WO2010046801A2

WO2010046801A2 - A process for the preparation of tolterodine tartrate

Info

Publication number: WO2010046801A2
Application number: PCT/IB2009/054473
Authority: WO
Inventors: Ravi Ponnaiah; Sanjay Desai; Chankrakant Chunilal Shah; Kalpesh Shantibhai Patel; Viral Maheshbhai Parekh
Original assignee: Alembic Limited
Priority date: 2008-10-21
Filing date: 2009-10-12
Publication date: 2010-04-29
Also published as: WO2010046801A3

Abstract

The present invention relates to provide an improved process for the preparation of tolterodine or salt thereof, comprises a step of reducing 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV).

Description

Title of Invention: A PROCESS FOR THE PREPARATION OF

TOLTERODINE TARTRATE

[i]

Field of the Invention

[2] [3] The present invention relates to an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate of formula (I)

[4]

Background of the invention

[6] [7] Tolterodine is a muscarinic receptor antagonist. The chemical name of Tolterodine tartrate is (+)- (R)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) - 3-phenylpropanamine-L-hydrogen tartrate and molecular formula is C₂₆H₃₇N0₇and molecular weight is 475.28 . (+)-(R)-Tolterodine tartrate is represented by formula (I):

[8]

formula (I)

[10] [H] Tolterodine tartrate is marketed by Pharmacia & Upjohn under brand name Detrol^® and is indicated for the treatment of Urinary incontinence.

[12] [13] US Patent no. 5,382,600 discloses a process for the preparation of Tolterodine tartrate as shown in Scheme- 1. This patent involves the reaction of 3,4-dihydro-6-methyl -4-phenyl-2H-benzopyran-2-one with methyl iodide and potassium carbonate in refluxing acetone/methanol to give methyl- 3-(2-methoxy-5-methylphenyl) -3-phenyl propionate. The ester thus obtained is reduced with lithium aluminum hydride in ether to the corresponding propanol, which is reacted with tosyl chloride and pyridine to yield the tosylate, which on condensation with diisopropylamine in hot acetonitrile is converted into the tertiary amine. The tertiary amine is treated with boron tribromide in dichloromethane to give the amine as a racemic mixture, which is resolved with L-(+) tartaric acid.

[14] [15] ether

TiCl , Pyridine chloroform dnsoprop} lether

I -( )-Uιrlrdte

Scheme -1

[16]

[17] Long reaction time and low overall yields makes this t process very expensivt productive. Further, the use of expensive and hazardous reagents like methyl iodide, lithium aluminum hydride, and boron tribromide also renders this process unsuitable and hazardous on a commercial scale.

[18] [19] U.S. Patent No. 5,922,914 provides an alternate method for the preparation of tolterodine as shown in scheme-2. The process involves the cyclization of trans- cinnamic acid with p-cresol in hot sulfuric acid to give 3,4-dihydro-6- methyl- 4-phenyl- 2H-benzopyran-2-one, which is reduced with diisobutyl aluminum hydride (DIBAL) in toluene to yield 6-methyl-4-phenyl- 3,4-dihydro- 2H-l-benzopyran-2-ol. This on reducto-condensation with diisopropylamine, by means of hydrogen over palladium on charcoal in methanol, affords racemic tolterodine, which is resolved with L- (+) -tartaric acid.

[20]

Scheme-2

[22] [23] This process is also not commercially feasible since it makes use of an expensive and hazardous reagent DIBAL. Although the numbers of steps are reduced, the cost incurred to produce tolterodine is still high.

[24] [25] U.S. Patent No. 6,822,119 provides another alternate method for the preparation of tolterodine as shown in Scheme-3. The process involves reacting 3,4-dihydro-6-methyl-4-phenyl- 2H-benzopyran-2-one with dimethyl sulphate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl-3- (2-methoxy-5-methylphenyl) -3-phenyl propionate. Reducing the ester thus obtained with a reducing agent in the presence of a Lewis acid to obtain

3-(2-methoxy-5-methylphenyl)-3-phenyl propanol. Protecting the hydroxy group of the alcohol to followed by aminating with diisopropylamine to give N, N-diisopropyl-3- (2-methoxy-5-methylphenyl)-3-phenylpropylamine and removing the hydroxy protecting group to obtain N, N-diisopropyl-3- (2-hydroxy- 5 -methylphenyl) -3 -phenylpropylamine hydrogen bromide .

[26] [27] hydroxide, PTC MDC

reducing agent (sodium borohydπde), lewis acid

(aluminium chloride), organic 1 solvent

acid,

Scheme-3

[28] [29] This process involves a large number of steps and isolation of intermediates at each step, leading to poor yields.

[30] [31] International Publication WO 2004/078700 describes preparation of pure tolterodine or a pharmaceutically acceptable salt thereof. It also discloses N, N-di-[3- [2-hydroxy-5-methylphenyl] -3-phenylpropyl] isopropyl amine, referred to as 'tolterodine dimer,' and a process for isolation of the same.

[32] [33] There are known several approaches of enantioselective synthesis of enantiomers of 3-(2-hydroxy-5-methylphenyl)-N, N-diisopropyl-3-phenylpropylamine.

[34] [35] US Patent No. 6,310,248 discloses the multiple step process for the preparation of enantiomerically enriched (+)-R-3-(2- hydroxy-5-methylphenyl) -N,N-diisopropyl- 3-phenylpropylamine relies on the synthesis of the enantiomerically enriched 3,4-dihydro-6-methyl- 4-phenyl-2- benzopyran-2-one. Enantiomerically enriched benzopyran-2-one intermediate is prepared by the 3-step process starting with enan- tioselective reduction of carbonyl group of 3-methyl-3-phenyl-l-inden-l-on followed by the sigmatropic rearrangement and Bayer- Villiger oxidation.

[36]

[37] US Patent No. 6,410,746 reveals application of the bis-transitional metal (rhodium) catalyst for the insertion reaction in the preparation of enantiomerically enriched gem- diarylalkyl derivatives.

[38]

[39] Journal of Organic Chemistry, 1998, 63, 8067-8070 discloses asymmetric synthesis of enantiomers of 3-(2-hydroxy-5- methylphenyl) -N, N- diisopropyl- 3-phenylpropylamine as shown in scheme-4. It comprises copper-assisted asymmetric conjugate addition of aryl Grignard reagent to phenylpropenoyl derivative of oxazo- lidinone used as a chiral auxiliary. The regioselective addition of 2-benzyloxy- 5 -methylphenyl bromide (II) to 4(R)-phenyl-3- [3-phenyl-2(E)- propenoyl]oxazolidin-2-one (I) by means of Mg/CuBr/dimethylsulfide in THF gives 3-[3(R)-(5-benzyloxy-2- methylphenyl) -3-phenylpropionyl]-4(R)- phenyloxazolidin- 2-one (III), which is hydrolyzed with LiOH/H₂O₂ in THF/water to the corresponding free acid (IV). The reaction of (IV) with SOCl₂/pyridine in benzene yields the acid chloride (V), which is treated with diisopropylamine to afford the corresponding amide (VI). The reduction of (VI) with LiAlH4 in ethyl ether gives the tertiary amine (VII), which is finally, debenzylated by hydrogenation with H2 over Pd/C in methanol.

[40]

[41]

Scheme-4

[42] [43] Organic Process Research & Development (2002), 6(4), 379-383 discloses another approach for the preparation of Tolterodine as shown in Scheme-5. It involves condensation of p-cresol (I) with phenylacetylene (II) by means of acidic activated alumina in refluxing dichlorobenzene gives 4-methyl-2- (1 -phenyl vinyl)phenol (III), which is hydroformylated with CO, H₂ and a Rh catalyst in hot toluene to yield 3-(2-hydroxy-5-methylphenyl) -3-phenylpropionaldehyde (IV), mostly in the hemi- acetalic form (V). The reaction of (V) with diisopropylamine (VI) in hot toluene catalyzed by molecular sieves gives the enamine (VII), which is finally hydrogenated with H2 over PtO₂ in refluxing toluene to afford the target racemic tolterodine. Alternatively, the reductocondensation of hemiacetal (V) with diisopropylamine (VI) by means of H₂ over Pd/C in hot methanol provides directly the target racemic tolterodine.

[44] [45]

H₃C

CH₃ CH₃

(VI) Scheme-5

[46] [47] Consequently, there is a long-felt need for a process for the preparation tolterodine which not only overcomes the problems in the art processes as mentioned above, but is also safe, cost effective, and industrially feasible.

[48] [49] The present inventors had tried reduction of 3-(2-methoxy-5-methylphenyl) - 3-phenyl propionic acid of formula (III) in the presence of sodium borohydride (NaBH 4) as a reducing agent and methanesulfonic acid (MeSO₃H) or sulfuric acid as an acidic reagent to achieve the 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV) .

[50] [51] Surprisingly, when present inventors had carried out reduction of 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent such as methanesulfonic acid (MeSO₃ H) or sulfuric acid and a solvent to achieve the 3-(2-methoxy-5-methylphenyl) - 3-phenyl propanol of formula (IV) with high yield and purity.

[52] [53]

SUMMARY OF THE INVENTION

[54] [55] The present invention relates to provide an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate , comprises a step of reducing

3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent such as methanesulfonic acid (MeSO₃

H) or sulfuric acid and a solvent to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol of formula (IV). [56] [57] The present invention relates to provide an improved process for the preparation of

(+)-(R)-Tolterodine-L-tartrate, comprises steps of: [58] a) reacting 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of formula (II) with dimethyl sulphate in the presence of aqueous alkali metal hydroxide followed by treatment with an inorganic acid to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III). [59] b) reducing 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain

3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV). [60] c) converting 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol of formula (IV) into

3-(2-methoxy-5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate of formula (V). [61] d) aminating 3-(2-methoxy-5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate of formula (V) with diisopropylamine to obtain N,N-diisopropyl-3-

(2-methoxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VI). [62] e) removing the hydroxy protecting group of

N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula

(VI) to obtain N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine of formula (VII). [63] f) resolving N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine of formula (VII) with L- (+) -tartaric acid to obtain (+)-(R)-Tolterodine-L-tartrate. [64] [65]

OBJECT OF THE INVENTION [66] [67] Therefore, it is an object of the invention is to provide an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate of formula (I). [68] [69] Another object of the invention is to provide process for the preparation of process for the preparation of (+)-(R)-Tolterodine-L-tartrate of formula (I) having high purity. [70] [71] Further object of the present invention is to provide an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate , comprises a step of reducing 3-(2-methoxy-5-methylphenyl) -3 -phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV).

[72]

[73] Yet another object of the present invention is to provide an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate, comprises steps of:

[74] a) reacting 3,4-dihydro-6-methyl- 4-phenyl-2H-benzopyran-2-one of formula (II) with dimethyl sulphate in the presence of aqueous alkali metal hydroxide followed by treatment with an inorganic acid to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III).

[75] b) reducing 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol of formula (IV).

[76] c) converting 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol of formula (IV) into

3-(2-methoxy-5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate of formula (V).

[77] d) aminating 3-(2-methoxy-5-methylphenyl)-3-phenyl propyl-p-toluene sulphonate of formula (V) with diisopropylamine to obtain N,N-diisopropyl-3- (2-methoxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VI).

[78] e) removing the hydroxy protecting group of N,N-diisopropyl-3-

(2-methoxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VI) to obtain N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VII).

[79] f) resolving N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine of formula (VII) with L- (+) -tartaric acid to obtain (+)-(R)-Tolterodine-L-tartrate.

[80]

DETAILED DESCRIPTION OF THE INVENTION

[81]

[82] Accordingly, the present invention relates to provide an improved process for the preparation of (+)-(R)-Tolterodine-L-tartrate , comprises a step of reducing 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (IV) .

[83]

[84] In a preferred embodiment of the present invention, the process for the preparation of

(+)-(R)-Tolterodine-L-tartrate, comprises steps of:

[85] a) reacting 3,4-dihydro-6-methyl- 4-phenyl-2H-benzopyran-2-one of formula (II) with dimethyl sulphate in the presence of aqueous alkali metal hydroxide followed by treatment with an inorganic acid to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III).

[86] b) reducing 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol of formula (IV).

[87] c) converting 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (IV) into 3-(2-methoxy-5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate of formula (V). [88] d) aminating 3-(2-methoxy-5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate of formula (V) with diisopropylamine to obtain N,N-diisopropyl-3- (2-methoxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VI).

[89] e) removing the hydroxy protecting group of N,N-diisopropyl-3- (2-methoxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VI) to obtain N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VII).

[90] f) resolving N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl)- 3-phenylpropyl amine of formula (VII) with L- (+) -tartaric acid to obtain (+)-(R)-Tolterodine-L-tartrate.

[91] [92] The process for the preparation of (+)-(R)-Tolterodine-L-tartrate for formula (I) depicts below in Scheme-6:

[93]

Scheme-6

[95] [96] The starting material, 3,4-dihydro-6-methyl- 4-phenyl-2H-benzopyran-2-one is prepared by reacting cinnamic acid with p-cresol in the presence of a cone, sulfuric acid and a solvent.

[97] [98] The reaction is carried out at 140-145⁰C. The solvent is selected from group comprising of xylene, toluene and tetraline or mixture thereof. After the completion of reaction, the reaction mixture is cooled at RT then is washed with DM water. The reaction mixture is cooled at 10-15⁰C & drop wise addition of solution of 0.5 N NaOH in DM water & reaction mixture is stirred at same temperature for 1 hrs. The organic layer is separated & washed with DM water. The organic layer is distilled out completely under reduced pressure to obtain 3, 4-dihydro-6-methyl- 4-phenyl-2H-benzopyran-2-one.

[99]

cmnamic acid

(H)

[101] [102] Step-a: The reaction of 3,4-dihydro-6-methyl- 4-phenyl-2H-benzopyran-2-one with dimethylsulphate is carried out in the presence of an aqueous alkali metal hydroxide followed by treatment with an inorganic acid.

[103] [104] The reaction is carried out at 80-85⁰C. Alkali metal hydroxide is selected from group comprising of sodium hydroxide, potassium hydroxide or mixture thereof. Most preferable alkali metal hydroxide is sodium hydroxide. Inorganic acid is selected from group comprising of hydrochloride, hydrobromic acid, hydroiodic acid and sulfuric acid or mixture thereof. Most preferable inorganic acid is hydrochloride. After completion of reaction, the reaction mixture is cooled to RT. Cone, hydrochloric acid is added drop wise to the reaction mixture. The Reaction mixture is stirred for 2 hrs then filtered it & washed with DM water to obtain wet cake. The wet cake is dried to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid.

[105] [106] Step-b: The reduction of 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid is carried out in the presence of a reducing agent, an acidic reagent and a solvent.

[107] [108] The reaction is carried out at 65-7O⁰C for 8-10 hrs. The reducing agent is selected from the group comprising of sodium borohydride. An acidic reagent is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixture thereof. Most preferable acidic reagent is methanesulfonic acid. The solvent is selected from the group comprising of dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, methyl t-butyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof. Most preferable solvent is tetrahydrofuran (THF). After completion of reaction, the reaction mixture is cooled at 0-5⁰C. The reaction mixture is acidified with IM aq. HCl up to pH 2-3, followed by extraction with ethyl acetate. The organic layers are washed with water and brine. The solvent is distilled out completely to dryness under reduced pressure to obtain 3-(2-methoxy-5-methylphenyl)- 3-phenyl propanol.

[109]

[110] Step-c: The conversion of hydroxy group of 3-(2-methoxy-5-methylphenyl)-

3-phenyl propanol into good leaving group in the presence of a base and a solvent.

[I l l]

[112] The reaction is carried out at RT for 4-5 hrs. The good leaving group can be generated by using reagent selected from the group comprising of p-toluenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride. Most preferable leaving group is p-toluenesulfonyl chloride. The base is selected from the group comprising of inorganic or organic base. The inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or mixture thereof. The organic base is selected from the group comprising of triethylamine, trimethyamine, pyridine or mixture thereof. Most preferable base is triethylamine. The solvent is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, acetone, dichloromethane, toluene, xylene, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof. Most preferable solvent is dichloromethane. After the completion of reaction, reaction mixture is acidified with IM aq.HCl up to pH 2-3. Then it is extracted with dichloromethane. The organic layers are washed with DM water, brine & dried over sodium sulfate. The solvent is completely distilled out at reduced pressure. Crude 3-(2-methoxy- 5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate is triturated with diisopropylether at 0⁰C for 4-5 hrs to obtain a solid. The solid is filtered, washed with chilled diisopropyl ether and dried to obtain 3-(2-methoxy- 5-methylphenyl)- 3-phenyl propyl-p-toluene sulphonate.

[113]

[114] Step-d: The amination reaction of 3-(2-methoxy-5-methylphenyl) -3-phenyl propyl- p-toluene sulphonate with diisopropyl amine is carried out in the presence of a solvent. [115]

[116] The reaction is carried out at 80-90⁰C for 55-60 hrs. The solvent is selected from group comprising of acetonitrile or ethylacetate or mixture thereof. Most preferable solvent is acetonitrile. After the completion of the reaction, solvent is distilled out completely and then basified it with IM NaOH up to pH 11-12, then it is extracted with dichloromethane. The organic layers are washed with DM water, brine & dried over sodium sulfate. The solvent is completely distilled out at reduced pressure to get Crude product. Crude product is dissolved in 50 % aq. HCl till pH 2-3 and then extracted with diisopropylether. Aqueous Layer is basified with IM NaOH to pH 11-12 and extracted with dichloromethane. The organic layers are washed with DM water, brine & dried over sodium sulfate. The solvent is completely distilled out at reduced pressure to obtain N,N-diisopropyl-3- (2-methoxy-5-methylphenyl) - 3-phenylpropyl amine.

[117]

[118] Step-e: The deprotection of hydroxy protecting group of N, N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropyl amine is carried out in presence of aqueous hydrobromic acid and acetic acid followed by treatment of a base in the presence of a solvent to obtain free base of N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine.

[119]

[120] The reaction is carried out at 110-115°C for 14-15 hrs. The base is selected from the group comprising of inorganic base. The inorganic base is selected from the group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or mixture thereof. Most preferable base is sodium hydroxide. The solvent is selected from the group comprising of dioxane, tetrahydrofuran, methyl t-butyl ether, ethylacetate, dichloromethane, diethyl ether, acetonitrile or mixture thereof. Most preferable solvent is dichloromethane. The reaction mixture is cooled to RT. The solid is filtered and washed with DM water to obtain wet cake. The wet cake is dissolved in 2N NaOH & stirred and extracted it with dichloromethane. The organic layer is separated and washed with DM water, brine & dried over sodium sulfate. The solvent is completely distilled out at reduced pressure to obtain N,N-diisopropyl-3- (2-hydroxy- 5-methylphenyl) -3-phenylpropyl amine.

[121]

[122] Step-f: The resolution of N,N-diisopropyl-3- (2-hydroxy- 5-methylphenyl) -

3-phenylpropyl amine is carried out with L-(+) tartaric acid in the presence of alcohol.

[123]

[124] The reaction is carried out at 80-85⁰C for 1 hrs. The solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, t-butanol or mixture thereof. Most preferable alcohol is ethanol. After completion of addition, the reaction mixture is cooled to RT and then at 0⁰C to obtain a solid. The solid is filtered & washed with ethanol. The solid is dried to obtain Crude (+)-(R)-Tolterodine-L-tartrate.

[125] [126] Crystallization: [127] [128] Crude (+)-(R)-Tolterodine-L-tartrate is dissolved in ethanol and refluxed at 80-85⁰C for 2-3 hrs. The solution is concentrated to half the initial volume by distilling and gradually cooled to RT and then at 0⁰C for 1 hrs. The product is filtered and washed with ethanol. The product is dried under reduced pressure to obtain pure (+)-(R)-Tolterodine-L-tartrate.

[129] [130] Following is the comparison of the result of the present invention vis-a-vis the process as disclosed in prior art.

[131] [132] Table-1

[Table 1] [Table ]

[133] [134] The results clearly depicts that the selective use of NaBH₄ and MeSO₃H or H₂SO₄ significantly improves the purity and yield of the intermediate.

[135] [136] The present invention provides process of preparation of

(+)-(R)-Tolterodine-L-tartrate of formula (I), which is simple, environment friendly, economical and leads to an enhanced purity.

[137] [138] Following are advantages of the present invention: [139] i) The present invention provides process which is economical, operationally simple and industrially applicable.

[140] ii) The process provides desired purity of tolterodine tartrate having the content of dimer impurity acceptable by ICH guidelines. [141] iii) The process avoids involve use of expensive and hazardous reagents. [142] [143] The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.

[144] [145] Example 1 [146] Preparation of 3, 4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one [147]

cmnamic acid

(H)

[149] [150] A mixture of 0.5 kg cinnamic acid, 0.401 kg p-cresol and 2.2 L xylene was stirred for 15 minutes. 0.132 kg cone, sulfuric acid was added under stirring. After completion of acid addition, reaction mixture was stirred at 140-145⁰C. After the completion of reaction, reaction was cooled at RT then washed with 1.0 L DM water. The reaction mixture was cooled at 10-15⁰C & solution of 0.5 N NaOH in DM water was added drop wise & stirred reaction mixture at same temperature for 1 hr. The organic layer was separated & washed with DM water. Organic layer was distilled out completely under reduced pressure (30-40 mm Hg) to obtain 3,4-dihydro-6-methyl - 4-phenyl-2H-benzopyran-2-one (Yield: 0.78 kg, 97%).

[151] HPLC Purity: > 95 %. [152] [153] Example 2 [154] Preparation of 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid [155]

[157] [158] A reaction mixture of 0.75 kg 3,4-dihydro-6-methyl -

4-phenyl-2H-benzopyran-2-one, 0.262 kg sodium hydroxide and 0.93 L DM water was stirred at 60-65⁰C for 2 hrs. The reaction was cooled to RT. 0.825 kg dimethylsulphate was added drop wise to reaction mixture within 1 hr. After the completion of addition, reaction mixture was stirred at same temperature for 2 hrs. Again solution of 0.186 kg sodium hydroxide in 0.93 L DM water was added at RT within 1 hr. The reaction mixture was stirred at 80⁰C for 4 hrs. After completion of reaction, reaction was cooled to RT. 0.3 L Cone, hydrochloric acid was added drop wise to the reaction mixture till washing is neutral. The reaction mixture was stirred for 2 hrs, then filtered & washed with 2.0 L DM water to obtain wet cake. The wet cake was dried at 60-65⁰C for 10-12 hrs to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (Yield: 0.71 kg, 83%).

[159] HPLC Purity: > 95 %. [160] [161] Example 3 [162] Preparation of 3- (2-methoxy-5-methylphenyl) -3-phenyl propanol (using methanesulfonic acid)

[163]

(III) (IV)

[165] [166] A solution of 0.5 kg 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid in 2.0 L tetrahydrofuran was added drop wise in the suspension of 0.105 kg sodium borohydride in 0.5 L tetrahydrofuran within 2 hrs. After completion of addition, reaction mixture was stirred at RT for 2 hrs. 0.177 kg methanesulfonic acid was added drop wise within 1 hrs. After completion of addition, reaction mixture was stirred at RT for 1 hr. The reaction mixture was stirred at 65-7O⁰C for 8-10 hrs. After completion of reaction, reaction mixture was cooled at 0-5⁰C. The reaction mixture was acidified with 0.25 L IM aq. HCl up to pH 2-3, and then reaction mixture was extracted with ethyl acetate (1 L x 2). The organic layers were washed with 2.0 L water & 2.0 L brine. The solvent was distilled out to dryness at reduced pressure (30-40 mm Hg) to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol (Yield: 0.462 kg, 97%)

[167] HPLC Purity > 95%. [168] [169] Example 4 [170] Preparation of 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol (using Sulfuric acid)

[171]

(III) (IV)

[173] [174] A solution of 25 gm of 3-(2-methoxy- 5-methylphenyl)- 3-phenyl propionic acid in 75 ml tetrahydrofuran was added drop wise in the suspension of 5.25 gm of sodium borohydride in 50 ml tetrahydrofuran under stirring within 2 hrs. After completion of addition, reaction mixture was stirred at RT for 2 hrs. 9.07 gm of Cone. Sulfuric acid was added drop wise within 1 hrs. After completion of addition, reaction mixture was stirred at RT for 1 hr. The reaction mixture was stirred at 65-7O⁰C for 8-10 hrs. After completion of reaction, reaction mixture was cooled to 0-5⁰C. Reaction mixture was acidified with 12.5 ml of IM aq. HCl up to pH 2-3, and then extracted with ethyl acetate (50 ml x 2). The organic layers were washed with 100 ml water & 100 ml brine. The solvent was distilled out to dryness at reduced pressure (30-40 mm Hg) to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol (Yield 19.0 gm, 82%).

[175] HPLC Purity > 95%. [176] [177] Example 5 [178] Preparation of 3-(2-methoxy-5-methylphenyl) -3-phenyl propyl-p-toluene sulphonate

[179]

[181] [182] 0.45 kg 3-(2-methoxy-5- methylphenyl) -3-phenyl propanol in 2.25 L dichloromethane was stirred and cooled at 0⁰C under stirring. 0.27 kg triethyl amine was added drop wise to the reaction mixture. 0.388 kg p-toluene sulfonylchloride was added to the reaction mixture. The reaction mixture was stirred at 0⁰C for 1 hrs, then at RT for 4-5 hrs. After the completion of reaction, the reaction mixture was acidified with 0.25 L IM aq. HCl up to pH 2-3. Then reaction mixture was extracted with dichloromethane (0.5 L x 2). The combined organic layers was washed with 1.0 L DM water, 1.0 lit brine & dried over 0.25 kg sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40 mm Hg). Crude 3-(2-methoxy- 5-methylphenyl) -3-phenyl propyl-p-toluene sulphonate was triturated with 1.5 lit di- isopropylether at 0⁰C for 4-5 hrs to obtain a solid. The solid was filtered & washed with chilled 0.3 L diisopropyl ether. The solid was dried at 50-55⁰C to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propyl-p-toluene sulphonate (Yield: 0.553 kg, 77%).

[183] HPLC Purity > 95 %.

[184]

[185] Example 6

[186] Preparation of N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)- 3-phenylpropyl amine

[187]

[189]

[190] The solution of 0.58 kg 3-(2-methoxy-5- methylphenyl) -3-phenyl propyl-p-toluene sulphonate in 0.725 L acetonitrile & 0.713 kg diisopropyl amine was stirred in an autoclave at 90⁰C for 55-60 hrs till completion of reaction. After the completion of the reaction, the solvent was completely distilled out and then basified it with 1.5 L IM NaOH up to pH 11-12, then extracted it with dichloromethane (1.0 L x T). The organic layers were washed with 2.0 L DM water, 2.0 L brine & dried over 0.25 kg sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40 mm Hg) to get Crude product. Crude product was dissolved in 0.5 L 50 % aq. HCl till pH 2-3 and then extracted with diisopropylether (0.5 L x 4). Aqueous layer was basified with 1.5 L IM NaOH to pH 11-12 and extracted with dichloromethane (1.0 L x T). The organic layers were washed with 1.0 L DM water, 1.0 L brine & dried over 0.25 kg sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40 mm Hg) to obtain N,N-diisopropyl-3- (2-methoxy-5- methylphenyl)3-phenylpropyl amine (Yield: 0.380 kg , 78%).

[191] HPLC Purity > 95 %. [192] [193] Example 7 [194] Preparation of N, N-diisopropyl-S-Cl-hydroxy-S-methylphenyl) -3-phenylpropyl amine

[195]

[197] [198] A solution of 0.065 kg N,N-diisopropyl-3-(2-methoxy-5- methylphenyl)- 3-phenylpropyl amine in 0.145 L aqueous hydrobromic acid & 0.087 L acetic acid was stirred at 110-115°C for 14-15 hrs till completion of reaction. The reaction mixture was cooled to RT to obtain a solid. The solid was filtered & washed with 0.5 L DM water till washing of cake was neutral. The wet cake was dissolved in 0.2 L 2N NaOH and stirred followed by extraction with 0.325 L dichlorome thane. Organic layer was separated and washed with 0.5 L DM water, 0.5 L brine & dried over 0.2 kg sodium sulfate. The solvent was completely distilled out at reduced pressure (30-40 mm Hg) to obtain N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine (Free base) (Yield: 0.054 kg, 86%).

[199] HPLC Purity > 95 %. [200] [201] Example 8 [202] Preparation of (+)-(R)-Tolterodine-L-tartrate [203]

[205] [206] A solution of 0.069 kg L-(+) Tartaric acid in 0.35 L ethanol was prepared and stirred. This solution was heated up to 60-65⁰C for 1 hr. To this solution, a solution of 0.1 kg N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine in 0.5 L ethanol was added slowly at 60-65⁰C. After completion of addition, the reaction mixture was stirred at 80-85 ° C for 1 hr and cooled gradually to RT and then to 0⁰C to obtain a solid. The solid was filtered and washed with chilled ethanol (0.1 L x 2) to obtain wet cake. The wet cake was dried at 60-65⁰C for 10-12 hrs to get white solid of Crude (+)-(R)-Tolterodine-L- tartrate (Yield: 0.058 kg).

[207]

[208] Crystallization: 1

[209] 0.058 kg Crude (+)-(R)-Tolterodine-L-tartrate was dissolved in 2.32 L ethanol and refluxed at 80-85⁰C for 2-3 hrs to obtain a solution. The solution was concentrated to half the initial volume by distilling 1.16 lit of ethanol and gradually cooled to RT and then at 0⁰C for 1 hr to obtain product. The product was filtered, washed with cooled ethanol (0.05 L x 2) & dried under reduced pressure (2-5 mm Hg) at 60 ° C for 12-14 hrs to obtain Tolterodine-L-(+)-tartrate -I (Yield: 0.044 kg, 28%).

[210]

[211] Crystallization: 2

[212] 0.044 kg (+)-(R)-Tolterodine-L-tartrate -I (First Crystallize Product) was dissolved in 1.76 L ethanol & refluxed at 80-85⁰C for 2-3 hrs to obtain a solution. The solution was concentrated to half the initial volume by distilling 0.88 L of ethanol. The solution was cooled to RT and then at 0⁰C for 1 hr to obtain product. The product was filtered, washed with cooled ethanol (0.04 L x 2) & dried under reduced pressure at 60⁰C for 12-14 hrs to obtain Tolterodine-L-(+) -tartrate (Yield: 0.025 kg, 18%).

[213] HPLC Purity > 98.5 %.

Claims

[Claim 1] 1. A process for the preparation of tolterodine or salt thereof, comprises astep of reducing 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (IV).

[Claim 2] 2. A process according to claim 1, wherein the reducing agent is sodium borohydride.

[Claim 3] 3. A process according to claim 1, wherein the acidic reagent is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixture thereof.

[Claim 4] 4. A process according to claim 1, wherein the solvent is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl t-butyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.

[Claim 5] 5. A process according to claim 1, wherein the reaction is carried out at 65-7O⁰C.

[Claim 6] 6. A process for the preparation of (+)-(R)-Tolterodine-L-tartrate of formula (I), comprises steps of a) reacting 3,4-dihydro-6-methyl-4- phenyl-2H-benzopyran-2-one of formula (II) with dimethyl sulphate in the presence of aqueous alkali metal hydroxide followed by treatment with an inorganic acid to obtain 3- (2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula(III); b) reducing 3-(2-methoxy-5-methylphenyl)- 3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV); c) converting 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV) into 3-(2-methoxy-5-methylphenyl) -3-phenyl propyl- p-toluene sulphonate of formula (V); d) aminating 3-(2-methoxy-5-methylphenyl) -3-phenyl propyl- p-toluene sulphonate of formula (V) with diisopropylamine to obtain N,N-diisopropyl-3-(2-methoxy-5-methylphenyl) -3-phenylpropyl amine of formula (VI); e) removing the hydroxy protecting group of N,N-diisopropyl-3- (2-methoxy-5-methylphenyl) -3-phenylpropyl amine of formula (VI) to obtain N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) - 3-phenylpropyl amine of formula (VII); f) resolving N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) - 3-phenylpropyl amine of formula (VII) with L- (+) -tartaric acid to obtain (+)-(R)-Tolterodine-L-tartrate.

[Claim 7] 7. A process according to claim 6, wherein the alkali metal hydroxide in step (a) is selected from the group comprising of sodium hydroxide, potassium hydroxide or mixture thereof.

[Claim 8] 8. A process according to claim 6, wherein the reaction in step (a) is carried out at 80-85⁰C.

[Claim 9] 9. A process according to claim 6, wherein the inorganic acid in step (a) is selected from the group comprising of hydrochloride, hydrobromic acid, hydroiodic acid and sulfuric acid or mixture thereof.

[Claim 10] 10. A process according to claim 6, wherein the reducing agent in step (b) is sodium borohydride.

[Claim 11] 11. A process according to claim 6, wherein the acidic reagent in step (b) is selected from the group comprising of methanesulfonic acid, sulfuric acid, trifluoroacetic acid or mixture thereof.

[Claim 12] 12. A process according to claim 6, wherein the solvent in step (b) is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl t-butyl ether, dimethyl- formamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethy- lacetamide or mixture thereof.

[Claim 13] 13. A process according to claim 6, wherein the reaction in step (b) is carried out at 65-7O⁰C.

[Claim 14] 14. A process according to claim 6, wherein the protection of hydroxy group in step (c) is carried out in the presence of a base and a solvent.

[Claim 15] 15. A process according to claim 14, wherein a base is selected from the group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, trimethy amine, pyridine or mixture thereof.

[Claim 16] 16. A process according to claim 14, wherein the solvent in step (c) is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, acetone, dichloromethane, toluene, xylene, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.

[Claim 17] 17. A process according to claim 6, wherein the conversion of hydroxy group in step (c) into good leaving group by using p-toluene sulphonyl chloride, methanesulfonyl chloride or p-nitrobenzensulfonyl chloride.

[Claim 18] 18. A process according to claim 6, wherein amination reaction in step (d) is carried out in the presence of a solvent.

[Claim 19] 19. A process according to claim 18, wherein solvent is selected from group comprising of acetonitrile or ethylacetate or mixture thereof.

[Claim 20] 20. A process according to claim 6, wherein reaction is carried out at 80-90⁰C.

[Claim 21] 21. A process according to claim 6, wherein deprotection of hydroxy protecting group is carried out in the presence of aqueous hydrobromic acid and acetic acid.

[Claim 22] 22. A process according to claim 6 or 21, wherein deprotection of hydroxy protecting group in the presence of aqueous hydrobromic acid and acetic acid followed by treatment of base in the presence of a solvent to obtain free base of N,N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine.

[Claim 23] 23. A process according to claim 22, wherein base is selected from group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or mixture thereof.

[Claim 24] 24. A process according to claim 22, wherein solvent is selected from group comprising of dioxane, tetrahydrofuran, methyl t-butyl ether, ethylacetate, dichloromethane, diethyl ether, acetonitrile or mixture thereof.

[Claim 25] 25. A process according to claim 6, wherein resolution in step (f) is carried out with L-(+) Tartaric acid in the presence of alcohol. [Claim 26] 26. A process according to claim 25, wherein alcohol is selected from group comprising of methanol, ethanol, isopropyl alcohol, t-butanol or mixture thereof.