed vardenafil process, wherein 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one of formula IV is reacted with excess quantity of chlorosulfonic acid to provide 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[l,5-fj[l,2,4]triazin-2-yl)benzene-l-sulfonyl chloride of formula III, followed by reaction with N-ethylpiperazine to give vardenafil of formula II. The reaction steps as illustrated by the following scheme:

In this process, the sulphonyl chloride of formula III intermediate is sensitive to hydrolysis, which in particular in the conversion of this preparation to the industrial scale can lead to not inconsiderable yield variations.

US 677551 patent disclosed the process of Vardenafil, wherein 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4- one of formula IV is reacted with sulfuric acid to provide 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,l-fj[l,2,4]triazin-2-yl) benzenesulfonic acid of Formula Ilia, which is then reacted with thionyl chloride and subsequently with N-ethylpiperazine to give vardenafil of formula II. The reaction steps as illustrated by the following scheme:

The inventors of the present invention have developed an alternate improved process with a chlorinating agent. The present process is simple, cost effective and feasible in large scale production.

SUMMARY OF THE INVENTION:

One aspect of the present invention provides a process for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV with chlorosulfonic acid and chlorinating agent to get 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-fJ [l,2,4]triazin-2-yl)benzene-l-sulfonyl chloride of formula III,

b) reacting4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-f][l,2,4]triazin-2-yl)benzene-l-sulfonyl chloride of formula HI with N-ethylpiperazine to give vardenafil free base of formula II, and

c) converting vardenafil free base of formula II to hydrochloride salt of formula I.

Another aspect of the present invention provides a process for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV with chlorosulfonic acid and phosphorous pentachloride to get acid chloride of formula III,

b) reacting acid chloride of formula HI with N-ethylpiperazine to give vardenafil free base of formula II, and

c) converting vardenafil freebase of formula II to hydrochloride salt of formula I.

The present invention is shown in the below scheme.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Vardenafil hydrochloride, wherein 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV is reacted with chlorosulfonic acid and phosphorous penta chloride to obtain acid chloride intermediate of formula III, followed by insitu reaction with N-ethyl piperazine to form Vardenafil free base of formula II and finally converted to hydrochloride salt.

One embodiment of the present invention provides a process for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV with chlorosulfonic acid and chlorinating agent to get acid chloride of formula HI,

b) reacting acid chloride of formula III with N-ethylpiperazine to give vardenafil free base of formula II, and

c) converting vardenafil free base of formula II to hydrochloride salt of formula I.

According to the present invention 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV is reacted with chlorosulfonic acid and a chlorinating agent in a solvent at 0 to 5°C for about 6-8hrs. After completion of the reaction, water is added and separated the organic layer. The organic layer containing acid chloride intermediate is reacted with N-ethylpiperazine at 20-25°C. The obtained product is separated by adjusting the pH to 7.5-9.0 to get vardenafil free base of formula II. The free base of formula II is reacted with aqueous hydrochloric acid in presence of ketone solvent to get vardenafil hydrochloride of formula I.

Another embodiment of the present invention provides a process for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV with chlorosulfonic acid and phosphorous pentachloride to get acid chloride of formula III,

b) reacting acid chloride of formula III with N-ethylpiperazine to give vardenafil free base of formula II, and

c) converting vardenafil freebase of formula II to hydrochloride salt of formula I.

According to the present invention 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one of formula IV is reacted with chlorosulfonic acid and phosphorous pentachloride in a dichloromethane at 0 to 5°C for about 6-8hrs. After completion of the reaction, water is added and separated the organic layer. The organic layer containing acid chloride intermediate is reacted with N-ethylpiperazine at 20-25°C. The obtained product is separated by adjusting the pH to 7.5-9.0 to get vardenafil free base of formula II. The free base of formula II is reacted with aqueous hydrochloric acid in presence of acetone to get vardenafil hydrochloride of formula I.

According to the present invention the solvent used for the reaction is selected from the group of chlorinated solvent, aromatic hydrocarbon solvent, aliphatic hydrocarbon solvent, nitrile solvents and ether solvent. The chlorinated solvent is selected from dichloromethane, dichlorethane, chlorobenzene; the aromatic hydrocarbon solvent is selected from toluene, xylene; aliphatic hydrocarbon solvent is selected from hexane, cyclohexane, methylecyclohexane, heptane, pentane; ether solvent is selected from diethyl ether, tetrahydrofuran; nitrile solvent is selected from acetonitrile.

According to the present invention the solvent used for isolation of vardenafil freebase is ester solvent selected from ethyl acetate, methyl acetate. Vardenafil hydrochloride trihydrate is isolated from ketone solvent in the presence of a seeding. The ketone solvent is selected from acetone, methylethylketone or methylisobutylketone.

According to the present invention the obtained vardenafil hydrochloride trihydrate has having particle size d90 less than 250microns, d50 is less than 100microns and d10 is less than 50microns.

According to the present invention, 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-f] [1, 2, 4] triazin-4-one of formula IV is prepared according to prior art process.

ADVANTAGES OF THE PRESENT INVENTION:

a) One-pot synthesis and all the steps are carried out in single solvent,
b) Cost effective as compared to prior art process,
c) Feasible in large scale production.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION:

Example-1: Preparation of Vardenafil (formula II)

To a stirred solution of chlorosulfonic acid (185gm), dichloromethane (300ml), phosphorous pentachloride (50gm) was added in lot wise manner at 25°C and cooled the reaction mass to 0-5°C, then 2-(2-ethoxyphenyl)-5-methyl-7-propyl- 3H-imidazo [5, 1-f][l,2,4]-triazin-4-one of formula IV(lOOgm) added slowly in lot wise and raised the temperature to 25°C, stirred the reaction mass for 7hr, crushed ice was added to this reaction mass, added dichloromethane (1200ml), stirred for 30minutes at 22°C and allowed it to separate the layers. Charged sodium bicarbonate solution to the organic layer for pH adjustment and separated the organic layer. Added N-ethylpiperazine (75gm) to above organic layer at 0-5° C stirred for 45min and raised the temperature to 30°C. Charged water to the reaction mass and allowed it to separate the layers, sodium chloride solution was added to organic layer and it distilled off solvent completely. Then washed with ethyl acetate and dried to get the vardenafil free base. Wt: HOgms

Example-2: Preparation of Vardenafil hydrochloride (formula I)

To a stirred solution of vardenafil free base (100gm), acetone (600ml), water (50ml), hydrochloric acid (20ml) was added at 25°C. The reaction mass temperature was raised to 50-60°C and maintained it for 30-45min. Temperature was cooled to 40-45°C.Seeding material (lgm) was added and stirred the reaction mass for 20-30min. cooled the reaction mass to 25-35°C and stirred it for 4-5hr.The reaction mass was filtered and washed with water. Dried the wet compound and obtained vardenafil hydrochloride trihydrate. Wt: 85gms

Example-3: Preparation of Vardenafil hydrochloride (formula I)

To a stirred solution of vardenafil of formula II (lOOgm), acetone (600ml), water (50ml), hydrochloric acid (20ml) was added at 25°C the reaction mass temperature was raised to 50-60°C and maintained it for 30-45min. temperature was cooled to 40-45°C and stirred the reaction mass for 20-30min. cooled the reaction mass to 25-35°C and stirred it for 4-5hr. The reaction mass was filtered and washed with water. Dried the wet compound and obtained vardenafil hydrochloride trihydrate.

Wt: 85gms

We Claim:

1. A process for the preparation of vardenafil hydrochloride comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one with chlorosulfonic acid and chlorinating agent to get 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-fJ [ 1,2,4]triazin-2-yl)benzene-1 -sulfonyl chloride,

b) reacting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-fJ[ 1,2,4] triazin-2-yl)benzene-l-sulfonyl chloride with N-ethylpiperazine to give vardenafil free base, and

c) converting vardenafil free base to hydrochloride salt.

2. The process according to claim 1, wherein chlorinating agent is selected from the group consisting of phosphorus penta chloride, phosphorus trichloride, phosphorus oxy chloride or oxalyl chloride.

3. A process for the preparation of vardenafil hydrochloride comprising the steps of:

a) reacting 2-[2-ethoxy-phenyl]-5-methyl-7-propyl-3H-imidazo [5, 1-fJ [1, 2, 4] triazin-4-one with chlorosulfonic acid and phosphorous pentachloride to get 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[l,5-f][l,2,4]triazin-2-yl)benzene-l-sulfonyl chloride,

b) reacting 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-fJ[ 1,2,4] triazin-2-yl)benzene-l-sulfonyl chloride with N-ethylpiperazine to give vardenafil free base, and

c) converting vardenafil freebase to hydrochloride salt.

4. The process according to claims 1 and 3, wherein said reaction is carried out in a solvent selected from dichloromethane, dichlorethane or chlorobenzene.

5. The process according to claims 1 and 3, wherein 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[ 1,5-f] [ 1,2,4]triazin-2-yl)benzene-1 -sulfonyl chloride is reacted insitu with N-ethylpiperazine.

6. The process according to claims 1 and 3, wherein vardenafil free base is converted to its hydrochloride salt using aqueous hydrochloride and ketone solvent.

7. The process according to claim 6, wherein ketone solvent is selected from acetone, butanone or methyl isobutyl ketone.

8. The process according to any preceding claims, wherein vardenafil hydrochloride has particle size d90 less than 250 microns, d50 is less than 100 microns and dlO is less than 50 microns.