WO2009153804A1 - Procédé de préparation de la forme 1 du rimonabant - Google Patents

Procédé de préparation de la forme 1 du rimonabant Download PDF

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Publication number
WO2009153804A1
WO2009153804A1 PCT/IN2009/000220 IN2009000220W WO2009153804A1 WO 2009153804 A1 WO2009153804 A1 WO 2009153804A1 IN 2009000220 W IN2009000220 W IN 2009000220W WO 2009153804 A1 WO2009153804 A1 WO 2009153804A1
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WIPO (PCT)
Prior art keywords
rimonabant
water
stirred
added
room temperature
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PCT/IN2009/000220
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English (en)
Inventor
Bipin Pandey
Mayank Ghanshyambhai Dave
Vismit Niranjanbhai Vyas
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Cadila Healthcare Limited
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Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2009153804A1 publication Critical patent/WO2009153804A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention describes new process for the preparation of Form I of Rimonabant. BACKGROUND OF THE INVENTION
  • Obese patients are at higher risk for coronary artery disease, hypertension, hyperlipidemia, and diabetes mellitus, among other diseases and thus their risk of morbidity and mortality increases. Due to many complex pathophysiological components which lead to obesity, the disease remains a challenging and significant clinical problem. Cannabinoides acting via cannabinoid receptors stimulate food intake and a particularly attractive antiobesity target is the cannabinoid CB 1 receptor, which has also been shown to play a role in reinforcing reward. (I. A. Sorbera et ah, Drugs of Future 2005; 30(2): 128-137). Rimonabant has been approved in Europe for the treatment of obesity. The agent also exhibited efficacy in phase III clinical trials and hold promise in the treatment of smoking cessation.
  • Rimonabant is _ 5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-N- (piperidin-l-yl) ⁇ yrazole- 3-carboxamide, having structural formula I.
  • WO 03040105 discloses one new crystalline form of Rimonabant designating it as Form II, which also states the earlier form disclosed in EP 0656354 is the Form I. It also states that the new form, Form II can be obtained by particular crystallization conditions, and the Form II is more stable than the Form I. This _ _ . _
  • Form II also differentiates the Form II from the earlier disclosed Form I through difference in XRD & IR data.
  • the application also described that the Form II can be obtained from the Form I by dissolving Form I in suitable solvent like methyl cyclohexane containing 1-10 % water or acetonitrile or acetone etc. in the hot state and subsequently cooling the mixture to obtain the crystals of Form II.
  • suitable solvent like methyl cyclohexane containing 1-10 % water or acetonitrile or acetone etc.
  • the present invention provides new process for preparing Form I of Rimonabant.
  • Figure 1 IR peaks of Rimonabant Form I prepared according to the invention.
  • Figure 2 XRD peaks of Rimonabant Form I prepared according to the invention.
  • the present invention thus provides an improved process for preparing Form I of Rimonabant.
  • the process according to the present invention involves following steps.
  • Rimonabant base (Forms H, III, IV-VI, amorphous, solvated, hydrated etc.) into acid addition salt of Rimonabant, using a suitable acid in suitable solvents and or water;
  • the reaction temperature is preferably maintained at 25-100 0 C; preferably the solvent used are water miscible solvents; (2) adding the reaction mixture to a suitable base, optionally in suitable solvent and or water at 25-100 0 C; preferably, the solvents used are water miscible solvents
  • Suitable salts which can be prepared from the Rimonabant includes but are not limited to suitable inorganic salts such as halides, nitrates, sulfates, bisulfates, phosphates, hexafluorophosphates and the like; organic salts such as oxalate, maleate, succinate, fumarate, tartarate, sulfonates such as mesylate, besylate, tosylate, triflate, trifluoro
  • Suitable solvents which can be used in either step (1) or (2) above may be independently selected from water or suitable water miscible solvents such as suitable alcohols, ethers, suitable ketones, DMF, DMSO and the like or their suitable mixtures.
  • suitable alcohols may be selected from (Ci-C 6 )alcohols such as methanol, ethanol, isopropanol, butanol and the like;
  • suitable ethers may be (C 1 -C 6 ) ethers such as dimethyl ether, diethyl ether, methyl ethyl ether and the like dioxane, tetrahydrofuran;
  • suitable ketones may be selected from (Ci-C 4 ) ketones such as dimethyl ketone, methyl ethyl ketone and the like;
  • Suitable bases may be selected from alkali or alkaline earth metal carbonates, bicarbonates or alkali metal hydroxides, ammonia, organic bases such as triethyl amine,
  • the base thus obtained was cooled gradually, filtered and washed with water and dried to obtain Rimonabant Form I.
  • the Rimonabant Form 1 obtained by the process of the present invention has residual solvents less than 1%, preferably less than 0.5%
  • Rimonabant hydrochloride (14 gm) obtained above was suspended in water (15 ml) at 50-100 0 C.
  • a solution of Potassium carbonate (0.5 gm) in 10 ml of water was prepared at 50-100 0 C.
  • To the flask containing potassium carbonate was added the suspension of the Rimonabant hydrochloride and further stirred for half an hour. The mixture was gradually cooled to room temperature. It was filtered, and washed with water, dried till constant weight when 9.0 g Rimonabant form-1 was obtained.
  • the crystalline polymorph Form I of Rimonabant is characterized by X-ray diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about, 9.181,10.757,1 1.7,12.319,13.078, 14.081, 16.120, 16.400, 16.840, 17.861, 18.439, 18.961, 19.420,20.239, 20.719,
  • Rimonabant (10 gm) was dissolved in ethyl acetate (100 ml) and stirred at 25-30 0 C. To the reaction mass HCl gas dissolved in isopropyl alcohol was added drop wise at room temperature until the pH of the reaction mass was 2-3. The resulting precipitate was stirred at 25-30 0 C for 2 hours and filtered. The solid was washed with ethyl acetate and dried under vacuum at 55-60 C to obtain Rimonabant hydrochloride (10 gm).
  • the crystalline Rimonabant hydrochloride obtained was characterized by X-ray diffraction pattern with 20 peaks ( ⁇ 0.2°) at about 9.559,. 10.379, 1 1.681, 13.079, 13.699, 14.400, 14.721, 15.121, 15.602, 16.520, 17.119, 17.701, 18.242, 18.500,
  • Rimonabant hydrochloride (10 gm) was suspended in water (15 ml) at 50-100
  • the Rimonabant Form I prepared was characterised by X-ray diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about 9.181,10.757,11.7,12.319,13.078, 14.081, 16.120,
  • the Rimonabant phosphate is characterized by X-ray diffraction pattern with 20 peaks ( ⁇ 0.2°) at about 5.501,9.459,10.640,11.660,12.860, 13.679, 15.440, 16.330, 17.161, 17.939, 19.319, 21.359, 22.480, 23.039, 23.754, 25.460, 26.261, 27.341, 29.640, 30.680, 31.161, 34.038, 34.719.
  • Rimonabant phosphate (10 gm) was suspended in water (15 ml) at 50-100 0 C, while in another flask Potassium carbonate (0.5 gm) was dissolved in 10 ml of water at 50-100 0 C. To this flask was added the suspension of Rimonabant phosphate and further stirred for half an hour. The mixture was gradually cooled to room temperature, filtered, washed with water & Dried to constant weight, to obtain the form I of Rimonabant.
  • Rimonabant hydrochloride and further stirred for half an hour. The mixture was gradually cooled to room temperature, filtered and washed with water. The residue was dried to constant weight to obtain form I of Rimonabant.
  • Rimonabant form I was obtained from Rimonabant sulphate & Rimonabant phosphate.
  • Example 10 Preparation of Rimonabant form 1:- Crystalline Rimonabant (10 gm) was suspended in water (100 ml) and stirred at
  • Rimonabant form I - Crystalline Rimonabant (10 gm) was suspended in water (100 ml) and stirred at 25-30 0 C. To the suspension was added cone. HCl (1 ml) & stirred at 55-100 0 C. In another flask Sodium hydroxide (9 gm) was dissolved in 50 ml of water at 50-100 0 C. To this flask was added the suspension of the Rimonabant hydrochloride and further stirred for half an hour. The solution was gradually cooled to room temperature. The separated solid was filtered, washed with water and dried till constant weight, to obtain form I of Rimonabant. XRD, DSC, IR matches with those reported. Example 13 Preparation of Rimonabant form I:-
  • the crystalline oxalate salt of Rimonabant was characterized by X-ray diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about, 5.641, 8.742, 10.041, 1 1.322, 1 1.860, 12.519. 15.419, 17.039, 18.139, 18.739, 19.600, 20.200, 21.061, 21.620, 21.979, 22.339, 22.920, 23.740, 23.979, 24.460, 25.001, 27.660, 28.500, 31.142, 31.421, 32.061, 32.401.
  • Rimonabant oxalate (10 gm) was suspended in water (15 ml) at 50-100 C. While in other flask a solution of potassium carbonate (11 gm) in 50 ml of water was warmed to 50-100 0 C. To this flask was added the suspension of the Rimonabant oxalate and further stirred for half an hour. The mixture was gradually cooled to room temperature, filtered, washed with water and dried till constant weight, to obtain form I of Rimonabant. XRD, DSC, IR matches with those reported. Example 17 i) Preparation of Rimonabant Maleate:-
  • the crystalline maleate salt of Rimonabant was characterized by X-ray diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about, 9.400, 10.521, 11.962, 13.698,
  • Rimonabant succinate (10 gm) was suspended in water (15 ml) at 50-100 0 C.
  • the crystalline fumarate salt of Rimonabant was characterized b> X-ra> diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about, 7.200, 9.200, 10.400, 13.420, 14.399, 15.140, 16.001, 16.940, 17.660, 18.981, 19.500, 20.180, 20.679, 21.060, 21.439,
  • Rimonabant fumarate (10 gm) was suspended in water (80 ml) at 50-100 0 C.
  • Sodium hydroxide (6 gm) in 50 ml of water was warmed to 50-100 0 C.
  • To this flask was added the suspension of the Rimonabant fumarate and further stirred. The mixture was slowly cooled to room temperature, filtered, washed with water and dried till constant weight, to obtain form I of Rimonabant.
  • the crystalline tartarate salt of Rimonabant was characterized by X-ray diffraction pattern with 2 ⁇ peaks ( ⁇ 0.2°) at about, 6.579, 9.280, 9.579, 10.442, 11.161,
  • Crystalline oxalic acid (1.3 gm) was dissolved in THF (90 ml) and stirred at 25- 30 0 C. To this solution Rimonabant (10 gm) was added at room temperature and further stirred at 55-60 0 C to get a clear solution. In other flask aqueous ammonia solution (10 gm) in 90 ml warmed to 50-100 0 C. To this flask was added the solution of the Rimonabant oxalate and further stirred for half an hour. The solution was slowly cooled to room temperature, filtered, washed with water and dried till constant weight, to obtain form I of Rimonabant. XRD, DSC, IR matches with those reported.
  • Rimonabant form I may be obtained from Rimonabant maleate, succinate, -tartarate, fumarate, sulfonates, triflate, trifluoroacetate, perchlorate, benzoate, napsylate, borates, antimonates etc.
  • Benefits of the process of the present invention 1. The process is scalable and does not use any difficult solvents like ethers or cyclohexane; 2. The process is economical as the solvents used are either water or low cost commercially viable solvents;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de la forme 1 du Rimonabant, par la formation intermédiaire du sel d'addition acide correspondant.
PCT/IN2009/000220 2008-06-16 2009-03-31 Procédé de préparation de la forme 1 du rimonabant WO2009153804A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1262/MUM/2008 2008-06-16
IN1262MU2008 2008-06-16

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WO2009153804A1 true WO2009153804A1 (fr) 2009-12-23

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO2003040105A1 (fr) * 2001-11-08 2003-05-15 Sanofi-Synthelabo Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant
EP1816125A1 (fr) * 2006-02-02 2007-08-08 Ranbaxy Laboratories, Ltd. Formes cristallines d'un antagoniste du récepteur cannabinoïde CB1 et son procédé de préparation
WO2008026219A2 (fr) * 2006-09-01 2008-03-06 Hetero Drugs Limited Nouveaux polymorphes de rimonabant
WO2008035023A1 (fr) * 2006-09-19 2008-03-27 Cipla Limited Formes polymorphes de rimonabant
WO2008062480A2 (fr) * 2006-11-24 2008-05-29 Ind-Swift Laboratories Limited Procédé amélioré de préparation du rimonabant
WO2008088900A2 (fr) * 2007-01-18 2008-07-24 Teva Pharmaceutical Industries Ltd. Formes polymorphes d'une base de rimonabant et procédés pour leur préparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO2003040105A1 (fr) * 2001-11-08 2003-05-15 Sanofi-Synthelabo Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant
EP1816125A1 (fr) * 2006-02-02 2007-08-08 Ranbaxy Laboratories, Ltd. Formes cristallines d'un antagoniste du récepteur cannabinoïde CB1 et son procédé de préparation
WO2008026219A2 (fr) * 2006-09-01 2008-03-06 Hetero Drugs Limited Nouveaux polymorphes de rimonabant
WO2008035023A1 (fr) * 2006-09-19 2008-03-27 Cipla Limited Formes polymorphes de rimonabant
WO2008062480A2 (fr) * 2006-11-24 2008-05-29 Ind-Swift Laboratories Limited Procédé amélioré de préparation du rimonabant
WO2008088900A2 (fr) * 2007-01-18 2008-07-24 Teva Pharmaceutical Industries Ltd. Formes polymorphes d'une base de rimonabant et procédés pour leur préparation

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