CLIAMS:1. A process for the preparation of N-(3,4-dimethoxyphenethyl)formamide, compound of formula II,

Formula II
the process comprises the steps of
a) reacting 2-(3,4-dimethoxyphenyl)-ethylamine with formic acid in hydrocarbon solvent,
b) removing water from the reaction mixture of step a),
c) isolating the N-(3,4-dimethoxyphenethyl) formamide compound from the reaction mixture thereof.

2. The process of claim 1, wherein hydrocarbon solvent is selected from the group comprising one or more toluene, o-xylene, p-xylene or mixture(s) thereof.

3. The process of claim 2, wherein hydrocarbon solvent is toluene.

4. The process of claim 1, wherein step (a) is carried out at temperature between in range of 60°C to 120°C for 1 to 2 hour

5. The process of claim 1, wherein step (b) removing water is carried out by azeotropic distillation.

6. The process of claim 1, wherein N-(3,4-dimethoxyphenethyl)formamide, compound has purity more than 90 %.

7. The process of claim 1, wherein N-(3,4-dimethoxyphenethyl)formamide is converted to Tetrabenazine

,TagSPECI:Field of Invention

The present invention relates to process for the preparation of N-(3,4-dimethoxyphenethyl) formamide, (referred hereinafter as “formamide intermediate”). In particular of the present invention relates to the improved process for the preparation of N-(3,4-dimethoxyphenethyl) formamide, wherein formed water during the reaction is removed by azeotropic distillation.

Background of the invention

Tetrabenazine is a hexahydro-dimethoxy­benzoquinolizine derivative and It has chemical name cis rac–1,3,4,6,7,11b­hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizin-2-one; and has the structural formula I

Formula I

Tetrabenazine is marketed under the brand name Xenazine® and is marketed by Biovail Americas. Xenazine® is indicated for the treatment of chorea associated with Huntington's disease.

The US patent no. 2,830,993 describes Tetrabenazine and its process for the preparation. There are several other processes described in the various patents, including U.S Patent Numbers. 4,678,792; 8,524,733; 8,039,627 and 4,678,792.

The US patent application No. 20120003330 A1 and PCT application No. 2011008597 A1 describe the process of preparation of N-(3,4-dimethoxyphenethyl)formamide, which involves the formylation of 2-(3, 4-dimethoxyphenyl)-ethylamine using ethyl formate on refluxing overnight.

The PCT patent application 2012081031A1 also describe the process of preparation of N-(3,4-dimethoxyphenethyl)formamide, compound of formula II, which is the synthetic intermediate of Tetrabenazine. The said process involves the formylation of 2-(3, 4-dimethoxyphenyl)-ethylamine using formic acid in toluene. The reported process are very tedious and cumbersome and suffers one or the other problems like reproducibility, takes longer time for making large-scale quantities of formamide intermediate and formation of formic acid adduct.

While developing the process of making Tetrabenazine present inventor developed a process of making formamide intermediate used in the preparation of Tetrabenazine. The process of invention solve the problems associated with the prior art and provides an efficient process. The process provided is reliable and reproducible, as well as conveniently scalable, takes less time and has obvious benefits with respect to economics and convenience to operate on a commercial scale.

Summary of the Invention

The present invention relates to a process for the preparation of Formamide Intermediate of Tetrabenazine and its conversion to Tetrabenazine or its pharmaceutically acceptable salt thereof.

The present invention relates to a process for the preparation of N-(3,4-dimethoxyphenethyl) formamide, compound of formula II

Formula II
the process includes the steps of
a) reacting 2-(3,4-dimethoxyphenyl)-ethylamine with formic acid in hydrocarbon solvent,
b) removing water from the reaction mixture of step a),
c) isolating the N-(3,4-dimethoxyphenethyl) formamide compound of structural formula II from the reaction mixture thereof.

The present invention also provides a Formamide Intermediate of Tetrabenazine compound of formula II obtained from the present invention is more than 90 % when measured by HPLC.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The N-(3,4-dimethoxyphenethyl) formamide, intermediates and starting materials of the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

In one aspect of the present invention provides a improved process for the preparation of preparation of pure N-(3,4-dimethoxyphenethyl)formamide, compound of formula II,

Formula II
the process includes the steps of
a) reacting 2-(3,4-dimethoxyphenyl)-ethylamine with formic acid in hydrocarbon solvent,
b) removing water from the reaction mixture of step a),
c) isolating the N-(3,4-dimethoxyphenethyl) formamide compound from the reaction mixture thereof.

The step a) of the present invention involves the heating the mixture of 2-(3,4-dimethoxyphenyl)-ethylamine in suitable hydrocarbon solvent at temperature between in range of 80°C to 90°C, followed by addition of formic acid to the reaction mixture. The reaction mixture stirred at temperature between in range of 100°C -110°C for 1 hour.

The step b) of the present invention involves the removing of water formed during the reaction. The removal of water may be carried out by means of azeotropic distillation using Dean-Stark apparatus.

The step c) of the present invention involves the isolation the compound to get N-(3,4-dimethoxyphenethyl) formamide compound by means of removal of the hydrocarbon solvent under vacuum, followed by degassing at temperature between in range of 50°C -60°C to get the light brown transparent thick mass of N-(3,4-dimethoxy phenethyl)formamide.

The hydrocarbon solvent is selected from group comprises one or more of benzene, toluene, o-xylene, p-xylene, petroleum ether and mixtures thereof.

In one aspect of the present invention, formic acid may be used as such or as a solution of formic acid in water. The concentration of formic acid in water may be in the range of 75% weight / volume to 99% weight /volume.

In one aspect of the present invention, formylation of 2-(3, 4-dimethoxyphenyl)-ethylamine with formic acid may be carried out for a period of 1 hours to 3 hours at temperature between in range of 60°C to 120°C.

The present invention provides a Formamide Intermediate of Tetrabenazine, has purity more than 90 % when measured by HPLC.

The conversion of N-(3,4-dimethoxyphenethyl)formamide to Tetrabenazine can be carried out by known method, e.g. US 20120003330 A1 and WO 2012/081031.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Example

Preparation of N-(3,4-dimethoxyphenethyl)formamide

Charged in a round bottom flask, 2-(3, 4-dimethoxyphenyl)-ethylamine (0.2 kg) and toluene (0.4 L) and reaction mixture were heated under stirring at temperature between in range 80ºC to 90ºC. To the above reaction mixture, formic acid (0.1 kg, about 98% w/v) was added. The reaction mass was heated to temperature range in between 100°C to 110ºC for 1 hour. The water formed during the reaction was removed from the reaction mass by azeotropic distillation. After completion of reaction, toluene was distilled off and the yellowish-brown transparent mass obtained was degassed at 50°C to 60ºC temperature to get the titled compound as a light brown transparent thick and viscous mass.
Yield: 0.245 kg
1H NMR (400 MHz, CDCl3, TMS): δ 2.78-2.81 (m, 2 H), 3.46-3.57 (m, 2H), 3.86 (s, 6H), 5.55 (s, 1H), 6.67-6.83 (m, 3H), 8.15 (s, 1H);
13C NMR (100 MHz, CDCl3, TMS): 35.06, 39.29, 55.87, 111.42, 111.90, 120.65, 130.98, 147.76, 149.06, 161.25