The present invention provides a process for the purification of moxonidine.

Background of the Invention

Moxonidine is chemically, 4-chloro-N-(4,5-dihydro-lH-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine and has the structural formula:
OMe

Moxonidine is a new generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favorable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is manufactured by Solvay Pharmaceuticals under the brand name Physiotens.

Moxonidine and its process were disclosed in U.S. patent no. 4,323,570. EP patent publication no. 1873152 disclosed a process for the purification of moxonidine. Moxonidine can be purified by the solvent system such as 2-propanol and dimethyl sulfoxide.

A process for preparing moxonidine was disclosed in European patent application publication no. 1982983. According to the publication, moxonidine can be prepared by reacting 4,6-dichloro-2-methyl-5-(l -acetyl-2-imidazolin-2-yl)amino-pyrimidine with sodium methoxide in an organic solvent such as methanol, teterahydrofuran, dimethyl sulfoxide or toluene and water and isolating.

An unpublished application, IN 3634/CHE/2011 assigned to Hetero Research Foundation discloses a process for the purification of moxonidine. According to the application, moxonidine can be purified by the solvent system such as methanol and ethyl acetate.

4,6-Dichloro-N-(imidazolidin-2-yldene)-2-methylpyrimidin-5-amine (6-chloromoxonidine), N-(imidazolidin-2-ylidene)-4,6-dimethoxy-2-methylpyrimidin-5-amine (4-methoxymoxonidine), 5-[(imidazolidin-2-ylidene)amino]-6-methoxy-2-methylpyrimidin-4-ol (4-hydroxymoxonidine), 6-chloro-5-[(imidazolidin-2-ylidene)amino]-2-methylpyrimidin-4-ol (6-desmethylmoxonidine) and 4,6-dichloro-2-methyl-5-(l-acetyl-2-imidazolin-2-yl)aminopyrimidine (6-chloro acetylmoxonidine) are potential impurities in moxonidine.

The chemical formula of 6-chloromoxonidine may be represented as:

The chemical formula of 4-methoxymoxonidine may be represented as:

The chemical formula of 4-hydroxymoxonidine may be represented as:

OMe The chemical formula of 6-desmethylmoxonidine may be represented as:

The chemical formula of 6-chloro acetylmoxonidine may be represented as:

The present invention is intended to enhance the purity of moxonidine. In particular, the present invention is directed to reduce or remove 6-chloromoxonidine, 4-methoxymoxonidine, 4-hydroxymoxonidine, 6-desmethylmoxonidine and 6-chloro acetylmoxonidine impurities from moxonidine.

Thus, an object of the present invention is to provide a process for the purification of moxonidine.

Summary of the Invention

In an aspect, the present invention provides a process for the purification of moxonidine, which comprises:

a) suspending moxonidine in a mixture of an alcoholic solvent and a ketonic solvent;
b) heating the suspension obtained in step (a) at above 50°C;
c) removing the solvent from the reaction mass obtained in step (b); and
d) isolating highly pure moxonidine.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 20 to 30°C. According to another aspect of the present invention, there is provided a process for the purification of moxonidine, which comprises:

a) suspending moxonidine in a mixture of an alcoholic solvent and a ketonic solvent;
b) heating the suspension obtained in step (a) at above 50°C;
c) removing the solvent from the reaction mass obtained in step (b); and
d) isolating highly pure moxonidine.

The term "highly pure moxonidine" refers to moxonidine having the purity greater than about 98% by weight, preferably greater than about 99% by weight, and more preferably greater than about 99.5% by weight.

The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol and n-butanol, and more preferably the alcoholic solvent is methanol.

Preferably the ketonic solvent used in step (a) may be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone. More preferably the ketonic solvent is methyl ethyl ketone.

The reaction in step (b) may preferably be heated at about 55 to 85°C.

Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure.

Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.

Highly pure moxonidine may be isolated in step (d) by methods known such as filtration or centrifugation.

The contents of moxonidine and the impurities are determined by High performance liquid chromatography (HPLC).

The invention will now be further described by the following example, which is illustrative rather than limiting.

Examples Preparative example 1: Preparation of moxonidine

Methanol (18000 ml) was added to 4,6-dichloro-2-methyl-5-(l -acetyl-2-imidazolin-2-yl)aminopyrimidine (600 gm) at room temperature and then heated to 30 to 35°C. To the reaction mass was added sodium methoxide (600 gm) slowly for 45 minutes. The solvent was distilled under vacuum below 30°C to obtain a residual solid and then added water (5500 ml). The reaction mass was stirred for 10 minutes and filtered. The solid thus obtained was dried to get 520 gm of moxonidine. Chromatographic purity of moxonidine: 99.0%; Content of 6-chloromoxonidine: 0.25%; Content of 4-methoxymoxonidine: 0.5%; Content of 4-hydroxymoxonidine: 0.05%; Content of 6-desmethylmoxonidine: 0.05%; Content of 6-chloro acetylmoxonidine: 0.1%.

Example 1:
Purification of moxonidine

Moxonidine (100 gm, HPLC Purity: 99.0%) as obtained in preparative example 1 was suspended in a mixture of methanol (1250 ml) and methyl ethyl ketone (1250 ml) at room temperature. The reaction mixture was heated to 70 to 75 C and stirred for 30 minutes at same temperature. The reaction mass was filtered through hi-flow bed and the solvent was distilled off. The reaction mass was stirred for 3 hours at room temperature and filtered. The solid obtained was dried at 50 to 60°C for 7 hours to provide 88 gm of pure moxonidine.

Chromatographic purity of moxonidine: 99.94%; Content of 6-chloromoxonidine: Not detected; Content of 4-methoxymoxonidine: 0.05%; Content of 4-hydroxymoxonidine: Not detected; Content of 6-desmethylmoxonidine: Not detected; Content of 6-chloro acetylmoxonidine: Not detected.

Example 2:
Purification of moxonidine
Example 1 was repeated using ethanol solvent instead of methanol solvent to provide pure moxonidine.

Example 3:
Purification of moxonidine
Example 1 was repeated using acetone solvent instead of methyl ethyl ketone solvent to provide pure moxonidine.

We claim:

1. A process for the purification of moxonidine, which comprises:

a. suspending moxonidine in a mixture of an alcoholic solvent and a ketonic solvent;
b. heating the suspension obtained in step (a) at above 50°C;
c. removing the solvent from the reaction mass obtained in step (b); and
d. isolating highly pure moxonidine.

2. The process as claimed in claim 1, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol and n-butanol.

3. The process as claimed in claim 2, wherein the alcoholic solvent is methanol.

4. The process as claimed in claim 1, wherein the ketonic solvent used in step (a) is a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.

5. The process as claimed in claim 4, wherein the ketonic solvent is methyl ethyl ketone.

6. The process according to claim 1, wherein the reaction in step (b) is heated at about 55 to 85°C.