WO2008062480A2

WO2008062480A2 - An improved process for the preparation of rimonabant

Info

Publication number: WO2008062480A2
Application number: PCT/IN2007/000546
Authority: WO
Inventors: Ashvin Kumar Aggarwal; Gurdeep Singh Sarin; Chidambaram Venkateswaran Srinivasan; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2006-11-24
Filing date: 2007-11-23
Publication date: 2008-05-29
Also published as: WO2008062480A3

Abstract

The present invention relates to an industrially advantageous, eco-friendly process for the re aration of rimonabant of formula-(I), staring from l-(4-chlorophenyl)-propan-l-one in high yields and high purity by using mild reaction conditions and avoiding use of toxic and expensive reagents, as well as stringent reaction conditions. The present invention relates to an isolated impurity of rimonabant, referred to as "Bis impurity" and removal thereof.1 The present invention also relates to novel crystalline form-Ill of rimonabant and processes for its preparation and conversion to form-I of rimonabant.

Description

'AN IMPROVED PROCESS FOR THE PREPARATION

OF RIMONABANT' FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of rimonabant of formula-I,

or salt thereof in high yield and purity using milder reaction conditions.

The present invention relates to an isolated impurity of rimonabant, referred to as "Bis impurity" and removal thereof.

The present invention also relates to novel crystalline form of rimonabant and processes for the preparation thereof.

BACKGROUND OF THE INVENTION

Rimonabant of formula I is a selective CBl endocannabinoid receptor antagonist and is chemically known as 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-iV-(piperidin-l- yl)pyrazole-3 -carboxamide.

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 -78⁰C, the resulting alkali metal salt of ketoester of formula II, Formula-II

wherein M is lithium or sodium is reacted with an aryl hydrazine derivative to form a hydrazone derivative of formula III,

Formula-Ill

which is further made to cyclize in the presence of acetic acid to form pyrazole-3-carboxylate ester of formula IV,

which upon basic hydrolysis forms pyrazole-3-carboxylic acid of formula V,

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 III to pyrazole-3-carboxylic acid of formula V is carried out by using para-toluenesulfonic acid in toluene followed by hydrolysis with base viz. potassium hydroxide in methanol.

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 pyrazole-3-carboxylate ester intermediate of formula IV. This ester is then converted to pyrazole-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 pyrazole-3-carboxylic 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-toluenesulfonic 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. 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. Like any synthetic compound, rimonabant can contain extraneous compounds or impurities that can come from many sources. They can be starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in rimonabant or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. There is a need in the art for a method for determining the level of impurities in rimonabant samples and removing the impurities.

Thus, there is a need in the art for a method for determining the level of impurities in rimonabant samples and removing the impurities. The present invention provides an isolated bis impurity of rimonabant.

In recent years, solid-state properties of drugs have received great attention in the pharmaceutical industry, as a major contributing factor to both bio-availability and formulation characteristics. The ability of some substances to exist in more than one crystalline form, called polymorphism, was accredited as one of the most important solid-state property of drugs. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form.

Consequently, there is an ongoing search for new polymorphic forms of drugs, which may provide for improved performance thereof. A single molecule, such as rimonabant, may give rise to amorphous and a variety of crystalline forms having distinct crystal structures and physical properties.

U.S. patent application 2005/0043356 characterized and described crystalline form II of rimonabant. According to this application, the method claimed in U.S. Patent No. 5,624,941 allows the preparation of rimonabant in crystalline form- 1.

The crystalline form-II of rimonabant, described in U.S. App. No. 2005/0043356 is prepared by dissolving rimonabant in the hot state in a solvent selected from methyl cyclohexane (containingl-10% water), acetone, acetonitrile or 4-methyl-2-pentanone or mixture thereof. The medium is cooled to 5-25°C to get crystalline form-II. Some of the methods used for obtaining the crystalline form-II of rimonabant described in the said application are cumbersome.

Thus, there is a widely recognized need for, and it would be highly advantageous to have new and distinct crystalline form of rimonabant and processes for the preparation thereof. SUMMARY OF THE INVENTION

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-N-(piperidin- l-yl)pyrazole-3-carboxamide (rimonabant) of formula-I and its salts thereof

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 0-40⁰C to get 4-(4-chlorophenyl)-3- methyl-2,4-dioxobutyric acid ethyl ester alkali metal salt of formula II,

Formula-H

Mis lithium or sodium 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,

Formula-Ill

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

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 pyrozole- 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

Formula-VI

e) reacting pyrazole-3-carbonyl chloride with 1-aminopiperidine in the presence of inorganic base to yield rimonabant.

In yet another embodiment, the present invention provides a process for the preparation of highly pure rimonabant of formula I by purifying crude rimonabant using alcoholic solvent.

Yet another embodiment of the present invention provides an isolated bis impurity, 5-(4-Chloro- phenyl)-l-(2,4-dichloro-phenyl)-4-methyl-lH-pyrazole-3-carboxylic acid [5-(4-chloro-phenyl)- l-(2,4-dichloro-phenyl)-4-methyl-lH-pyrazole-3-carbonyl]-piperidin-l-yl-amide of following formula:

Yet another embodiment of the present invention provides a novel crystalline form of rimonabant and processes for the preparation thereof and conversion to form-I of rimonabant. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the powder X-ray diffraction pattern for crystalline rimonabant Form- III. Figure 2 illustrates the powder X-ray diffraction pattern for crystalline rimonabant Form-I. DETAILED DESCRIPTION OF THE INVENTION In the detailed embodiment of the present invention, rimonabant of formula I

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-l-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, Formula-II

Mis lithium or sodium ,

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,

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 C₁-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.

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 foπnula IV 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-lH-pyrazole-3-carboxylic acid of 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-li7-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-lH-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,

Formula- 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-lH-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 solvent can be selected from methanol, ethanol, isopropanol, isopropyl ether, methyl tert. -butyl ether and the like or mixture thereof. 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.

Yet another another embodiment of the present invention provides an isolated impurity, 5-(4- chloro-phenyl)-l-(2,4-dichloro-phenyl)-4-methyl-lH-pyrazole-3-carboxylic acid [5-(4-chloro- phenyl)- 1 -(2,4-dichloro-phenyl)-4-methyl- 1 H-pyrazole-3 -carbonyl] -piperidin- 1 -yl- amide of following formula:

This impurity, referred to as "bis impurity", contaminates rimonabant of formula I.

It can be characterized by data selected from the group consisting of an RRT, HNMR, or API- MS with an m/z peak at about 825.07.

Bis impurity may be isolated by column chromatography using a mixture of hexane and ethylacetate as an eluent. Preferably, the eluent contains hexane and ethylacetate gradient 9.9:0.1 to 8.0:2.0. Preferably, bis impurity contains about 0% to about 8% area by HPLC of rimonabant.

The present invention further provides a process of determining the presence of a compound in a sample comprising carrying out HPLC or TLC with bis impurity as a reference marker.

The present invention provides a process of determining the amount of bis impurity in a rimonabant sample comprising carrying out HPLC or TLC. It is observed that in lab scale batches, bis impurity of formula 11 does not torm, but in scale up batches the rimonabant is contaminated with bis impurity in up to 8% area by HPLC and can be removed during the course of converting rimonabant to its hydrochloride salt.

In another aspect, the present invention also provides a process for preparing rimonabant from 5- (4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid having less than about 0.10% area by HPLC of bis impurity.

Rimonabant so formed from 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole- 3-carboxylic acid by the processes of the present invention is further converted to its hydrochloride salt by contacting with alcoholic-hydrochloride at a temperature of 20-40⁰C in the presence of suitable solvent to crystallize the hydrochloride salt. Rimonabant hydrochloride so formed is further basifϊed with base such as sodium or ammonium hydroxide, triethylamine or an alkali metal carbonate or bicarbonate like sodium or potassium carbonate or bicarbonate. The reaction is further worked up to give highly pure rimonabant having less than about 0.10% area by HPLC of bis impurity.

The inventors also observed that 1-aminopiperidine is very sensitive and easily converts to piperidine even during handing and leads to the formation of impurity of following formula,

during condensation reaction with 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-carboxylic acid chloride. This impurity is removed during workup and purification steps.

The present invention provides an HPLC method used to determine the presence and amount of bis impurity in a rimonabant sample comprising: combining a rimonabant sample with acetonitrile and diluent to obtain a solution; injecting the obtained solution into a 250.X.4.6 mm, 3.5μm Xterra RP 18 (or equivalent) column; eluting the sample from the column at about 90 minutes using mobile phase (gradient) as an eluent, and measuring the bis impurity content in the relevant sample with a UV detector (preferably at a 254 nm wavelength). Preferably, the eluent used may be a mixture of eluent A and eluent B, wherein the ratio of them varies over the time, i.e. a gradient eluent.

Another embodiment of the present invention encompasses a novel crystalline form of rimonabant, characterized by X-ray powder diffraction peaks at about 7.2, 9.3, 10.5, 13.4, 14.5, 15.2, 16.0, 17.0, 17.7, 18.9, 20.7, 21.1, 22.4, 22.9, 24.6, 27.2 and 29.5 degrees two-theta, ± 0.2 degrees two-theta. This foπn is herein denominated as form III as depicted in figure 1. Further the novel crystalline form III of rimonabant is characterized by infrared spectrum having peaks at about 3641, 3385, 3207, 3080, 2935, 2806, 1657, 1554, 1496, 1383, 1263, 1138, 1091, 970, 917, 833, 814,and 634 cm^"1. Crystalline form III of rimonabant is further characterized by melting point of about 106-111⁰C.

The X-ray diffraction patterns are measured on a PANalytical XTert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.

All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.

Melting point was conducted using a Polmon MP Apparatus MP 96 with a sample weight of about 10 mg.

Another embodiment of the invention encompasses a process for preparing rimonabant crystalline Form III. The process comprises providing slurry of rimonabant or any other crystalline form of rimonabant in protic organic solvent like alcohols. The alcohols can be selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and the like.

The crude rimonabant or any crystalline form of rimonabant is stirred for a sufficient period of time and at temperature sufficient to form rimonabant crystalline form- III.

Preferably ,> the slurry is stirred for about 30 minutes to 3 hours, at a temperature of from about 10°C to reflux temperature. Thereafter product is isolated by conventional methods such as filtration or centrifugation and dried to obtain pure crystalline form III of rimonabant.

Another embodiment of the invention encompasses a process for preparing rimonabant crystalline Form I as depicted in figure 2. The process comprises stirring of rimonabant form-Ill or crude rimonabant in a suitable solvent selected from isopropylether, cyclohexane or methyl cyclohexane under refluxing conditions for about 15 minutes to 4 hours.

It is advantageous to prepare form-I using cyclohexane or isopropyl ether, as these are very cheap solvents as compared to methylcyclohexane used for the preparation of form-I.

Specifically, the process comprises providing a solution of rimonabant form-Ill in ethereal solvent such as isopropyl ether at the reflux temperature of the solvent, and cooling to a temperature sufficient to form crystals of rimonabant. Preferably, the solution is cooled to about room temperature and further to about 5-15°C. Preferably, prior to cooling, the solution is maintained, while stirring, for about 30 minutes to 2 hours at reflux temperature. Yet another embodiment of the present invention provides pharmaceutically acceptable salts of rimonabant, prepared by obtaining crystalline form III of one of rimonabant, and converting the same to pharmaceutically acceptable salts of rimonabant. In the preferred embodiment crystalline form III of rimonabant is converted to its pharmaceutically acceptable salts by the reaction with mineral acids. Preferably, the crystalline form III of one of rimonabant is converted to rimonabant hydrochloride by reaction with hydrochloric acid.

The following examples further illustrate the present invention but are not construed limiting in any manner to the scope of the invention as substantially described.

EXAMPLES

Example 1; Preparation of 4-(4-chlorophenyl)-3-methyl- 2,4-dioxobutyric acid ethyl ester lithium salt

To a stirred solution of 4-chloroproρiophenone (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 14 Ig 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-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-carboxylic acid

2,4-Dichlorophenylhydrazine hydrochloride( 13 Ig, 0.61 mol) was dissolved in methanol (945 ml) and the solution was cooled to -5 to -1O⁰C 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-lH-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-lH-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 10-15⁰C 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-f(2,4-dichIorophenyI)-hvdrazonol-3- methyI-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, 0.091mol) 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 30-35⁰C 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. Example 5; Preparation of 4-(4-chlorophenyD-3-methyl- 2,4-dioxobutyric acid ethyl ester lithium salt

To a stirred solution of 4-chloropropiophenone (4kg, 23.73 mol) in isopropyl ether (41), 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 (Al, 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-ChlorophenylVl-(2,4-dkhlorophenylV4-methyl-liy- pyrazole-3-carboxylic 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-lH-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-chlorophenyi)-l-(2,4- dichlorophenyl)-4-methyl-l/J-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 rinionabant 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.

Example 8; Preparation of Rinionabant

Thionyl chloride (67Og) was added to a suspension of 5-(4-chloropb.enyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1.0 Kg,) in toluene (5.0 It) at 25-28⁰C. 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 (1000 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene chloride (5.0 It), the mixture was cooled to 10-15⁰C and was added to a stirred mixture of a solution of 1-aminopiperidine (408g) in methylene chloride (5.0 It) and anhydrous powdered potassium carbonate (72Og) at 10-15⁰C. The reaction mixture was stirred at 25-3O⁰C 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 and 20% brine solution and dried over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give title compound having purity 93.5%; bis impurity 3.5 %.

Example 9: Purification of Rimonabant

A solution of rimonabant (50g) in dichloromethane (150ml) was acidified with methanolic- hydrochloride (20ml) at 25-30⁰C which was saturated with isopropyl ether (200ml) to crystallize its hydrochloride salt. The salt was taken in dichloromethane (500ml) and the suspension was basified with 20% aqueous sodium hydroxide (lOOml).The immiscible layers were separated and the aqueous layer was again extracted with dichloromethane. The separated dichloromethane layer was washed with 20% aqueous sodium chloride (150ml) and was concentrated under vacuum to give solid which was stirred with isopropyl ether (200ml) under reflux condition for 2 hours. The reaction mass was cooled, filtered, washed with isopropyl ether and dried under vacuum to give 35g of purified title compound (yield 75%) having purity 99.76% by HPLC; bis impurity 0.05%. Example 10; Purification of Rimonabant

A solution of rimonabant (5Og) in dichloromethane (150ml) was acidified with methanolic- hydrochloride (20ml) at 25-3O⁰C which was saturated with isopropyl ether (200ml) to crystallize its hydrochloride salt. The salt was taken in dichloromethane (500ml) and the suspension was basifϊed with 20% aqueous sodium hydroxide (100ml). The separated dichloromethane layer was washed with 20% aqueous sodium chloride (150ml) and was concentrated under vacuum to give 35g of purified title compound (yield 75%) having purity 99.50% by HPLC; bis impurity 0.07%

Example 11: Isolation of bis impurity

A sample of rimonabant containing bis impurity was purified by flash column chromatography eluting with a mixture of hexane/ethyl acetate gradient 9.9:0.1 to 8.0:2.0 and analyzing the fractions with TLC/ HPLC. Fractions containing bis impurity with purity greater than 97.0% were pooled and the solvent was removed under vacuum to isolate the title compound.

¹H-NMR (CDCl₃) (δ): 1.38-1.39 (2H, brs, piperidine protons); 1.60-1.63 (4H,brs, piperidine protons); 2.10 (6H, s, methyl groups); 3.30-3.32 (4H, t, piperidine protons); 6.86-6.90 (4H, m, aromatic protons); 7.01-7.04 (2H, s, aromatic protons); 7.11-7.14 (2H, d, aromatic protons); 7.17-7.21 (4H, m, aromatic protons); 7.23-7.24 (2H, s, aromatic protons) ppm.

APCI-MS (m/z): [M.F.: C₃₉H₃₀Cl₆ ³⁵N₆O₂] 825.07[M+l] Method for HPLC analysis:

The Analysis of bis impurity in rimonabant sample is done using the HPLC: Column & Packing: Xterra RP18 (or equivalent); 250 mm x 4.6 mm, Eluent A: mixture of water:triethylamine(950:5) and pH adjusted, to4.0+ 0.05with dilute phosphoric acid and make up the volume up to 1000ml with water. Eluent B: Acetonitrile, gradient and stop time: 90 minutes; Equilibrium time: 5 minutes; Flow Rate: 1.0 ml/min; Detector: UV at 254 nm.

The Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.

Example 12: Preparation of rimonabant form-HI Step 1: Preparation of Rimonabant

To a suspension of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (4Og, O.lmol) in 200 ml of toluene, was added thionyl chloride (24.79g, 0.2mol) at 30±5°C. The reaction mass was stirred for 4 hours at reflux temperature and then evaporated to dryness under vacuum to give the expected acid chloride. The acid chloride was dissolved in methylene chloride (200 ml) and treated with a solution of 1-aminopiperidine (12.16g, 0.12mol) in methylene chloride (700 ml) in presence of triethyl amine (13.29g, 0.13mol ) at 5- 10° C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass was quenched with demineralized water (160 ml) and the organic layer was washed with IN hydrochloric acid and demineralized water followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give the crude product.

Step 2- Preparation of Rimonabant Form-Ill

The crude rimonabant obtained above was slurried in methanol (120ml) at ambient temperature for one hour and was filtered and dried to give 38g of off white crystalline rimonabant which displayed XRD pattern as depicted in Fig. 1.

Example 13: Preparation of rimonabant form-IH

Rimonabant form-I (5 g) was added to ethanol (10 ml) and the reaction mixture was heated to reflux for 30 minutes and cooled to 5-10°C. The reaction mass was stirred for lhours at the same temperature. The precipitated product was filtered, washed with chilled ethanol and dried under vacuum at 40-45° C for 4 hours to afford 4.4 g of rimonabant form-Ill.

Example 14: Preparation of rimonabant form-Ill

Rimonabant form-I (5 g) was added to methanol (10 ml) and the reaction medium was heated to reflux for 30 minutes and cooled to 5-10⁰C. The reaction mass was stirred for lhours at the same temperature. The precipitated product was filtered, washed with chilled methanol and dried under vacuum at 40-45°C for 4 hours to yield 4.5 g of rimonabant form-Ill.

Example 15: Preparation of rimonabant form-I

Rimonabant form-Ill (38g) was slurried in isopropyl ether (200ml) and heated to reflux temperature (60-65°C). The reaction mixture was stirred at 60-65°C for 1.3 hours. The mass was cooled to 10-15°C, filtered and washed with isopropyl ether (3x100 ml). The product was dried under vacuum at 45-50° C for 4 hours to give 30 g of almost white crystalline product as form-I (yield 78.94 %).

Claims

WE CLAIM

1. A process for the preparation of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-N- (piperidin-l-yl)pyrazole-3-carboxamide (Rimonabant) of formula I,

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,

Formula-II

M is lithium or sodium 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 (C₁-C₄ alcohol) to give 4-(4-chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethyl ester of formula III,

Formula-Ill

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,

d) reacting 5-(4-chlorophenyl)-l-l-(3,4-dichlorophenyl)-4-methyl-lH^'-pyrazole-3-carboxylic acid with thionyl chloride to give 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l/J-pyrazole- 3-carbonyl chloride of formula VI,

FormuLa-VI

e) reacting 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-li7-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. The 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. The process according to claim 1, wherein in step c, the suitable inorganic base used is selected from alkali metal hydroxides, preferably sodium hydroxide, potassium hydroxide and calcium hydroxide.

4. The process according to claim 1, wherein in step e, inorganic base used is selected from alkali metal carbonates and bicarbonates, preferably potassium carbonate.

5. The process according to claim 1, wherein in step f, suitable solvent is selected from alcoholic solvent such as methanol, ethanol, isopropanol. _<

6. A process for the preparation of 4-(4-chlorophenyl)-3-methyl-2,4-diox'obutyric acid ethyl ester alkali metal salt of formula II,

M is lithium or sodium 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 0-40⁰C preferably at 25-30⁰C, 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,

Formula-V

by reacting alkali metal salt of ketoester of formula II with 2,4-dichlorophenylhydrazine hydrochloride in a suitable alcoholic solvent (C₁-C₄ alcohol) 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, FormuIa-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. The process according to claim 1, 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,

by reacting 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-liϊ-pyrazole-3-carbonyl chloride of formula VI,

Formula-VI

with 1-aminopiperidine in the presence of inorganic base.

10. The 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.

11. An isolated 5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4-methyl-lH-pyrazole-3-carboxylic acid[5-(4-chloro-phenyl)-l-(2,4-dichloro-phenyl)-4-methyl-lH-pyrazole-3-carbonyl]- piperidin-1-yl-amide ( Bis impurity ) of the following formula:

12. Rimonabant and its pharmaceutically acceptable salts containing less than approximately 0.1 % area by HPLC of bis impurity or a salt thereof.

13. A novel crystalline form III of rimonabant, characterized by atleast one of:

(a) an X-ray powder diffraction pattern having peaks at about 7.2, 9.3, 10.5, 13.4, 14.5, 15.2, 16.0, 17.0, 17.7, 18.9, 20.7, 21.1, 22.4, 22.9, 24.6, 27.2 and 29.5 degrees two-theta, ± 0.2 degrees two-theta and as depicted in figure 1;

(b) infrared spectrum having peaks at about 3641, 3385, 3207, 3080, 2935, 2806, 1657, 1554, 1496, 1383, 1263, 1138, 1091, 970, 917, 833, 814,and 634 cm^"1 and

(c) a melting point of 106- 111 °C.

14. A process for preparing the crystalline form III of rimonabant, comprising: slurring/ dissolving crude rimonabant or any other form of rimonabant in alcoholic solvent at temperature of 10⁰C to reflux for sufficient time to convert to form-Ill , cooling the reaction mass, and isolating crystalline form III of rimonabant.

15. The process according to claim 14 wherein the solution is heated at a temperature of about 10°C to reflux for 30 minutes to 3 hours.

16. The 'process according to claim 14 wherein the solvent used is methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and the like.

17. The process according to claim 14 wherein the solvent used is preferably methanol.

18. A process for preparing rimonabant form I, comprising: providing a solution of crystal form III of rimonabant in a solvent selected from diisopropyl ether, cyclohexane or methylcyclohexane, refluxing for sufficient time to convert to form-I , cooling the reaction mass, and isolating crystalline form I of rimonabant.