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WO2011019781A1 - Procédé pour la préparation de composés de benzimidazole substitués par 2-arylamino ou hétéroarylamino - Google Patents

Procédé pour la préparation de composés de benzimidazole substitués par 2-arylamino ou hétéroarylamino Download PDF

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Publication number
WO2011019781A1
WO2011019781A1 PCT/US2010/045110 US2010045110W WO2011019781A1 WO 2011019781 A1 WO2011019781 A1 WO 2011019781A1 US 2010045110 W US2010045110 W US 2010045110W WO 2011019781 A1 WO2011019781 A1 WO 2011019781A1
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WO
WIPO (PCT)
Prior art keywords
process according
optionally substituted
pyridyl
compound
formula
Prior art date
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Ceased
Application number
PCT/US2010/045110
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English (en)
Inventor
John J. Shay, Jr.
Sithamalli V. Chandramouli
Xiaojie Li
Matthew R. Powers
Timothy A. Ayers
Andrea Hillegass
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Sanofi Aventis US LLC
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Sanofi Aventis US LLC
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Publication of WO2011019781A1 publication Critical patent/WO2011019781A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention is related to a process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds.
  • the '333 patent discloses the preparation of 3-chloro-3N-(2-benzimidazolyl)-4-methyl-3- thienylamine hydrochloride, wherein 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine is an intermediate, see Scheme I.
  • the preparation of 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine involves three steps of reactions starting from 4-methyl-3-thienylamine. Difficulties have also been report regarding direct coupling of heteroarylamine, specifically pyridylamine, with 2- methylsulfonylbenzimidazole (See P. Lan et al., Tetrahedron Letters 49 (2008) 1910-1914). Thus, there is a need for a simpler process for preparing 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine.
  • the present invention is also related to a process for preparing a compound of formula (I)
  • Ri, R 2 . R 3 , and R 4 are each independently H, halogen, hydroxyl, d-C ⁇ alkyl optionally substituted with up to three fluorine, CVC ⁇ alkoxy optionally substituted h up to three fluorine, Ci-C ⁇ alkoxycarbonyl, C 1 -C4 alkoxycarbonylamido, amino or carboxy; and
  • Ar is phenyl, naphthyl, 3-pyridyl, 4-pyridyl or thienyl, wherein the phenyl and naphthyl are independently optionally substituted by halogen, C r C 6 -alkyl optionally substituted with up to three fluorine, or Ci-C ⁇ alkoxy optionally substituted up to three fluorine, and wherein the 3-pyridyl, 4-pyridyl and thienyl are independently optionally substituted by C r C 6 -alkyl optionally substituted with up to three fluorine, or Ci-C 6 alkoxy optionally substituted up to three fluorine;
  • Acid addition salt includes hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis- ⁇ - hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and laurylsul
  • Ci-C 6 alkoxy means -O- d-Ce-alkyl.
  • Halogen means fluoro, chloro, bromo, or iodo. Particular halogen is fluoro or chloro.
  • Substituted means substituted one or more times by same or different substituent groups, particularly substituted one, two or three times by same or different substituent groups; more particularly substituted once by a substituent group.
  • Suitable base includes, for example, potassium dihydrogen phosphate
  • KH 2 PO 4 potassium carbonate (K 2 CO 3 ), potassium bicarbonate (KHCO 3 ), sodium carbonate (Na 2 CC> 3 ), sodium bicarbonate (NaHCOa), and 1 ,8- diazabicyclo (5.4.0)undec-7-ene, particularly potassium dihydrogen phosphate.
  • Suitable solvent includes, for example, an alcohol solvent, 2- methyltetrahydrofuran, dimethoxyethane, dimethylformamide (DMF), dioxane, N- methylpyrrolidone (NMP), toluene, dioxolane, dimethyl sulfoxide (DMSO), or 2- ethoxyethylether, or a mixture thereof, particularly an alcohol solvent, more particularly 2-propanol, 1-butanol, sec-butanol, 1-pentanol, or t-amyl alcohol.
  • One particular embodiment of the invention is a process for preparing the compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) or an acid addition salt thereof, in the present of a suitable base.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I) 1 wherein R-i, R ⁇ , R 3 , and R 4 are H.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein Ar is phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-ditrifluoromethyl-phenyl, 3-pyridyl, 4-pyridyl or 4-methyl- thiophenyl.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein R 3 , R 4 , R 5 and Re are H, and Ar is 4-methyl- thiophenyl.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the suitable base is potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium bicarbonate, or 1 ,8-diazabicyclo (5.4.0)undec-7-ene.
  • the suitable base is potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium bicarbonate, or 1 ,8-diazabicyclo (5.4.0)undec-7-ene.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the suitable base is potassium dihydrogen phosphate.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of a suitable solvent.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of an alcohol solvent, 2-methyltetrahydrofuran, dimethoxyethane, dimethylformamide, dioxane, N-methylpyrrolidone, toluene, dioxolane, dimethyl sulfoxide, or 2- ethoxyethylether, or a mixture thereof.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of 2- propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, 2-methyl tetrahydrofuran, dioxane, toluene or a mixture thereof.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out in the presence of 2- propanol, 1-butanol, 1-pentanol, sec-butanol, T-amyl alcohol, or a mixture thereof.
  • Another particular embodiment of the invention is a process for preparing the compound of formula (I), wherein the reaction is carried out at a temperature about 70 0 C to about 120 0 C.
  • Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate.
  • Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate, and 1-butanol.
  • Another particular embodiment of the invention is a process for preparing (1 H- Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride, comprising reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate, and 1-butanol, and at a temperature at about 9O 0 C to about 98 0 C.
  • the process of the present invention provides a simpler process for the direct coupling of certain arylamines and heteroarylamines with 2-chlorobenzimidazole compounds.
  • Example 1 The present invention may be better understood by reference to the following non-limiting Examples, which are exemplary of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
  • Example 1 The present invention may be better understood by reference to the following non-limiting Examples, which are exemplary of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.
  • a reactor is charged with 0.9 kg (6.01 mol) of 3-amino-4-methylthiophene HCI salt followed by 0.882 kg (5.78 mol) of 2-chlorobenzimidazole, 0.82 kg (6.03 mol) potassium dihydrogen phosphate, and 3 kg (3.7 L) of 1-butanol.
  • the suspension is warmed to 90 °C over an hour and held between 90-98 0 C for 5 h. 3 kg (3.7 L) of 1-butanol is then added.
  • the temperature is adjusted to 50°C.
  • the solids are filtered and washed with 1.5 kg (1.86 L) of 1-butanol warmed to 38°C.
  • the filtrates are combined in a clean reactor and then are distilled under reduced pressure at 100 mbar and at a temperature of 68-71 0 C until 4.83 kg (5.75 L) of distillate is removed. A total of 6.55 kg (7.43 L) of n-butyl acetate is added. The temperature is adjusted to 25°C and held for 30 min. The solids are filtered and washed with a solution of 0.62 kg (0.7 L) of n-butyl acetate and 0.19 kg (0.23 L) of 1-butanol. The filter cake is subsequently washed with 0.79 kg (0.9 L) of n- butyl acetate.

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

Abstract

La présente invention porte sur un procédé pour la préparation de composés de benzimidazole substitués par 2-arylamino ou hétéroarylamino.
PCT/US2010/045110 2009-08-11 2010-08-11 Procédé pour la préparation de composés de benzimidazole substitués par 2-arylamino ou hétéroarylamino Ceased WO2011019781A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23293209P 2009-08-11 2009-08-11
US61/232,932 2009-08-11

Publications (1)

Publication Number Publication Date
WO2011019781A1 true WO2011019781A1 (fr) 2011-02-17

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Application Number Title Priority Date Filing Date
PCT/US2010/045110 Ceased WO2011019781A1 (fr) 2009-08-11 2010-08-11 Procédé pour la préparation de composés de benzimidazole substitués par 2-arylamino ou hétéroarylamino

Country Status (3)

Country Link
AR (1) AR077823A1 (fr)
TW (1) TW201111350A (fr)
WO (1) WO2011019781A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3015469A1 (fr) 2014-10-30 2016-05-04 Idemitsu Kosan Co., Ltd. 5-((benz)imidazol-2-yl)benzimidazo[1,2-a]benzimidazoles pour des applications électroniques
KR101850282B1 (ko) * 2014-11-26 2018-05-31 한국과학기술연구원 단백질 키나아제 저해제로 유용한 헤테로아릴아민 유도체
CN111978319A (zh) * 2014-06-27 2020-11-24 诺格拉制药有限公司 芳基受体调制剂及其制备和使用方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058870A1 (fr) * 2003-12-18 2005-06-30 Tibotec Pharmaceuticals Ltd. Derives amino-benzimidazoles utilises en tant qu'inhibiteurs de la replication du virus syncytial respiratoire
US7049333B2 (en) 2002-06-04 2006-05-23 Sanofi-Aventis Deutschland Gmbh Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7049333B2 (en) 2002-06-04 2006-05-23 Sanofi-Aventis Deutschland Gmbh Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis
WO2005058870A1 (fr) * 2003-12-18 2005-06-30 Tibotec Pharmaceuticals Ltd. Derives amino-benzimidazoles utilises en tant qu'inhibiteurs de la replication du virus syncytial respiratoire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
OZDEN S ET AL: "Synthesis, potent anti-staphylococcal activity and QSARs of some novel 2-anilinobenzazoles", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR LNKD- DOI:10.1016/J.EJMECH.2007.10.009, vol. 43, no. 7, 1 July 2008 (2008-07-01), pages 1390 - 1402, XP022795983, ISSN: 0223-5234, [retrieved on 20071011] *
P. LAN ET AL., TETRAHEDRON LETTERS, vol. 49, 2008, pages 1910 - 1914
TUNCBILEK M ET AL: "SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW ANILINO BENZIMIDAZOLES", ARCHIV DER PHARMAZIE, WILEY - VCH VERLAG GMBH & CO. KGAA, DE LNKD- DOI:10.1002/ARDP.19973301203, vol. 330, no. 12, 1 December 1997 (1997-12-01), pages 372 - 376, XP001064267, ISSN: 0365-6233 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111978319A (zh) * 2014-06-27 2020-11-24 诺格拉制药有限公司 芳基受体调制剂及其制备和使用方法
CN111978319B (zh) * 2014-06-27 2023-08-11 诺格拉制药有限公司 芳基受体调制剂及其制备和使用方法
EP3015469A1 (fr) 2014-10-30 2016-05-04 Idemitsu Kosan Co., Ltd. 5-((benz)imidazol-2-yl)benzimidazo[1,2-a]benzimidazoles pour des applications électroniques
WO2016067261A1 (fr) 2014-10-30 2016-05-06 Idemitsu Kosan Co., Ltd. 5-((benz)imidazol-2-yl) benzimidazo[1,2-a]benzimidazoles utilisés pour des applications électroniques
KR101850282B1 (ko) * 2014-11-26 2018-05-31 한국과학기술연구원 단백질 키나아제 저해제로 유용한 헤테로아릴아민 유도체

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Publication number Publication date
AR077823A1 (es) 2011-09-28
TW201111350A (en) 2011-04-01

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