WO2008044153A2

WO2008044153A2 - Improved method for synthesizing rimonabant

Info

Publication number: WO2008044153A2
Application number: PCT/IB2007/004313
Authority: WO
Inventors: Monica Benito Velez; Stephen Winter; Ernesto Duran Lopez
Original assignee: Medichem, S.A.
Priority date: 2006-08-29
Filing date: 2007-08-29
Publication date: 2008-04-17
Also published as: AR062593A1; WO2008044153A3

Abstract

The invention relates to a process for preparing rimonabant. In particular, the invention relates to minimizing the presence and effects of certain by-products of formula (III) and impurities present in rimonabant occurring during the synthesis of rimonabant.

Description

IMPROVED METHOD FOR SYNTHESIZING RIMONABANT CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application Nos. 60/840,695 (filed August 29, 2006) and 60/924,096 (filed April 30, 2007), which applications are expressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to a process for preparing rimonabaπt. In particular, the invention relates to minimizing the presence and effects of certain by-products and impurities present in rimonabant occurring during the synthesis of rimonabant.

Discussion of the Related Art

Rimonabant is the common name for 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- W-piperidin-l-yl-lH-pyrazole-3-carboxamide. Rimonabant is an active pharmaceutical substance with an empirical formula of C2₂CI3H₂1N4O and a molecular weight of 463.787 (Formula I).

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Preparation of rimonabant and/or its salts and solvates thereof is reported in U.S. Patent No. 5,624,941 ("the '941 patent"). According to the '941 patent, rimonabant is synthesized in six chemical steps from 4-chloroproρiopheπone, using the pyrazole-3- carboxylic acid of Formula II, or one of its activated forms, as an intermediate.

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In particular, the '941 patent describes the reaction of the carboxylic acid of Formula H, or one of its activated forms, with 1-aminopiperidine in the presence of a base to produce rimonabant. In this regard, the '941 patent discloses several different processes for preparing the pyrazole-3-carboxylic acid of Formula II. Scheme 1 (below) illustrates some of the synthetic procedures described in the '941 patent.

{Scheme 1

In the '941 patent, rimonabant is prepared by reacting the acid of Formula II, or one of its activated forms, with 1-aminopiperidine in a solvent (e.g., dichloromethane) in an inert atmosphere, at a temperature between 0° C and room temperature, in the presence of a base such as triethylamine.

Alternatively, rimonabant can also be prepared through a one-pot synthesis by reacting the acid of Formula II with thionyl chloride in methylcyclohexane as a solvent, followed by the addition of a solution of 1-aminopiperidine and triethylamine in tetrahydrofuran. This process, however, presents an important drawback, i.e., the low solubility of rimonabant in methylcyclohexane requires the use of a co-solvent such as tetrahydrofiiran, which is partially soluble in water, and hence decreases the yield of rimonabant when purifying by washing with aqueous solvents.

Additionally only one reference, Dutta et al., Med Chεm. Res., 5, 54-62 (1995), describes isolation of rimonabant as a white solid with a melting point of 154- 156° C after column chromatography purification and crystallization from ether / petroleum ether mixture. This process is not industrially applicable since it requires the use of a chromatographic column and, in general, chromatographic columns are rarely desirable for performing purifications at industrial scales. It has been observed, however, that rimonabant is usually obtained as a yellow solid under standard synthetic conditions. In this regard, the color must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC.

In view of the foregoing, there is therefore the need for an alternative cost-effective process for preparing rimonabant which avoids the drawbacks of the known processes, and which involves simple experimental procedures well suited to industrial production. Additionally, there is a need for a method for preparing rimonabant having enhanced color quality (i.e., whiteness) without the need to perform expensive purification steps {e.g., column chromatography, and crystallization).

BRIEF DESCRIPTION OF THE DRAWING

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings:

Figure I illustrates the powder X-ray diffractogram of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid according to one embodiment of the invention; and

Figure 2 illustrates the powder X-ray diffractogram of rimonabant (Form 1) according to one embodiment of the invention.

SUMMARY OF THE INVENTION

Rimonabant is an active pharmaceutical substance that is included in pharmaceutical compositions. As such, it is necessary to obtain it as a high purity product with a minimum amount of undesired by-products. In particular, the presence of impurities may adversely effect the safety and shelf life of formulations.

The invention relates to a process for preparing rimonabant. In particular, the invention relates to minimizing the presence and effects of certain by-products and impurities present in rimonabant occurring during the synthesis of rimonabant.

It has been observed that during the synthesis of rimonabant the compound of Formula III can be obtained as a by-product.

The compound 1-aminopiperidine, used as a reagent for the preparation of rimonabant, usually contains a percentage ofpiperidine as a contaminant. During the synthesis of rimonabant this contaminant reacts with the 5-(4-chlorophenyI)-l -(2,4-dichlorophenyl)-4-methyl-l//- pyrazole-3-carboxylic acid of Formula II to produce the compound of Formula III.

It has been observed that the percentage ofpiperidine as a contaminant in 1 - aminopiridine, which is liquid at room temperature, increases under certain storage conditions. However, solid I -aminopiperidine hydrochloride is highly stable for storage, and hence can be used for preparing rimonabant with a minimum amount of the compound of Formula III.

According to one aspect, the invention includes identification of and a method for preparing an impurity (i.e., the compound of Formula III and derivatives thereof) that is formed during the synthesis of rimonabant when 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid of Formula II, or one of its activated forms, reacts with 1-aminopiperidine.

In another aspect, the invention includes using a reference marker for analyzing rimonabant and/or pharmaceutical dosages containing rimonabant. This reference marker is a potential contaminant which can be formed in a side reaction during the synthesis of rimonabant. Namely, the compound of Formula III has utility as a reference marker because it is a potential contaminant which can be produced in a side reaction that can occur during the synthesis of rimonabant. According to this aspect of the invention, the level of this contaminant is controlled in order to achieve the required purity level for commercial production of the active pharmaceutical ingredient rimonabaπt.

In another aspect of the invention, the compound l-{[5-(4-chIorophenyl)-l -(2,4- dichlorophenyl)-4-methyl-l//-pyrazole-3-yl]carbonyl}piperidine (as depicted in Formula S III) is used as a reference marker analyzing the purity of a sample of rimonabant and/or of a pharmaceutically acceptable dosage form containing rimonabant.

In another aspect, the invention includes a process for producing the compound of Formula III that includes reacting the pyrazoIe-3-carboxylic acid of Formula H, or one of its activated forms, with piperidine. 0 In another aspect, the invention includes a process for preparing rimonabant that provides a maximum yield of desired product with a minimum amount of the compound of Formula III. These aims can be achieved by:

1. Measuring the level of piperidine present in each batch of 1 -aminopiperidine and selecting the more appropriate batches. The level of piperidine present in the raw material can be S determined by standard techniques including, for example, gas chromatography (GC).

In cases where the starting material has a high amount of piperidine, the starting material can be purified by conventional techniques before using it to prepare rimonabant and in order to ensure an appropriate level of the compound of Formula III. In this regard, the invention enables the production of rimonabant having approximately less than 0.1%0 area by HPLC of the compound of Formula III without requiring procedures to separate the compound of Formula III from the crude rimonabant reaction product.

2. Adjusting the crystallization conditions to avoid co-crystallization of the compound of Formula III in the presence of rimonabant.

In another aspect, the invention includes monitoring the reaction products obtained5 from the reaction of the compound of Formula II, or one of its activated forms, with 1- aminopiperidine for the presence of undesirable by-products. In a preferred aspect, the invention includes monitoring the products for the presence of the compound of Formula III.

In another aspect, the invention includes rimonabant substantially free of l-{[5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-yl]carbonyl}piperidine (/.e.,0 the compound of Formula III). In another aspect, the invention includes rimonabant having a purity of at least approximately 99%, preferably of at least approximately 99.5% and more preferably of at least approximately 99.7% when analyzed by HPLC.

In another aspect, the invention includes rimonabant having less than approximately S 1% of individual impurities, preferably having less than approximately 0.5% of individual impurities, and more preferably having less than approximately 0.3% of individual impurities.

In another aspect, the invention includes rimonabant having less than approximately 1% of the compound of Formula III, preferably having less than approximately 0.5% of the compound of Formula HI, more preferably having less than approximately 0.3% of the compound of Formula 0 UI, and most preferably having less than approximately 0.1 % of the compound of Formula III.

In another aspect, the invention includes an improved process for preparing rimonabant with enhanced color quality (Le., "whiteness") and a high level of purity that includes the steps of:

1. Reacting the acid of Formula II, or one of its activated forms, with 1 - aminopiperidine in a hydrophobic rimonabant-high capacity solvent, (i) in an inert atmosphere 5 (if desired), (ii) at a temperature between 0° C and room temperature, and (iii) in the presence of a base, to obtain a first solution containing rimonabant;

2. Removing unreacted starting materials and impurities from the first solution of rimonabant by water extraction processes to obtain a second solution containing rimonabant. Optionally, these extraction processes can be performed in the presence of a nonpolar solvent to0 improve the separation of layers;

3. Precipitating the rimonabant from the second solution by adding a solvent in which rimonabant shows low solubility, and obtaining a first suspension;

4. Optionally, performing a partial distillation of the first suspension to improve the isolated yield of rimonabant and obtaining a second suspension; 5 5. Isolating rimonabant from either the first or second suspension, wherein the rimonabant has enhanced color quality (i.e., "whiteness") and high level of purity; and

6. Optionally, treating the rimonabant with one or more decolorization agents.

In the above-described process, the base used in step 1 is an organic base, preferably an amine base, and more preferably triethylamine. The hydrophobic rimonabant-high0 capacity solvent of step 1 is preferably an aromatic solvent, more preferably toluene. In another aspect, the 1-aminopiperidine of step 1 is generated from a solid acid addition salt thereof. The acid addition salt is a mineral acid addition salt, preferably is a hydrogen halide addition salt, and more preferably is 1-aminopiperidine hydrochloride.

The noπpolar solvent of step 2 is preferably an alkane solvent, more preferably heptane. The solvent in which rimonabant shows low solubility (step 3) is preferably an alkane solvent, more preferably heptane.

Suitable decolorizing agents for use in step 6 can be any conventional decolorizing agents, including, for example, alumina, activated alumina, silica and charcoal. The preferred decolorizing agent is charcoal. The technical problem solved by the invention is preparing rimonabant with enhanced color quality {i.e., "whiteness") and high level of purity without the need to employ expensive purification methods, such as column chromatography, and crystallization and without the need to use hydrophilic co-solvents, such as THF, and without the need of azeotropic distillation. In another aspect, the invention includes a method for assessing the purity of rimonabant by means of a quantitative colorimetric measurement of solid rimonabant. The method includes using a colorimeter or spectrophotometer apparatus to measure the L*, a* and b* coordinates of the solid sample of rimonabant. Thus, the color of the solid sample is located in the CIE 1976 L*, a*, b* Color Space (CIELAB; CIE stands for Commission Internationale de l'Eclairage or International Commission on Illumination). The three parameters in the model represent the lightness of the color (i.e., L*, an L* = 0 indicates black and L* = 100 indicates white), its position between magenta and green (i.e., a*, negative values indicate green while positive values indicate magenta) and its position between yellow and blue (i.e., b*, negative values indicate blue and positive values indicate yellow). Thus, the color quality (i.e., "whiteness") of rimonabant is corroborated by the colorimetric measurements that yield values in the CIELAB color space that are very close to the values of absolute white, namely L* = 100, a* = 0; b* = 0. See, e.g., US Pharmacopoeia 29^th ed., General Chapter 1061, p. 2896.

In another aspect, the invention includes rimonabant with enhanced color quality (i.e., "whiteness") and high level of purity that is prepared by the above-described process. In particular, the rimonabant prepared by the above-described process has a purity greater than approximately between 98.5% and 99.5% as measured by HPLC.

The rimonabant prepared by the above-described process also exhibits enhanced whiteness in the CIE (1976) L*, a*, b* Color Space (CIELAB). In particular, the obtained rimonabant has the following CIE (1976) L*, a*, b* Color Space (CIELAB) measurements when using a colorimeter or spectrophotometer, illuminant D65 (daylight) and a 2° angle of observation: L* = 93 to 100, and a* = -1.00 to +1.00, and b* = -10.00 to +10.00; preferably L* = 97 to 100, and a* = -0.10 to +0.10, and b* = -2.00 to +2.00.

In another aspect, the invention includes rimonabant prepared by the above- described process having a particle size distribution in which approximately 10% of the total volume includes particles having a diameter below approximately 2.5 μm, approximately 50% of the total volume includes particles having a diameter below about approximately 8.5 μm, approximately 90% of the total volumeincludses particles having a diameter below approximately 37.5 μm. In another aspect, the invention includes rimonabant prepared by the above- described process having high level of purity and low levels of a particular impurity. The impurity is l-{[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3- yl]carbonyl}piperidine (Formula III).

The various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully. Specific Examples

The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.

General Experimental Conditions: HPLC Method 1:

The chromatographic separation was carried out at room temperature (approximately 25° C) in a Symmetry Cl 8 , 5 μm, 250 x 4.6 mm I. D. column.

The mobile phase A was prepared by dissolving 0.77 g of ammonium acetate in 1000 mL of water and by adjusting the pH to 6.S with acetic acid. The mobile phase A was filtered through 0.22 μm nylon filter under vacuum.

The mobile phase B was acetonitrile.

The chromatograph was programmed as follows: Initial 0-2 minutes isocratic 60% mobile phase A, 2-13 minutes linear gradient to 30% mobile phase A, 13-40 minutes isocratic 30% mobile phase A, 40-45 minutes linear gradient to 60% mobile phase A and 45-50 minutes equilibration to 60% mobile phase A.

The chromatograph was equipped with a 230 nm detector, and the flow rate was 1.0 mL per minute. Test samples (10 μl) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of acetonitrile.

Approximate HPLC Retention Times:

HPLC Method 2:

The chromatographic separation was carried out at room temperature (approximately 25° C) in a Waters Symmetry C 18, 3.5 μm, 50 x 4.6 mm I. D column.

The mobile phase A was prepared from 0.63 g of ammonium formate dissolved in 1000 mL of water and by adjusting the pH to 3.0 with formic acid. The mobile phase A was filtered through 0.22 μm nylon filter.

The mobile phase B was acetonitrile. The chromatograph was programmed as follows: Initial 0-5 minutes isocratic 35% mobile phase A, 5-8 minutes linear gradient to 20% mobile phase A, 8-18 minutes isocratic 20% mobile phase A, 18-19 minutes linear gradient to 35% mobile phase A and 19-20 minutes equilibration to 35% mobile phase A.

The chromatograph was equipped with a 260 nm detector, and the flow rate was 1.0 mL per minute. Test samples (3 μl) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of acetonitrile.

Approximate HPLC Retention Times:

HPLC Method 3:

The chromatographic separation was carried out at room temperature (approximately 25° C) in a Symmetry C 18, 5 μm, 150 x 4.6 mm I. D column.

The mobile phase A was prepared by dissolving 0.63 g of ammonium formate in 1000 mL of water and by adjusting the pH to 3.0 with formic acid. The mobile phase A was filtered through 0.22 μm nylon filter under vacuum.

The mobile phase B was acetonitrile.

The chromatograph was programmed as follows: Initial 0-25 minutes isocratic 50% mobile phase A, 25-45 minutes linear gradient to 20% mobile phase A, 45-88 minutes isocratic 20% mobile phase A, 88-93 minutes linear gradient to 50% mobile phase A and 93-103 minutes equilibration to 50% mobile phase A.

The chromatograph was equipped with a 260 nm detector, and the flow rate was 1.0 mL per minute. Test samples (10 μL) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of acetonitriie.

Approximate HPLC Retention Times:

Gas Chromatography (GC) Method:

Chromatographic separation is carried out in an Agilent 6890 Series GC System using a WCOT HP-I silica capillary, nominal length 30 m, nominal internal diameter 0.32 mm, stationary phase OV-101, nominal film thickness 0.25 μm and nitrogen (10.7 psi) as the carrier gas. The injector temperature was 275° C and the detector temperature (FID) was 300° C. The GC was programmed using a 40° C isothermal temperature program having a 10 minute analysis time for 1 uL injection volumes (Autosampler; 12 mg/mL in ethyl acetate).

Approximate GC Retention Times:

Particle Size Distribution Method:

The particle size for rimonabant was measured using a Malvern Mastersizer S particle size analyzer with an MSl Small Volume Sample Dispersion Unit stirred cell. A 300RF mm lens and a beam length of 2.4 mm were used. Samples for analysis were prepared by dispersing a weighed amount of rimonabant (approximately 30 mg) in 1 mL of sample dispersant, previously prepared by dilution of 2.5 mL of Tween 80 (1% v/v solution) to 250 mL with deionized water, and further mixture of this dispersion with 20 mL of deionized water. After sonication for 15 seconds, the suspension was delivered drop-wise to a background corrected measuring cell previously filled with dispersant (prepared by mixture of 20 mL of Tween 80 (1% v/v solution) with 1 L of deionized water) until the obscuration reached the desired level. Volume distributions were obtained for three times. After completing the measurements, the sample cell was emptied and cleaned, refilled with suspending medium, and the sampling procedure repeated again. For characterization, the values of Dio, D₅₀ and D₉₀ (by volume) were specifically listed, each one being the mean of the six values available for each characterization parameter. Colorimetric Measurement:

Colorimetric measurements of the solid samples were obtained using a Minolta Chroma meter CR-300, using illuminant D65 and a measurement geometry of 2°. Example 1: Preparation of l-{[5-(4-chlorophenyl)-l-(2,4-dich!orophenyl)-4- methyl-l//-pyrazoIe-3-yl]carbonyl}piperidine (Compound III)

Thionyl chloride (1.9 g; 15.97 mmol) was added to a suspension of 5-(4-chlorophenyl)- l-(2,4-dichIorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (2g; 5.24 mmol) in 21 mL of toluene. The mixture was next heated at reflux for 3 hours. Additional thionyl chloride (1.9 g; 15.97 mmol) was then added and the mixture was heated at reflux for an additional 3 hours. The mixture was cooled, and the toluene was removed under vacuum. The residue was taken up in 20 mL of toluene and the solvent was removed under vacuum. The residue was then dissolved in 20 mL of dichloromethane and the resulting solution was added slowly to a previously cooled (0° C) solution of triethylamine (687 mg; 6.79 mmol) and piperidine (578 mg; 6.79 mmol) in 30 mL of dichloromethane. The mixture was then stirred at ambient temperature until the reaction was complete. The mixture was next washed successively with 40 mL of water, 40 mL of an aqueous solution of 4% acetic acid, 40 mL of 1.5% sodium hydroxide and 40 mL of water. The organic layer was then dried over magnesium sulfate and concentrated under vacuum to yield 2.1 g of the product as an oil (Purity: 98% by ΗPLC

Method 1). Next, the residue was crystallized in isopropaπol to yield 1.6g (Yield: 68%; Purity: 98.4% by ΗPLC Method 1) of Compound III as a white powder.

Analytical data: m.p. = 142-143° C; IR (KBr disc): 3400 (br), 3082.2, 3042.9, 2939.0, 2855.9, 1626.0, 1497.1, 1447.0, 1362.4, 1259.1, 1091.0, 1 104.4, 967.5, 842.4, 825.9, 814.7 cm ¹; ¹³C NMR (CDCl₃, 100.7MHz): 163.4, 147.2, 141.7, 136.0, 135.6, 134.7, 133.0, 130.6, 130.6, 130.3, 128.9, 127.8, 127.5, 1 16.1, 48.4, 43.1, 26.8, 25.7, 24.7, 8.9 ppm; ¹H NMR: (CDCl₃, 400MHz): 7.44 (IH, d, J = 2.0Hz), 7.32-7.28 (2H, m), 7.24 (IH, ddd, J = 8.4, 2.0), 7.17 (IH, d, J = 8.4), 7.09-7.05 (2H, m), 3.78-3.65 (4H, m), 2.19 (3 H, s), 1.74- 1.65 (4H, m), 1.65-1.56 (2H, m) ppm. Example 2: Preparation of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-./V-piperidin-l-yl-l//-pyrazole-3-carboxamide (Compound I)

The reaction was carried out under an argon atmosphere. In a 500 mL reactor equipped with thermometer, condenser, addition funnel and magnetic stirring were added 9.15 g (24 mmol) white, previously-purified of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-carboxylic acid (Karl Fischer < 0.2%) and 90 mL of methylcyclohexane. The mixture formed a slurry and was heated at 80° C. Once heated, a solution of thionyl chloride (3.56 g; 29.9 mmol) in methylcyclohexane (10 mL) was added. The reaction was stirred at 80-83° C for three hours, heated to reflux and then the excess thionyl chloride was removed by distillation (-10 mL). The mixture was next cooled to 10-15° C₁ and a solution of triethylamine (2.67 g; 26.4 mmol) and aminopiperidine (2.64 g; 26.4 mmol in THF (18 mL)) was slowly added. The mixture was then stirred for 17 hours at room temperature and washed with 60 mL of water and 60 mL of aqueous AcOH (4%). Thereafter, the organic phase was heated to 70° C and washed with 60 mL of aqueous NaOH (1.5%) and 60 mL of water. The THF and water were removed by azeotropic distillation at atmospheric pressure. The solution was then cooled and the product crystallized as a white solid. The slurry was filtered at room temperature, and the solid was washed with hexane and dried under vacuum to yield 7.05 g of rimonabant (Yield: 63%; Purity (HPLC Method 1): 99.0%; compound of Formula III: 0.6% of relative peak area) as a white powder. Analytical data: m.p. = 154-155° C; Loss on Drying: 0.0%; Titration (HClO₄): 98.47%; IR:

3453.0 (br), 3267.4, 2925.0, 2858.0, 1667.6, 1497.7, 1484.7, 1453.3, 1398.5, 1385.6, 1360.7, 1290.0, 1250.5, 1208.8, 1136.1, 1099.8, 1091.1, 1062.8, 1012.7, 969.0, 901.5, 874.6, 835.2, 8272, 815.1, 618.9, 602.8, 497.9, 402.8 on ¹; ¹³C NMR (CDCl₃, 100.7MHz): 159.9, 144.4, 142.9, 136.0, 135.9, 134.9, 133.0, 130.8, 130.6, 130.3, 128.9, 127.9, 127.2, 1 18.2, 57.1, 25.4, 23.4, 9.3 ppm; ¹H NMR (CDCI₃, 400MHz): 7.62 ( 1 H, br s), 7.43 ( 1 H.d, J= 2.0Hz), 7.31 -7.28 (4H,m), 7.07-7.03 (2H,m), 2.90-2.82 (4H, m), 236 (3H, s), 1.75 (4H, qn , J=5.7), 1.48-1.40 (2H, m) ppm.

Example 3

5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylic acid (10.0 g; 26.2 mmol) was suspended in 90 mL of methylcyclohexane under nitrogen atmosphere, and the resulting suspension was heated to 80° C. At this temperature, a solution of 2.2 mL (29.7 mmol) of thionyl chloride in 10 mL of methylcyclohexane was added over the reaction mixture, and the resulting suspension was stirred for 3 hours at 83 ± 3° C. An in process control by thin layer chromatography ("TLC") of the reaction mixture showed the presence of unreacted starting material. Therefore, an additional 2.2 mL (29.7 mmol) of thionyl chloride was added to the reaction mixture. After stirring for 3 hours at 83 ± 3° C no starting material was detected by TLC. The reaction mixture was then heated to reflux, and 35 mL of solvent was removed by distillation. Next, the suspension was cooled to 10° C, and a solution of 3.1 mL (28.8 mmol) of 1 -aminopiperidine and 4.0 mL (28.8 mmol) of triethylamine in 20 mL of tetrahydrofuran was added drop wise. The reaction mixture was stirred at room temperature overnight. Then water (20 mL) was added to the suspension, and the resulting solution was heated to 70° C. At this temperature, the aqueous phase was extracted, and the organic phase was washed with 20 mL of a 4% solution of acetic acid, 30 mL of a 1.3% solution of sodium hydroxide (twice), and finally with 20 mL of water. A yellowish solid precipitated from the reaction mixture after cooling to room temperature to yield 3.3 g of rimonabant after filtration. Yield: 27%. Purity (HPLC Method 2): 99.18%, containing 0.18% of 5-(4-chlorophenyl)-l-(2,4-dichIoro phenyl)-4- methyl-lH-pyrazole-3-carboxylic acid and 0.44% of l-{[5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazol-3-yl]carbonyl}piperidine. Particle size distribution: Dio (v) = 2.7 μm, D₅₀ (v) = 12.1 μm, D₉₀ (v) = 36.3 μm.

Example 4

5-(4-chlorophenyl)-l-(2,4^ichlorophenyl)-4-methyl-lH-pyrazole-3-carboxyIic acid (30.0g, 78.6 mmol, same batch as Example 3) was suspended in 300 mL of toluene under nitrogen atmosphere, and the resulting suspension was heated to reflux temperature. During the heating, 1 1.5 mL (157.2 mmol) of thionyl chloride was added over the reaction mixture, and the resulting suspension was stirred for 2 hours at reflux temperature. No starting material was detected by in process control TLC. Then, 200 mL of solvent was removed by distillation under atmospheric pressure. The suspension was then cooled to 10° C, and 10.2 mL (94.3 mmol) of 1-aminopiperidiπe (same batch as Example 3) followed by 22.0 mL (157.2 mmol) of triethylamine were added drop wise. The reaction mixture was stirred at room temperature overnight. Next, 65 mL of water and 100 mL of n-heptane were added to the suspension, and the resulting suspension was heated to 70° C. At this temperature, the aqueous phase was extracted, and the organic phase was washed with 65 mL of a 4% solution of acetic acid, 90 mL of a 1.5% solution of sodium hydroxide (three times), and finally with 65 mL of water. The resulting organic phase was heated to reflux temperature, and 300 mL of n-heptane was added drop wise. A yellowish solid precipitated from the reaction mixture after cooling to 40° C. At this temperature, the reaction mixture was concentrated to about half of its volume by distillation under reduced pressure. The mixture was then cooled to 0° C and filtered to yield 25.2 g of rimonabant. Yield: 69%. Purity (ΗPLC method 2): 98.94%, containing 0.54% of 5-(4-chloropheny I)-I -(2,4- dichlorophenyI)-4-methyl-lH-pyrazole-3-carboxylic acid and 0.08% of l-{[5-(4- chlorophenyl)-l-(2,4-dichlorophenyI)-4-methyl-lH-pyrazol-3-yl]carbonyl}piperidine. Particle size distribution: Dio (v) = 2.3 μm, D50 (v) = 8.2 μm, D90 (v) = 37.4 μm. Example S

Rimonabant (25.1 g, as obtained in Example 4) was dissolved in 75 mL of toluene at room temperature. Activated charcoal (1.3 g) was added to the solution, and the resulting suspension was stirred at room temperature for 90 minutes. The charcoal was removed by filtration and washed with 10 mL of toluene. The filtered solution was then heated to reflux temperature, and 340 mL of n-heptane was added drop wise. The resulting solution was cooled to 70° C and was seeded using 0.27 g of the desired polymorph of rimonabant (Form I). A white solid precipitated off the reaction mixture after cooling to 40° C. At this temperature, the reaction mixture was concentrated to about the half of its volume by distillation under reduced pressure. After cooling to 0° C and filtration, 22.7 g of rimonabant (Form I) was isolated. Yield: 90%. Purity (HPLC Method 2): 99.66%, containing 0.11% of 5-(4-chlorophenyl)-l-(2,4-dichloropheπyl)-4-methyl-lH-pyrazole-3- carboxylic acid and 0.04% of l-{[5-(4-chlorophenyl)-I-(2,4-dichlorophenyl)-4-methyl-lH- pyrazol-3-yl]carbonyl}piperidine. Example 6: Colorimetric Measurement

The color quality (i.e., "whiteness") of the rimonabant samples was measured by depositing, leveling and measuring the sample without any special compacting treatment. The results of the color quality measurements, using illuminant D65 (daylight) and a 2° angle of observation, are illustrated in Table 1, below.

Table 1

The White Index (WI) was calculated according to ASTM E313-05 "Standard Practice for Calculating Yellowness and Whiteness Indices from Instrumentally Measured Color Coordinates" using the following formula:

WI = Y + (WI,_X) (x_n - x) + (my) (y_n - y) where: x_n and y_n are the chromaticity coordinates for the CIE Standard illuminant and source used, WI, x and Wl.y are numerical coefficients, and Y, x, and y are the luminance factor and the chromaticity coordinated of the specimen (which can be derived from the L*, a*, and b* coordinates for a given illuminant and measurement geometry). Values for all these variables (except those measured for the specimen), for illuminant D65 (daylight) and a 2° angle of observation, are provided in Table 2.

5 Table 2

Example 7

A mixture of 13.83 g (97.9 mmol) of 1-amiπopiperidiπe hydrochloride and 9.0 g of potassium hydroxide (assay 82%, 131.5 mmol) was suspended in 26 mL of toluene and stirred at room temperature for 1 hour. The suspension was filtered, the solid was 0 discarded, and the resulting solution was heated to reflux temperature. Residual water was removed by azeotropic distillation. The concentration of 1-aminopiperidine base in the resulting solution was calculated by potentiometric titration (28 % w/w).

5-(4-chlorophenyl)- 1 -(2,4-dichIorophenyl)-4-methyl- 1 /f-pyrazole-3-carboxylic acid (14.0 g, 36.7 mmol, same batch as Example 3) was suspended in 161 mL of toluene under S nitrogen atmosphere, and the resulting suspension was heated to reflux temperature. Ttoluene (21 mL) were distilled off to remove any residual amount of water by azeotropic distillation. After cooling to 70-75° C, 5.4 mL (74.0 mmol) of thionyl chloride was added over the reaction mixture, and the resulting suspension was stirred for 2 hours at 100° C. No starting material was detected by in-process control TLC. Then, 95 mL of solvent was removed by distillation0 under atmospheric pressure. The suspension was then cooled to 0° C, and 10.2 mL (73.9 mmol) of triethylamine, followed by 19.7 g of the previously prepared solution of 1 -aminopiperidine in toluene (28 % w/w, 55.0 mmol) were added dropwise. The reaction mixture was stirred at room temperature overnight Next, 30 mL of water and 23 mL of n-heptane were added to the suspension, and the resulting suspension was heated to 65° C. At this temperature, the aqueous5 phase was extracted, and the organic phase was washed with 29 mL of a 4 % solution of acetic acid, 42 mL of a 1.5 % solution of sodium hydroxide (twice), and finally with 30 mL of water. The resulting organic phase was heated to reflux temperature, and 63 mL of toluene was removed by distillation under atmospheric pressure. The resulting brownish solution was cooled to 85° C. At this temperature, 94 mL of n-heptane was added dropwise to the reaction mixture and precipitation of a solid was observed. The resulting suspension was cooled to 0° C, filtered and washed with n-heptane to yield 13.6 g of crude rimonabant (Yield: 80%).

The crude rimonabant was then dissolved in 40 mL of toluene at room temperature. Activated charcoal (0.7 g) was added to the solution, and the resulting suspension was stirred at room temperature for 1 hour. The charcoal was removed by filtration and washed with 9 mL of toluene. The filtered solution was men heated to reflux temperature, and 29 mL of toluene was removed by distillation under atmospheric pressure. The resulting solution was cooled to 75° C, and was seeded using 0.14 g of the desired polymorph of rimonabant (Form I). A white solid precipitated from the reaction mixture after cooling to 60° C. At this temperature, 80 mL of n-heptane was added dropwise to the reaction mixture. After cooling to 0° C and filteringn, 12.6 g of rimonabant (Form I) was isolated. Overall yield: 74 %. Purity (HPLC Method 3): 99.79 %, containing 0.03 % of l-{[5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-l//-pyrazol-3-yI]carbonyl}piperidine. White Index: 61.65 (L* = 94.81, a* = -0.02, b* = 5.59, Y = 87.17, x = 0.3225, y = 0.3394). It will be apparent to those skilled in the art that various modifications and variations can be made in the invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the invention covers the modifications and variations of this invention mat come within the scope of any claims and their equivalents.

Claims

1. I -{ [5-(4-chloropheπyI)- 1 -(2,4-dichlorophenyl)-4-methyl- 1 H-pyrazole-3- yl]carbonyl}pipcridine (Formula III) and its salts and solvates thereof.

2. A process for preparing l-{[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- l//-pyrazole-3-yl]carbonyl}piperidine (Formula III) comprising reacting 5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxyIic acid (Formula II) or one of its activated forms with piperidine.

3. A process for preparing [(5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-/H- pyrazole-3-yl)carbonyl] piperidine (Formula III) comprising reacting [5-(4-chlorophenyl)- l^^-dichlorophenyO^-methyl-lH-pyrazole-S-carbonyllchloride with piperidine in the presence of triethylamine in dichloromethane.

4 A process for analyzing the purity of rimonabaπt and/or its salts and solvates thereof comprising monitoring the amount of 1 -{[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-S-yrjcarboπyllpiperidine (Formula III) in a sample of rimonabant and/or its salts and solvates thereof.

5. A process for analyzing the purity of a composition containing rimonabant and/or its salts and solvates thereof comprising monitoring the amount of l-{[5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-yl]carbonyl}piperidine (Formula III) in a sample of said composition.

6. A process for analyzing the purity of a formulation containing rimonabant and/or its salts and solvates thereof comprising monitoring the amount of l-{[5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lH-pyra2ole-3-yl]carbonyl}piperidine (Formula III) in said formulation.

7. Rimonabant substantially free of 1 -{[5-(4-chlorophenyl)-l -(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-yl]carbonyl}piperidine (Formula 111).

8. The rimonabant and/or its salts and solvates thereof of claim 7, wherein said rimonabant and/or its salts and solvates thereof has less than approximately 1.0% of 1 -{[5- (4-chlorophenyl)- 1 -(2,4-dichloropheny l)-4-m ethy 1- 1 H-pyrazol e-3 -y 1] carbony I } piperidine (Formula III) as measured by ΗPLC.

9. The rimonabant and/or its salts and solvates thereof of claim 7, wherein said rimonabant and/or its salts and solvates thereof has less than approximately 0.5% of 1 - { [5- (4-chlorophenyl)- 1 -(2,4-dich!orophenyl)-4-methyI- 1 H-pyrazole-3-yl]carbonyl} piperidine (Formula III) as measured by ΗPLC.

10. The rimonabant and/or its salts and solvates thereof of claim 7, wherein said rimonabant and/or its salts and solvates thereof has less than approximately 0.3% of l-{[5- (4-chlorophenyl)-l -(2,4-dichlorophenyl)-4-methyl-lH-pyrazo!e-3-yl]carbonyl}piperidine (Formula III) as measured by ΗPLC.

1 1. The rimonabant and/or its salts and solvates thereof of claim 7, wherein said rimonabant and/or its salts and solvates thereof has less than approximately 0.1% of l-{[5- (4-chlorophenyl)-l-(2,4-dichIorophenyl)-4-methyl-l//-pyrazole-3-yl]carbonyl}piperidine (Formula III) as measured by ΗPLC.

12. A process for preparing rimonabant with enhanced color quality and a high purity comprising: i. reacting an acid of Formula II or one of its activated forms with I- aminopiperidine in at least one hydrophobic rimonabant-high capacity solvent in an inert atmosphere, at a temperature between 0° C and room temperature, and in the presence of at least one base, to obtain a first solution containing rimonabant; ii. extracting said first solution containing rimonabant to obtain a second solution containing rimonabant; iii. precipitating said rimonabant from said second solution containing rimonabant by adding at least one solvent in which rimonabant has low solubility to obtain a suspension; and iv. isolating said rimonabant from said suspension.

13. The process of claim 12, further comprising generating said 1-aminopiperidine from a solid acid addition salt thereof.

14. The process of claim 13, wherein said solid acid addition salt is a mineral acid 5 addition salt.

15. The process of claim 13, wherein said solid acid addition salt is a hydrogen halide addition salt.

16. The process of point 13, wherein said solid acid addition salt is 1-aminopiperidine hydrochloride. 0

17. The process of claim 12, further comprising performing said extracting step in the presence of at least one nonpolar solvent.

18. The process of claim 17, wherein said at least one nonpolar solvent is at least one alkane solvent.

19. The process of claim 18, wherein said at least one alkane solvent is heptane. S

20. The process of claim 12, further comprising performing a partial distillation of said suspension.

21. The process of claim 12, further comprising treating said rimonabant with at least one decolorizing agent.

22. The process of claim 21 , wherein said at least one decolorizing agent is at least one0 of alumina, activated alumina, silica, charcoal and combinations thereof.

23. The process of claim 12, wherein said at least one base is at least one organic base.

24. The process of claim 23, wherein said at least one organic base is at least one amine organic base.

25. The process of claim 24, wherein said at least one amine organic base is triethylamine.5

26. The process of claim 1 1, wherein said at least one hydrophobic rimonabant-high capacity solvent is at least one aromatic solvent.

27. The process of claim 26, wherein said at least one aromatic solvent is toluene.

28. The process of claim 1 1, wherein said at least one solvent in which rimonabant has low solubility is at least one alkane solvent.

29. The process of point 29, wherein said at least one alkane solvent is heptane.

30. Rimonabant prepared by the process of any one of claims 19 through 29.

31. The rimonabant of claim 30, wherein said rimonabant has a purity of greater than approximately between 98.5% and 99.5% as measured by HPLC.

32. The rimonabant of claim 30, wherein said rimonabant has a CIE (1976) L*, a*, b* Color Space (CIELAB) measurement when using a colorimeter or spectrophotometer, illuminant D65 (daylight) and a 2° angle of observation of approximately L* = 93 to 100, an a* = -1.00 to +1.00, and a b* = -10.00 to +10.00.

33. The rimonabant of claim 32, wherein said rimonabant has a CIE (1976) L*, a^φ, b* Color Space (CIELAB) measurements when using a colorimeter or spectrophotometer, illuminant D65 (daylight) and a 2° angle of observation of approximately L* = 97 to 100, an a* = -0.10 to +0.10, and a b* = -2.00 to +2.00.

34. The rimonabant of claim 30, wherein said rimonabant has a particle size distribution in which approximately 10% of the total volume comprises particles having a diameter below approximately 2.5 μm.

35. The rimonabant of claim 30, wherein said rimonabant has a particle size distribution in which approximately 50% of the total volume comprises particles having a diameter below about approximately 8.5 μm.

36. The rimonabant of claim 30, wherein said rimonabant has a particle size distribution in which approximately 90% of the total volume comprises particles having a diameter below approximately 37.5 μm.

37. The rimonabant of claim 30, wherein said rimonabant has less than approximately 1.0% of l-{[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazoIe-3- yl]carbonyl}piperidine (Formula III) as measured by ΗPLC.

38. The rimonabant of claim 30, wherein said rimonabant has less than approximately 0.5% of l-{[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- yl]carbonyl}piperidine (Formula III) as measured by ΗPLC.

39. The rimonabant of claim 30, wherein said rimonabant has less than approximately 0.3% of 1 -{ [5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- 17/-pyrazole-3- yl]carbonyl}piperidine (Formula III) as measured by HPLC.

40. The rimonabant of claim 30, wherein said rimonabant has less than approximately 0.1% of ^{[S^-chlorophenyO-l^^-dichlorophenylM-methyl-l/f-pyrazole-S- yl]carbonyl}piperidine (Formula III) as measured by HPLC.

41. A formulation comprising rimonabant and/or its salts and solvates thereof according to any of claims 7-1 1 and 30-40.