FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of rimonabant of formula-I.
(Figure Remove)
Formula-I
In more precise words, the present invention particularly relates to an advantageous process that results in the production of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-yV-(piperidin-l-yl)pyrazole-3-carboxarnide or salt thereof in high yield and purity using milder reaction conditions,
BACKGROUND OF THE INVENTION
Rimonabant of formula I is a selective CB1 endocannabinoid receptor antagonist and is chemically known as 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-l-yl)pyrazole-3-carboxamide.
(Figure Remove)
Formula-I
It is indicated for the treatment of obesity, smoking cessation, overweight and related diseases.
Rimonabant, its salts or solvates were first disclosed in US patent 5,624,941. Several processes for the preparation of rimonabant are reported therein. According to one of the processes, rimonabant is prepared by the reaction of 4-chloropropiophenone with diethyl oxalate in the presence of alkali metal salt of hexamethyldisilazane in ether at -78°C, the resulting alkali metal salt of ketoester of formula II,

OCH2CH3
M

M is lithium or sodium
Formula-II
is reacted with an aryl hydrazine derivative to form a hydra/one derivative of
formula III,
Cl

Formula-Ill
which is further made to cyclize in the presence of acetic acid to form pyrazole-3-
carhoxylate ester of formula IV,
'OCH2CH3
CH,
(Figure Remove) CL
Formula-IV
which upon basic hydrolysis forms pyrazole-3-carboxylic acid of formula V,
(Figure Remove)
CHa
cr
Formula-V
Alternatively alkali metal salt of ketoester of formula II is prepared by reaction of alkali metal salt of hexamethyldisilazane with 4-chloropropiophenone in methylcyclohexane at ambient temperature.
Further conversion of hydrazone intermediate of formula 111 to pyra/ole-3-carboxylic acid of formula V is carried out by using para-toluenesulIonic acid in toluene followed by hydrolysis with base viz. potassium hydroxide in melhanol.
According to another process, alkali metal salt of ketoester of formula II is refluxed with excess of hydrazine derivative in acetic acid to form a pyra/ole-3-earboxylate ester intermediate of formula IV. This ester is then converted to pyra/ole-3-carboxylic acid of formula V using alkaline agent in the presence of methanol, followed by acidification.
The pyrazole-3-carboxylic acid of formula V, formed by any of the above processes can be converted to its activated functional derivative and is reacted with 1-aminopiperidine to form rimonabant.
In exemplified process, rimonabant is prepared via the conversion of pyra/olc-3-earboxyiie acid to its chloride derivative by reaction with thionyl chloride in toluene and further condensation with 1-aminopiperidine in the presence of triethylamine in dichloromethane.

There are several drawbacks in the prior art process. In the exemplified process for the preparation of lithium salt of ketoester of formula II, the reaction is carried out at -78°C and further reported yields are very low i.e. around 37 %. In another example, although reaction is carried out at ambient temperature, the solvent used is methylcyclohexane which is very costly.
Moreover, during the process of formation of pyrazole-3-carboxylic acid, the above invention teaches the use of acids like acetic acid or para-toluenesui Ionic acid.
Another major drawback of the reported process is the use of triethylamine as acid scavenger during condensation of acid chloride derivative of pyrazole-3-carboxylic acid with 1-aminopiperidine to prepare rimonabant. Triethylamine is not listed in ICH guidelines and is considered to be carcinogenic, harmful and corrosive and may cause damage to liver and mucous membranes. Therefore it should be absent or be present in very less amounts and hence is not acceptable from ecological standpoint. Another drawback of the reported process is that crude rimonabant is purified by column chromatography, and the concentrated desired fractions are crystallized from isopropyl ether and in another exemplified process crude product is crystallized from methyl cyclohexane to give purified rimonabant.
It should be noted that the prior art process makes use of corrosive and costly reagents and solvents, stringent reaction conditions and results in low yields of rimonabant and its intermediates and hence is not suitable from commercial point of view. Moreover purification using tedious and cumbersome column chromatography makes the process impractical for industrial scale.
Therefore, there is an urgent need to develop a simple and cost effective process to prepare rimonabant which is easy to implement on industrial scale. It is therefore, an object of the present invention to provide an efficient, improved and cost effective
process for preparing rimonabant, which is environment friendly by avoiding the use of harmful acidic reagents and stringent reaction conditions.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an industrially advantageous process for the preparation of rimonabant by using milder reaction conditions, thus reducing the formation of impurities, eliminating the use of costly and corrosive reagents and providing rimonabant in exceptionally high purity and yield.
One embodiment of the present invention provides an improved and industrially advantageous process for the preparation of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-A^-(piperidin-l-yl)pyrazole-3-carboxamide (rimonabant) of formula-I and its salts thereof
(Figure Remove)
FormuIa-I
which comprises:
a) condensing l-(4-chlorophenyl)-propan-l-one with diethylester of oxalic acid in the presence of alkali metal hexamethyldisilazide in an ethereal solvent at 0-40°C to get 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester alkali metal salt of formula II,


M is lithium or sodium
Formula-H
b) reacting alkali metal salt of ketoester of formula II with 2,4-dichlorophenylhydrazine hydrochloride in a suitable alcoholic solvent to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl ester of formula III,
(Figure Remove)


Formula-Ill
along with 5-(4-chlorophenyl)-1 -(3,4-dichlorophenyl)-4-methyl-1 -pyrozole-3-carboxylic acid ethyl ester of formula IV,

0
CH,
c) reacting the mixture of compounds of formula III and IV obtained in step b with a suitable inorganic base in water or optionally water with water miscible organic solvent to give pyro/ole-3-carboxylic acid of formula V,

Formula-V
d) reacting the above formed pyrazole-3-carboxylic acid with thionyl chloride to give pyrazole-3-carbonyl chloride of formula VI, and
CH,
CU
Formula-VI
e) reacting pyrazole-3-carbonyl chloride with 1-aminopiperidine in the presence of inorganic base to yield rimonabant.
According to another embodiment, the present invention provides a process for the preparation of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester alkali metal salt of formula II,
(Figure Remove)
Formula-II
by condensing l-(4-chlorophenyl)-propan-l-one with diethylester of oxalic acid in the presence of alkali metal hexamethyldisilazide in an ethereal solvent at 0-40°C, isolating the product by filtration under inert atmosphere, and converting to rimonabant of formula I.
In yet another embodiment, the present invention provides a process for the preparation of 5-(4-chlorophenyl)-l-(3,4-dichlorophenyl)-4-methyl-l-pyrozole-3-carboxylic acid of formula V,
CH3
ci,
Formula-V
by reacting alkali metal salt of ketoester of formula II with 2,4-dichlorophenylhydrazine hydrochloride in a suitable alcoholic solvent to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl
ester of formula III,

Formula-Ill
along with 5-(4-chlorophenyl)-l-(3,4- dichlorophenyl)-4-methyl-l-pyrozole-3-carboxylic acid ethyl ester of formula IV,
(Figure Remove) and by reacting the above mixture of compounds so formed with a suitable inorganic base in water.
In yet another embodiment, the present invention provides a process for the preparation of rimonabant of formula I
(Figure Remove)
Formula-I
by reacting functional derivative of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl) 4-methyl-l//-pyrazole-3-carboxylic acid of formula V with 1-aminopiperidine in the presence of inorganic base.
In yet another embodiment, the present invention provides a process for the preparation of highly pure rimonabant of formula I
(Figure Remove)can be prepared from the commercially available l-(4-chlorophenyl)propane-l-one by an improved, simple and industrially viable process. Generally, l-(4-chlorophenyl)propane-1-one is taken in an ethereal solvent and is slowly added to a solution of alkali metal hexamethyldisilazide at a temperature of 0 to 40°C. The alkali metal can be selected from lithium, sodium and the like and preferably lithium is used. The ethereal solvent is preferably selected from, but not limited to aliphatic and aromatic ethers. Aliphatic and aromatic ethers can be selected from diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane, dibutyl ether, 1,4-dimethyl tertahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like. Preferably the ether is isopropyl ether. Generally, the reaction mixture is stirred for few minutes to few hours at ambient temperature. Preferably, the reaction mixture is stirred for 15 to 45 minutes. After stirring, a solution of diethyl oxalate in ethereal solvent is added to the reaction mass over a period of few minutes to one hour at the same temperature. The reaction mass is further stirred for few hours at 0 to 40°C. Preferably, the reaction is conducted at 25-35°C and it takes about 4 to 8 hours for completion of reaction. The resulting solid is isolated by filtration under inert atmosphere. It is advantageous to filter under inert atmosphere as product is very much sensitive and hygroscopic and turns to gummy material after coming in contact with air. The inert atmosphere can be generated by any means such as using dry gases like nitrogen, argon etc.
The resulting solid is further dried to obtain crystalline 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester alkali metal salt of formula II,
OCH2CH3
(Figure Remove) • ©
M is lithium or sodium
Formula II
Thus, the present invention provides a process for preparing alkali metal salt of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester in high yield. Inventors of the present invention have been successful in performing the reaction at nearly ambient temperature using ethereal solvent, avoiding low temperature reaction conditions and expensive solvents like methylcyclohexane, reported in the prior art. Thus the reaction can be easily, conveniently and inexpensively scaled-up for industrial production.

According to yet another embodiment of the present invention, alkali metal salt of keto ester of formula II can be converted to 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono|-3-methyl-4-oxo-butyric acid ethyl ester of formula III,
OCH2CH3
CH3 O
(Figure Remove) Cl
Formula-Ill
by reacting with 2,4-dichlorophenylhydrazine hydrochloride.

In a detailed embodiment, alkali metal salt of keto ester of formula II is added to a suspension of 2,4-dichlorophenylhydrazine hydrochloride in an alcoholic solvent at -10°C to ambient temperature. Alcoholic solvent is preferably selected from Ci-C4 alcohols. Most preferably, the solvent used is methanol. The reaction is conducted at a temperature of about -10°C to ambient temperature and it takes 1 to 4 hours for the completion of reaction. The precipitated solid is diluted with water and isolated by filtration, washed with chilled aqueous alcoholic solvent and dried under vacuum to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl ester of formula III.
Formula-Ill
The product is isolated as a pale yellow solid and is found to contain 5-(4-chlorophenyl)- l-(3,4-dichlorophenyl)-4-methyl-l-pyrozole-3-carboxylic acid ethyl ester of formula IV
(Figure Remove) Formula-IV
It is observed that compound of formula IV is present in small to moderate quantity and its presence does not lead to reduction of the yield and purity of the next stage
intermediates used in the preparation of rimonabant. Therefore, the compound of formula III is neither treated with acids to cyclize completely to pyrazole derivative of formula IV nor purified to remove the compound of formula IV. The isolated mixture of formula III and formula IV is used as such in the next step. It is advantageous to avoid the use of acids at this stage since their presence causes formation of large number of impurities thus reducing the purity and yield which further requires complicated separation and purification steps.
According to another embodiment of the present invention, the compound of formula III is converted to 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid of formula V,
(Figure Remove) cu
//
CH3
^ 0
Formula-V
by treating with inorganic bases in water.
Generally, the invention encompasses mixing the dried or semi dried mixture of compounds of formula III and IV with aqueous solution of inorganic base. Typically, inorganic bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. In particular, the base used is potassium hydroxide. Particularly reaction is carried out at reflux temperature and completion of reaction monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mass is cooled to ambient temperature and is acidified with dilute hydrochloric acid to adjust pH of 1.0-1.5. The product, thus precipitated is filtered, washed with chilled water and dried under vacuum to afford 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-
1//-pyrazole-3-carboxylic acid of formula V having purity greater than 98% by HPLC. Thus the present invention provides an environment friendly and cost effective process for the preparation of pyrazole-3-carboxylic acid of formula V, wherein the use of organic solvents is minimized and can be easily, conveniently and inexpensively scaled-up for industrial production.
According to yet another embodiment of the present invention, rimonabant of formula I is prepared from 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid of formula-V or its reactive derivative in exceptionally high purity and yield without involving the use of organic Lewis bases like triethylamine. The reactive derivative that can be used is the acid chloride, the anhydride, a mixed anhydride, an alkyl ester, an activated ester.
Preferably rimonabant of formula I is prepared by reacting pyrazole-3-carboxylic acid chloride of formula VI,
CL
(Figure Remove)
cr
FormuIa-VI
with 1-aminopiperidine in a solvent in the presence of inorganic base.
Generally rimonabant of formula I can be prepared with or without isolating pyrazole-3-carboxylic acid chloride of formula VI. Typically, pyrazole-3-carboxylic acid of formula V is converted to its chloride derivative by reacting with thionyl chloride at a temperature of 20-40°C and further heating at reflux temperature. The reaction can be conducted in the presence or absence of suitable organic solvent. Preferably the organic solvent used is aromatic hydrocarbon selected from amongst
benzene, toluene, xylenes and the like. The reaction mass is refluxed for period of 3-7 hours preferably for 5 hours. Thereafter, the solvent and thionyl chloride are distilled off under vacuum and traces of thionyl chloride are removed by treating the resulting residue with same organic solvent and distilling off the solvent again under vacuum to give 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carbonyl chloride of formula VI.
Additionally, the acid chloride of formula VI is dissolved in halogenated solvent selected from amongst methylene chloride, chloroform, 1,2-dichloroethane, etc. The mixture is cooled to a temperature of about 10-15°C and a solution of 1-aminopiperidine in the halogenated solvent and anhydrous inorganic base is added to the mixture. Typically, inorganic bases may include, alkali metal carbonates, and bicarbonates. The alkali metal carbonates, and bicarbonates may be sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like. In particular, the base used is potassium carbonate. The reaction mixture is stirred at 0-40°C, preferably at 20-30°C. The progress of the reaction is monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass is filtered, washed with demineralized water and dried over anhydrous sodium sulphate to yield rimonabant.
Rimonabant can be purified by using alcoholic solvent or ethers. The alcoholic solvent can be selected from methanol, ethanol, isopropanol and the like. Typically the crude rimonabant is stirred for about 30 minutes to 3 hours, at a temperature of from about 10°C to reflux temperature. The resulting product is filtered and dried to give rimonabant as almost white solid in high yield, having purity greater than 99% by high performance liquid chromatography. Alternatively, rimonabant can be purified by suspending rimonabant in isopropyl ether and then heated to reflux temperature and maintained at the same temperature for a period of about 2-5 hours. The reaction mass is cooled to a temperature of below 20°C, filtered and the resulting
solid is washed with isopropyl ether. The product is dried to give rimonabant as almost white solid in high yield, having purity greater than 99.5% by high performance liquid chromatography. Rimonabant is converted to its salts by the reaction with mineral acids as reported in prior art.
Major advantages realized in the present invention are high yield and purity by using milder reaction conditions which are easy to operate at industrial scale and are environment friendly.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
EXAMPLES Example 1
Preparation of 4-(4-chlorophenvl)-3-methyl- 2,4-dioxobutvric acid ethyl ester lithium salt
To a stirred solution of 4-chloropropiophenone (100 g, 0.59 mol) in isopropyl ether (100 ml), was slowly added a solution of lithium hexamethyldisilazide (98.8g, 0.59 mol, solution in isopropyl ether) at 30-35°C. After stirring for 30 minutes, diethyl oxalate (107g, 0.73 mol) was added over 20 minutes at the same temperature and the reaction mass was stirred for 8 hours at 28-30°C. The solid was filtered under nitrogen atmosphere, washed with isopropyl ether and dried to give 141g of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (yield 86.5%) as a pale yellow moisture sensitive crystalline solid.
Example 2
Preparation of 5-(4-chlorophcnyl)-l-(2,4-dichlorophenyn-4-methvl-ljy-pyrazolc-3-carboxylic acid
2,4-Dichlorophenylhydrazine hydrochloride( 13Ig, 0.61 mol) was dissolved in methanol (945 ml) and the solution was cooled to -5 to -10°C under nitrogen atmosphere. 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (135g, 0.49 mol), was added and the reaction mass was stirred for 5 hours at the same temperature and progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, demineralized water (675 ml) was added to reaction mixture and the mass was stirred for 1 hour at 0-5°C. The resulting solid was filtered, washed with chilled 50% aqueous methanol (540 ml) to afford a pale yellow solid ( 292 g) which was directly mixed with aqueous solution of potassium hydroxide (65g, 1.158 mol and 1500 ml of water) and heated to reflux with stirring till completion of the reaction. The reaction mass was cooled to 20-25°C and acidified with 5 N hydrochloric acid to a pH of 1.0-1.5, filtered, washed with chilled water (675 ml) and dried under vacuum at 45-55°C for 24 hours to give 122 g of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid (65% yield) as a off white solid having purity of 98.98% by high performance liquid chromatography.
Example 3
Preparation of Rimonabant
Thionyl chloride (93.4g, 0.78 mol) was added to a suspension of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid ( 150 g, 0.39 mol) in toluene (750 ml) at 25-28°C. The reaction mass was stirred for 5 hours at reflux temperature and then toluene and thionyl chloride were evaporated to under vacuum. The resulting residue was taken up in toluene (75 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene
chloride (750 ml), the mixture was cooled to 10-15°C and was added to a stirred mixture of a solution of 1-aminopiperidine (59.39 g, 0.59 mol) in methylene chloride (700 ml) and anhydrous powdered potassium carbonate (108.46 g, 0.78mol) at 10-15°C. The reaction mixture was stirred at 25-30"C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass was filtered and the filtrate was successively washed with demineralized water (450ml) and 20% brine solution (450ml) and dried over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give residue. The resulting residue was taken up in methanol (75 ml) and the solvent was again evaporated under vacuum to give the solid product which was slurried in methanol (450 ml) and stirred for 20 minutes at 0-5°C, filtered, washed with chilled methanol (150ml) and dried. The isolated solid was suspended in isopropyl ether (750 ml) and then heated to reflux temperature (60-65°C) and maintained the same temperature for 3 hours. The mass was cooled to 10-15°C, filtered and washed with isopropyl ether (3 x 100 ml). The product was dried under vacuum at 45-50°C for 4 hours to give 125 g of rimonabant having purity of 99. 86% by high performance liquid chromatography.
Example 4
Preparation of 4-(4-chlorophenyI)-2-K2,4-dichlorophenyn-hydrazonol-3-mcthyl-4-oxobutyric acid ethyl ester
To a stirred suspension of 2,4-dichlorophenylhydrazine hydrochloride(19.4g, 0.09 mol) in 250 ml of ethanol, 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (25g, 0.091 mol) was added at 28-30°C. The reaction mass was cooled to 0 to -5°C and stirred for 2 hours. After completion of the reaction, the precipitated solid was filtered, washed with chilled ethanol (50 ml) and dried under vacuum at 30-35°C for 4 hours to give 21.5 g of 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethylester ( yield 55%) as
pale yellow solid having purity of 97.51 % by high performance liquid chromatography.
Examples
Preparation of 4-(4-chlorophenyl)-3-methyl- 2,4-dioxobutyric acid ethyl ester lithium salt
To a stirred solution of 4-chloropropiophenone (4kg, 23.73 mol) in isopropyl ether (4/), was slowly added a solution of lithium hexamethyldisilazide (3.84kg, 22.85 mol, solution in isopropyl ether) at 14-28°C. After stirring for 30 minutes, diethyl oxalate (4/, 29.31 mol) was added over 30 minutes at the same temperature and the reaction mass was stirred for 15 hours at 25-30°C. The solid was filtered under nitrogen atmosphere, washed with isopropyl ether and dried to give 5.8 kg of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (yield 88.95%) as a pale yellow moisture sensitive crystalline solid.
Example 6
Preparation of 5-(4-Chlorophenyl)-l-(2,4-dichlorophenylM-methyl-l//-pyrazole-3-carboxyHc acid
2,4-Dichlorophenylhydrazine hydrochloride(4.8 kg, 22.48 mol) was dissolved in methanol (40/) and the solution was cooled to -5 to -15°C under nitrogen atmosphere. 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (5.8 kg, 21.13 mol) was added to it and the reaction mass was stirred for 5 hours at the same temperature and progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, demineralized water (30/) was added to reaction mixture and the mass was stirred for 1 hour at 0-5°C. The resulting solid was filtered, washed with chilled 50% aqueous methanol (20/) to afford a pale yellow solid which was directly mixed with aqueous solution of potassium hydroxide (3kg, 53.57 mol and 31/ of water) and heated to reflux with stirring till completion of the reaction. The reaction mass was cooled to 20-25°C and acidified with 5 N
hydrochloric acid to a pH of 1.2 and extracted with methylene dichloride (110/), treated with activated carbon , filtered and recovered the methylene dichloride under vacuum to give the product. The product was slurried in cyclohexane, filtered and dried under vacuum at 45-55°C for 12 hours to give 4 kg of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid as a off white solid having purity of 98.96% by high performance liquid chromatography.
Example 7
Preparation of Rimonabant
Thionyl chloride (12.38 g, 0.1 mol) was added to a suspension of 5-(4-chlorophenyl)-l-(2,4-dichiorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid (20 g, 0.053 mol) in toluene (100 ml) at 25-28°C. The reaction mass was stirred for 4 hours at reflux temperature and then toluene and thionyl chloride were recovered under vacuum. The resulting residue was taken up in toluene (20 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene chloride (100 ml), the mixture was cooled to 5-15°C and was added to a stirred mixture of a solution of 1-aminopiperidine (7.85 g, 0.078 mol) in methylene chloride (100 ml) and anhydrous powdered potassium carbonate (14.5 g, 0.1 mol) at 5-15°C. After completion of the reaction, the reaction mass was filtered and the filtrate was successively washed with demineralized water and 20% brine solution. The organic layer was charcolized and then evaporated under vacuum to give the crude product. The crude rimonabant was refluxed in isopropyl ether (100 ml) for two hours. The product was filtered and dried to give 18 g of off white rimonabant having purity of 99.57 % by high performance liquid chromatography.

WE CLAIM
1. A process for the preparation of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-7V-(piperidin-l-yl)pyrazole-3-carboxamide (Rimonabant) of formula I,
((
((Figure Remove) Formula-I
and its salts which comprises:
a) condensing l-(4-chlorophenyl)-propan-l-one with diethylester of oxalic acid in the presence of alkali metal hexamethyldisilazide in a suitable ethereal solvent and at a temperature of 0-40°C to get 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester alkali metal salt of formula II,
(Figure Remove) Wl
M is lithium or sodium
Formula-II
b) by reacting 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl alkali metal salt of formula II with 2,4-dichlorophenylhydrazine hydrochloride in a suitable alcoholic solvent (Ci-C4 alcohol) to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl ester of formula III,
(Figure Remove) along with 5-(4-chlorophenyl)-1 -(3,4-dichlorophenyl)-4-methyl-1 -pyrozole-3-carboxylic acid ethyl ester of formula IV,

c) reacting the mixture of compounds of formula III and IV so formed with a suitable inorganic base in water to give 5-(4-chlorophenyl)-l-(3,4-dichlorophenyl)-4-methyl-l-pyrozole-3-carboxylic acid of formula V,

Formula V
d) reacting 5-(4-chlorophenyl)-l-l-(3,4-dichlorophenyl)-4- methyl -I//- pyrazole -3-carboxylic acid with thionyl chloride to give 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl) -4- methyl- l//-pyrazole-3-carbonyl chloride of formula VI,
e) (Figure Remove) reacting 5-(4- chlorophenyl)-!- (2,4- dichlorophenyl) -4- methyl -IH- pyrazole-
3-carbonyl chloride of formula VI with 1-aminopiperidine in the presence of
inorganic base to yield rimonabant of formula I,
f) and optionally purifying rimonabant using suitable solvent.

2. A process according to claim 1, wherein in step a, the ethereal solvent is selected
from diethyl ether, isopropyl ether, tetrahydofuran, dioxane,methyl tert. butyl
ether, dibutyl ether, 1,4-dimethyl tertahydrofuran, 1,2-dimethoxy ethane, 1,2-
diethoxy ethane and preferably isopropyl ether.
3. A process according to claim 1, wherein in step c, the suitable inorganic base used
is selected from alkali metal hydroxides, preferably potassium hydroxide.
4. A process according to claim 1, wherein in step e, inorganic base used is selected
from alkali metal carbonates and bicarbonates, preferably potassium carbonate.
5. A process according to claim 1, wherein in step f, alcoholic solvent is selected
from methanol, ethanol, isopropanol.
6. A process for the preparation of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric
acid ethyl ester alkali metal salt of formula II,
(Figure Remove)
M is lithium or sodium
FormuIa-II
by condensing l-(4-chlorophenyl)-propan-l-one with diethylester of oxalic acid in the presence of lithium hexamethyldisilazide in an ethereal solvent at a temperature of 0-4Q°C preferably at 25-30°C, isolating the product by filtration under inert atmosphere and converting to rimonabant of formula I. 7. A process for the preparation of 5-(4-chlorophenyl)-l-(3,4-dichlorophenyl)-4-methyl-l-pyrozole-3-carboxylic acid of formula V,

FormuIa-V
(Figure Remove) by reacting alkali metal salt of ketoester of formula II with 2,4-dichlorophenylhydrazine hydrochloride in a suitable alcoholic solvent (Ci-C4 alcohol) to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl ester of formula III,
Cl
(Figure Remove) Formula-Ill
along with 5-(4-chlorophenyl)-1 -(3,4-dichlorophenyI)-4-methyl-1 -pyrozole-3-carboxylic acid ethyl ester of formula IV,


Formula-IV
reacting the above mixture of compounds so formed with a suitable inorganic base in water and further converting to rimonabant of formula I.
8. A process according to claim 7, wherein suitable inorganic base is selected from
alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and
calcium hydroxide.
9. A process for the preparation of rimonabant of formula I,
(Figure Remove)
Formula-I
by reacting 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl) -4- methyl-l//-pyrazole-3-carbonyl chloride of formula VI,
(Figure Remove)
Formula-VI
with 1-aminopiperidine in the presence of inorganic base.
10. A process according to claim 9, wherein inorganic base is selected from alkali metal carbonates and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.