WO2009053551A1 - Rimonabant n,n-dimethylformamide solvate, and method for preparing same - Google Patents
Rimonabant n,n-dimethylformamide solvate, and method for preparing same Download PDFInfo
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- WO2009053551A1 WO2009053551A1 PCT/FR2008/001160 FR2008001160W WO2009053551A1 WO 2009053551 A1 WO2009053551 A1 WO 2009053551A1 FR 2008001160 W FR2008001160 W FR 2008001160W WO 2009053551 A1 WO2009053551 A1 WO 2009053551A1
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- rimonabant
- dimethylformamide
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- dimethylformamide solvate
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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 subject of the present invention is the N, N-dimethylformamide (DMF) solvate of rimonabant and its process of preparation.
- DMF N, N-dimethylformamide
- Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
- said solvate consists of a molecule of rimonabant and a molecule of N, N-dimethylformamide (monosolvate).
- the N, N-dimethylformamide solvate of rimonabant preferentially exists in crystallized form.
- the present invention relates to the N, N-dimethylformamide solvate of rimonabant, and more particularly to a crystalline form of the N, N-dimethylformamide solvate of rimonabant.
- Rimonabant can thus be prepared by desolvation of the N, N-dimethylformamide solvate of rimonabant according to methods known to those skilled in the art.
- the desolvation can for example be carried out by drying optionally at reduced pressure. Alternatively, it can also be carried out by drying at elevated temperatures.
- the process for the preparation of rimonabant characterized in that the rimonabant is obtained by desolvation of the N, N-dimethylformamide solvate of rimonabant constitutes an object of the present invention.
- the crystalline form of the rimonabant N.N-dimethylformamide solvate constitutes a powder whose characteristics are improved with respect to the powders constituted either by the crystalline form I of rimonabant or by the crystalline form II of rimonabant.
- the present invention also relates to the process for obtaining the NN-dimethylformamide solvate from rimonabant.
- This process is characterized in that the rimonabant is dissolved in NN-dimethylformamide. More particularly, this process is characterized in that: a) a suspension of rimonabant in N 1 N -dimethylformamide is prepared; b) the rimonabant NN-dimethylformamide solvate thus formed is isolated.
- step a) is carried out at room temperature.
- the solvate of the process for preparing N 1 N- dimethylformamide rimonabant according to the invention is characterized in that: a) preparing a suspension of rimonabant in N 1 N- dimethylformamide; b) heating until solubilization; c) isolating the solvate of NN-dimethylformamide rimonabant thus formed.
- the solvate of the process for preparing N 1 N- dimethylformamide rimonabant according to the invention is characterized in that: a) preparing a suspension of rimonabant in N 1 N- dimethylformamide; b) heating until solubilization; c) cooling; d) the N, N-dimethylformamide solvate of rimonabant thus formed is isolated.
- the heating step is carried out at a temperature of between 40 ° C. and the boiling point of the solvent, preferably about 60 ° C.
- the cooling step is performed at a temperature such that crystallization occurs; preferably, the temperature is between 0 0 C and 40 0 C 1 , preferably at room temperature.
- the rimonabant N-dimethylformamide solvate formed by the process according to the invention is isolated by filtration.
- a suspension of rimonabant preferably in form II (as described in WO 2003/040105), is prepared in N, N-dimethylformamide, with a concentration of between 5 and 70.degree. %, preferably 30 to 60%, more preferably about 50%.
- the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
- N, N-dimethylformamide solvate of rimonabant is characterized by various elements of its physicochemical analysis.
- the crystalline form of rimonabant N, N-dimethylformamide solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
- Thermogravimetric analysis is carried out for the rimonabant N 1 N-dimethylformamide solvate by a thermogravimetric analysis device NETZSCH TG 209; it operates at a speed of 2 ° C / minute.
- the diagram of the TG analysis is shown in FIG.
- N, N-dimethylformamide solvate of rimonabant can also be analyzed by differential scanning calorimetry (TSC) analysis.
- the crystalline form of the N, N-dimethylformamide solvate of rimonabant can also be characterized by its infra-red spectrum (I.R.).
- the crystalline form of the N, N-dimethylformamide solvate of rimonabant can also be characterized by its crystalline structure for which the mesh parameters are determined by X-ray diffraction on single crystal. From the mesh parameters and the atomic coordinates x, y, z of the atoms of the molecule, computation software makes it possible to draw projected views of the crystal lattice of the molecule concerned.
- the RX diagram on powder, represented in Figure 1 (3,000 ° - 30,000 °, not 0.040 °, duration: 4 s, temperature 25 ° C) shows a new diffraction profile, whose characteristic lines are reported in Table 1 next :
- Thermogravimetric analysis confirms the stoichiometry (1-1) of the N, N-dimethylformamide solvate.
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Abstract
Description
LE SOLVATE DE N,N-DIMETHYLFORMAMIDE DE RIMONABANT, ET SON PROCEDE DE PREPARATION. RIMONABANT N, N-DIMETHYLFORMAMIDE SOLVATE AND PROCESS FOR PREPARING THE SAME
La présente invention a pour objet le solvate de N,N-diméthylformamide (DMF) de rimonabant et son procédé de préparation.The subject of the present invention is the N, N-dimethylformamide (DMF) solvate of rimonabant and its process of preparation.
Le rimonabant est la dénomination commune internationale du N- pipéridino-5-(4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthylpyrazole-3- carboxamide.Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
Ce composé, ses sels et ses solvats sont décrits dans le brevet européen 656354.This compound, its salts and its solvates are described in European Patent 656354.
On a maintenant trouvé un solvat particulier : le solvate de N1N- diméthylformamide de rimonabant qui présente des propriétés avantageuses.We have now found a particular solvate: the solvate of N 1 N-dimethylformamide rimonabant which has advantageous properties.
Selon la définition de solvate donnée par Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, on entend par solvate de N,N-diméthylformamide de rimonabant tout complexe moléculaire à base de rimonabant incorporant le N,N-diméthylformamide dans son réseau cristallin.According to the definition of solvate given by Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, the term "Rimonabant N, N-dimethylformamide solvate" is understood to mean any n-incorporating rimonabant-based molecular complex. N-dimethylformamide in its crystal lattice.
Selon un autre objet de la présente invention, ledit solvate est constitué d'une molécule de rimonabant et d'une molécule de N,N-diméthylformamide (monosolvate).According to another object of the present invention, said solvate consists of a molecule of rimonabant and a molecule of N, N-dimethylformamide (monosolvate).
Le solvate de N,N-diméthylformamide de rimonabant existe préférentiellement sous forme cristallisée. La présente invention est relative au solvate de N,N-diméthylformamide de rimonabant, et plus particulièrement à une forme cristalline du solvate de N,N-diméthylformamide de rimonabant.The N, N-dimethylformamide solvate of rimonabant preferentially exists in crystallized form. The present invention relates to the N, N-dimethylformamide solvate of rimonabant, and more particularly to a crystalline form of the N, N-dimethylformamide solvate of rimonabant.
Le fait d'obtenir un solvate du rimonabant avec le N,N-diméthylformamide est particulièrement avantageux à titre d'intermédiaire dans l'(es) étape(s) finale(s) de synthèse du rimonabant.The fact of obtaining a solvate of rimonabant with N, N-dimethylformamide is particularly advantageous as an intermediate in the final stage (s) of synthesis of rimonabant.
Le rimonabant peut ainsi être préparé par désolvatation du solvate de N,N-diméthylformamide de rimonabant selon les méthodes connues de l'homme du métier.Rimonabant can thus be prepared by desolvation of the N, N-dimethylformamide solvate of rimonabant according to methods known to those skilled in the art.
La désolvatation peut par exemple être réalisée par séchage éventuellement à pression réduite. Alternativement, elle peut également être réalisée par séchage à des températures élevées. Le procédé de préparation du rimonabant caractérisé en ce que le rimonabant est obtenu par désolvatation du solvate de N,N-diméthylformamide de rimonabant constitue un objet de la présente invention.The desolvation can for example be carried out by drying optionally at reduced pressure. Alternatively, it can also be carried out by drying at elevated temperatures. The process for the preparation of rimonabant, characterized in that the rimonabant is obtained by desolvation of the N, N-dimethylformamide solvate of rimonabant constitutes an object of the present invention.
Ainsi, la forme cristalline du solvate de N.N-diméthylformamide de rimonabant constitue une poudre dont les caractéristiques sont améliorées par rapport aux poudres constituées soit par la forme cristalline I du rimonabant, soit par la forme cristalline II du rimonabant.Thus, the crystalline form of the rimonabant N.N-dimethylformamide solvate constitutes a powder whose characteristics are improved with respect to the powders constituted either by the crystalline form I of rimonabant or by the crystalline form II of rimonabant.
La présente invention est également relative au procédé d'obtention du solvate de N.N-diméthylformamide de rimonabant. Ce procédé est caractérisé en ce que l'on dissout le rimonabant dans le N.N-diméthylformamide. Plus particulièrement, ce procédé est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N1N- diméthylformamide, b) on isole le solvate de N.N-diméthylformamide de rimonabant ainsi formé.The present invention also relates to the process for obtaining the NN-dimethylformamide solvate from rimonabant. This process is characterized in that the rimonabant is dissolved in NN-dimethylformamide. More particularly, this process is characterized in that: a) a suspension of rimonabant in N 1 N -dimethylformamide is prepared; b) the rimonabant NN-dimethylformamide solvate thus formed is isolated.
Préférentiellement, selon le procédé de l'invention, l'étape a) est réalisée à température ambiante.Preferably, according to the method of the invention, step a) is carried out at room temperature.
De manière particulière, le procédé de préparation du solvate de N1N- diméthylformamide de rimonabant selon l'invention est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N1N- diméthylformamide ; b) on chauffe jusqu'à solubilisation; c) on isole le solvate de N.N-diméthylformamide de rimonabant ainsi formé.Particularly, the solvate of the process for preparing N 1 N- dimethylformamide rimonabant according to the invention is characterized in that: a) preparing a suspension of rimonabant in N 1 N- dimethylformamide; b) heating until solubilization; c) isolating the solvate of NN-dimethylformamide rimonabant thus formed.
De manière plus particulière, le procédé de préparation du solvate de N1N- diméthylformamide de rimonabant selon l'invention est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N1N- diméthylformamide ; b) on chauffe jusqu'à solubilisation ; c) on refroidit ; d) on isole le solvate de N,N-diméthylformamide de rimonabant ainsi formé.More particularly, the solvate of the process for preparing N 1 N- dimethylformamide rimonabant according to the invention is characterized in that: a) preparing a suspension of rimonabant in N 1 N- dimethylformamide; b) heating until solubilization; c) cooling; d) the N, N-dimethylformamide solvate of rimonabant thus formed is isolated.
De préférence, l'étape de chauffage est réalisée à une température comprise entre 400C et la température d'ébullition du solvant, de préférence environ 600C.Preferably, the heating step is carried out at a temperature of between 40 ° C. and the boiling point of the solvent, preferably about 60 ° C.
De préférence, l'étape de refroidissement est réalisée à une température telle qu'une cristallisation se produise ; de préférence, la température est comprise entre 00C et 400C1 de préférence à température ambiante.Preferably, the cooling step is performed at a temperature such that crystallization occurs; preferably, the temperature is between 0 0 C and 40 0 C 1 , preferably at room temperature.
Le solvate de N.N-diméthylformamide de rimonabant formé par le procédé selon l'invention est isolé par filtration.The rimonabant N-dimethylformamide solvate formed by the process according to the invention is isolated by filtration.
De façon particulière, à l'étape a), on prépare une suspension de rimonabant, de préférence sous forme II (telle que décrite dans WO 2003/040105), dans le N,N-diméthylformamide, avec une concentration comprise entre 5 et 70%, de préférence de 30 à 60%, plus préférentiellement environ 50%.In a particular way, in step a), a suspension of rimonabant, preferably in form II (as described in WO 2003/040105), is prepared in N, N-dimethylformamide, with a concentration of between 5 and 70.degree. %, preferably 30 to 60%, more preferably about 50%.
Après la filtration de la dernière étape, le produit obtenu est avantageusement séché à une température comprise entre la température ambiante et 400C, préférentiellement à température ambiante.After filtration of the last step, the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
Le solvate de N,N-diméthylformamide de rimonabant est caractérisé par différents éléments de son analyse physico-chimique.The N, N-dimethylformamide solvate of rimonabant is characterized by various elements of its physicochemical analysis.
La forme cristalline du solvate de N,N-diméthylformamide de rimonabant est caractérisée par les raies caractéristiques du diffractogramme de rayons X sur poudre.The crystalline form of rimonabant N, N-dimethylformamide solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
Le profil de diffraction des rayons X (RX) de la poudre (angle de diffraction) est établi avec un diffractomètre Siemens D5005; source CuKa, λ = 1.54178A.The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; CuKa source, λ = 1.54178A.
Les raies caractéristiques du diffractogramme sont reportées dans le tableau 1 suivant : TABLEAU 1 :The characteristic lines of the diffractogram are reported in the following Table 1: TABLE 1:
Rayons X sur poudre, forme cristalline du solvate de N,N-diméthylformamide de rimonabantX-rays on powder, crystalline form of rimonabant N, N-dimethylformamide solvate
Le diffractogramme correspondant au solvate de N,N-diméthylformamide de rimonabant est reproduit dans la figure 1.The diffractogram corresponding to the N, N-dimethylformamide solvate of rimonabant is reproduced in FIG.
Tteneuren N,N-diméthylformamide :Ttaineuren N, N-dimethylformamide:
L'analyse TG (thermogravimétrique) permet de confirmer la stoechiométrie 1-1 du solvate de N,N-diméthylformamide.TG (thermogravimetric) analysis makes it possible to confirm the stoichiometry 1-1 of the N, N-dimethylformamide solvate.
L'analyse thermogravimétrique est réalisée pour le solvate de N1N- diméthylformamide de rimonabant par un appareil d'analyse thermogravimétrique NETZSCH TG 209; on opère à vitesse de 2°C/minute. Le diagramme de l'analyse TG est représenté à la figure 2.Thermogravimetric analysis is carried out for the rimonabant N 1 N-dimethylformamide solvate by a thermogravimetric analysis device NETZSCH TG 209; it operates at a speed of 2 ° C / minute. The diagram of the TG analysis is shown in FIG.
Le solvate de N,N-diméthylformamide de rimonabant peut également être analysé par analyse enthalpique différentielle (TSC).The N, N-dimethylformamide solvate of rimonabant can also be analyzed by differential scanning calorimetry (TSC) analysis.
La forme cristalline du solvate de N,N-diméthylformamide de rimonabant peut également être caractérisée par son spectre infra-rouge (I. R.).The crystalline form of the N, N-dimethylformamide solvate of rimonabant can also be characterized by its infra-red spectrum (I.R.).
La forme cristalline du solvate de N,N-diméthylformamide de rimonabant peut également être caractérisée par sa structure cristalline pour laquelle les paramètres de maille sont déterminés par diffraction des rayons X sur monocristal. A partir des paramètres de maille et des coordonnées atomiques x, y, z des atomes de la molécule, des logiciels de calcul permettent de tracer des vues projetées de la maille cristalline de la molécule concernée.The crystalline form of the N, N-dimethylformamide solvate of rimonabant can also be characterized by its crystalline structure for which the mesh parameters are determined by X-ray diffraction on single crystal. From the mesh parameters and the atomic coordinates x, y, z of the atoms of the molecule, computation software makes it possible to draw projected views of the crystal lattice of the molecule concerned.
Les exemples suivants sont donnés à titre illustratif et non limitatif de la présente invention.The following examples are given by way of non-limiting illustration of the present invention.
Exemple : préparation de la forme cristalline du solvate de N,N-diméthylformamide de rimonabant.Example: preparation of the crystalline form of the N, N-dimethylformamide solvate of rimonabant.
A température ambiante, une suspension de 2 g de rimonabant sous forme II micronisée est réalisée dans 2 g de DMF (pureté : 99%) puis homogénéisée à 600C. Une cristallisation se produit en refroidissant lentement la solution à température ambiante. La phase solide est récupérée par filtration ; des analyses XRPD1 thermogravimétrique et DSC ont permis de mettre en évidence un nouveau composé défini de stcechiométrie 1-1 : solvate de DMF. a) Analyse XRPDAt room temperature, a suspension of 2 g of rimonabant in micronized form II is carried out in 2 g of DMF (purity: 99%) and then homogenized at 60 ° C. Crystallization occurs by slowly cooling the solution to room temperature. The solid phase is recovered by filtration; Thermogravimetric XRPD 1 and DSC analyzes have made it possible to demonstrate a new defined compound of stoichiometry 1-1: DMF solvate. a) XRPD analysis
Le diagramme de diffraction des rayons X est enregistré sur un diffractomètre Siemens D5005 (Cu Kα,λ = 1 ,54178 A). Le Diagramme RX sur poudre, représenté à la figure 1 (3.000° - 30.000° ; pas 0.040° ; durée : 4 s ; température 25°C) fait apparaître un nouveau profil de diffraction, dont les raies caractéristiques sont reportées dans le tableau 1 suivant :The X-ray diffraction pattern is recorded on a Siemens D5005 diffractometer (Cu Kα, λ = 1, 54178 A). The RX diagram on powder, represented in Figure 1 (3,000 ° - 30,000 °, not 0.040 °, duration: 4 s, temperature 25 ° C) shows a new diffraction profile, whose characteristic lines are reported in Table 1 next :
b) Analyse thermogravimétrique : L'analyse thermogravimétrique permet de confirmer la stœchiométrie (1-1) du solvate de N,N-diméthylformamide.(b) Thermogravimetric analysis: Thermogravimetric analysis confirms the stoichiometry (1-1) of the N, N-dimethylformamide solvate.
Appareil : NETZSCH TG 209Device: NETZSCH TG 209
Vitesse de chauffe : 2°C/minHeating rate: 2 ° C / min
L'analyse effectuée de 20 à 5000C sur le solvate obtenu dans le DMF (figure 2) montre une perte de masse de 13,70% avant la dégradation du rimonabant vers 2800C ; cette perte de masse correspond à la stœchiométrie d'un monosolvate de DMF (Δm/m théorique=13,6%). The analysis carried out at 20 to 500 ° C. on the solvate obtained in DMF (FIG. 2) shows a loss of mass of 13.70% before the degradation of rimonabant at around 280 ° C. this weight loss corresponds to the stoichiometry of a DMF monosolvate (Dm / m theo riqu e = 13.6%).
Claims
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0756965 | 2007-08-06 | ||
| FR0756965A FR2919868A1 (en) | 2007-08-06 | 2007-08-06 | RIMONABANT N, N-DIMETHYFORMAMIDE SOLVATE AND PROCESS FOR PREPARING THE SAME |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0656354A1 (en) * | 1993-12-02 | 1995-06-07 | Sanofi | Substituted N-piperidino 3-pyrazolecarboxamide |
| EP0658546A1 (en) * | 1993-12-17 | 1995-06-21 | Sanofi | Novel 3-pyrazolecarboxamide derivatives with cannabinoid receptor affinity |
| WO1998043636A1 (en) * | 1997-03-28 | 1998-10-08 | Sanofi-Synthelabo | Pharmaceutical composition for oral administration of a n-piperidino- 3-pyrazolecarboxamide derivative, its salts and their solvates |
| WO2008035023A1 (en) * | 2006-09-19 | 2008-03-27 | Cipla Limited | Polymorphs of rimonabant |
-
2007
- 2007-08-06 FR FR0756965A patent/FR2919868A1/en active Pending
-
2008
- 2008-08-04 WO PCT/FR2008/001160 patent/WO2009053551A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0656354A1 (en) * | 1993-12-02 | 1995-06-07 | Sanofi | Substituted N-piperidino 3-pyrazolecarboxamide |
| EP0658546A1 (en) * | 1993-12-17 | 1995-06-21 | Sanofi | Novel 3-pyrazolecarboxamide derivatives with cannabinoid receptor affinity |
| WO1998043636A1 (en) * | 1997-03-28 | 1998-10-08 | Sanofi-Synthelabo | Pharmaceutical composition for oral administration of a n-piperidino- 3-pyrazolecarboxamide derivative, its salts and their solvates |
| WO2008035023A1 (en) * | 2006-09-19 | 2008-03-27 | Cipla Limited | Polymorphs of rimonabant |
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| FR2919868A1 (en) | 2009-02-13 |
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