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WO2011019784A1 - Procédé pour la préparation de 2-chloro-3n-(2-benzimidazolyl)-4-méthyl-3-thiénylamine utile comme inhibiteur de l'échangeur sodium/proton de type 3 - Google Patents

Procédé pour la préparation de 2-chloro-3n-(2-benzimidazolyl)-4-méthyl-3-thiénylamine utile comme inhibiteur de l'échangeur sodium/proton de type 3 Download PDF

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Publication number
WO2011019784A1
WO2011019784A1 PCT/US2010/045113 US2010045113W WO2011019784A1 WO 2011019784 A1 WO2011019784 A1 WO 2011019784A1 US 2010045113 W US2010045113 W US 2010045113W WO 2011019784 A1 WO2011019784 A1 WO 2011019784A1
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WO
WIPO (PCT)
Prior art keywords
methyl
benzimidazolyl
thienylamine
chloro
hydrochloride
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/US2010/045113
Other languages
English (en)
Inventor
Timothy A. Ayers
Michael Ferro
Matthew R. Powers
Sithamalli V. Chandramouli
Xiaojie Li
Jr. John J. Shay
Andrea Hillegass
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.)
Sanofi Aventis US LLC
Original Assignee
Sanofi Aventis US LLC
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 Sanofi Aventis US LLC filed Critical Sanofi Aventis US LLC
Publication of WO2011019784A1 publication Critical patent/WO2011019784A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is related to an improved process for preparing 2- chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine as an NHE-3 inhibitor which is useful for treating respiratory disorders, disorders of the central nervous system, etc.
  • This invention is related to a process for preparing 2-chloro-3N-(2- benzimidazolyl)-4-methyl-3-thienylamine, comprising reacting an acid addition salt of 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, with N-chlorosuccinimide (NCS), in the presence of a suitable solvent.
  • NCS N-chlorosuccinimide
  • This invention is also related to a process for preparing an acid addition salt of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, comprising: (a) reacting an acid addition salt of 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine, with N-chlorosuccinimide (NCS) 1 in the presence of a suitable solvent to obtain 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3- thienylamine; and
  • 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 laurylsulfonate salts, and the like, particularly hydrochloride.
  • Suitable solvent means N-methylpyrrolidone (NMP), or a mixture of tetrahydrofuran/N-methylpyrrolidone (THF/NMP), particularly a mixture of
  • THF/NMP more particularly a mixture of THF/NMP having a ration of 1:3 to 3:1 by weight, even more particularly a mixture of THF/NMP having a ration of 2:1.
  • One particular embodiment of the invention is a process for preparing 2- chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, wherein the suitable solvent is a mixture of tetrahydrofuran and N-methylpyrrolidone.
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, wherein the suitable solvent is a mixture of tetrahydrofuran and N-methylpyrrolidone, and the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
  • the suitable solvent is a mixture of tetrahydrofuran and N-methylpyrrolidone, and the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, wherein the acid addition salt of 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine is 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, comprising reacting 3N- (2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride thereof, with N- chlorosuccinimide (NCS), in the presence of a mixture of tetrahydrofuran and N- methylpyrrolidone.
  • NCS N- chlorosuccinimide
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, comprising reacting 3N- (2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride thereof, with N- chlorosuccinimide (NCS), in the presence of a mixture of tetrahydrofuran and N- methylpyrrolidone, and the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
  • NCS N- chlorosuccinimide
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, comprising:
  • Another particular embodiment of the invention is a process for preparing an acid addition salt of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, wherein the suitable solvent is a mixture of tetrahydrofuran and N- methylpyrrolidone.
  • Another particular embodiment of the invention is a process for preparing an acid addition salt of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, wherein the suitable solvent is a mixture of tetrahydrofuran and N- methylpyrrolidone, and the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
  • Another particular embodiment of the invention is a process for preparing an acid addition salt of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, wherein the acid addition salt of 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine is 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, comprising:
  • Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, comprising:
  • the process of the present invention provides a method for preparing 2- chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine that can selectively chlorinate 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine and thus, the by product 2,5-dichloro 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine is produced at a level less than about 0.5%.
  • the process requires a simpler purification method, such as recrystallization.
  • a first reactor is charged with 1.5 kg (8.76 mol) methyl 3-amino-4- methylthiophene-2-carboxylate followed by 3 kg of water and 1.5 kg (12.3 mol) of 45% KOH solution at room temperature under nitrogen.
  • the suspension is warmed to 8O 0 C over 45 min and held at 8O 0 C for 30 minutes.
  • This solution (hereinafter solution A) is then cooled to 2O 0 C over 1 h.
  • a second separate reactor is charged with 3 kg of water followed by 2.8 kg (28.9 mol) of 37% aqueous HCI solution.
  • the resulting solution is warmed to 55°C.
  • To this is added the above solution A at a temperature of 50-60°C.
  • the resulting aqueous solution (hereinafter the solution B) is cooled to room
  • a third reactor is then charged with 2.58 kg (3 L) of toluene and 3.46 kg (28.1 mol) of 45% aqueous KOH solution and cooled to 0°C.
  • the above solution B is then added while keeping the temperature lower than 1O 0 C.
  • 4.165 kg (4.84 L) of toluene is added.
  • the mixture is stirred for 15 min while maintaining a temperature of 0 -10 0 C.
  • the phases are separated and the aqueous phase is removed.
  • the organic phase is used in the salt forming step.
  • a fourth reactor is charged with 2.43 kg (3 L) of 1-butanol followed by 0.94 kg (9.64 mol) of 37% HCI aqueous solution and 5.16 kg (6 L) of toluene.
  • the solution is cooled to 9 0 C and then the above organic phase is added while keeping the temperature lower than 15 0 C.
  • a rinse of 1 kg (1.16 L) of toluene is used.
  • the mixture is stirred at 3 0 C.
  • the solids are filtered and washed with a solution of 0.48 kg (600 mL) of 1-butanol and 2.58 kg (3 L) of toluene that is cooled to 0-10 0 C.
  • Step 2 Preparation of (1 H-Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)-amine hydrochloride
  • 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 0 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 0 C.
  • the solids are filtered and washed with 1.5 kg (1.86 L) of 1-butanol warmed to 38 0 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 0 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.
  • Step 3 Preparation of N-(2-chloro-4-methyl-3-thienyl)-1 H-benzimidazol-2-amine
  • a reactor is charged with 100 g (376 mmol) of (1 H-Benzoimidazol-2-yl)-(4- methyl-thiophen-3-yl)-amine hydrochloride followed by 500 g of THF and 250 g of NMP at 22 ⁇ 3 0 C.
  • ⁇ /-ch!orosuccinimide 49.3 g, 369 mmol
  • a reactor is charged with N-(2-chloro-4-methyl-3-thienyl)-1H- benzimidazol-2-amine (200 g, 0.758 mol) followed by 1-butanol (900 mL) at 22 ⁇ 3°C.
  • the suspension is treated with 37.6% aqueous hydrochloric acid (81.1 g, 0.836 mol).
  • the solution is stirred at 24 ⁇ 4°C for 45 min and then distilled to remove water at a pressure of 100 mbar and a maximum reaction temperature of 67°C.
  • the amount of distillate collected is 455 mL / 372 g.
  • the solution is warmed to 75°C and 4 L of BuOAc is charged over 1.5 h keeping the reaction temperature between 70-80 0 C.
  • Step 5 Re-crystallization of N-(2-chloro-4-methyl-3-thienyl)-1 H-benzimidazol-2- amine hydrochloride
  • a reactor is charged with 15O g (501 mmol) of N-(2-chloro-4-methyl-3- thienyl)-1 H-benzimidazol-2-amine hydrochloride and 341 g (420 mL) of 1-butanol. The mixture is heated to 70 0 C until a solution is obtained. The hot solution is filtered and the filtrate is charged to a separate reactor utilizing a rinse of 24.3 g (30 mL) of 1-butanol. To the reactor is charged 2.24 kg (2.55 L) of n-butyl acetate while keeping the temperature between 70-80 0 C.

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

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation de 2-chloro-3N-(2-benzimidazolyl)-4-méthyl-3-thiénylamine comme inhibiteur du NHE-3 qui est utile pour le traitement de troubles respiratoires, de troubles du système nerveux central, etc. (1).
PCT/US2010/045113 2009-08-11 2010-08-11 Procédé pour la préparation de 2-chloro-3n-(2-benzimidazolyl)-4-méthyl-3-thiénylamine utile comme inhibiteur de l'échangeur sodium/proton de type 3 Ceased WO2011019784A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23292809P 2009-08-11 2009-08-11
US61/232,928 2009-08-11

Publications (1)

Publication Number Publication Date
WO2011019784A1 true WO2011019784A1 (fr) 2011-02-17

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Country Status (3)

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AR (1) AR077822A1 (fr)
TW (1) TW201113278A (fr)
WO (1) WO2011019784A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180044313A (ko) * 2015-08-13 2018-05-02 프로바이오티컬 에스.피.에이. 프로피오니박테리움 아크네스로 인한 감염, 특히 여드름을 치료하는데 사용하기 위한 유산균 조성물

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006119A1 (en) * 2002-06-04 2004-01-08 Aventis Pharma Deutschland Gmbh Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis
WO2009006066A2 (fr) * 2007-06-28 2009-01-08 Sanofi-Aventis U.S. Llc Procédé de préparation de composés à base de benzimidazole thiénylamine et leurs dérivés utiles en tant qu'inhibiteurs de type 3 d'échangeur sodium-protons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006119A1 (en) * 2002-06-04 2004-01-08 Aventis Pharma Deutschland Gmbh Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis
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
WO2009006066A2 (fr) * 2007-06-28 2009-01-08 Sanofi-Aventis U.S. Llc Procédé de préparation de composés à base de benzimidazole thiénylamine et leurs dérivés utiles en tant qu'inhibiteurs de type 3 d'échangeur sodium-protons

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DELANEY, P.A.; JOHNSTONE, R.A.W.: "Solvent effects in the chlorination of tetrahydrothiophens with N-chlorosuccinimide", TETRAHEDRON, vol. 41, no. 18, 1985, pages 3845 - 3851, XP002609066 *
ESTHER ARRANZ M ET AL: "Synthesis of Hetero[1,2,4]thiadiazine 1,1-Dioxides", HETEROCYCLES, vol. 45, no. 9, 1 January 1997 (1997-01-01), ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, pages 1767 - 1774, XP001525482, ISSN: 0385-5414, DOI: 10.3987/COM-97-7882 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180044313A (ko) * 2015-08-13 2018-05-02 프로바이오티컬 에스.피.에이. 프로피오니박테리움 아크네스로 인한 감염, 특히 여드름을 치료하는데 사용하기 위한 유산균 조성물
KR102692232B1 (ko) 2015-08-13 2024-08-05 프로바이오티컬 에스.피.에이. 프로피오니박테리움 아크네스로 인한 감염, 특히 여드름을 치료하는데 사용하기 위한 유산균 조성물

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TW201113278A (en) 2011-04-16
AR077822A1 (es) 2011-09-28

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