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WO2010149359A1 - Procédé et intermédiaires pour la préparation d'acides benzimidazolecarboxyliques - Google Patents

Procédé et intermédiaires pour la préparation d'acides benzimidazolecarboxyliques Download PDF

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Publication number
WO2010149359A1
WO2010149359A1 PCT/EP2010/003787 EP2010003787W WO2010149359A1 WO 2010149359 A1 WO2010149359 A1 WO 2010149359A1 EP 2010003787 W EP2010003787 W EP 2010003787W WO 2010149359 A1 WO2010149359 A1 WO 2010149359A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
methyl
alkyl
defined above
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2010/003787
Other languages
English (en)
Inventor
Paul Hanselmann
Heilam Wong
Ellen Klegraf
Florencio ZARAGOZA DÖRWALD
Zunliang Ding
Wei He (Ryan)
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lonza AG
Original Assignee
Lonza AG
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 Lonza AG filed Critical Lonza AG
Publication of WO2010149359A1 publication Critical patent/WO2010149359A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated

Definitions

  • the invention relates to a process for the production of substituted benzimidazole- 6-carboxylic acids of formula
  • R 1 and R 2 independently are hydrogen, C1-6 alkyl or C3-6 cycloalkyl. It further relates to novel intermediates in the process of the invention.
  • Ci-/ralkyl e.g. "Ci- ⁇ -alkyl” represents any linear or branched alkyl group having 1 to n carbon atoms.
  • Ci-6-alkyl represents for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te/?-butyl, and the various isomeric pentyls and hexyls.
  • C3-6 cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Benzimidazoles of formula I are useful as intermediates in the synthesis of pharmaceutically active compounds.
  • the benzimidazolecarboxylic acids of formula I can exist in two tautomeric forms, namely the 1 H form depicted above and the 3// form (I ' ) depicted below:
  • AII compound names and structural formulas used hereinbelow are intended to encompass both tautomeric forms, although, for the sake of simplicity, only the ⁇ H form will be mentioned and/or depicted.
  • R 1 and R 2 independently are hydrogen, Ci_ ⁇ aikyl or C3-6 cycloalkyl, are prepared in a process comprising the steps of (i) cyanating an ⁇ Aacyl-4-haloaniline of formula
  • R 1 is as defined above, R 3 is alkyl and X is chlorine or bromine, to obtain the corresponding cyano compound of formula
  • R 1 and R 3 are as defined above :
  • step (ii) hydrolyzing the cyano and acylamino groups of the nitro compound obtained in step (i) to obtain the corresponding yo-aminobenzoic acid of formula
  • R 1 is as defined above, and (iii) reacting said p-aminobenzoic acid in the presence of a reducing agent with an aldehyde of formula
  • R 2 is as defined above, to obtain the target compound of formula I.
  • the cyanation in step (i) is effected with potassium hexa- cyanoferrate( ⁇ ) in a polar aprotic solvent and in the presence of a palladium phosphine complex as catalyst.
  • This embodiment is particularly advantageous since potassium hexacyanoferrate( ⁇ ) is much less toxic than the cyanides usually employed in cyana- tion reactions.
  • Suitable polar aprotic solvents are for example the commonly used amides, ureas or sulfoxides, such as /V. ⁇ Adimethylformamide, /V, ⁇ /-dimethylacetamide, ⁇ Amethylpyrrolidone, ⁇ /,/V,/V ⁇ /V-tetramethylurea or dimethyl sulfoxide.
  • the palladium phosphine complex is tetrakis(triphenylphosphine)- palladium(O)
  • the nitration in step (ii) is effected using an alkali metal nitrate in sulfuric acid as nitrating agent.
  • This embodiment is particularly advantageous since the usage of large amounts of nitric acid is avoided.
  • the hydrolysis in step (iii) is effected using an aqueous hydrohalic acid such as hydrochloric, hydrobromic or hydriodic acid. Hydrochloric acid is particularly preferred.
  • an alkali metal dithionite is used as reducing agent in step (iv), sodium dithionite (Na2S2 ⁇ 4 ) being particularly preferred.
  • R 1 in the final product (I), the starting material (II) and the intermediates (III) through (V) is methyl.
  • R 2 in the final product (I) and the aldehyde (Vl) is propyl.
  • R 3 in the starting material (II) and the intermediates (III) and (IV) is methyl or propyl.
  • R 1 is Ci- ⁇ alkyl or C3-6 cycloalkyl and R 3 is propyl, are novel and also an embodiment of the invention.
  • R 1 is methyl.
  • R 1 is Ci_ ⁇ alkyl or C3-6 cycloalkyl and R 3 is C1-4 alkyl, are likewise novel and an embodiment of the invention.
  • R 1 is methyl
  • R 3 is methyl or propyl.
  • Butyryl chloride (36.0 g, 0.338 mol, 1.2 eq.) was added to a solution of 2-methylaniline (30.O g, 0.28 mol, 1.0 eq.) and triethylamine (31.2 g, 0.308 mol, 1.1 eq.) in dichloro- methane (250 ml_) within 35 min at room temperature. The mixture was stirred at room temperature for another 3.5 h and then washed with water and aqueous sodium carbo- nate solution. The organic layer was dried with anhydrous sodium sulfate and concentrated to give ⁇ A(2-methylphenyl)butyramide as a white solid (45.27 g, 90%) which was used in the next step without further purification.
  • the filter cake was dried under vacuum to give a brown solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Des acides benzimidazolecarboxyliques substitués de formule (I), dans laquelle R1 et R2 représentent chacun indépendamment hydrogène, alkyle en C1-6 ou cycloalkyle en C3-6, sont préparés dans une synthèse en quatre étapes à partir de N-acyl-4-haloanilines de formule (II), dans laquelle R1 est tel que défini ci-dessus, R3 représente alkyle en C1-4 et X représente chlore ou brome.
PCT/EP2010/003787 2009-06-26 2010-06-24 Procédé et intermédiaires pour la préparation d'acides benzimidazolecarboxyliques Ceased WO2010149359A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP09008391.6 2009-06-26
EP09008391 2009-06-26
EP09010390 2009-08-12
EP09010390.4 2009-08-12

Publications (1)

Publication Number Publication Date
WO2010149359A1 true WO2010149359A1 (fr) 2010-12-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/003787 Ceased WO2010149359A1 (fr) 2009-06-26 2010-06-24 Procédé et intermédiaires pour la préparation d'acides benzimidazolecarboxyliques

Country Status (2)

Country Link
TW (1) TW201100388A (fr)
WO (1) WO2010149359A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013007603A1 (fr) 2011-07-08 2013-01-17 Bayer Intellectual Property Gmbh Procédé de préparation de 2-amino-5-cyano-n,3-diméthylbenzamide
CN107021889A (zh) * 2017-06-08 2017-08-08 联化科技（台州）有限公司 一种芳香族氯化物的制备方法及装置
CN108658861A (zh) * 2018-06-01 2018-10-16 成都福柯斯医药技术有限公司 一种1-氧-1,2,3,4-四氢异喹啉-5-甲酸的合成方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018790A (en) * 1975-05-08 1977-04-19 Eli Lilly And Company Substituted 1-sulfonylbenzimidazoles
US4880804A (en) 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
US5591762A (en) 1991-02-06 1997-01-07 Dr. Karl Thomae Gmbh Benzimidazoles useful as angiotensin-11 antagonists
DE19917524A1 (de) 1999-04-17 2000-10-19 Boehringer Ingelheim Pharma Verfahren zur Nitrierung von Anilinderivaten
US20040204397A1 (en) * 2002-06-05 2004-10-14 Chaturvedula Prasad V. Calcitonin gene related peptide receptor antagonists
WO2005080388A1 (fr) * 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
WO2006044754A2 (fr) 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Procede pour preparer du telmisartan

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018790A (en) * 1975-05-08 1977-04-19 Eli Lilly And Company Substituted 1-sulfonylbenzimidazoles
US4880804A (en) 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
US5591762A (en) 1991-02-06 1997-01-07 Dr. Karl Thomae Gmbh Benzimidazoles useful as angiotensin-11 antagonists
DE19917524A1 (de) 1999-04-17 2000-10-19 Boehringer Ingelheim Pharma Verfahren zur Nitrierung von Anilinderivaten
US20040204397A1 (en) * 2002-06-05 2004-10-14 Chaturvedula Prasad V. Calcitonin gene related peptide receptor antagonists
WO2005080388A1 (fr) * 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Inhibiteurs de la polymerase virale
WO2006044754A2 (fr) 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Procede pour preparer du telmisartan

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CZARNY A ET AL, JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 33, 1 January 1996 (1996-01-01), pages 1393 - 1397, XP000914681, ISSN: 0022-152X *
NAVARRO-OCANA ARTURO ET AL: "Reductive cyclization with baker's yeast of 4-alkyl-2-nitroacetanili des to 6-alkylbenzimidazoles and 1-hydroxy-2-methyl-6-alkylbenzimidazole", PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, GB LNKD- DOI:10.1039/B107492J, vol. 1, no. 21, 1 January 2001 (2001-01-01), pages 2754 - 2756, XP002540450, ISSN: 1472-7781 *
RANGARAJAN, MEERA ET AL: "Topoisomerase I inhibition and cytotoxicity of 5-bromo- and 5-phenylterbenzimidazoles", BIOORGANIC & MEDICINAL CHEMISTRY , 8(11), 2591-2600 CODEN: BMECEP; ISSN: 0968-0896, 2000, XP002540449 *
RIES, U.J. ET AL., J. MED. CHEM., vol. 36, 1993, pages 4040 - 4051
TERAMOTO, S. ET AL., J. MED. CHEM., vol. 46, 2003, pages 3033 - 3044

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013007603A1 (fr) 2011-07-08 2013-01-17 Bayer Intellectual Property Gmbh Procédé de préparation de 2-amino-5-cyano-n,3-diméthylbenzamide
US9169198B2 (en) 2011-07-08 2015-10-27 Bayer Intellectual Property Gmbh Method for the production of 2-amino-5-cyano-N,3-dimethylbenzamide
CN107021889A (zh) * 2017-06-08 2017-08-08 联化科技（台州）有限公司 一种芳香族氯化物的制备方法及装置
CN108658861A (zh) * 2018-06-01 2018-10-16 成都福柯斯医药技术有限公司 一种1-氧-1,2,3,4-四氢异喹啉-5-甲酸的合成方法

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