WO2008101860A1 - Nouveau procédé de préparation de 5-(4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthyl-n-(pipéridin-1-yl)pyrazole-3-carboxamide - Google Patents

Nouveau procédé de préparation de 5-(4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthyl-n-(pipéridin-1-yl)pyrazole-3-carboxamide Download PDF

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Publication number
WO2008101860A1
WO2008101860A1 PCT/EP2008/051802 EP2008051802W WO2008101860A1 WO 2008101860 A1 WO2008101860 A1 WO 2008101860A1 EP 2008051802 W EP2008051802 W EP 2008051802W WO 2008101860 A1 WO2008101860 A1 WO 2008101860A1
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WIPO (PCT)
Prior art keywords
alkyl
group
methyl
pyrazole
substituted
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PCT/EP2008/051802
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English (en)
Inventor
Sven Nerdinger
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Sandoz Ag
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Publication of WO2008101860A1 publication Critical patent/WO2008101860A1/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 relates to a process for the synthesis of Rimonabant, 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-N-(piperidin-l-yl)pyrazole-3-carboxamide.
  • Rimonabant is a drug with the CAS name 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-N- (piperidin-l-yl)pyrazole-3-carboxamide, having structural formula 1
  • Rimonabant as a free base is presently being used for the treatment of obesity and its mode of function is presumed to be via inhibition of the CBi-receptor.
  • the compound was first disclosed in EP 656354 and also in US 5624941.
  • Rimonabant may be prepared according to the process disclosed in EP 656354, by a general condensation reaction to produce the pyrazole-ring system 5 (according to Murray et al., J. Heterocycl. Chem. 1989, 26, 1389ff.) which is further modified by a coupling reaction to obtain Rimonabant, as described in Scheme 1.
  • the present invention relates to a novel process for the preparation of pyrazole derivatives of formula (10), in particular for the preparation of Rimonabant.
  • the process employs carbon-nitrogen-coupling of a pyrazole-derivative in the presence of a transition metal catalyst and optionally a suitable phosphine- derived ligand.
  • the process of the present invention is applicable to pilot plant and even industrial scale synthesis. It has been found that no regioselectivity problems occur during the synthesis of the pyrazole- derivative by the inventive process.
  • the present invention provides a process for the preparation of pyrazole-derivatives of structural formula 10:
  • U is CN or a group of formula R , wherein the carbon atom of the carbonyl group is bonded to pyrazol heterocycle, g 2 , g 3 , g 4 , g 5 and g 6 , and w 2 , w 3 , w 4 , w 5 and w 6 are identical or different from another and may independently be hydrogen, chlorine, bromine , (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, trifluoromethyl or a nitro group; R 3 may be hydrogen or (Ci-C 3 )alkyl, in particular methyl;
  • R may be a group NR 1 R 2 in which R 1 and R 2 are independently selected from the group of
  • g 2 , g 3 , g 4 , g 5 , g 6 are all independently selected from hydrogen, halogen, (Ci-C 3 )alkyl or (Ci-C 3 )alkoxy and w 2 , w 3 , w 4 , w 5 and w 6 are all independently selected from hydrogen, halogen, (Ci-C 3 )alkyl or (Ci-C 3 )alkoxy.
  • g 2 , g 3 ,g 5 , g 6 are all hydrogen and g4 is chlorine, bromine, (Ci-C 3 )alkyl, or (Ci-C 3 )alkoxy and w 3 , w 5 , w 6 are all hydrogen and w 2 , w 4 are chlorine or bromine. Even more preferably g 2 , g 3 ,g 5 , g 6 are all hydrogen and g 4 is chlorine and w 3 , w 5 , w 6 are all hydrogen and w 2 , w 4 are chlorine.
  • U is a group of formula a non-aromatic C 3 -Ci 5 carbocyclic radical or a saturated 5- to 8-membered heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl.
  • the process of the present invention comprises carbon-nitrogen-bond formation, in particular a step wherein a compound of formula 11:
  • X is a suitable leaving group, in particular a leaving group selected from a halogen , for example chloro, bromo and iodo, a sulfonate-type leaving-group, for example trifluoromethansulfonate (triflate), nonafluorotrimethylmethanesulfonate (nonaflate), methanesulfonate, Benzenesulfonate, para- toluenesulfonate, and B(OH) 2 ; in the presence of a base and a transition metal catalyst, in particular a transition metal catalyst selected from group 5-12 metals, preferably the group VHIA metals.
  • a suitable leaving group in particular a leaving group selected from a halogen , for example chloro, bromo and iodo
  • a sulfonate-type leaving-group for example trifluoromethansulfonate (triflate), nonafluorotrimethylmethanesulfonate
  • X is a halogen atom or a sulfonate-type leaving-group
  • the transition metal catalyst is selected from the group consisting of V, Mn, Fe, Co, Ni, Rh, Pd, Ir and Pt, with Pd and Ni being particularly preferred, and the reaction is carried out in the presence of a trisubstituted phosphine.
  • the trisubstituted phosphine is a ligand of formula 13:
  • Xi is a carbon- or nitrogen atom
  • X 2 . 5 are independently from each other either carbon or nitrogen, wherein X 1 ⁇ combine with the carbon atom bonded to X 1 and X 5 to form an aromatic-type heterocycle
  • Q 2"10 is independently selected from the group of hydrogen, methyl, branched or unbranched C 2 - 2o alkyl, wherein optionally one or more hydrogen atoms are replaced by fluoro, chloro or bromo, cycloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, arylmino, diarylamino, alkylarylamino, pentafluorsulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, alkylarylphosphino, if necessary substituted aminocarbonyl, CO 2 -, alkyl or alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, nitro, cyano, aryl- or alkylsulfone, arylsulfonyl and alkylsulfonyl, or two neighbouring
  • Q' and Q" independently from each other may be identical or different residues selected from the group of hydrogen, methyl, branched or unbranched C 2 . 20 alkyl, optionally substituted, C 5 . s cycloalkyl, and phenyl, optionally substituted, or Q' and Q" may together constitute a ring, wherein the bridging element may be selected from substituted alkyliden, branched alkyliden and eyelid alkyliden or Q' and Q" are independently from each other one or two polycyclic residues for example norbornyl or adamantyl.
  • Preferred trisubstituted phosphines are described in WO 00/02887 on page 328, claim 1.
  • X is B(OH) 2 and the transition metal is selected from groups 5-12 metals, preferably from group IXA metals, in particular wherein the transition metal catalyst is copper or silver.
  • bases are hydroxides, alcoholates and fluorides of alkaline and alkaline earth metal, carbonates, hydrogencarbonates, tertiary amines, pyridine and its substituted derivatives, alkali phosphates and mixtures thereof, hi a preferred embodiment of the invention bases are selected from the group of potassium tert-butoxide, sodium tert-butoxide, cesium tert-butoxide, lithium tert-butoxide as well as the corresponding isopropylates, triethylamine and pyridine.
  • the amount of base used in the reaction corresponds to the amount of formula (11), mostly 0.6 to 6.0 equivalents, preferentially 1.2 to 3.0 equivalents of base referring to compound (11) are used.
  • the reaction is performed in a suitable solvent or in a one phase or multiphasic solvent mixture, which can dissolve all reactands whereas heterogenic performance is also possible (example via use of nearly unsoluble bases).
  • a suitable solvent or in a one phase or multiphasic solvent mixture, which can dissolve all reactands whereas heterogenic performance is also possible (example via use of nearly unsoluble bases).
  • the reaction is done in polar, aprotic or protic solvents.
  • one or more solvents are selected from diglyme, substituted glymes, 1,4-dioxane, isopropanol, tert-butanol, 2,2-dimethyl-l-propanol, toluene, xylene.
  • the reaction is preferably performed at temperatures between room temperature and the boiling point of the used solvent. More preferably the reaction takes place at elevated temperatures, for example in the preferred range from 0 to 240 0 C, to achieve a faster reaction. In a preferred embodiment of the present invention the temperature range is being selected from 20 to 200 0 C, particularly from 50 to 150 0 C.
  • Pyrazole of formula (11) and the aromatic reaction partner (12) can be used in molar ratios of 10: 1 to 1: 10, preferred are ratios from 3: 1 to 1:3, particularly preferred are ratios from 1,2: 1 to 1 : 1,2.
  • the compound of formula (11) may be prepared, for example, according to the process disclosed in J. Med. Chem 2003, 46, 3945 or with herein found compounds to further transformation to compounds of formula (11) following known methods, eg. amide bond formation.
  • Li a preferred embodiement of the present invention all substances are charged to a suitable vessel and the resulting mixture is heated under stirring to its reaction temperature, hi a further preferred embodiment, which is particularly suitable for large-scale synthesis, substance of formula (11) and if necessary further substances, for example base, transition metal catalyst or pre-catalyst are added during the reaction to the reaction mixture via dosage. Alternatively the base can be added slowly via controlled dosage which leads to controlled reaction.
  • substance of formula (11) and if necessary further substances for example base, transition metal catalyst or pre-catalyst are added during the reaction to the reaction mixture via dosage.
  • the base can be added slowly via controlled dosage which leads to controlled reaction.
  • the invention relates to a process for the preparation of 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid comprising the step of reacting a) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate with 2,4-dichlorophenylboronic acid in the presence of copper catalyst and a base; or b) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate with 2,4-dichloro-l-bromobenzene in the presence of a palladium catalyst, a trisubstituted phosphine and a base.
  • the invention relates to a process according to the present invention for the preparation of Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylate comprising the step of reacting Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate with 2,4- dichlorophenylboronic acid in the presence of a copper catalyst and a base.
  • the invention relates to a process according to the present invention for the preparation of N-piperidino- 5 -(4-chlorophenyl)- 1 -(2, 4-dichlorophenyl)-4-methyl-pyrazole-3 - carboxamide comprising the step of reacting a) N-piperidino-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide with 2,4-dichlorophenylboronic acid in the presence of a copper catalyst and base; or b) N-piperidino-5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxamide with 2,4-dichloro-l-bromobenzene in the presence of a palladium catalyst, a trisubstituted phosphine and a base.
  • Example 1 Preparation, 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid
  • Method 1 529 mg (2 mmol) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate, 452 mg (2 mmol) 2,4- dichloro-1-bromobenzene, 384 mg (4 mmol) NaOt-Bu, 23.0 mg Bis(dibenzylideneacetone)palladium(0) (2 mol%) and 31.5 mg 2-(N,N-dimethylamino)-2'-(dicyclohexylphosphino)biphenyl (4 mol%) are heated in 12 ml degassed toluene, free of water for 15 h to 120 C until the starting aryl bromide has been completely comsumed as judged by GC analysis.
  • Example 2 Preparation, Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylate 264 mg (1 mmol) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate, 381.6 mg (2 mmol) 2,4- dichlorophenylboronic acid, 81 ⁇ l (2 mmol) pyridine, 18.1 mg cupric acetate (0.1 mol) and 375 mg 4 A molecular sieves are stirred at room temperature in 8 ml dry dichloromethane under air for 48 h. The progress of the reaction is being monitored by by by GC analysis.
  • reaction is quenched with a 3 ml of 4M NH 3 in MeOH and filtered through celite. After separation of the phases the solvent of the organic alyer is evaported and the resutling residue is purified by chromatography on 230-400 mesh silica gel using cyclohexane/ethyl acetate (85/15; v/v).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un nouveau procédé destiné à la préparation de certains dérivés de pyrazole, en particulier la préparation de Rimonabant. Le procédé utilise le couplage carbone-azote d'un dérivé de pyrazole en présence d'un catalyseur à base de métaux de transition.
PCT/EP2008/051802 2007-02-20 2008-02-14 Nouveau procédé de préparation de 5-(4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthyl-n-(pipéridin-1-yl)pyrazole-3-carboxamide WO2008101860A1 (fr)

Applications Claiming Priority (2)

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EP07102714 2007-02-20
EP07102714.8 2007-02-20

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WO2008101860A1 true WO2008101860A1 (fr) 2008-08-28

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0576357A1 (fr) * 1992-06-23 1993-12-29 Sanofi Dérivés du pyrazole, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO2005115989A1 (fr) * 2004-05-10 2005-12-08 Sanofi-Aventis Procede de preparation de derives de l'acide 1,5-diphenylpyrazole carboxylique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0576357A1 (fr) * 1992-06-23 1993-12-29 Sanofi Dérivés du pyrazole, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0656354A1 (fr) * 1993-12-02 1995-06-07 Sanofi N-pipéridino-3-pyrazolecarboxamide substitué
WO2005115989A1 (fr) * 2004-05-10 2005-12-08 Sanofi-Aventis Procede de preparation de derives de l'acide 1,5-diphenylpyrazole carboxylique

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