WO2007039918A1

WO2007039918A1 - Novel process for the preparation of tolterodine

Info

Publication number: WO2007039918A1
Application number: PCT/IN2006/000400
Authority: WO
Inventors: Muddasani Pulla Reddy; Peddi Rajasekhara Reddy; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2005-10-06
Filing date: 2006-10-05
Publication date: 2007-04-12

Abstract

The present invention relates to a novel and improved process for the preparation of tolterodine of formula I. Key steps involved in the process are a vinyl Grignard reaction on a benzophenone derivative of formula XXI to get the vinyl carbinol derivative of formula XXII and rearrangement of the carbinol derivative to an allylic alcohol derivative of formula XXIII to get the required carbon framework. Compound of formula XXIII is further converted to tolterodine in four steps. Tolterodine is a muscarinic receptor antagonist useful in treatment of urinary urge incontinence and other symptoms of bladder over activity.

Description

NOVEL PROCESS FOR THE PREPARATION OF TOLTERODINE FIELD OF THE INVENTION

The present invention relates to a novel and improved process for the preparation of tolterodine, and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Tolterodine is a muscarinic receptor antagonist, which has recently been launched for the treatment of urinary urge incontinence and other symptoms of bladder over activity. Tolterodine, which is (+)-R-3-(-hydroxy-5-methylphenyl)-N,N-diisopropyl-3 -phenyl- propylamine has the formula-I and was first disclosed in US patent No. 5,382,600.

I

A process for preparing tolterodine is described in US Patent No. 5,382,600. The process involves the reaction of 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (Scheme- I) with methyl iodide to get the methyl ester derivative of formula III. Reduction of this ester with lithium aluminum hydride gave the alcohol of formula IV. The alcohol of formula IV is converted into a tosylate and reacted with diisopropylamine to get the amine derivative of formula V, which on treatment with boron tribromide gave racemic tolterodine. Treatment of racemic tolterodine with (+)-tartaric acid gave tartrate salt of tolterodine.

Main drawbacks in this process are usage of expensive and hazardous reagents like lithium aluminum hydride, methyl iodide, and boron tribromide. Therefore the process is not suitable for commercial scale.

Scheme-I

In US patent 5922914 a simpler process for the preparation of tolterodine is disclosed (Scheme-II). Accordingly, trans-cinnamic acid of formula VII is reacted with p-cresol of formula VIII in sulfuric acid medium to get the benzopyranone derivative of formula IX.

VII VIII IX

Scheme-II Partial reduction of the carbonyl group of compound of formula IX with DIBAL gave the hemi-acetal derivative of formula X. Reductive amination of compound of formula X with diisopropylamine using palladium-on-carbon under hydrogen pressure gave racemic tolterodine, which is resolved into (+)-isomer using (+)-tartaric acid.

Although number of steps is reduced the cost incurred in making tolterodine is high due to usage of expensive and hazardous DIBAL. Therefore the process is not commercially viable.

An enantioselective process for the preparation of tolterodine of formula I is disclosed in WO01/49649 (Scheme-Ill). Accordingly, acetophenone of formula XI is condensed with

XVII ⁽⁺H

Scheme-Ill benzaldehyde to get the enone derivative of formula XII. Palladium acetate catalyzed intramolecular Heck reaction of compound XII gave the indenone derivative XIII. Asymmetric reduction of indenone XIII using CBS reagent gave the chiral indenol XIV. Treatment of this indenol with a base gave the chiral indanone derivative XV. Baeyer- Williger oxidation of the indanone XV gave the pyranone derivative of formula XVI. Conversion of pyranone XVI into tolterodine of formula I is done by following the process disclosed in US pat. 5922914.

Main drawbacks in this process are requirement of rare and expensive CBS reagent used in making the chiral indenol, requirement of expensive DIBAL, and palladium catalyzed hydrogenation. Also, the process is lengthy requiring more reagents, solvents, and operational time.

A new route for the synthesis of tolterodine is described in Org. Proc. Res. Dev., 2002, 6, 379 (Scheme IV). p-Cresol is reacted with phenylacetylene to get the styrene derivative of formula XIX. Carbonylation of compound of formula XIX with carbon monoxide in the presence of phosphine ligands gave the aldehyde compound XX. Conversion of this

X

Scheme-IV aldehyde to dl-tolterodine was done by the earlier process disclosed in US pat. 5922914.

Main drawback in this route is handling of carbon monoxide which is toxic and also usage of rare and expensive phosphine reagents used in carbonylation of styrene intermediate of formula XIX.

All the above mentioned processes are requiring one carbonyl group reduction step in the synthesis of tolterodine. The reduction step is done by using reagents like LAH or DIBAL. Therefore the processes are not commercially viable. Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of tolterodine, we aimed to develop a simple and economical process for commercial production of tolterodine.

We observed that a promising approach for a process for the preparation of tolterodine will be to (a) avoid the usage of costly reagents like methyl iodide (b) avoid the costly and hazardous reagents like lithium aluminum hydride or DIBAL (c) avoid toxic gases like carbon monoxide in making tolterodine thereby making the process commercially viable and economical.

Accordingly, the main objective of the present invention is provide a simple and economically viable commercial process for the preparation of tolterodine of formula I.

Still another objective of the present invention is to provide a process for the preparation of tolterodine which does not require costly and hazardous reagents like methyl iodide, lithium aluminum hydride, DIBAL, etc.

SUMMARY OF THE INVENTION

Extensive laboratory research by us led to a novel and commercially viable process for the preparation of tolterodine of formula I. Retrosynthetic analysis of tolterodine led to identification of an allylic rearrangement as the key step in building the required carbon chain of tolterodine. Process of the present invention is as shown in Scheme-V.

XXI XXII XXIII

XXVII

Scheme-V

The starting benzophenone derivative is readily prepared from benzoyl chloride and A- methyl anisole under Friedel-Crafts acylation conditions or it can be prepared by the literature procedure (Chem. Abstr. VoI 63, 13026b). The benzophenone derivative of formula XXII is reacted with vinylmagnesium bromide in the presence of an ether solvent at elevated temperature to get the vinyl derivative of formula XXIII. The ether solvent employed is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane. Rearrangement of vinyl group is accomplished in the presence of an acid catalyst such as sulfuric acid, trifluoromethanesulfonic acid, perchloric acid, etc. to get the corresponding allyl alcohol derivative of formula XXIII.

The compound of formula XXIII is reacted with a halide source such as thionyl chloride, thionyl bromide, hydrobromic acid, PX₃, POX₃, PX₅ to get the corresponding allyl halide derivative of formula-XXIV (X = Cl, Br₅ or I). Optionally the allyl alcohol derivative of formula XXIII is reacted with an acid anhydride such as acetic anhydride, propionic anhydride, methanesulfonic anhydride, benzenesulfonic anhydride, toluenesulfonic anhydride, trifluoromethanesulfonic anhydride to get the corresponding ester derivative of formula XXIV (X = OCOR, OSO₂R). The allyl derivative of formula XXIV is reacted with diisopropylamine to get the amino compound of formula XXV.

The hydroxy protecting group present in compound of formula XXV is removed using Lewis acid catalysts such as BBr₃, BCl₃, BF₃, hydrobromic acid, hydroiodic acid to get the compound of formula XXVI. For removing arylmethyl protecting group present in compound of formula XXV metal catalyzed hydrogenation techniques are used. The metal catalysts employed are selected from Raney neckel, Pd/C, Rh/alumina, platinum oxide. The olefinic group present in compound of formula XXVI is reduced by hyrogenation techniques using a metal catalyst. The metal catalysts employed are selected from Raney nickel, 2-20% Pd/C, palladium hydroxide, 2-10% Rh/alumina, platinum oxide. Optionally the deprotection step when R is arylmethyl and double bond reduction step using metal catalysts can be combined together to get tolterodine in a single step.

Optionally the double bond present in compound of formula XXV is reduced under hydrogenation techniques using a metal catalyst to get the known compounds of formula XXVII. Deprotection of the hydroxy group can be accomplished by known processes from the prior art to get dl-tolterodine of formula I.

The invention provides novel compounds of formula XXII,

XXII wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl.

The invention also provides novel compounds of formula XXIV,

XXIV wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; X = OH, Cl₅ Br, I, OCOR', wherein R' = C1-C4 alkyl, phenyl, substituted phenyl; OSO₂R", wherein R" = C1-C4 alkyl or perfluoroalkyl, phenyl, tolyl.

The invention also provides novel compounds of formula XXV,

XXV wherein R = H, C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl. The invention provides a novel and improved process for the preparation of tolterodine of formula I,

and its pharmaceutically acceptable salts thereof, comprising the steps of:

(i) Reacting the benzophenone derivative of formula XXI,

XXI wherein R = C1-C4 alkyl, ArCH₂, Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; with vinylmagnesium halide in a suitable solvent at a suitable temperature to get the vinyl carbinol derivative of formula XXII,

XXII wherein R = C1-C4 alkyl, ArCH₂, Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; (ii) Rearranging the vinyl carbinol of formula XXII with an acid catalyst in a suitable solvent at a suitable temperature to get the allylic alcohol derivative of formula XXIII₅

XXIII wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl;

(iii) Reacting the compound of formula XXIII with a halide source or an acid anhydride in a suitable solvent to get the compound of formula XXIV,

XXIV wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; X = Cl, Br, I, OCOR', wherein R' = C1-C4 alkyl, phenyl, substituted phenyl; OSO₂R", wherein R" = C1-C4 alkyl or perfluoroalkyl, phenyl, tolyl; (iv) Reacting the compound of formula XXIV with N,N-diisopropylamine in a suitable solvent at a suitable temperature and pressure to get the amine derivative of formula XXV,

XXV wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl;

(v) Removing the hydroxy protecting group present in compound of formula XXV to get the compound of formula XXVI,

XXVI

(vi) Hydrogenating the compound of formula XXVI in the presence of a metal catalyst in a suitable solvent and hydrogen pressure to get tolterodine base of formula I; and

(vii) Optionally hydrogenating the amine derivative of formula XXV in the presence of a metal catalyst in a suitable solvent at a suitable temperature and pressure to get the compound of formula XXVII,

XXVII wherein R = C1-C4 alkyl, nitrophenyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; (viii) Removing the hydroxy protecting group present in compound of formula

XXVII by known methods to get tolterodine base of formula I.

Vinylmagnesium halide used in step (i) is vinylmagnesium bromide. The organic solvent used in step (i) is selected from ethers like diethyl ether, 1,4-dioxane, tetrahydrofuran, diisopropyl ether, hydrocarbon solvents like hexane, heptane, tolune, xylenes, halogenated solvents like methylene chloride. Temperature of the reaction in step (i) is - 30°C to 6O⁰C or reflux temperature of the solvent employed, preferably 25-40°C.

The acid catalyst employed in step (ii) is sulfuric acid, hydrobromic acid, sulfonic acids

5 like methanesulfonic acid, perfluoroalkanesulfonic acids, benzenesulfonic acid, toluenesulfonic acid, Lewis acids like borontrifluride etherate, zinc chloride, stannous chloride, ferric chloride, and titanium tetrachloride, preferably sulfuric acid: Suitable solvent employed in step (ii) is selected from solvents such as heptane, cylohexane, toluene, methylene chloride, chloroform, dichloroethane, acetic acid, sulfonic acids,

10 preferably, acetic acid or dichloromethane. Temperature of the reaction in step (ii) is 0-

80°C, preferably 20-30°C.

Halide source used in step (iii) is thionyl chloride, thionyl bromide, hydrogen bromide, hydrogen iodide, phosphorous trihalide, phosphornyl trihalide, phosphorous pentahalide. 15 The solvent employed in step (iii) along with halide source is selected from a group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene chloride, chloroform, toluene, xylene, heptane, cyclohexane, dimethylformamide, dimethylacetamide.

>0 Acid anhydride used in step (iii) is selected from a group consisting of C1-C4 alkaneanhydride, C1-C4 alkanesulfonic anhydride, C1-C4 perfluoroalkanesulfonic anhydride, benzenesulfonic anhydride, toluenesulfonic anhydride. Solvent employed in step (iii) along with acid anhydride is selected from a group consisting of C1-C4 alkanoic acid, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, diisopropyl ether,

.5 methyl tert-butyl ether, methylene chloride, chloroform, toluene, xylene, heptane, cyclohexane. Temperature of the reaction in step (iii) is O⁰C to 100⁰C or reflux temperature of the solvent employed, preferably 20-60⁰C.

Solvent used in step (iv) is selected from a group consisting of acetonitrile, heptane,

30 toluene, xylene, ethyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, diisopropyl ether. Pressure of the reaction in step (iv) is 0-20atmosphere of inert gas such as nitrogen argon, preferably 0-5atmosphere. Temperature of the reaction in step (iv) is 25⁰C to 15O⁰C preferably 40-80⁰C.

The hydroxy protective group in step (v) is removed by using aqueous hydrobromic acid or a Lewis acid such as trihaloborane, ZnCl₂, AlCl₃, SnCl₂, TiCl₄. The hydroxy protective group (ArCH₂) in step (v) is removed under hydrogenolysis conditions. The hydrogenolysis is performed using a metal catalyst such as Raney nickel, Palladium-on- carbon, platinum oxide, Rhodium-on-alumina under hydrogen atmosphere in a suitable solvent medium. Solvent medium used in hydrogenolysis is methanol, ethanol, isopropanol, acetic acid, ethyl acetate, toluene, dimethylformamide.

The metal catalyst used in step (vi) and (vii) is Raney nickel, Pd/C, Rh/C, PtO, preferably 2-20% Pd/C. The solvent used in step (vi) and (vii) s selected from toluene, cyclohexane, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, diisopropyl ether. The hydrogen pressure of the reaction in step (vi) and (vii) is 0- lOatmosphere, preferably 0-5atmosphere.

The details of the invention are given in the Example given below which is provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example

(i) Preparation of 2-methoxy~5-methylbenzophenone

Into a IL three-necked RB flask was charged 600ml of methylene chloride. The solvent was cooled to 0⁰C and added 12Og of powdered aluminum chloride. Benoyl chloride (134g) was added to the reaction mass keeping the temperature below 5°C. After the addition reaction mass was maintained at same temperature for another 30min.

Into a 2L, three-necked RB flask was charged 200ml of methylene chloride and lOOg of 4-methylanisole. The reaction mass was cooled to -10⁰C. Above prepared aluminum chloride-benzoyl chloride complex was taken into a addition funnel and added to the reaction mass slowly below — 5°C. After the addition reaction mass was maintained at same temperature for Ih. The reaction mass was quenched into a flask containing 160ml of cone HCl and 100ml of water. After stirring for one at 25°C layers were separated and the aqueous layer extracted with 150ml of methylene chloride. The combined organic layer was washed with 2x200ml of 5% sodium bicarbonate solution. The organic layer was dried with sodium sulfate and distilled of solvent to get 188g of crude benzophenone derivative.

The above crude compound was distilled under high vaccum keeping the bath temperature 170-180°C. Distillate was collected into fractions. The main fraction (158g) was obtained in 97% purity. IR (neat): 3061.5, 3025.9, 2944.1, 2836.5, 1666.9, 1597.9, 1596.3, 1581.4, 1497.1, 1448.9, 1405.5, 1315.4, 1295.9, 1285.3, 1244.3, 1212.1, 1177.2, 1153.3, 1118.0, 1028.8, 966.7, 848.5, 809.3, 739.8, 698.0, and 648.2cm^'1.

(ii) Preparation of l-(2-methoxy-5-methylphenyI)-l-phenyl-prop-2-ene-l-ol

Into a 500ml four-necked RB flask was charged 8g of magnesium turnings and 50ml of dry THF under nitrogen. A solution of vinyl bromide (4Og) in THF (75ml) was slowly added to the reaction mass at 35°C. Initiation of the reaction was observed after adding about one tenth of the solution. Remaining quantity of the reagent was added to the reaction mass keeping the temperature at 45-6O⁰C. After the addition reaction mass was maintained at 45-50⁰C for 45min and cooled to 25°C.

Into a 500ml four-necked RB flask was charged 50ml of THF and 25g of 2-methoxy-5- methylbenzophenone under nitrogen. Above prepared Grignard solution was taken into an addition funnel and added to the reaction mass keeping the temperature below -1O⁰C. After maintaining at same temperature reaction mass was allowed to reach 25°C and left for overnight. Aqueous ammonium chloride (1Og in 50ml of water) slowly added to the reaction mass at 5-10⁰C. The reaction mass was stirred at 25-30⁰C for Ih and separated the layers. The aqueous layer was extracted with 80ml of toluene. Combined organic layer was washed with 50ml of brine solution. The organic layer was dried and the solvent distilled under reduced pressure to get 22g of crude title compound as syrup. A small sample was purified by column chromatography to get pure sample. IR (neat): 3515.5, 3058.3, 3026.1, 2943.7, 2838.4, 1608.0, 1497.5, 1463.3, 1447.8, 1406.2, 1355.8, 1315.5, 1289.0, 1241.0, 1212.3, 1178.3, 1155.3, 1134.2, 1029.7, 927.8, 889.0, 847.3, 810.3, 764.7, 737.7, 702.7, and 646.0cm^"1. ¹H-NMR (300MHz, CDCl₃): 7.17-7.34 (m, 5 5H, Ar. H); 7.04-7.10 (m, 2H, Ar. H); 6.79 (d, J = 8.10Hz, IH, Ar. H); 6.39 (dd, J = 10.6Hz and 17.2Hz, IH, -CH=CH₂); 5.27 (dd, J = 1.5Hz and 10.6Hz, IH, -CH=CH₂); 5.06 (dd, J = 1.5Hz and 17.2Hz, IH, -CH=CH₂); 4.76 (s, exch with D₂O, -OH); 3.58 (s, 3H, -OCH₃); 2.28 (s, 3H, ArCH₃).

10 (iii) Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenylallyl acetate

Into a 500ml four-necked RB flask was charged 80ml of acetic acid, 80ml of acetic anhydride, 4g of p-tpoluenesulfonic acid and 2Og of l-(2-methoxy-5-methylphenyl)-l- phenyl-ρrop-2-ene-l-ol under nitrogen atmosphere. The reaction mixture was stirred at 25⁰C for 30min and found to be over by TLC. The reaction mass was poured into water

15 (400ml) and stirred for 30min. Isopropyl ether (150ml) was added to the reaction mass and stirred for 20min. Layers were separated and the aqueous layer extracted with 2 x 80ml of diisopropyl ether. Combined extracts were washed with 100ml of water. The organic layer was dried and distilled under vaccum to get 21 g of title compound as syrup. IR (neat): 3023.6, 2942.7, 2835.2, 1739.1, 1607.3, 1498.3, 1446.9, 1406.6, 1377.8,

>0 1362.5, 1315.4, 1238.6, 1179.1, 1030.4, 965.5, 809.5, 767.4, and 698.4cm^"1. ¹H-NMR (300MHz, CDCl₃):

(iv) Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenyl-prop-2-en-l-ol

Into a 500ml four-necked RB flask was charged 2Og of 3-(2-methoxy-5-methylphenyl)-3-

!5 phenylallyl acetate and 100ml of 20% methanolic ammonia. The reaction mass was heated 40-45°C and maintained for 2Oh. Methanol was distilled of from he reaction mass under vaccum. The residue was dissolved in 100ml of isopropyl ether and added 30ml of water. After stirring the mixture for 30min layers were separated and the aqueous layer extracted with isopropyl ether. Combined organic layer was washed with 50ml of water

10 and dried with sodium sulfate. Distillation of solvent under vaccum gave 2Og of crude title compound as syrup. IR (neat): 3357.4, 3021.6, 2941.3, 2834.0, 1605.3, 1496.1, 1462.6, 1444.4, 1406.5, 1240.2, 1180.8, 1152.8, 1124.7, 1088.7, 1028.5, 969.8, 808.4, 766.5, 738.7, and 699.3cm^"1. ¹H-NMR (300MHz, CDCl₃): 7.04-7.35 (m, 6H, Ar. H); 6.83-6.91 (m, 2H, Ar. H); 6.41 (t, J = 7.33Hz, IH, =CHCH₂OH); 4.03 (d, J = 7.00Hz, 2H, ^CHCH₂OH); 3.73 (s, 3H, OCH₃); 2.27 (s, 3H, ArCH₃); 1.78 (br. s, exch. with D₂O, IH, -OH).

(v) Preparation of 3-(2-methoxy-5-methylphenyl)-3-phenylallyl benzenesulfonate

Into a 500ml four-necked RB flask was charged 7g of 3-(2-methoxy-5-methylphenyl)-3- phenyl-prop-2-en-l-ol and 150ml of methylene chloride under nitrogen atmosphere. The reaction mixture was cooled to -1O⁰C. Triethylamine (6g) was added to the reaction mass. Benzenesulfonyl chloride (10.5g) was slowly added to the reaction mass keeping the temperature below -10°C. The reaction was maintained at -10⁰C for 4h and at 25°C for 15h. The reaction mass was cooled to 10°C and added 100ml of water. Cone. HCl (17.5ml) was added to the reaction mass and stirred for 30min. Reaction temperature was raised to 25°C and separated the layers. Aqueous layer was extracted with 80ml of methylene chloride. Combined organic layer was washed with 75ml of water. Organic layer was dried over sodium sulfate and distilled of solvent under vaccum to get 7g of crude title compound as syrup. IR (neat): 3067.3, 1581.7, 1498.8, 1477.6, 1450.0, 1378.8, 1336.0, 1313.7, 1290.3, 1247.1, 1100.6, 1080.8, 1030.6, 753.3, 718.6, 681.5, 577.5, and 550.0cm^"1.

(vi) Preparation of N,N-diisopropyI-3-(2-methoxy-5-methylphenyI)-3-phenylprop-2- ene-1-amine

Into a 100ml Stainless steel kettle was charged 7g of 3-(2-methoxy-5-methylphenyl)-3- phenylallyl benzenesulfonate, 25ml of acetonitrile and 25ml of diisopropylamine. The kettle was filled nitrogen and sealed. The reaction mass was heated to about 100°C and maintained for 24h. The reaction mass was cooled to 25°C. The reaction mass was transferred into a single necked RB flask and distilled of volatiles. The residue was dissolved in 80ml of toluene and washed with 50ml of water. Aqueous layer was extracted with 80 ml of toluene. Combined toluene layer was washed with 20ml of water.

Toluene layer was extracted with 2 x 60ml of 10% acetic acid. Combined aq. acetic acid layer was neutralized with sodium carbonate and the liberated base extracted with 2 x 100ml of toluene. Combined toluene layer was dried and evaporated to get 5.2g of crude title compound as syrup. IR (neat): 3056.4, 3020.8, 2982.5, 2832.9, 1599.3, 1496.1, 1463.3, 1445.1, 1380.1, 1362.5, 1287.4, 1245.4, 1202.4, 1177.7, 1154.6, 1118.3, 1087.6, 5 1033.9, 952.0, 886.3, 806.1, 766.4, 737.5, 695.3, and 546.7cm^"1.

(vii) Preparation of N,N-diisopropyl-3-(2-methoxy-5-methylphenyI)-3-phenyIpropyl amine

Into a 100ml stainless steel kettle was charged 5g of N,N-diisopropyl-3-(2-methoxy-5-

10 methylphenyl)-3-phenylprop-2-ene-l -amine, 75ml of methanol and Ig of 10% Pd/C. The kettle was filled with hydrogen and subjected to hydrogenation at 40-60psi. After the completion of reduction mass was filtered and methanol distilled of from filtrate to get 4.5g of title compound as syrup. IR (neat): 3026.2, 2963.5, 2869.3, 2833.1, 1601.4, 1490.5, 1463.4, 1385.6, 1360.0, 1288.8, 1241.4, 1204.6, 1163.4, 1116.1, 1036.1, 804.3,

15 736.1, and 699.3cm^'1. ¹H-NMR (300MHz, CDCl₃): 7.23-7.29 (m, 4H, ar. H); 7.12-7.15 (m, IH, ar. H); 7.05 (s, IH, ar. H-5); 6.94 (d, J = 7.82Hz, ar. H-4); 6.71 (d, J = 7.82Hz, ar. H-3); 4.33 (t, J = 7.82Hz₅ -CHCH₂CH₂); 3.74 (s, 3H, -OCH₃), 2.97 (br. s, 2H, 2 x NCH(CH₃)₂); 2.33 (br. s, 2H, -NCH₂); 2.25 (s, 3H, ArCH₃); 2.13 (br. s, 2H, CHCH₂CH₂); 0.93 (br. s, 12H₅ 4 x CH₃).

>0

(viii) Preparation of N,N-diisopropyl-3-(2-hydroxy-5-methyIphenyI)-3-phenyIpropyl amine (tolterodine)

Into a 250ml three-necked RB flask was charged 4g of N,N-diisopropyl-3-(2-methoxy-5- methylphenyl)-3-phenylpropyl amine, 25ml of hydrobromic acid in acetic acid, and 5ml

»5 of water. The reaction mass was heated to reflux temperature and maintained for 10-12h. The reaction mass was cooled to 10-15⁰C and maintained for 30min. The reaction mass was filtered and the wet cake washed with 10ml of chilled acetone. The wet cake was dried and the solid taken into a flask containing 50ml of water. pH of the reaction mass was adjusted to 8.0-8.5 using ammonia solution. Product was extracted into methylene

(0 chloride and the methylene chloride distilled off to get 3.2g of title compound as syrup. HPLC purity is >98%. IR (neat): 3280.9, 3026.1, 2969.4, 2870.7, 1601.5, 1494.3, 1452.2, 1366.1, 1327.8, 1251.3, 1162.9, 1110.0, 1013.4, 814.9, 755.7, and 700.1cnϊ'. ¹H-NMR (300MHz, CDCl₃): 7.21-7.33 (m, 5H, ar. H); 6.79-6.85 (m, 2H, ar. H); 6.55 (s, IH, ar. H); 4.47 (dd, J = 3.90, 10.75Hz, IH, -CHCH₂CH₂); 3.23 (septet, J = 5.86Hz, 2H, 2 x - CH(CHa)₂); 2.71-2.74 (m, 2H, -NCH₂CH₂); 2.32-2.39 (m, 2H, -NCH₂CH₂), 2.12 (s, 3H, ArCH₃); 1.13 (d, J = 6.84Hz, 6H, 2 x CH₃); 1.08 (d, J = 5.86 Hz, 6H, 2 x CH₃).

Advantages of the present invention:

1. Present invention avoids the usage of costly and hazardous reagents.

2. Present invention does not require any carbonyl reduction step, which is unavoidable in the prior art processes.

3. Present invention is novel and easily adaptable to commercial scale.

4. Present invention involves the usage of novel intermediates of formulae-XXII, XXIV, and XXV.

Claims

We claim

1. A novel and improved process for the preparation of tolterodine of formula I,

I and its pharmaceutically acceptable salts thereof, comprising the steps of:

(i) Reacting the benzophenone derivative of formula XXI,

XXII wherein R = C1-C4 alkyl, ArCH₂, Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; (ii) Rearranging the vinyl carbinol of formula XXII with an acid catalyst in a suitable solvent at a suitable temperature to get the allylic alcohol derivative of formula XXIII,

XXIV wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; X = Cl, Br, I, OCOR', wherein R' = C1-C4 alkyl, phenyl, substituted phenyl; OSO₂R", wherein R" = C1-C4 alkyl or perfluoroalkyl, phenyl, tolyl; (iv) Reacting the compound of formula XXIV with N,N-diisoproρylamine in a suitable solvent at a suitable temperature and pressure to get the amine derivative of formula XXV,

XXVI

XXVlI wherein R = C1-C4 alkyl, nitrophenyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; (viii) Removing the hydroxy protecting group present in compound of formula

XXVII by known methods to get tolterodine base of formula I.

2. The process according to claim 1 wherein the vinylmagnesium halide used in step (i) is vinylmagnesium bromide.

3. The process according to claims 1 and 2 wherein the organic solvent used in step (i) is selected from ethers like diethyl ether, 1,4-dioxane, tetrahydrofuran, diisopropyl ether, hydrocarbon solvents like hexane, heptane, tolune, xylenes, halogenated solvents like methylene chloride.

4. The process according to claims 1 to 3 wherein the temperature of the reaction in step (i) is -30°C to 60⁰C or reflux temperature of the solvent employed, preferably 25-4O⁰C.

5. The process according to claims 1-4 wherein the acid catalyst employed in step (ii) is sulfuric acid, hydrobromic acid, sulfonic acids like methanesulfonic acid, perfluoroalkanesulfonic acids, benzenesulfonic acid, toluenesulfonic acid, Lewis acids like borontrifluride etherate, zinc chloride, stannous chloride, ferric chloride, and titanium tetrachloride, preferably sulfuric acid.

6. The process according to claims 1-5 wherein the suitable solvent employed in step (ii) is selected from solvents such as heptane, cylohexane, toluene, methylene chloride, chloroform, dichloroethane, acetic acid, sulfonic acids, preferably, acetic acid or dichloromethane.

7. The process according to claims 1-6 wherein the suitable temperature of the reaction in step (ii) is 0-80°C, preferably 20-30⁰C.

8. The process according to claims 1-7 wherein the halide source used in step (iii) is thionyl chloride, thionyl bromide, hydrogen bromide, hydrogen iodide, phosphorous trihalide, phosphornyl trihalide, phosphorous pentahalide.

9. The process according to claims 1-8 wherein the solvent employed in step (iii) along with halide source is selected from a group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene chloride, chloroform, toluene, xylene, heptane, cyclohexane, dimethylformamide, dimethylacetamide.

10. The process according to claims 1-9 wherein the acid anhydride used in step (iii) is selected from a group consisting of C1-C4 alkaneanhydride, C1-C4 alkanesulfonic anhydride, C1-C4 perfluoroalkanesulfonic anhydride, benzenesulfonic anhydride, toluenesulfonic anhydride.

11. The process according to claims 1-10 wherein the solvent employed in step (iii) along with acid anhydride is selected from a group consisting of C1-C4 alkanoic acid, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylene chloride, chloroform, toluene, xylene, heptane, cyclohexane,

12. The process according to claims 1-11 wherein the temperature of the reaction in step (iii) is 0⁰C to 100⁰C or reflux temperature of the solvent employed, preferably 20-60°C.

13. The process according to claims 1-12 wherein the solvent used in step (iv) is selected from a group consisting of acetonitrile, heptane, toluene, xylene, ethyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, diisopropyl ether.

14. The process according to claims 1-13 wherein the pressure of the reaction in step (iv) is 0-20atmosphere of inert gas such as nitrogen argon, preferably 0-5 atmosphere.

15. The process according to claims 1-14 wherein the temperature of the reaction in step (iv) is 25⁰C to 150°C preferably 40-80⁰C.

16. The process according to claims 1-15 wherein the hydroxy protective group in step (v) is removed by using aqueous hydrobromic acid or a Lewis acid such as trihaloborane,

ZnCl₂, AlCl₃, SnCl₂, TiCl₄.

17. The process according to claims 1-16 wherein the hydroxy protective group (ArCH₂) in step (v) is removed under hydrogenolysis conditions.

18. The process according to claim 17 wherein the hydrogenolysis is performed using a metal catalyst such as Raney nickel, Palladium-on-carbon, platinum oxide, Rhodium-on- alumina under hydrogen atmosphere in a suitable solvent medium.

5 19. The process according to claims 17 and 18 wherein the solvent medium used in hydrogenolysis is methanol, ethanol, isopropanol, acetic acid, ethyl acetate, toluene, dimethylformamide.

20. The process according to claims 1-19 wherein the metal catalyst used in step (vi) and [ 0 (vii) is Raney nickel, Pd/C, Rh/C, PtO, preferably 2-20% Pd/C.

21. The process according to claims 1-20 wherein the solvent used in step (vi) and (vii) s selected from toluene, cyclohexane, methanol, ethanol, isopropanol, ethyl acetate,

15 isopropyl acetate, tetrahydrofuran, diisopropyl ether and the hydrogen pressure of the reaction in step (vi) and (vii) is 0-10 atmosphere, preferably 0-5 atmosphere.

22. Novel compounds of formula XXII,

XXII

!0 wherein R = C1-C4 alkyl, ArCH₂, Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl.

!5

23. Novel compounds of formula XXIV,

XXIV wherein R = C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl; X = OH, Cl, Br, I, OCOR', wherein R' = C1-C4 alkyl, phenyl, substituted phenyl; OSO₂R", wherein R" = C1-C4 alkyl or perfluoroalkyl, phenyl, tolyl.

24. Novel compounds of formula XXV,

XXV wherein R = H, C1-C4 alkyl, ArCH₂, wherein Ar = phenyl or alkylphenyl, alkoxyphenyl, nitrophenyl, halophenyl.

25. A novel and improved process for the preparation of tolterodine of formula I and novel compounds of formula XXl 1, formula XXIV, formula XXV substantially as herein described in Examples.