WO2006134078A1 - Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci - Google Patents

Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci Download PDF

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Publication number
WO2006134078A1
WO2006134078A1 PCT/EP2006/063062 EP2006063062W WO2006134078A1 WO 2006134078 A1 WO2006134078 A1 WO 2006134078A1 EP 2006063062 W EP2006063062 W EP 2006063062W WO 2006134078 A1 WO2006134078 A1 WO 2006134078A1
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WIPO (PCT)
Prior art keywords
compound
formula
ethyl
methyl
general formula
Prior art date
Application number
PCT/EP2006/063062
Other languages
English (en)
Inventor
Francisco Palomo Nicolau
Antonio Cosme Gomez
Mercedes Vicioso Sanchez
Original Assignee
Quimica Sintetica, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Quimica Sintetica, S.A. filed Critical Quimica Sintetica, S.A.
Priority to EP06763628A priority Critical patent/EP1891053A1/fr
Publication of WO2006134078A1 publication Critical patent/WO2006134078A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a new method for obtaining benzimidazole derivatives and intermediates thereof .
  • Candesartan and candesartan cilexetil are compounds having an intense selective angiotensin II receptor blocking activity which are useful in the treatment of hypertension .
  • Candesartan is the international nonproprietary name of 2-ethoxy-l-[ [2 '- (lH-tetrazole-5-yl) [1, 1 ' -biphenyl] -4- yl] methyl] -lH-benzimidazole-7-carboxylic acid of Formula (I) , finding application in medicine and used in the treatment of hypertension.
  • European patent EP 459.136 Bl discloses candesartan and candesartan cilexetil for the first time, as well as several methods for preparing benzimidazole derivatives, among which are candesartan and its corresponding cilexetil ester.
  • Said methods are characterised in that in the final step of the synthesis the benzimidazole ring is generated, inserted or substituted from the biphenyltetrazolyl group, as shown in the following schema:
  • Patent EP 668.272 Bl describes a method for obtaining a number of compounds derived from tetrazole, among which methods are included candesartan and candesartan cilexetil, which method comprises deprotection of an N- tetrazolyl compound protected with a mineral acid in the presence of an alcohol, with a concentration of water of up to 1 mole per mole of the aforesaid protected N- tetrazolyl compound.
  • Patent EP 881.212 Bl claims a method for preparing a compound of formula (VII), which is an intermediate useful in the synthesis of candesartan.
  • the method comprises reacting a mixture that contains a monohalogenated compound of formula (VIII) or a dihalogenated compound of formula (VIII') or a salt thereof, with Y being a halogen atom, with a compound of formula (IX) .
  • the object of the present invention is a method for obtaining derivatives of benzimidazole and intermediates thereof, in particular for obtaining Candesartan and Candesartan cilexetil.
  • the present invention provides a method for obtaining the benzimidazole derivatives of general formula (I) :
  • R represents H, methyl, ethyl or cilexetil
  • P represents H, cumyl, diphenylmethyl or trityl, and pharmaceutically acceptable salts thereof, which comprises reacting the compound of general formula (H) :
  • A represents B (OH) 2 or ZnX; where X represents a halogen group, and
  • P represents H, cumyl, diphenylmethyl or trityl; with a compound of general formula (III) :
  • R represents H, methyl, ethyl or cilexetil
  • Y represents an halogen atom, in the presence of a palladium catalyst, or in an organic solvent .
  • the method object of the invention is particularly suitable for obtaining candesartan and candesartan cilexetil, compounds that present an intense selective angiotensin II receptor blocking activity, and which are useful in the treatment of hypertension.
  • the coupling reaction is carried out in the presence of palladium catalysts such as trans- dichlorobis (triphenylphosphine) palladium (II) , tetrakis (triphenylphosphine) palladium (0), tetrakis (methyldiphenylphosphine) palladium (0).
  • palladium catalysts such as trans- dichlorobis (triphenylphosphine) palladium (II) , tetrakis (triphenylphosphine) palladium (0), tetrakis (methyldiphenylphosphine) palladium (0).
  • the catalyst of the coupling reaction can be generated in situ, by carrying out the reaction in the presence of palladium acetate and triphenylphosphine.
  • an inert organic solvent preferably aprotic, such as toluene, acetonitrile, THF, dimethoxyethane, N, N-dimethylacetamide and the like can be used as a reaction solvent.
  • aprotic such as toluene, acetonitrile, THF, dimethoxyethane, N, N-dimethylacetamide and the like
  • the reaction is carried out at a temperature between 30 and 100°C, preferably between 60 and 70°C, for 1-20 hours.
  • the benzimidazole derivative of general formula (I) can be converted, if desired, by means of hydrolysis, esterification, protection and/or deprotection to form another compound of formula (I) , by means of methods known in the state of the art.
  • the starting compounds of general formula (II) can be synthesised according to methods known in the state of the art, such as those described in patent application DE 4313747, European patent EP 455.423, or application PCT/EP2004/008576 (application date: 30.07.04) and comprising the reaction of the corresponding phenyl tetrazole with BuLi and the subsequent transmetalation reaction.
  • the benzimidazole derivatives of general formula (I) obtained in accordance with the first aspect of the invention can be isolated and/or purified from the reaction mixture in accordance with conventional methods, such as recrystallisation and column chromatography, to obtain a crystalline product.
  • the present invention provides an intermediate of general formula (III) :
  • R is methyl
  • Y represents a halogen atom.
  • the present invention provides a method for obtaining intermediates of general formula (III) :
  • R represents hydrogen, methyl, ethyl or cilexetil
  • Y represents a halogen atom; which comprises: a) reacting a compound of general formula (IV)
  • R 1 is methyl or ethyl, with a 4-halobenzylamine, in the presence of a base and an organic solvent, to obtain the compound of general formula
  • the first step of the reaction is an aromatic nucleophilic substitution of the general compound (IV) by a 4-halobenzylamine in the presence of a base.
  • the reaction is carried out in solvents such as toluene, THF, acetonitrile, DMF and the like.
  • suitable bases include, but are not limited to, triethylamine, sodium hydride, potassium carbonate and sodium carbonate.
  • the second step of the method in accordance with the third aspect of the invention is a reduction reaction of the intermediate of general formula (V) , which can be carried out by using, for example, tin chloride.
  • the reaction solvent can be a protic organic solvent such as EtOH.
  • the reaction is normally carried out at a temperature between 30 and 100°C, for 1 to 4 hours.
  • the third step of the method in accordance with the third aspect of the invention comprises the reaction of the intermediate of general formula (VI) with ethyl orthocarbonate, in the presence of an acid such as acetic acid or p-toluene sulphonic acid.
  • an acid such as acetic acid or p-toluene sulphonic acid.
  • the reaction solvent halogenated hydrocarbons and ethers can be used, although it is normally more convenient to carry out the reaction without solvent.
  • the reaction is normally carried out at a temperature between 30 and 100°c, preferably between 70 and 80°C, for 1 to 3 hours.
  • reaction intermediates (V) and (VI) obtained as described above can easily be isolated and/or purified by means of, or in accordance with, conventional methods such as, for example, evaporation of solvents, extraction by means of water or organic solvents, concentration, neutralisation, recrystallisation, distillation and column chromatography .
  • the compounds (I) and (III) obtained in the above- mentioned way can be in the form of solvates or salts (including addition salts) from pharmaceutically or physiologically acceptable acids or bases.
  • the following examples illustrate the invention but must not be considered as limiting the scope thereof.
  • Tin (II) chloride dihydrate 14.87 g is added to a solution of ethyl 2- (4-bromobenzylamine) -3-nitrobenzoate (5.0 g) in ethyl alcohol (25 ml) .
  • the mixture is heated at reflux for 2 hours, following which the solvent is distilled at reduced pressure to dryness.
  • the concentration residue is cooled with an ice bath and sodium hydroxide 2 N (265 ml) is added dropwise.
  • the aqueous phase is extracted with ethyl acetate (2 x 150 ml) .
  • the organic phases are combined, washed with water, dried over anhydrous sodium sulphate and filtered.
  • the solvent is concentrated at reduced pressure to a final volume of 100 ml, and a current of HCl gas (at least 1 equivalent) is passed over said solution, to obtain the ethyl 3-amino-2- (4-bromobenzylamine) benzoate hydrochloride .
  • Acetic acid (1 g) is added to a solution of ethyl 3- amino-2- (4-bromobenzylamine) benzoate (5.0 g) in ethyl orthocarbonate (25 ml) and is heated at 80°C for 1 hour. The reaction is concentrated and the residue is dissolved in ethyl acetate. The so obtained solution is washed with a sodium bicarbonate solution in water and afterwards with water. The organic phase is dried over anhydrous magnesium sulphate and is concentrated, to obtain a residue which is recrystallised in ethyl acetate and heptane (1:5). A yellow solid (4.33 g, 75%) is obtained in the form of needles .
  • Tin (II) chloride dihydrate (244.1 g) in a mixture of 35% hydrochloric acid (307.5 g) and water (93 ml) is added to a suspension of methyl 2- (4-bromobenzylamine) -3- nitrobenzoate (123.0 g) in toluene/THF (3:2 v/v) (615 ml).
  • the mixture is heated at 55 0 C for 2 hours, following which the mixture is cooled to room temperature and the phases are separated.
  • the organic phase is washed with water and to the resulting organic phases, sodium hydroxide 30% (175 ml) is added dropwise. Once the addition is finished, water is added (900 ml) and phases are separated.
  • the aqueous phase is extracted with toluene (2 x 300 ml) .
  • the organic phases are combined, washed with water, dried over anhydrous sodium sulphate and filtered.
  • the solvent is concentrated at reduced pressure to yield 144 g of an orange oily mixture of methyl 3-amino-2- (4- bromobenzylamine) benzoate (113 g) and toluene (31 g) .
  • reaction mixture is heated between 60 and 75°C and stirred for approximately 18 hours at that temperature.
  • reaction is completed, the mixture is washed with 100 ml of water and the organic phase is dried with
  • the so obtained oil is suspended in water and washed with ethyl acetate.
  • the phases are separated and the aqueous phase is acidified with concentrated HCl to pH 4-4.5.
  • a solid is precipitated and filtered, washed with water and dried in a vacuum oven at 40°C, obtaining 0.58 g (60%) of a white solid.
  • Methane sulphonic acid (62 mg) is added to a solution of cilexetil 2-ethoxy-l- [2 '- (trityl) -2H-tetrazole-5- yl) [ 1, 1 ' -biphenyl] -4-yl] methyl] - lH-benzimidazole-7- carboxylate (0.42 g) , which can be obtained from candesartan according to the method described in examples 7 and 8 of European patent EP 459.136 Bl, in methylene chloride, keeping the temperature between -5 and 0°C. Once the acid has been added, the ice bath is removed and the mixture is stirred for 2 hours at room temperature.

Abstract

La présente invention concerne un procédé permettant d'obtenir des dérivés de benzimidazole et des intermédiaires de ceux-ci, de préférence un procédé permettant d'obtenir candesartan et candesartan cilexetil. ce procéder permet d'obtenir ces dérivés benzimidazole avec de meilleurs rendements.
PCT/EP2006/063062 2005-06-17 2006-06-09 Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci WO2006134078A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06763628A EP1891053A1 (fr) 2005-06-17 2006-06-09 Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200501480A ES2264641B1 (es) 2005-06-17 2005-06-17 Procedimiento para la obtencion de derivados de bencimidazol y sus intermedios.
ESP-200501480 2005-06-17

Publications (1)

Publication Number Publication Date
WO2006134078A1 true WO2006134078A1 (fr) 2006-12-21

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PCT/EP2006/063062 WO2006134078A1 (fr) 2005-06-17 2006-06-09 Procede permettant d'obtenir des derives benzimidazole et des intermediaires de ceux-ci

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Country Link
EP (1) EP1891053A1 (fr)
ES (1) ES2264641B1 (fr)
WO (1) WO2006134078A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101781286A (zh) * 2010-01-28 2010-07-21 青岛黄海制药有限责任公司 一种制备坎地沙坦酯的方法
CN101880241A (zh) * 2010-07-14 2010-11-10 浙江美诺华药物化学有限公司 一锅法制备2-(取代苯基)甲氨基-3-硝基苯甲酸甲酯的方法
CN115181108A (zh) * 2016-10-24 2022-10-14 艾奇实验室制药有限公司 化合物及其制备方法、药物组合物和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016313A1 (fr) * 1990-04-13 1991-10-31 Smithkline Beecham Corporation Benzimidazoles substitues
EP0455423A2 (fr) * 1990-05-02 1991-11-06 Merck & Co. Inc. Procédé pour lithiation en position ortho pour la synthèse de 1-(tétrazol-5-yl) benzènes substitués en position 2
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
CN1510031A (zh) * 2002-12-23 2004-07-07 重庆圣华曦药业有限公司 苯并咪唑的酯类化合物及其制备方法和在制备药用化合物坎地沙坦酯中的应用
WO2006063578A2 (fr) * 2004-12-16 2006-06-22 Ratiopharm Gmbh Procede de production de candesartan

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1660463T3 (da) * 2003-08-08 2008-04-14 Dipharma Francis Srl Fremgangsmåde til fremstilling af phenyltetrazolderivater

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016313A1 (fr) * 1990-04-13 1991-10-31 Smithkline Beecham Corporation Benzimidazoles substitues
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
EP0455423A2 (fr) * 1990-05-02 1991-11-06 Merck & Co. Inc. Procédé pour lithiation en position ortho pour la synthèse de 1-(tétrazol-5-yl) benzènes substitués en position 2
CN1510031A (zh) * 2002-12-23 2004-07-07 重庆圣华曦药业有限公司 苯并咪唑的酯类化合物及其制备方法和在制备药用化合物坎地沙坦酯中的应用
WO2006063578A2 (fr) * 2004-12-16 2006-06-22 Ratiopharm Gmbh Procede de production de candesartan

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101781286A (zh) * 2010-01-28 2010-07-21 青岛黄海制药有限责任公司 一种制备坎地沙坦酯的方法
CN101880241A (zh) * 2010-07-14 2010-11-10 浙江美诺华药物化学有限公司 一锅法制备2-(取代苯基)甲氨基-3-硝基苯甲酸甲酯的方法
CN101880241B (zh) * 2010-07-14 2013-04-17 浙江美诺华药物化学有限公司 一锅法制备2-(取代苯基)甲氨基-3-硝基苯甲酸甲酯的方法
CN115181108A (zh) * 2016-10-24 2022-10-14 艾奇实验室制药有限公司 化合物及其制备方法、药物组合物和用途

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Publication number Publication date
EP1891053A1 (fr) 2008-02-27
ES2264641B1 (es) 2008-03-01
ES2264641A1 (es) 2007-01-01

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