WO2011019784A1 - Process for preparing 2-chloro-3n-(2-benzimidazolyl)-4-methyl-3-thienylamine useful as a sodium/proton exchanger type 3 inhibitor - Google Patents

Process for preparing 2-chloro-3n-(2-benzimidazolyl)-4-methyl-3-thienylamine useful as a sodium/proton exchanger type 3 inhibitor Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
benzimidazolyl
thienylamine
chloro
hydrochloride
Prior art date
Application number
PCT/US2010/045113
Other languages
French (fr)
Inventor
Timothy A. Ayers
Michael Ferro
Matthew R. Powers
Sithamalli V. Chandramouli
Xiaojie Li
Jr. John J. Shay
Andrea Hillegass
Original Assignee
Sanofi-Aventis U.S. 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 U.S. Llc filed Critical Sanofi-Aventis U.S. Llc
Publication of WO2011019784A1 publication Critical patent/WO2011019784A1/en

Links

Classifications

    • 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.

Abstract

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. (Formula I )

Description

PROCESS FOR PREPARING 2-CHLORO-3N-(2-
BENZIMIDAZOLYL)-4-METHYL-3-THIENYLAMINE USEFUL AS
A SODIUM/PROTON EXCHANGER TYPE 3 INHIBITOR
Field of the Invention
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.
Background of the Invention
United States Patent No. 7,049,333 (hereinafter the '333 patent) to Lang et. al. discloses certain 2-thienylamino-benzimidazole compounds, particularly 2-chloro- 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine and its hydrochloride salt, possess potent inhibitory properties on the sodium/proton exchanger of subtype 3 ("NHE-3"), which makes the compounds useful for treating respiratory disorders, disorders of the central nervous system, etc. In addition, the '333 patent discloses the preparation of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3- thienylamine hydrochloride as shown in Scheme I. The preparation of the free base 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine by reacting 2- chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with aqueous sodium hydroxide solution is also disclosed therein.
Scheme
Figure imgf000003_0001
However, the process disclosed by the '333 patent is not suitable for scale up. Specifically, last chlorination step of the process as shown in Scheme I, carried out in the presence glacial acetic acid, is not sufficiently selective and thus, produces an amount of the by-product, 2,5-dichloro 3N-(2-benzimidazolyl)- 4-methyl-3-thienylamine hydrochloride, which requires column chromatography purification. Such process is not suitable for large scale manufacture.
Thus, there is a need for an improved process that requires simpler purification procedure.
Summary of the Invention
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.
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
(b) treating 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine with an acid.
Detailed Description of the Invention
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
"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-β- 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.
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.
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.
Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, comprising:
(a) reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene
hydrochloride in the presence of potassium dihydrogen phosphate to obtain 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; and
(b) reacting 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with N-chlorosuccinimide (NCS) in the presence of 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. 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:
(a) reacting 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with N-chlorosuccinimide (NCS) in the presence of a mixture of tetrahydrofuran and N-methylpyrrolidone to obtain 2-chloro-3N-(2- benzimidazolyl)-4-rnethyl-3-thienylamine; and
(b) reacting 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine with hydrochloric acid.
Another particular embodiment of the invention is a process for preparing 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, comprising:
(a) reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene
hydrochloride in the presence of potassium dihydrogen phosphate to obtain 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride;
(b) reacting 3N-(2-benzimidazolylH-methyl-3-thienylamine hydrochloride with N-chlorosuccinimide (NCS) in the presence of a mixture of tetrahydrofuran and N-methylpyrrolidone to obtain 2-chloro-3N-(2- benzimidazolyl)-4-methyl-3-thienylamine; and (c) reacting 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine with hydrochloric acid.
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.
Examples
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 :
2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride
Figure imgf000007_0001
Step 1 : Preparation of 3-amino-4-methylthiophene hydrochloride
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 8O0C over 45 min and held at 8O0C for 30 minutes. This solution (hereinafter solution A) is then cooled to 2O0C 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
temperature.
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 1O0C. At the end of the addition, 4.165 kg (4.84 L) of toluene is added. The mixture is stirred for 15 min while maintaining a temperature of 0 -10 0C. 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 90C and then the above organic phase is added while keeping the temperature lower than 150C. A rinse of 1 kg (1.16 L) of toluene is used. The mixture is stirred at 30C. 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 0C. The filtercake is subsequently washed with 1.29 kg (1.5 L) of toluene that is cooled to 0-10 0C. After drying in the vacuum oven (45 0C, 12 mbar), a total of 932 g (71%) of 3-amino-4-methylthiophene hydrochloride as a solid is obtained. 1H NMR (d6-DMSO) δ 10.50.(bs, 3H), 7.51 (d, 1 H), 7.31 (m, 1 H), 2.23 (d, 3H); 13C NMR (d6-DMSO) δ 132.7, 129.6, 124.0, 119.3, 13.7; mp 194- 199°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 0C over an hour and held between 90-980C for 5 h. 3 kg (3.7 L) of 1-butanol is then added. The temperature is adjusted to 500C. The solids are filtered and washed with 1.5 kg (1.86 L) of 1-butanol warmed to 38 0C. The filtrates are combined in a clean reactor and then are distilled under reduced pressure at 100 mbar and at a temperature of 68-710C 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 250C 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. After drying in the vacuum oven (45 0C, 12 mbar) overnight, a total of 1.19 kg (77%) of (1 H-Benzoimidazol-2-yl)-(4-methyl-thiophen-3-yl)- amine hydrochloride as a solid is obtained. 1H NMR (d6-DMSO) δ 12.93 (bs, 2H), 11.41 (bs, 1 H), 7.72 (d, 1 H), 7.49 (m, 2H), 7.38 (m, 1 H), 7.27 (m, 2H), 2.19 (d, 3H); 13C NMR (d6-DMSO) δ 149.4, 134.0, 133.8, 130.4, 123.9, 123.1 , 120.3, 112.5, 14.0; mp 239-245 0C.
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 0C. Λ/-ch!orosuccinimide (49.3 g, 369 mmol) is added in five equal portions (9.86 g each) over 1 h at 22 ± 3 0C. After 1.5 h, 800 g of water is added, followed by the addition of a pre-made solution of 1.18 g (11.3 mmol) of sodium bisulfite in 16.7 g of water. A pre-made solution of 35.85 g of 50% aqueous NaOH solution and 53.8 g of water is added. The solids are filtered and washed with a solution of 180 g of water and 17.8 g of THF. The filter cake is
subsequently washed with 200 g of water. After drying in the vacuum oven (50 0C, 12 in Hg), 76.05 g (78%) of N-(2-chloro-4-methyl-3-thienyl)-1 H- benzimidazol-2-amine as a solid is obtained. 1H NMR (d6-DMSO) δ 10.76 (bs, 1H)1 8.99 (bs, 1H), 7.15 (m, 3H), 6.91 (m, 2H), 2.05 (d, 3H); 13C NMR (d6- DMSO) δ 153.2, 136.1 , 135.9, 121.5, 120.2, 118.6, 15.3; mp 170-1760C; HPLC purity 99.2%; the dichloro by-product is less than about 0.2%.
Step 4: Preparation of N-(2-chloro-4-methyl-3-thienyl)-1 H-benzimidazol-2-amine hydrochloride
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 0C. The mixture is cooled to 22 ± 3°C over 1 h. The solids are filtered and washed with 400 mL of π-butyl acetate. After drying in the vacuum oven (55 0C, 270 mbar), 186 g (82%) of N-(2-chloro-4-methyl-3-thienyl)- 1 H-benzimidazol-2-amine hydrochloride as a solid is obtained. 1H NMR (dβ- DMSO) δ 13.21 (bs, 2H)1 11.80 (bs, 1H), 7.47 (m, 1 H), 7.37 (s, 1H), 7.29 (m, 2H), 2.17 (s, 3H); 13C NMR (d6-DMSO) δ 149.0, 135.0, 131.2, 130.4, 125.5, 124.2, 120.4, 112.6, 14.9.
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 700C 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 0C. The mixture is cooled to 22 ± 3°C and the solids are filtered and washed with n-butyl acetate (132 g / 150 mL). After drying in the vacuum oven (45 °C, 200 mbar), 138 g (92%) of N- (2-chloro-4-methyl-3-thienyl)-1 H-benzimidazol-2-amine hydrochloride as a solid is obtained. 1H NMR (d6-DMSO) δ 13.21 (bs, 2H), 11.86 (bs, 1 H), 7.49 (m, 1 H), 7.38 (S, 1 H), 7.30 (m, 2H), 2.18 (s, 3H); 13C NMR (d6-DMSO) δ 148.9, 135.0, 131.2, 130.4, 125.5, 124.1 , 120.4, 112.6, 14.9.

Claims

We claim:
1. 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, in the presence of a suitable solvent.
2. The process according to claim 1 , wherein the suitable solvent is a mixture of tetrahydrofuran and N-methylpyrrolidone.
3. The process according to claim 2, wherein the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 1 :3 to 3:1 by weight.
4. The process according to claim 2, wherein the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
5. The process according to claim 1 , wherein the acid addition salt of 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine is 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine hydrochloride.
6. The process according to claim 1 , 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.
7. The process according to claim 6, wherein the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
8. The process according to claim 1 comprising: (a) reacting 2-chloro-benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate to obtain 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride; and
(b) reacting 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with N-chlorosuccinimide in the presence of a mixture of
tetrahydrofuran and N-methylpyrrolidone.
9. 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, in the presence of a suitable solvent to obtain 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3- thienylamine; and
(b) treating 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine with an acid.
10. The process according to claim 9, wherein the suitable solvent is a mixture of tetrahydrofuran and N-methylpyrrolidone.
11. The process according to claim 10, wherein the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 2:1 by weight.
12. The process according to claim 10, wherein the ratio of the amount of tetrahydrofuran and the amount of N-methylpyrrolidone is 1 :3 to 3:1 by weight.
13. The process according to claim 9, wherein the acid addition salt of 3N-(2- benzimidazolyl)-4-methyl-3-thienylamine is 3N-(2-benzimidazolyl)-4-methyl-3- thienylamine hydrochloride.
14. The process according to claim 9, wherein the acid addition salt of 2- chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine is 2-chloro-3N-(2- benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.
15. The process according to claim 14, comprising:
(a) reacting 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride with N-chlorosuccinimide in the presence of a mixture of
tetrahydrofuran and N-methylpyrrolidone to obtain 2-chloro-3N-(2- benzimidazolyl)-4-methyl-3-thienylamine; and
(b) treating 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine with hydrochloric acid.
16. The process according to claim 15, wherein the 3N-(2-benzimidazolyl)-4- methyl-3-thienylamine hydrochloride is prepared by reacting 2-chloro- benzimidazole with 3-amino-4-methylthiophene hydrochloride in the presence of potassium dihydrogen phosphate.
PCT/US2010/045113 2009-08-11 2010-08-11 Process for preparing 2-chloro-3n-(2-benzimidazolyl)-4-methyl-3-thienylamine useful as a sodium/proton exchanger type 3 inhibitor WO2011019784A1 (en)

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 (en) 2011-02-17

Family

ID=43020405

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/045113 WO2011019784A1 (en) 2009-08-11 2010-08-11 Process for preparing 2-chloro-3n-(2-benzimidazolyl)-4-methyl-3-thienylamine useful as a sodium/proton exchanger type 3 inhibitor

Country Status (3)

Country Link
AR (1) AR077822A1 (en)
TW (1) TW201113278A (en)
WO (1) WO2011019784A1 (en)

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 (en) * 2007-06-28 2009-01-08 Sanofi-Aventis U.S. Llc Process for the preparation of benzimidazol thienylamine compounds and intermediates thereof

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 (en) * 2007-06-28 2009-01-08 Sanofi-Aventis U.S. Llc Process for the preparation of benzimidazol thienylamine compounds and intermediates thereof

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 *

Also Published As

Publication number Publication date
AR077822A1 (en) 2011-09-28
TW201113278A (en) 2011-04-16

Similar Documents

Publication Publication Date Title
TWI720803B (en) Process for the preparation of a pde4 inhibitor
KR101310191B1 (en) Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide
WO2008102369A1 (en) Novel polymorphs of erlotinib hydrochloride and method of preparation
JP2016155810A (en) Process for preparation of dipyridamole
WO2017039537A1 (en) Novel forms of apremilast and the process of making the same
CN105906627A (en) Synthesis method of linagliptin intermediate
HUE034770T2 (en) Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2,6-dione
CN105906628A (en) Preparation method of linagliptin
MXPA04002706A (en) Process for the preparation of citalopram.
CN108530364B (en) Crystal form of 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline monohydrochloride and application thereof
WO2016150283A1 (en) Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride, preparation method therefor and uses thereof
CN114008027B (en) Salts of diaminopyrimidines, solid forms thereof, process for their preparation and their use
CN105440034A (en) Preparation method of linagliptin and intermediate thereof
WO2011019784A1 (en) Process for preparing 2-chloro-3n-(2-benzimidazolyl)-4-methyl-3-thienylamine useful as a sodium/proton exchanger type 3 inhibitor
WO2011019781A1 (en) Process for preparing 2-arylamino or heteroarylamino substituted benzimidazole compounds
CN101723885A (en) Improved method for preparing diaminopyridine
CN103562207B (en) For preparing the preparation method of 2-amino-9-((2-phenyl-1,3-dioxane-5-base epoxide) methyl)-1H-purine-6 (9H) the-one compound of valganciclovir
KR101680000B1 (en) Process for synthesizing substituted isoquinolines
CN113583003A (en) Vardenafil analogue and synthetic method and application thereof
JP6375374B2 (en) Method for producing pyrimidine intermediate
CN103896889B (en) Lapatinib intermediate and its preparation method and application
CN106831739A (en) It is a kind of for synthesizing according to a preparation method for piperazine azoles
JP2023112012A (en) Novel Benzimidazole Derivatives as Dual Histamine H1 and Histamine H4 Receptor Ligands
CN103848813B (en) The preparation method of imatinib
WO2017029584A1 (en) Amorphous form of bosutinib

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10747349

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10747349

Country of ref document: EP

Kind code of ref document: A1