WO2011019680A1

WO2011019680A1 - Process for preparing 4-methyl-3-thienylamine hydrochloride

Info

Publication number: WO2011019680A1
Application number: PCT/US2010/044951
Authority: WO
Inventors: Jr. John J. Shay; Timothy A. Ayers; Andrea Hillegass
Original assignee: Sanofi-Aventis U.S. Llc
Priority date: 2009-08-11
Filing date: 2010-08-10
Publication date: 2011-02-17
Also published as: AR077821A1; TW201120025A

Abstract

This invention is related to a process for preparing 3-amino-4-methylthiophene hydrochloride.

Description

PROCESS FOR PREPARING 4-METHYL-3-THIENYLAMINE HYDROCHLORIDE

Field of the Invention

The present invention is related to a process for preparing 4-methyl-3- thienylamine hydrochloride.

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 3-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. The '333 patent discloses the preparation of 3-chloro- 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, wherein 4-methyl-3- thienylamine is used as the starting material, see Scheme I.

It is discovered, however, 4-methyl-3-thienylamine is unstable. Thus, there is a need for a process for producing a stable form of 4-methyl-3-thienylamine that can be stored and used for large scale manufacture.

Scheme I

Summarv of the Invention

This invention is related to a process for preparing 3-amino-4-methylthiophene hydrochloride, comprising:

(a) reacting a (C1 -C6)-alkyl ester of 3-amino-4-methyl-thiophene-2-carboxylate with an aqueous solution of a first suitable base, in the presence of a suitable solvent to obtain 3-amino-4-methyl-thiophene-2-carboxylate;

(b) adding the reaction mixture of step (a) containing 3-amino-4-methyl- thiophene-2-carboxylate to an aqueous solution of a suitable acid to obtain 3-amino-4-methyl-thiophene wherein the amount of the suitable acid is sufficient to maintain the pH of the resulting mixture at or below about 1 after the addition of the reaction mixture of step (a);

(c) adding the reaction mixture of step (b) containing 3-amino-4-methyl- thiophene to a mixture of a second suitable base and a suitable organic solvent, wherein the amount of the second suitable base is sufficient to maintain the pH of the resulting mixture at or above about 13 after the addition of the reaction mixture of step (b);

(d) separating the organic phase and the aqueous phase; and

(e) adding the organic phase to hydrochloric 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.

"Ci-Cβ-alkyl" means straight or branched aliphatic hydrocarbon having 1 to 6 carbon atoms.

"First suitable base" includes, for example, an inorganic base, particularly, potassium hydroxide, lithium hydroxide or sodium hydroxide.

"Second suitable base" includes, for example, an inorganic base, particularly, potassium hydroxide, lithium hydroxide or sodium hydroxide.

"Suitable acid" includes, for examples, an inorganic acid, such as sulfuric acid, hydrochloric acid, or hydrobromic acid, particularly hydrochloric acid. "Suitable organic solvent" means a water-immiscible organic solvent, such as acetate solvent, toluene, ether, 2-methyltetrahydrofuran, particularly toluene.

One particular embodiment of the invention is a process for preparing 3-amino- 4-methylthiophene hydrochloride, wherein the first suitable base is potassium hydroxide.

Another particular embodiment of the invention is a process for preparing 3- amino-4-methylthiophene hydrochloride, wherein the second suitable base is potassium hydroxide.

Another particular embodiment of the invention is a process for preparing 3- amino-4-methylthiophene hydrochloride, wherein the suitable organic solvent is toluene.

The free base of 3-amino-4-methylthiophene is in an oil form that is difficult to handle during manufacture. Furthermore, production of the free base as an intermediate is very unmanageable as the free base is highly unstable at neutral pH, particularly in the presence of water. The process of the present invention provides an efficient method at industrial or commercial scale level for preparing the

hydrochloride salt of 3-amino-4-methylthiophene, which is in a solid form that can be easily used an intermediate for the manufacturing process. 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. 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 80⁰C over 45 min and held at 80⁰C for 30 minutes. This solution (hereinafter solution A) is then cooled to 20°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 50-60⁰C. 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 O⁰C. The above solution B is then added while keeping the temperature lower than 10°C. At the end of the addition, 4.17 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 9°C and then the above organic phase is added while keeping the temperature lower than 15°C. A rinse of 1 kg (1.16 L) of toluene is used. The mixture is stirred at 3°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 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 (dβ-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

Claims

We claim:

1. A process for preparing 3-amino-4-methylthiophene hydrochloride, comprising:

(b) adding the reaction mixture of step (a) containing 3-amino-4-methyl- thiophene-2-carboxylate to an aqueous solution of a suitable acid to obtain 3-amino-4-methyl-thiophene wherein the amount of the suitable acid is sufficient to maintain the pH of the resulting mixture at or below 1 after the addition of the reaction mixture of step (a);

(c) adding the reaction mixture of step (b) containing 3-amino-4-methyl- thiophene to a mixture of a second suitable base and a suitable organic solvent, wherein the amount of the second suitable base is sufficient to maintain the pH of the resulting mixture at or above 13 after the addition of the reaction mixture of step (b);

(d) separating the organic phase and the aqueous phase; and

(e) adding the organic phase to hydrochloric acid.

2. The process according to claim 1 , wherein the first suitable base is potassium hydroxide.

3. The process according to claim 1 , wherein the second suitable base is potassium hydroxide.

4. The process according to claim 1 , wherein the suitable organic solvent is toluene.