DESCRIPTION

The present invention provides a process for the preparation of Fesoterodine or its pharmaceutically acceptable salt, which comprises reaction of 5-hydroxy methyl Tolterodine with isobutyryl chloride in absence of base in organic solvents to provide Fesoterodine.

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 patent No. 6,713,464 describes Fesoterodine and its salt with physiologically acceptable acids. US patent No. 6,858,650 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 base (e.g. amine) and dichloromethane.

PCT application No. 2007/140986 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 application Nos. 2010/0292502 A1 and 2011/105783 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 condensation of 5-hydroxy methyl Tolterodine with isobutyryl chloride in absence of base unexpectedly leads to significant improvement in yield and reduction of the formation of related impurities in Fesoterodine, which is further subjected to conversion of salt of Fesoterodine.

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 absence of base in organic solvents 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 1.1 to 1.4 molar equivalents of isobutyryl chloride in absence of base to provide Fesoterodine.

The condensation reaction is performed in presence of organic solvent includes but are not limited to 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 1.4 or about 1.3 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°C to about -15 °C.

After completion of the reaction, the reaction mixture may be quenched with water and then extracted with halogenated solvent. 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.

The purity of Fesoterodine obtained from the process of present invention is more than 99% when measured 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 Fumaric ester and provides highly pure Fesoterodine.

Fesoterodine obtained from the present invention is converted to Fesoterodine acid addition salt, comprises reaction of Fesoterodine with an acid in presence of methyl ethyl ketone and cyclohexane. The acid is selected from fumaric acid, maleic acid, succinic acid, acetic acid, and the like. The reaction is performed at a temperature of about room temperature to reflux temperature depends on the solvent used. The suitable temperature for preparing Fesoterodine fumarate is reflux temperature.

In another aspect of the present invention provides a process for purification of Fesoterodine Fumarate, which comprises crystallization of Fesoterodine fumarate from the solution of Fesoterodine fumarate in solvent, optionally crystallization may initiated by seeding of fesoterodine fumarate crystals.

The solution of Fesoterodine fumarate is formed by the dissolution of Fesoterodine Fumarate in a solvent or it can be obtained from the previous reaction step. The solvent is selected from ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; the hydrocarbon is selected from hexane, heptane, cyclohexane, toluene and the like or any combination thereof. The solution may be prepared and maintained at a temperature below 45°C.

The solid is precipitated using techniques such as cooling, sudden cooling, and anti-solvent technique. The solution may be cooled to a temperature below 25 °C and below 10°C to precipitate the solid.

The obtained solid is filtered using any suitable filtration techniques and then it may be dried for a sufficient period of time at a temperature below 45°C.

The purity of Fesoterodine Fumarate is more than about 99% determined by HPLC.

The proposed purification may be repeated to improve the purity of Fesoterodine Fumarate.

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.

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 fumarate

5-Hydroxy methyl tolterodine (25 gm) was dissolved in Methylene Chloride and cooled to get 0 to 5°C. To the reaction mixture added isobutyryl chloride (10.2 gm in Methylene Chloride) and stirred at 0-5°C for 2-3 hrs. After completion of reaction, reaction mixture was quenched using water. Methylene chloride layer washed with 10% sodium bicarbonate solution. Finally methylene chloride layer washed with Water and then concentrated over rotavapour at 40°C till dryness to get oily mass of fesoterodine base.

Fesoterodine base was treated with fumaric acid (8 gm) in methyl ethyl ketone below 45°C temperature. Obtained clear reaction mixture was further treated with cyclohexane below 45°C temperature, reaction mixture was cooled to room temperature, and then 0-5°C, finally precipitated solid was stirred, filtered, washed with mixture of methyl ethyl ketone and cyclohexane. Finally material was dried below 45 °C to get fesoterodine fumarate crude (28 gm)

Example-2:
Purification of Fesoterodine fumarate
Fesoterodine fumarate crude was treated with methyl ethyl ketone below 45°C temperature. Obtained clear reaction mixture was further treated with cyclohexane below 45°C temperature, cooled to room temperature, and then 0-5°C. The precipitated solid was stirred, filtered, washed with mixture of methyl ethyl ketone and cyclohexane. Finally material was dried below 45 °C to get fesoterodine fumarate (26 gm).
Yield: 94% w/w
Purity: 99.29%

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 absence of base in organic solvents to provide Fesoterodine.

2. The process of claim 1, wherein said isobutyryl chloride is 1.1 to 1.4 molar equivalents.

3. The process according to claim 1, wherein said organic solvents comprising one or more solvents selected from halogenated solvents, ketones, esters, nitrile and hydrocarbon or mixture thereof.

4. The process of claim 3, wherein said halogenated solvent is methylene chloride.

5. The process of claim 1, wherein Fesoterodine is converted into fesoterodine fumarate.

6. A process for purification of Fesoterodine Fumarate, which comprises precipitation of Fesoterodine fumarate from its solution.

7. The process of claim 6, wherein precipitation process initiated by seeding of fesoterodine fumarete.

8. The process of claim 6, wherein said solution is provided by the dissolution of fesoterodine fumarate in solvent.

9. The process of claim 6, wherein said solvent is selected from ketone, hydrocarbon or mixture thereof.

10. The process of claim 6, wherein said process provides purity of Fesoterodine fumarate 99.5% and above when measured by HPLC.