FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - IMPROVED PROCESS FOR THE PREPARATION
OF TOLTERODINE TARTRATE

2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :

LUPIN LIMITED
An Indian Company.
159, CST Road, Kalina, Santacruz (East), Mumbai - 400 098, State of Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an industrial process to manufacture tolterodine and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Tolterodine, chemically known as (+)-(R)-3-(2-Hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl propylamine is a muscarinic receptor antagonist, useful for the treatment of urinary incontinence. Tolterodine marketed as tolterodine tartrate of formula (I) was first disclosed in US Patent No. 5,382,600.

A process for preparing tolterodine starting from the lactone of formula (II) is described in US Patent No. 5,382,600.


(II)


(Ill)
The lactone is converted to the methyl ester compound of formula (III) by treating with methyl iodide and potassium carbonate under reflux condition in mixture of acetone and methanol.

The ester of formula (III) is reduced using Lithium Aluminum Hydride (LAH) in ether to get the alcohol of formula (IV)


(IV)


OTs
(V)
which is reacted with tosyl chloride in presence of pyridine to yield the tosyl derivative of formula (V).
The tosyl derivative is converted to amine of formula (VI) by treating with diisopropylamine in acetonitrile.

The compound of formula (VI) is treated with BBr3 in methylene chloride to give the racemic mixture of tolterodine of formula (VII),


(VII)

which is resolved with L-(+) tartaric acid to get tolterodine tartrate of formula (I)
The process disclosed in US Patent No. 5,382,600, is a lengthy process involving the usage of reagents like methyl iodide, lithium aluminum hydride, and boron tribromide which renders the process not suitable for cost effective, industrial scale production of tolterodine.
US Patent No. 5,922,914 teaches an alternate process for the preparation of tolterodine, wherein the lactone of formula (II) is reduced with diisobutyl aluminum hydride (DIBAL) in toluene to get a compound of formula (VIII).

Reductive amination of the compound of the formula (VIII) using Pd/C in methanol afforded racemate tolterodine of formula (VII), which was resolved using L-tartaric acid.
The process though consists of fewer number of steps, the use of expensive and hazardous reagent DIBAL does not suit for commercially viable synthesis of tolterodine of high purity.
PCT Publication No. WO 03/014060 discloses a process for the manufacture of tolterodine, from the lactone of formula (II). According to the process, the lactone (II) is converted to ester of formula (III) by treating with dimethyl sulphate and sodium hydroxide, in presence of a phase transfer catalyst. Further, the ester was reduced to alcohol of formula (IV) with NaBH4 in presence of a Lewis acid like AICI3. The alcohol is tosylated, followed by conversion to amine of formula (V) by treating with diisopropylamine. The deprotection of the methoxy group is achieved through hydrobromoic acid in acetic acid.

The object of the present invention is to provide a cost effective process that is suitable for large-scale production of tolterodine.
SUMMARY OF THE INVENTION
The present invention provides an efficient, cost-effective industrial process for the manufacture of tolterodine.
In one aspect of the invention, the lactone of formula (II) is converted to the alcohol (Ila) without the intermediacy of ester by simple reduction with NaBH4 in suitable organic solvent.
In another aspect, the invention provides selective methylation of the phenolic group of the alcohol of formula (Ila) using dimethyl sulphate under basic conditions.
In yet another aspect of the invention, the deprotection of methoxy group in compound of formula (VI) is achieved with aqueous hydrohalic acid such as hydrobromic acid.
In a further aspect, the purification of tolterodine tartrate (I) is accomplished using methanol.
Accordingly, the present invention provides a process for the preparation of tolterodine tartrate of formula (I), which comprises:
i) converting the lactone of formula (II) to the compound of formula (lla) by treating with sodium borohydride in a alcoholic solvent such as isopropyl alcohol,

ii) methylating the phenolic group in compound of formula (lla) using dimethyl sulphate under basic conditions to get compound of formula (IV),
iii) tosylating the alcohol of formula (IV) in presence of an organic base such as triethyl amine,
iv) condensing the tosyl derivative of formula (V) with diisopropylamine in a suitable organic solvent such as acetonitrile to get the amine compound of formula (VI),
v) deprotecting the phenolic group of compound of formula (VI) using aqueous solution of hydrobromic acid,
vi) liberating the free base tolterodine from the hydrobromide salt, by treating with a inorganic base such as ammonia,
vii) resolving the racemic tolterodine obtained in step-vi, by treating with L-tartaric acid in an alcoholic solution,
viii) purifying L-tolterodine tartrate from a methanolic solution.

DETAILED DESCRIPTION
The process of the present invention is represented in Scheme-1.

(V)

The starting material, lactone of formula (II) is prepared by methods known in literature (example 1 of US Patent No. 5,922,914).
Reduction of the lactone of formula (II) to the corresponding diol compound of formula (Ila) is carried out in one step by reduction. The reduction is done with sodium borohydride in alcoholic solvents. The temperature of the reaction mass is maintained below the boiling point of the alcoholic solvent, especially below 60°C. Isopropyl alcohol is the most preferred alcoholic solvent for the said reaction though others are not excluded. Completion of the reaction is monitored by HPLC. After the completion, the reaction mixture is acidified with inorganic acids like dil. HCI, stirred further to get the diol intermediate of formula (Ha), which is isolated by commonly known techniques like filtration or centrifugation. The isolated product is then dried under vacuum at 45 to 50°C.
In the next step the diol intermediate of formula (lla) is selectively methylated at the phenolic hydroxy group. The selective methylation is achieved by using dimethyl sulphate as reagent. The reaction is performed in presence of a suitable base like sodium hydroxide in aqueous medium at a preferred temperature range of 60-65°C. Preferably, dimethyl sulphate is added to the reaction mixture over an extended period, for example, over 3 to 4 hrs, though the time may vary depending on the batch size and other factors during large scale operation.
The compound of formula (IV) is then tosylated at the alcoholic hydroxy group functionality by p-toluenesulfonyl chloride. The reaction is carried out using toluene as a solvent and triethyl amine as base at 0 to 5°C, though other solvents and bases are not excluded. After the completion of the reaction (monitored by HPLC) the reaction mixture is quenched by adding water, the toluene layer is separated and treated with dilute hydrochloric acid to remove the base. The toluene layer is concentrated under vacuum to obtain a thick viscous liquid, from which the crystalline material is precipitated by adding diisopropyl ether and subsequent stirring.

The tosyl derivative (V) is then converted to the tertiary amine of formula (VI) by heating with diisopropylamine in acetonitrile and at 80°C to 100°C in an autoclave at about 0.5-2.0 kg/cm2 pressure for 20 to 35 hrs. However, most preferable temperature range is 95°C to 100°C and pressure range is 1-2kg/cm2. The optimum time for the completion is 27-30 hrs. After the completion of the reaction, the white solid formed in the reaction mass is filtered off. The filtrate is concentrated till a thick mass is obtained to which cyclohexane is added and stirred. A slurry is resulted which is filtered, the solid discarded and the filtrate is concentrated under vacuum to get a gummy mass. The gummy mass is dissolved in dilute HCI and toluene is added and stirred for 30 min for further purification. The aqueous phase is separated and treated with cyclohexane. The mixture is basified with NaOH solution to obtain the freebase, which is extractable in cyclohexane. The compound of formula (VI) is finally recovered from cyclohexane by distillation or other equivalent procedure.
The O-methyl group of the compound of formula (VI) is then converted to the hydroxy group to yield the compound (VII). In the present invention this step is carried out by using aqueous hydrobromic acid as the reagent. The reaction is preferably carried out in dichloromethane as medium. The compound of formula (VI) is dissolved in dichloromethane, and the solution is added slowly to an aqueous hydrobromic acid over a prolonged period. Typically the time taken for such an addition is 1 to 2 hrs though it may vary depending on the scale of operation. After addition, the dichloromethane is removed by distillation and the reaction mixture is then refluxed for a few hours, preferably for 3 to 5 hrs, at 100 to 115°C. After the reaction is complete, the product is filtered, washed with water and dried to afford the compound of formula (VII).
Alternatively, the compound of formula (VI) is not isolated from cyclohexane. In this case the cyclohexane layer containing the compound of formula (VI) is

directly utilized for the preparation of the compound of the formula (VII) in one step.
The compound of formula (VII), prepared by either way described hereinbefore, may exist in the corresponding hybromide salt form. Hence before proceeding for the preparation of tolterodine tartrate, the hydrobromide salt is neutralized with a base and thereby tolterodine free base is generated. Preferably such a type of base used is ammonia, though other bases like hydroxides, carbonates or bicarbonates are not excluded. Tolterodine hydrobromide is charged into water or other water miscible solvents and ammonia solution is added till the pH range of 11-12. A typical water miscible solvent is methanol though other alcohols, ketones, nitriles are not excluded. Water is then added to the reaction mixture, stirred, followed by extraction in hexane. The hexane layer is separated and distilled out under vacuum to yield tolterodine free base.
The tolterodine free base exists as a gummy mass which is not isolated. Typically, the gummy mass is dissolved in ethanol and heated to reflux. To this reaction mixture, (L)-Tartaric acid in ethanol is added and reflux continued over a few hours period, for example, for 3 to 4 hrs. The reaction mixture was cooled, filtered to obtain tolterodine tartarate.
Finally, the tolterodine tartrate obtained at this stage is purified further from methanol to get the desired purity level. The chemical purity (by chemical HPLC) obtained by the process described in this invention is not less than 99.9% and the presence of the other isomeric impurity, i.e., the (-)S-isomer of tolterodine/tolterodine tartrate (obtained by chiral HPLC) is not more than 0.1%.
The invention is further illustrated by the following non-limiting example.
EXAMPLE-1 : Preparation of (+)-(R)-3-(2-Hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl propylamine (tolterodine tartrate)

Step-1: Reduction of lactone compound of formula (II)
To a stirred solution of the Lactone of formula (II) (400 gm, 1.68 moles) in isopropanol (1400 ml) was added NaBH4 (73.44 gm, 1.15 moles), controlling the temperature to below 60°C. After the completion of the reaction (monitored by HPLC), the reaction mixture was rendered acidic by adding dil. HCI, stirred further to get a slurry of the compound of formula (lla), which was filtered, and dried under vacuum at 45 to 50°C. Net weight: 240gm.
Step-2: Selective methylation of compound of formula (lla)
To a stirred solution of NaOH (165.3 gm, 4.23 moles) in water (750 ml), at 30 to 35°C was added compound of formula (lla) (250 gm, 1.033 mole) and heated to 60 to 65°C. Dimethyl sulphate (260.3 gm, 1.066 moles) was charged over a period of 3 to 4 hrs. After the completion of the reaction, toluene (750 ml) was charged into the reaction mixture, stirred, and layers separated. The toluene layer was stirred with dilute hydrochloric acid, layers separated, and toluene was distilled out under vacuum at 30°C to afford 264gm of 3-(2-methoxy-5-methyl-phenyl)-3-phenylpropanol (IV).
Step-3: Preparation of 3-(2-methoxy-5-methyl-phenyl)-3-phenylpropyl-p-toluene sulphonate (V)
3-(2-methoxy-5-methyl-phenyl)-3-phenylpropanol (250 gm, 0.976 mol) was dissolved in toluene (750 ml) and stirred for 30 to 60 min to get a clear solution. p-Toluene sulphonyl chloride (278.3 gm, 1.46 moles) was added and stirred further till a clear solution was obtained. The reaction mixture was cooled to 0 to 5°C and triethyl amine (197.15 gm, 1.952 moles) was added, stirred till the completion of the reaction (monitored by HPLC). Water (500 ml) was added and stirred, toluene layer separated and stirred with dilute hydrochloric acid to remove the base. The toluene layer was concentrated under vacuum to obtain a thick viscous liquid, to which diisopropyl ether (500 ml) was added and stirred to

get the crystalline material, which was filtered, again stirred in diisopropyl ether, filtered, and dried to obtain 338gm of the tosyl derivative.
Step-4: Preparation of N, N-diisopropylamine-3-(2-methoxy-5-methyl-phenyl)-3-phenylpropyl amine (VI)
The tosyl derivative (V) (300 gm, 0.73 mol) was heated with acetonitrile (714 ml) and diisopropylamine (900 ml) at 95 to 100°C in an autoclave at about 1-2 kg/cm2 pressure for 27 to 30 hrs. After the completion of the reaction, the white solid formed in the reaction mass was filtered off. The filtrate was concentrated to afford a thick mass to which cyclohexane (300 ml) was added and stirred. The slurry obtained was filtered, the solid discarded and the filtrate was concentrated under vacuum to get a gummy mass. The gummy mass was stirred with 2N HCI for 30 to 60 min and toluene (150 ml) was added and stirred for 30 min to remove organic impurities. The aqueous phase was separated and stirred with cyclohexane (300 ml). The mixture was basified with 20% NaOH to form the freebase, which was extracted into cyclohexane. The cyclohexane layer was distilled out to afford the compound of formula (VI). Net weight: 248gm.
Step-5: Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropyl amine hydrobromide (tolterodine hydrobromide, VII in HBr form)
The amine of formula (VI) (170 gm, 0.50 mol), dissolved in dichloromethane (170 ml), was added slowly to an aqueous hydrobromic acid (680 ml) over a period of 1 to 2 hrs. The dichloromethane was distilled at 40°C and the reaction mixture was refluxed for 3 to 5 hrs at 100 to 115°C. After the reaction was complete, the slurry obtained was filtered, washed with water (510 ml), and dried to obtain 115gm of tolterodine hydrobromide.

Step-6: Preparation and purification of tolterodine tartrate (I)
Tolterodine hydrobromide (200 gm, 0.49 mol) was charged into methanol (200 ml). Ammonia solution (150 ml) was added till the pH reached 11 to 12. Water (600 ml) was added, stirred, followed by hexane (600 ml) and stirred for 1 hr. The hexane layer was separated and distilled out under vacuum a gummy mass was obtained. The gummy mass was dissolved in ethanol (200 ml) and refluxed at 60 to 65°C. (L)-Tartaric acid (110.0 gm, 0.74 mole) in ethanol was added and refluxed at 60 to 65°C for 3 to 4 hrs. The reaction mixture was cooled, filtered to obtain tolterodine tartarate.
Purity (before purification): 92-95%(Chemical HPLC), 92-95% (Chiral HPLC)
The tolterodine tartrate was dissolved in methanol, refluxed at 60 to 65°C, concentrated to obtain a slurry, which was cooled to 0 to 5°C, and filtered to obtain pure tolterodine tartrate.
Net weight after drying: 40gm.
Purity (after purification): Not less than 99.9% (Chemical HPLC), Not less than
99.9% (Chiral HPLC)
EXAMPLE-2 : Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropyl amine hydro bromide (tolterodine hydrobromide, VII in HBr form) from tosyl derivative of formula (V) without isolating the compound of formula (VI)
The tosyl derivative (300 gm, 0.73 moles) of formula (V) was heated with acetonitrile (714 ml) and Diisopropyl amine (900 ml) at 95 to 100°C in an autoclave at about 1-2Kg/cm2 pressure for 27 to 30 hrs. After the completion of reaction, the white solid formed in the reaction mass was filtered off. The filtrate was concentrated to afford a thick mass to which cyclohexane (300 ml) was

added and stirred. The slurry obtained was filtered, solid was discarded and filtrate was concentrated under vacuum to get a gummy mass. The gummy mass is dissolved in 2N HCI for 30-60 min and treated with toluene (150 ml) to remove organic impurities. The aqueous phase was separated and stirred with cyclohexane (300 ml). The mixture was basified with 20% NaOH to form freebase, which was extracted in cyclohexane.
The cyclohexane extract was added slowly to an aqueous solution of hydrobromic acid (680 ml) over a period of 1-2 hrs. Cyclohexane was distilled at 80-85°C and reaction mixture was refluxed for 3-5 hrs at 100-115°C. After the reaction was complete, the slurry obtained was filtered off, washed with water (510 ml) and dried to afford 198g of tolterodine hydrobromide.

We claim-
1. A process for the preparation of tolterodine tartrate of formula (I)

which comprises:
(i) converting the lactone of formula (II) to the compound of formula (lla) in one step by treating with sodium borohydride in an alcohol,

(ii) selectively methylating the phenolic group in compound of formula (lla) to get compound of formula (IV),


tosylating the alcohol of formula (IV) in presence of an organic base to obtain the tosyl derivative of formula (V),

(V)
condensing the tosyl derivative of formula (V) with diisopropylamine in a suitable organic solvent to get the amine compound of formula (VI),

(VII)
deprotecting the phenolic group of compound of formula (VI) to obtain the compound of formula (VII),


(vi) resolving the racemic tolterodine obtained in step-(v), by treating with L-tartaric acid.
2. A process as claimed in claim 1 wherein the alcohol in the step (i) is isopropyl alcohol.
3. A process as claimed in claim 1 wherein in the step (i) the temperature of the reaction is maintained below 60°C.
4. A process for the preparation of the compound of formula (Ila) in one step by treating a compound of formula (II) with sodium borohydride in alcohol.

A process as claimed in claim 4 wherein the alcohol is isopropyl alcohol.
6. A process as claimed in claim 4 wherein the temperature of the reaction is maintained below 60°C.
7. A process as claimed inclaim 1 wherein in the step (ii) methylation of the phenolic group in compound of formula (lla) is carried out using dimethyl sulphate.
8. A process as claimed in any of claims 1 and 7 wherein in the step (ii) dimethyl sulphate is added to the reaction mixture over an extended period of time, preferably over 2 hours to 5 hours.
9. A process as claimed inclaim 1 wherein in the step (iii) the organic base is triethyl amine.

10. A process as claimed inclaim 1 wherein in the step (iv) the organic solvent is acetonitrile.
11. A process as claimed inclaim 1 wherein in the step (v) the deprotection of the phenolic group of compound of formula (VI) is carried out using aqueous hydrobromic acid.
12. A process as claimed inclaim 1 wherein the step (v) further comprises of liberating the free base tolterodine from the hydrobromide salt by treating with an inorganic base.
13. A process as claimed in claim 12 where the inorganic base is ammonia.
14. A process for the preparation of the compound of formula (VII) comprising treating a compound of formula (VI) with aqueous HBr.

(VI)

(VII)

15. A process as claimed in claim 1, wherein the compound of formula VII is prepared from the tosyl derivative of formula V without isolating the amine compound of formula VI.
16. A process as claimed in claim 1 further comprising purifying L-tolterodine tartrate from methanol.
17. A process as claimed inclaim 16 wherein purification of L-tolterodine tartrate comprises of refluxing L-tolterodine tartrate in methanol.

18. A process for the preparation of a compound of formula IV comprising selective methylation of the phenolic group of the alcohol of formula ll(a) using dimethyl sulfate under basic conditions.
19. A process as claimed in claim 18, wherein the said reaction is carried out in 10% NaOH solution.
20. A process for the preparation of pure (R) - Tolterodine L-tartarate comprising crystallizing the crude compound of formula I in methanol.
21. A process substantially as described herein with reference to the examples.
Dated this 2nd day of November 2005

Raju Kumar Of S. Majumdar & Co. Applicant's Agent