DESCRIPTION

The present invention provides a process for the preparation of Fesoterodine from 5-hydroxy methyl Tolterodine by using a mixture of organic solvents to reduce the formation of structural related impurities in Fesoterodine or its pharmaceutically acceptable salt.

Fesoterodine Fumarate of Formula I is chemically known as Isobutyricacid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate.

Formula I

Fesoterodine is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Fesoterodine Fumarate is marketed under the trade name Toviaz® by Pfizer.

US 6713464 describes Fesoterodine and its salt with physiologically acceptable acids. US 6858650 describes Fesoterodine Fumarate. Further, these patents disclose process for the preparation of Fesoterodine, which involves reaction of 5-hydroxy methyl Tolterodine (deacyl Fesoterodine) with isobutyryl chloride in presence of triethyl amine and dichloromethane.

WO 2007140986 A1 describes a process for the preparation of Fesoterodine, which involves reaction of 5-hydroxy methyl Tolterodine with isobutyryl chloride in presence of N,N-diisopropyl ethyl amine (Huenig’s base) and dichloromethane.

US 20100292502 A1 and US2011105783 A1 describes process for the preparation of Fesoterodine, which involves reaction of 5-hydroxy methyl Tolterodine with isobutyryl chloride by using solution of inorganic base, for example, sodium bicarbonate, sodium hydroxide and potassium hydroxide in water in the presence of organic solvent such as dichloromethane, toluene and dimethyl acetamide.

The present inventors observed one or the other problems, for example, yield and impurities of Fesoterodine, while developing the process for Fesoterodine as per the procedure disclosed in the prior art references. Further, the present inventors surprisingly discovered that the use of a mixture of organic solvents unexpectedly leads to significant improvement in yield and reduction of the formation of related impurities in Fesoterodine, which is further subjected to conversion of Fesoterodine Fumarate.

In an aspect of the present invention provides a process for the preparation of Fesoterodine of Formula II

Formula II
free from its impurities, which comprises reaction of 5-hydroxy methyl Tolterodine of Formula III

Formula III
with isobutyryl chloride in presence of activated inorganic base and a mixture of organic solvent to provide Fesoterodine.

In another aspect of the present invention provides a process for the preparation of Fesoterodine of Formula II free from its impurities, which comprises reaction of 5-hydroxy methyl Tolterodine of Formula III with isobutyryl chloride in presence of inorganic base and a mixture of organic solvent to provide Fesoterodine.

Suitable inorganic base used for performing the reaction includes, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and the like.

In another aspect of the present invention provides a process for the preparation of Fesoterodine of Formula II free from its impurities, which comprises reaction of 5-hydroxy methyl Tolterodine of Formula III with isobutyryl chloride in presence of inorganic base and a mixture of organic solvent to provide Fesoterodine, wherein the inorganic base is activated.

The inorganic base used for conducting reaction may be activated at a temperature of about 50 to about 120 ° or about 100 to about 120 °C.

Mixture of organic solvents contains more than one organic solvent. The mixture of organic solvent comprises two or more organic solvents, which are selected from halogenated solvents such as dichloromethane, chloroform, chlorobenzene and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; esters such as ethyl acetate, 2-methoxyethyl acetate and the like; hydrocarbon such as hexane, heptane, cyclohexane, toluene and the like; nitrile such as acetonitrile, propionitrile and the like.

The reaction may involve lot wise addition of isobutyryl chloride in presence of organic solvent to avoid the formation of impurities. Lot wise addition may involve addition of distinct portions of isobutyryl chloride to a reaction mixture at least more than once. The molar equivalent of isobutyryl chloride is from about 1.1 to about 1.5 or about 1.2 per a molar equivalent of 5-hydroxy methyl Tolterodine of Formula III.

The reaction may be conducted at a temperature below 25°C, for example, at a temperature of about 0 to about -15 °C.

After completion of the reaction, the reaction mixture may be combined with water and then extracted with dichloromethane. The resultant organic layer may be separated and concentrated completely. The obtained Fesoterodine reaction mixture may be utilized for the reaction or it may be subjected to isolation of solid by using suitable techniques, such as, recrystallization, anti-solvent technique, and the like.

Fesoterodine obtained from the present invention may contain yield more than or equivalent to 98%.

The purity of Fesoterodine obtained from the process of present invention is more than or equal to 97% determined by High-performance liquid chromatography (HPLC).

The process for Fesoterodine of present invention reduces formation of impurities such as diester of Fesoterodine, (R)-deacyl Fesoterodine, and Fesoterodine and Fumaric ester and provides highly pure Fesoterodine.

Fesoterodine obtained from the present invention may be converted to Fesoterodine diester by the reaction of Fesoterodine with isobutyryl chloride in presence of solvent. Solvent is selected from halogenated solvents, ketones, esters, hydrocarbon, nitrile, water or mixture thereof.

In another aspect of the present invention provides a process for the preparation of Fesoterodine acid addition salt free from its impurities comprises reaction of Fesoterodine obtained from the present invention with an acid or its derivatives.

The acid is selected from fumaric acid, maleic acid, succinic acid, acetic acid, and the like. The acid derivative is selected from acid anhydride such as maleic anhydride, succinic anhydride, acetic anhydride and the like.

The reaction may be performed at a temperature of about room temperature to reflux temperature depends on solvent used. The suitable temperature for preparing Fesoterodine fumarate is reflux temperature.

The salt of Fesoterodine may be prepared in presence of organic solvent such as ketone solvent, nitrile solvent, hydrocarbon solvent, halogenated solvent, ester solvent or in combination with water thereof.

The resultant salt of Fesoterodine, which is free from its impurities, is utilized for the preparation of stable pharmaceutical composition and used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

In another aspect of the present invention provides Fesoterodine ester comprises reaction of Fesoterodine of the present invention with an acid or acid derivative. The acid derivative is selected from ester or anhydride. Fesoterodine ester is selected from Fesoterodine fumaric ester, Fesoterodine maleic ester and the like.

The ester may be prepared in presence of condensing agent. The condensing agent may be selected from dicyclohexyl carbodiamide, N-hydroxy succinamide and the like, where appropriate in presence of base.

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.

EXAMPLES
Example -1
Fesoterodine Base:
Dichloromethane (300 ml) was added to the solution of 5-hydorxymethyl Tolterodine (25 g) in acetone (125 ml). The reaction mixture was cooled to a temperature of–5 to–10 °C. Sodium bicarbonate (freshly activated at 110 °C, 6.14 g) followed by isobutyryl chloride solution (7.79 g in 75 ml dichloromethane) were added to the reaction mixture. The obtained reaction mixture was stirred at 0 to –5 °C for 2 hours. After completion of reaction, added chilled water (125 ml) and separated two layers. The aqueous layer washed with dichloromethane (25 ml) and then combined total organic layers. The resultant organic layer was washed with water (250 ml x 2) followed by drying over sodium sulphate and concentration gives Fesoterodine base (29.5 g).
Yield: 98%.
Purity: 97.49%
Diester Impurity: 0.69%
5-hydorxy methyl Tolterodine: 0.39%.

Example-2:
Fesoterodine Fumarate:
Fesoterodine base (25.5 g) was treated with fumaric acid (6.97 g) in methyl ethyl ketone (55 ml) at reflux temperature. The reaction solution was further treated with cyclohexane (17.85 ml) at reflux temperature and then cooled to room temperature and then 0-5 °C. The precipitated solid was stirred, filtered, washed with mixture of methyl ethyl ketone and cyclohexane (10:90; 25 ml). The solid was dried at 55-60 °C to get Fesoterodine fumarate (25.5 g).

Yield: 78%
Purity: 98.8%
Diester impurity: 0.23%.

Example –3:
Process for Fesoterodine Maleic ester
Fesoterodine base (1.6 g) was dissolved in acetonitrile (8 ml) at room temperature. To the reaction solution of maleic anhydride (0.4 g in 8 ml) acetonitrile) over period of 15-30 min, the reaction mixture was stirred for 6 hours After completion of the reaction, the reaction mixture was subjected for distillation under reduced pressure. The obtained reaction residue was extracted with dichloromethane (10 ml) and demineralised water (15 ml). Finally, organic layer was washed with demineralised water and then concentrated under reduced pressure to get solid of title compound (2.0 g).

Mass: 508.3 (negative mode)
Purity:92%

We Claim:

1. A process for the preparation of Fesoterodine of Formula II

Formula II
free from its impurities, which comprises reaction of 5-hydroxy methyl Tolterodine of Formula III

Formula III
with isobutyryl chloride in presence of activated inorganic base and a mixture of organic solvents to provide Fesoterodine.

2. The process according to claim 1, wherein said base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.

3. The process according to claim 1, wherein said base is activated at a temperature of about 50 °C or more.

4. The process according to claim 1, wherein said the mixture of organic solvents comprising two or more solvents selected from halogenated solvents, ketones, esters, nitrile and hydrocarbon.

5. The process according to claim 1, wherein said Fesoterodine is further converted to pharmaceutically acceptable salt or ester thereof.

6. A process for the preparation of Fesoterodine pharmaceutically acceptable salt free from its impurities comprising reaction of Fesoterodine, obtained according to process of claim 1, with an acid or its derivative.

7. The process according to claim 6, wherein said acid is selected from maleic acid, fumaric acid, acetic acid, and succinic acid.

8. The process according to claim 1 or 6, wherein said impurities are diester of Fesoterodine, (R)-deacyl Fesoterodine, and Fesoterodine and Fumaric ester.

9. The process according to claim 1 or 6, wherein Fesoterodine or its pharmaceutically acceptable salt contains total impurities less than or equal to 1.5 % by HPLC.