This application claims priority to Indian patent application number 341/CHE/2011 filed onMarll,2011.

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of Tiotropium bromide monohydrate.

BACKGROUND OF THE INVENTION:

Tiotropium bromide (1), first disclosed in EP 0418716, is a highly effective anticholinergic agent with specificity for muscarinic receptors and it is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

Tiotropium bromide is used in low (microgram) therapeutic doses and it is therefore particularly necessary to develop an industrial process for the commercial preparation of tiotropium bromide which ensures that the product is prepared not only in a high, economical yield but also with exceptional chemical and polymorphic purity.

A process for the preparation of tiotropium bromide was first reported in EP 0418716. Tiotropium bromide monohydrate is disclosed in W02002/30928 along with a method of its preparation by heating anhydrous tiotropium bromide in water in the presence of activated charcoal. In addition, there have been several subsequent disclosures of methods to prepare anhydrous tiotropium bromide from tiotropium bromide monohydrate or solvate.

The process reported in prior art for preparing Tiotropium bromide involves two steps; 1) quaternization of the Tiotropium base with methyl bromide to give Tiotropium bromide, 2) which is further treated with water to acquire monohydrate from. This increases the number of steps and reduces the overall yield.

There exists a need in the art for the preparation of tiotropium bromide monohydrate with enhanced purity and yield.

The present invention involves preparation of Tiotropium bromide monohydrate in a single step, which decreases the number of steps and consequently increases the yield of the desired product.

OBJECT OF THE INVENTION:

Principle object of the present invention is to provide a novel process for the preparation of Tiotropium bromide monohydrate.

SUMMARY OF THE INVENTION:

Main aspect of the present invention is to provide a novel process for the preparation of Tiotropium bromide monohydrate with enhanced yield. The novel process involves preparation of Tiotropium bromide monohydrate in single step.

In one aspect, the present invention provides a novel process for the preparation of Tiotropium bromide monohydrate comprising:

a) treating Tiotropium base with water and methyl bromide in organic solvent: and

b) isolating Tiotropium bromide monohydrate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel process for the preparation of Tiotropium bromide monohydrate with enhanced yield.

The phrase Tiotropium base used herein means scopine di-2-thienyl glycolate, which is an intermediate for the preparation of Tiotropium bromide.

The schematic representation of the present invention is given in the scheme-I.


Tiotropium Base

Tiotropium bromide monohydrate

In one aspect, the present invention provides a novel process for the preparation of Tiotropium bromide monohydrate comprising:

a) treating Tiotropium base with water and methyl bromide in organic solvent: and

b) isolating Tiotropium bromide monohydrate.

In one embodiment of the present invention, Tiotropium base is added to an organic solvent, where in the organic solvent is selected from polar aprotic solvents such as 1,4 dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, methylethylketone, diethylketone, preferably acetone and added water to the above reaction mixture. To the obtained reaction mixture a solution of methyl bromide is added, wherein, the solution of methyl bromide is prepared by taking methyl bromide in an organic solvent. The organic solvent used for preparing methyl bromide solution is selected from polar aprotic solvents, such as 1,4 dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, preferably acetonitrile to isolate Tiotropium bromide monohydrate.

In another embodiment of the present invention, water is added to the solution of methyl bromide in an organic solvent, where in the organic solvent is selected from polar aprotic solvents such as 1,4 dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide; preferably acetontitrile. To the above obtained solution, a solution Tiotropium base in an organic solvent is added to isolate Tiotropium bromide monohydrate. The organic solvent is selected from polar aprotic solvents such as 1,4 dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide; acetone, methylethylketone, diethylketone.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

EXAMPLES: Example 1:

350 ml of acetone and 10 g of Tiotropium base was (leq) added to a round bottom flask at 25-30 °C. 10 ml of water was added to the reaction mixture and stirred for 30 min. To the reaction mixture 50 ml of 50% solution of methyl bromide in acetonitrile was added slowly and stirred at 25-30 °C for 24 hours. The precipitated solid was filtered and dried at 25-30°C under vacuum for 15min. w/w yield = lOg, (100%); HPLC purity = >99%

Example 2:
10 ml of water was added to 50 ml of 50% solution of methyl bromide in acetonitrile. To this solution was added solution of 10 g Tiotropium base in 350 ml of acetone slowly at 25-30 °C and stirred fro 24 hrs. The obtained solid was filtered and dried at 25-30°C under vacuum for 15min. w/w yield = lOg, (100%) HPLC purity = >99%

We claim:

1. A process for preparation of Tiotropium bromide monohydrate comprising:

a) treating Tiotropium base with water and methyl bromide in organic solvent; and

b) isolating Tiotropium bromide monohydrate.

2. The process according to the claim 1, wherein in step a) water is added to Tiotropium base followed by the addition of methyl bormide solution.

3. The process according to the claim 1, wherein in step a) water is added to methyl bromide solution followed by the addition of Tiotropium base.

4. The process according to the claim 1, wherein the organic solvent is polar aprotic solvent.

5. The process according to the claim 4, wherein the polar aprotic solvent is selected from 1,4 dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, methylethylketone, diethylketone.

6. The process according to the claim 5, wherein the polar aprotic solvent is acetone.

7. The process according to the claim 1, wherein the Tiotropium bromide monohydrate is isolated by filtration.