FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
"PROCESS FOR PREPARATION OF URAPIDIL"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of urapidil and its pharmaceutically acceptable salt. The present invention further relates to a process for the preparation of the 6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino]-l,3-dimethyluracil compound of formula II which is a useful intermediate in the preparation of urapidil.
BACKGROUND OF THE INVENTION
Urapidil is a sympatholytic antihypertensive drug, which is chemically known as 6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino]-1,3-dimethyluracil, free base CAS No.34661-75-1. Urapidil Formula I has the following structure:

Formula I Urapidil is currently available in Europe under the brand names of Ebrantil®, Eupressyl®, Uraprene®.
United States Pat. No 3,957,786 (US,786) discloses multiple processes for the preparation of urapidil. Among these processes, one process comprises the condensation of 6-chloro-l,3-dimethylpyrimidine-2,4(lH,3H)-dione compound of formula VI with 3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-1-amine compound of Formula-VII in the presence of a base.


Formula VI Formula VII
US'786 also discloses a process for the preparation of urapidil, which comprises the condensation of 6-((3-chloropropyl)amino)-1,3-dimethylpyrimidine-2,4(lH,3H)-dione with l-(2-methoxyphenyl)piperazine by means of addition of a base.
The present invention provides a novel process for preparing urapidil, compound of formula I, in robust yields, hitherto unreported, which involves the condensation of two intermediates. The present invention provides the preparation of a compound of formula II, which is one of the intermediates used for the novel process for preparing urapidil, herein described.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of urapidil, compound of formula-I and its pharmaceutically acceptable salt.


comprising reacting a compound of formula-II with a compound of formula-Ill, wherein L in formula II represents a leaving group selected from a group consisting of a halogen, an alkylsulfonyloxy or an arylsulfonyloxy group.

The present invention provides a process for preparation compound of formula II comprising reacting a compound of formula-IV with a compound of formula-V, wherein L in formula II is a halogen and X in formula V is a halogen, in the presence of a base, a phase transfer catalyst and a metal halide.

Formula-IV Formula-V
The present invention also provides urapidil having a chemical purity of greater than about 99.5% as measured by high performance liquid chromatography (HPLC).
The present invention also provides urapidil compound of formula-I prepared by the process herein described above, having less than about 0.5 area % of total impurities, as measured by HPLC.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for preparation of urapidil, compound of formula-I

Formula I comprising reacting a compound of formula-II with a compound of formula-Ill, wherein L of formula II, represents a leaving group selected from a group consisting of a halogen, an alkylsulfonyloxy or an arylsulfonyloxy group.

Formula II Formula III
The term "halogen" as used herein means iodine, bromine, chlorine and fluorine.
The term "alkylsulfonyloxy" as used herein means any alkylsulfonyl group appended to the parent molecular moiety through an oxygen atom, as for example mesyloxy.

The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "arylsulfonyloxy" as used herein means any arylsulfonyl group appended to the parent molecular moiety through an oxygen atom for example benzenesulfonyloxy and tosyloxy.
The reaction of compound of formula-II with compound of formula-Ill may be carried out in the presence of a base. The base may be selected from a group consisting of an inorganic base and an organic base.
The inorganic base may be selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, and potassium hydride and the like.
The organic base may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, N-methylmorpholine and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium methoxide, potassium ethoxide, potassium-tert-butoxide lithium methoxide, lithium ethoxide, lithium-tert-butoxide and the like.
Preferably, the base is an inorganic base.
The reaction of a compound of formula-II with a compound of formula-Ill may be carried out in a solvent. The solvent may be selected from the group consisting of nitrile solvent such as acetonitrile, phenylacetonitrile, isobutyronitrile, benzonitrile, propinitrile and the like; dinitrile solvents such as 2-methylglutaronitrile and glutaronitrile and the like; amide solvent such as

dimethylformamide the like; hydrocarbon solvents such as toluene, hexane and the like; ether solvent such as tetrahydrofuran and the like.
Preferably, the solvent is a nitrile like acetonitrile.
The reaction of compound of formula-II with compound of formula-Ill may be carried out in presence of phase transfer catalyst optionally in presence of metal halide.
The phase transfer catalyst may be selected from the group consisting of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands and polyethylene glycols and the like. Preferably, the phase transfer catalyst is a quaternary ammonium salt like methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide and the like.
The metal halide is selected from the group consisting of metal iodide like calcium iodide, sodium iodide, potassium iodide, magnesium iodide, zinc iodide, cupric iodide, and manganese iodide and the like; metal bromide like potassium bromide, sodium bromide and the like.
Preferably, the metal halide is a metal iodide like potassium iodide.
The reaction of compound of formula-II with compound of formula-Ill may be carried at temperature of about 20 °C to about 80°C.
In one embodiment, the compound of formula II is reacted with compound of formula III in the presence of an alkali metal carbonate.
In one embodiment, the compound of formula II is reacted with compound of formula III in the presence of an alkali metal carbonate and a phase transfer catalyst. Preferably the alkali metal carbonate is potassium carbonate and the phase transfer catalyst is tetrabutylammonium iodide.
In one embodiment, the compound of formula II is reacted with compound of formula III in the presence of a base, a phase transfer catalyst and a metal halide. Preferably, the base is alkali

metal carbonate or alkali metal hydride and the phase transfer catalyst is tetrabutylammoniumbrornide and metal halide is potassium iodide.
In one embodiment, the compound of formula II is reacted with a compound of formula III in the presence of potassium carbonate and tetrabutylammonium bromide and potassium iodide, wherein L of formula II, is a halogen.
In one embodiment, the compound of formula II is reacted with a compound of formula III in the presence of potassium carbonate and tetrabutylammonium bromide and potassium iodide, wherein L of formula II, is chlorine.
In one embodiment, the compound of formula II is reacted with a compound of formula III in the presence of sodium hydride and tetrabutylammonium bromide and potassium iodide, wherein L of formula II, is a halogen.
In one embodiment, the compound of formula II is reacted with a compound of formula III in the presence of sodium hydride and tetrabutylammonium bromide and potassium iodide, wherein L of formula II, is chlorine.
The compound of formula-I, optionally, may be subjected to solvent purification. The purification and isolation of compound of formula I, optionally, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization
The recrystallization solvent may be selected from the group consisting of hydrocarbons, esters and the like.
In another aspect, the present invention provides a process for preparing a compound of formula I comprising reacting a compound formula-IV with a compound formula-V in the presence of a base, a phase transfer catalyst and a metal iodide, wherein L of formula II, is a halogen and X of formula V, is a halogen,


The base may be selected from the group consisting of organic base and inorganic base.
The inorganic base may be selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, and potassium hydride and the like.
The organic base may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, N-methylmorpholine and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium methoxide, potassium ethoxide, potassium-tert-butoxide lithium methoxide, lithium ethoxide, lithium-tert-butoxide,
Preferably, the base is an alkali metal carbonate like potassium carbonate.
The phase transfer catalyst may be selected from the group consisting of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands and polyethylene glycols and the like. Preferably, the phase transfer catalyst is a quaternary ammonium salt like methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide and the like.

The metal halide is selected from the group consisting of metal iodide like calcium iodide, sodium iodide, potassium iodide, magnesium iodide, zinc iodide, cupric iodide, and manganese iodide and the like; metal bromide like potassium bromide, sodium bromide and the like.
Preferably, metal halide is a potassium iodide.
The reaction of compound of formula-IV with compound of formula-V may be carried out in a solvent. The solvent may be selected from the group consisting of nitrile solvent such as acetonitrile, phenylacetonitrile, isobutyronitrile, benzonitrile, propinitrile and the like; dinitrile solvents such as 2-methylglutaronitrile and glutaronitrile and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ketone solvents such as acetone and the like; amide solvent such as dimethylformamide the like; hydrocarbon solvents such as toluene, hexane and the like; halogenated solvents such as methylene dichloride and ethylene chloride and the like; ether solvent such as tetrahydrofuran and the like.
Preferably, the solvent is a ketone like acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone and methyl tert-butyl ketone. More preferably, acetone.
The reaction of compound of formula-IV with compound of formula-V may be carried at temperatures of about 20°C to about 80°C.
In one embodiment, the present invention presents the preparation of the compound of formula II comprising reacting compound of formula-IV with a compound of formula-V in the presence of potassium carbonate, tetrabutylammonium bromide and potassium iodide in acetone, wherein L of formula II, is a halogen.
In one embodiment, the present invention presents the preparation of the l-(3-chloropropyl)-4-(2-methoxyphenyl) piperazine compound of formula II, wherein L of formula II is chlorine, comprising reacting a compound of formula-IV with 1-bromo-3-chloropropane, compound of formula-V wherein one X is C1 and the other X is Br, in the presence of potassium carbonate, tetrabutylammonium bromide and potassium iodide in acetone.

The present invention provides the preparation of the compound of formula-I as herein described further optionally comprising solvent purification. The purification solvent is selected from a group consisting of ketone, alcohols, acetate, nitriles and the like.
The present invention provides urapidil having a chemical purity of greater than about 99.5%, as measured by HPLC.
The present invention provides urapidil prepared by the process herein described, having less than about 0.5 area % of total impurities as measured by HPLC.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. These examples are not intended to limit the scope of the invention as defined hereinabove.

EXAMPLES
EXAMPLE 1: Preparation of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine compound of Formula-II
Into a clean round bottom flask 1 litre of acetone was charged. The flask was cooled to about 15°C 20°C. 100gm of l-(2-Methoxy phenyl) piperazine, 122.83g of 1-bromo-3-chloropropane, 7.67gm of potassium carbonate, 4.3 g. potassium iodide, 8.38g. Tetrabutylammonium bromide was charged. The reaction mixture was stirred at about 15°C to about 20 for about 28-30 hr. After completion of reaction, the reaction mass was filtered and wet cake was washed with about 200ml of acetone. The filtrate and washings were combined and the acetone was distilled out followed by degassing completely under vacuum below about 40°C. To the degassed mass was charged 500mlof methylene dichloride and stirred at room temperature for about 15-20min. The organic layer was washed with water 500 ml x 3. The organic layer was separated and methylene dichloride was distilled out under vacuum. 400ml acetone was charged in the degassed mass and stirred at room temperature for about 25-30min. The reaction mixture was cooled to about 10°Cto about 15°C and purified water was added slowly to the reaction mixture by maintaining temperature below about 15°C. After addition of purified water, the reaction mixture was cooled to about 5°C 10°C and temperature was maintained for about 3-4 hours. The reaction mass was filtered and wet cake was washed with water. The material was dried in vacuum dryer at about 30°C 35°C.
Yield: 110-127g
EXAMPLE 2: Preparation of 6-[3-[4-(2-Methoxyphenyl) piperazin-l-yl]propylamino]-l,3-dimethyluracil (Urapidil) Formula-I
Into a clean round bottom flask containing 750ml of acetonitrile, 100g of compound of formula II (as prepared in Example 1) 77gm of potassium carbonate, 57g of 6-aminol,3-dimethylpyrimidine-2,4(lH,3H)-dione and potassium iodide(3.5 g) and tetrabutylammonium bromide (TBAB 5.96 g) was charged. The reaction mass was heated to reflux and the temperature of the reaction mass was maintained for about 20-24 hr. After completion of

reaction, the reaction mass was cooled to about 20°C to about 25°C and filtered. The wet cake was washed with acetonitrile. The combined filtrate was subjected to distillation under vacuum at about 45°C to about 50°C. The residue obtained was dissolved in 500ml methylene dichloride. The methylene dichloride layer was washed with water 500 ml x 3, and dried over sodium sulphate and distilled out under vacuum followed by stripping out by 100ml of toluene. 400ml toluene was charged to mass and the reaction mixture was heated to about 65°C to about 70°C. The temperature was maintained for about 15 min. The reaction mass was cooled to about 20°C to about 25°C.and maintained at that temperature for about 4 hr. The reaction mass was filtered and the wet cake was washed with 50 ml of toluene. The material was dried in vacuum dryer at about 40°C to about45°C.
Yield: 55g
Example 3 Purification of 6-[3-[4-(2-Methoxyphenyl) piperazin-1-yl]propylamino]-l,3-dimethyluracil
Into a clean round bottom flask containing toluene (1000ml) was charged crude urapidil (100gm) (as prepared in Example 2) at about 20°C to about 25°C. The reaction mass was heated to about 80°C to about 85°C for about 25-30 minutes. The reaction mixture was cooled at about 20°C to about 25°C. The reaction mixture was stirred for about lhr and filtered. Finally the precipitate was washed with toluene (50ml). The reaction mixture was dried at about 40°C to about 45°C for about 12-16hrs. Yield: 70-85g HPLC Purity: 97%
Example 4: Purification 6-[3-[4-(2-Methoxyphenyl) piperazin-l-yl]propylamino]-l,3-dimethyluracil
lOOg of Urapidil (as prepared in Example 3) was dissolved in 250ml of ethyl acetate at about 80°C to about 85°C. The temperature was maintained for about 30 min. The reaction mass was cooled to about 70°C to about 75°C. If not clear, the hot mass was filtered and heated to about 75°C to about 80°C. The temperature was maintained for about 60 min. The reaction mass was cooled to about 20°C to about 25°C and maintained at that temperature for about 2 hours. The

reaction mass was filtered and washed with chilled ethyl acetate. The material was dried at about 45°C to about 50°C under vacuum.
Yield: 50 gm HPLC Purity: 99.5
EXAMPLE 5: Preparation of 6-[3-[4-(2-Methoxyphenyl) piperazin-1-yl] propylamino]-l, 3-dimethyluracil (Urapidil)
Into a clean round bottom flask containing 50ml of dimethylformamide was charged with 6-aminol,3-dimethylpyrimidine-2,4(lH,3H)-dione (2.88g) and sodium hydride (0.8gm). The reaction mixture was heated at about 80°C to about 85°C for about 2 hr. The reaction mixture was cooled at room temperature. The reaction mixture was charged with compound of formula II (5g), potassium iodide (0.18 g) and tetrabutylammoniumbromide (0.2 g). The reaction mass was heated to reflux and temperature of the reaction mass was maintained for about 10-12 hr. After completion of reaction the reaction mass was cooled at about 20°C to about 25°C. The reaction mixture was charged with methanol (5ml) and methylenedichloride. The reaction mixture was washed with water. The organic layer was subjected to distillation under vacuum at about 40 °C to about 45°C. The obtained residue was dissolved in hexane (5ml) and ethyl Acetate (15ml). The reaction mass was heated at about 40°C to about 45 °C and the reaction mixture was maintained temperature to about 40°C to about 45°C for about 15-30 min. The reaction mixture was cooled at about 5°C to about 10°C. The reaction temperature was maintained for about 2 hr. The reaction mass was filtered and the wet cake was washed with chilled ethyl acetate (10ml). The material was dried in dryer at about 40 °C to about 45°C under vacuum.
Yield: 1.6 g
HPLC Purity: 99.05 %

We claim
1. A process for preparation of urapidil compound of formula-I,

Formula I comprising reacting a compound of formula-II with a compound of formula-Ill, wherein L of formula II, represents a leaving group selected from a group consisting of a halogen, an alkylsulfonyloxy or an arylsulfonyloxy group.

Formula II Formula III
2. The process as claimed in claim 1, wherein L is a halogen.
3. The process as claimed in claim 1, wherein the reaction is carried out in presence of a base.

4. The process as claimed in claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst, and optionally in the presence of a metal halide.
5. A process for the preparation of compound of formula-II, wherein L of formula II is a halogen, the process comprising reacting a compound of formula-IV with a compound of formula-V wherein X of formula II is halogen, in the presence of a base, a phase transfer catalyst and a metal halide.

Formula-IV Formula-V
6. The process as claimed in claim 5, wherein the base is selected from the group consisting of an organic base and inorganic base.
7. The process as claimed in claim 5, wherein the phase transfer catalyst is selected from the group consisting of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands and polyethylene glycols
8. The process as claimed in claim 5, wherein the reaction is carried out in a solvent selected from the group consisting of ketone, alcohols, amides and nitriles.
9. Urapidil having a chemical purity of greater than about 99.5% as measured by high performance liquid chromatography.

10. Urapidil prepared by the process herein described above, having less than about 0.5 area % of total impurities as measured by high performance liquid chromatography.