Field of the invention

The present invention relates to an improved  commercially viable and industrially advantageous process for the preparation of Tolterodine or a pharmaceutically acceptable salt thereof in high yield and purity. More specifically the present invention relates to an improved and industrially advantageous optical resolution method of racemic benzyl Tolterodine in the process for preparation of Tolterodine and its related compound.

Background of the invention

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 C26H37NO7 and molecular weight is 475.28. (+)-(R)-Tolterodine tartrate is represented by formula (I):

Tolterodine tartrate is marketed by Pharmacia & Upjohn under brand name Detrol® and is indicated for the treatment of Urinary incontinence.
Few processes for the synthesis of 3 3-diphenylpropylamine derivatives have been described in the literature.
Tolterodine and other 3 3-diphenylpropylamine analogs were first described in US patent 5 382 600. Said patent described several methods for preparing Tolterodine and its analogs generally based a process for the preparation of Tolterodine which is shown in the Scheme-I.

Scheme-I
The main problem associated with this process is that it involves use of less economical reagent and which requires specific handling skill when used. Moreover  some of the reagents like Lithium aluminum hydride should be avoided while using at plant because it hazardously reacts towards water and being more hygroscopic in nature compared to other reducing reagents like sodium borohydride. Further use of pyridine is some time prone to hazardous and biologically nondegradable and therefore it is not environment friendly. Further use of boron tribromide is also non appropriate. All these drawbacks make the process less economical and unsuitable at industrial level.
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-1-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.

Scheme-2
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.

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.

Scheme-3
This process involves a large number of steps and isolation of intermediates at each step  leading to poor yields. Moreover  the preparation of the tertiary amine by the condensation of tosylate with diisopropylamine in the presence of acetonitrile leads to form dimmer impurities which provides final product with low yields.

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.

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 oxazolidinone 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.

Scheme-4
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-phenylvinyl)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 hemiacetalic 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.

Scheme-5

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.

Based on the aforementioned drawbacks  prior art processes find to be unsuitable for preparation of tolterodine at lab scale and commercial scale operations.
Hence  a need still remains for an improved and commercially viable process of preparing pure tolterodine or a pharmaceutically acceptable salt thereof that will solve the aforesaid problems associated with process described in the prior art and will be suitable for large-scale preparation  in lesser reaction time  in terms of simplicity  purity and yield of the product.
Summary of the invention

The present inventors have focused on the problems associated with the prior art process and has developed an improved process for the preparation of Tolterodine.
As a whole  a process such as the one provided by the present invention has the advantage of considerably reducing the number of synthetic steps with respect to the processes of the state of the art  while at the same time high yields are achieved with very simple steps. Likewise  said process is not toxic and allows starting from inexpensive and non-hazardous reactants  providing 3 3-diphenylpropylamines  and  particularly  Tolterodine  with a good yield and pharmaceutical quality. All of this contributes to reducing the overall cost of the process  making it commercially interesting and allowing it to be put into practice on an industrial level.
Therefore  in one aspect the present invention provides a process for preparing Tolterodine or its enantiomer  or a salt thereof  comprising a step of obtaining a compound of formula IV(a) or formula IV(b) or a salt there of 
IV (a) IV (b)
Wherein Bn is benzyl group  by the resolution of the corresponding racemic compound of formula (III):
III
In another aspect the present invention provides a novel compound of formula VII 
VII
Wherein Bn is benzyl group.
In another aspect of the present invention provides a process for the preparation of N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III).
As a whole  a process such as the one provided by this invention relates to improved process for the preparation of Tolterodine and pharmaceutically acceptable salts.

Detailed description of the invention:

The present invention provides a process for preparation of Tolterodine or a pharmaceutically acceptable salt there of  which comprises: Reacting N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl- propane amide of formula (II) with reducing agent such as sodium borohydride  potassium borohydride and sodium cyano borohydride in the presence of a Lewis acid such as aluminum chloride  calcium chloride  boron trifluoride and zinc chloride to give N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III);
II III
An embodiment of the present invention provides a process for the preparation of N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III).

Another embodiment of the present invention provides a process for resolving compound of formula (III) using a suitable optically active acid such as (+) tartaric acid  (-) tartaric acid  (+) 2 3-dibenzoyl-D-tartaric acid  (-) 2 3-dibenzoyl-L-tartaric acid  mandelic acid  3-chloro mendalic acid  abietic acid  S-(+)-camphorsulfonic acid   di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid to give (R) N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula IV(a);
IV (a)
In another embodiment of the present invention provides a novel compound of formula VII and process for preparation of this compound.
VII

In yet another object of the present invention provides a resolution process for the preparation of (R)-N N-diisopropyl-3-(2-(benzyloxy-5-halophenyl)-3-phenylpropyl amine compound of formula IV(a) or a salt thereof  which comprises: reacting racemic (+)N N-diisopropyl-3-(2-(benzyloxy-5-halophenyl)-3-phenylpropylamine of formula III; with a di-p-tolyl-D-tartaric acid in a mixture of water and isopropanol  to produce a diastereomeric excess of di-p-tolyl-D-tartaric acid salt of compound of formula VII.
Separating the diastereomers and neutralizing the separated diastereomers with a base in a suitable solvent to provide enantiomerically pure compound of formula IV (a).
In yet another object of the present invention provides a process for preparation of Tolterodine or it’s a physiologically acceptable salt comprises a step of crystallizing the compound of formula II in isopropanol.

In another object of the present invention provides a solid form of N  N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide.
The embodiments of present invention are shown in below given scheme.

The process for preparation of Tolterodine is shown in the scheme III.
Scheme-III
The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention.

Examples
Example-1
Preparation of methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate:

Trans-cinammic acid (1.0 Kg) was added to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer  thermocouple  and nitrogen inlet. Para-cresol (0.766 Kg) was preheated in a water bath at 60 °C and added to the cinammic acid (II) followed by concentrated sulfuric acid (13.0 mL  243 mmol). The reaction was immediately heated to a set point of 127 °C and stirred at 120 °C -125 °C for 6-7hours. When the reaction was complete the mixture was cooled to 90 °C and toluene (3.0L) and water (0.5 L) are added to the crude product. The layers are separated and the organic layer was concentrated under reduced pressure. Methanol (1.0L) was added and distillation is continued to give 3 4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one as oily mass.
Benzyl bromide (1.372 Kg)  potassium carbonate (1.275 Kg)  acetone (5.0L) and methanol (5.0L) were loaded in to the mixture. The contents were heated to reflux temperature for about 4-5 hours and then distilled off the solvent from the reaction mass. 13L of water was added to the residue and extracted the solution twice with ethyl acetate (5.0L). Combined organic layers and distilled the solvent completely under vacuum. Methanol (5.3L) was added to the residue and heated for 30 to 45 min at 55±5°C to get clear solution  then stirred the solution at 0-5°C for about 2 hours. The formed solid was filtered and washed with methanol (1.6 L) and the material was dried to give 1.8kg of methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate. Yield 74%.

Example-2
Preparation of N  N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide (II):

Methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate (1.0 kg) was dissolved in Methanol (4.0 L) to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer  thermocouple  and nitrogen inlet. The solution of Potassium hydroxide (0.232 Kg) in Process water (0.550 L) was added and refluxed reaction mixture for 3 to 4 hours. After completion of the reaction solvent was distilled out and stirred the reaction mass with Process water (3.6 L) and Dichloromethane (4.0 L). Then adjusted the pH to 1-2 using conc. HCl (0.5-0.8 L). Separated organic layer and distilled out solvent completely to give oil.
Toluene (3.0 L)  Dimethylformamide (0.01 L) and Thionyl chloride (0.411 Kg) were added in reaction mass and heated the reaction mass at 62±3°C for 2-3 hours. After completion of reaction distilled Toluene completely and again charged Toluene (3.0 L) into the residue below 60°C and cooled the reaction mass to 2±3°C. Meanwhile prepared solution of Diisopropylamine (0.70 Kg) in Toluene (3.0 L) and added slowly into the reaction mass at 5±5°C. Stirred the reaction mass for 3- 4 hrs at 30±5°C. Process water (5.0 L) was added and separated out the organic layer. Distilled out Toluene completely under vacuum and charged Isopropyl alcohol (1.0 L) that also distilled under vacuum below 60°C and again Isopropyl alcohol (4.0 L) was added to the residue. Heated to 55±5°C to get clear solution and then cooled the mass to 2±3°C. Filtered the solid under nitrogen atmosphere and washed with chilled Isopropyl alcohol. The material was dried under vacuum to obtain 0.98Kg solid N  N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide. Yield 82%.

Example-3
Preparation of R-(+)-N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di-p-toluoyl L-tartaric acid salt (VII):

N  N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide (1.0 Kg )  Tetrahydrofuran (5.0 lit) and Sodium borohydride (0.43 Kg) were taken into the round bottom flask. The contents were cooled to 2±3°C followed by drop wise addition of Borontrifluoride etherate (1.93 Kg). The reaction mixture was stirred for 10-12 hrs at 33±2°C. After completion of the reaction a solution of Conc. Hydrochloric acid (2.83 L) into Process water (2.83 L) was added to the reaction mass at 40±10°C and stirred for 2-3 hrs at 62±3°C. The product was extracted in dichloromethane (4.0 L). Dichloromethane distilled out completely under vacuum below 50°C. This was followed by addition of Isopropyl alcohol (1.0L) and distilled it completely to give (+) N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine.
Isopropyl alcohol (8.0 L)  water (0.8L) and Di-p-toluoyl-L-tartaric acid (0.901 Kg) was added in reaction mixture and refluxed for 50-60 min. Gradually cooled the reaction mass at 32±3°C within 5-6 hrs and Stirred it for 2.0-3.0 hrs. Filtered the solid and washed with Isopropyl alcohol (1.11 L). Obtain solid was recrystallized several times in Isopropyl alcohol and water to give 0.64 Kg R-(+)-N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di-p-toluoyl L-tartaric acid salt. Yield 34%.
1H NMR (CDCl3)300mHz d (ppm): 1.10-1.21(12H m); 2.10-2.32 (9H d); 2.43-2.59 (2H m); 2.59-2.76 (2H  m); 4.21-4.26 (1H  t); 4.96 (2H  s); 5.91 (2H  s); 6.77-6.80(1H  d); 6.94-6.95 (1H  dd); 7.06-7.09 (5H  d); 7.17-7.38 (10H  m); 7.85-7.88 (4H  d). IR : 2966  1719  1704  1611  1499  1246.

Example-4
Preparation of Tolterodine Tartarate:

R-(+)-N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di-p-toluoyl L-tartaric acid salt (100 g)  Dichloromethane (400 ml) and process water (300 ml) were added in RB Flask. Followed by addition of a solution of sodium carbonate (50 g) in Process water (500 ml) and stirred for 25-30 min. Separated out organic layer and distilled out Dichloromethane to give amine.
The amine was transferred to an autoclave with 100ml methanol  15 gm of Raney nickel and 25ml of water were added to the reaction solution  and a hydrogen pressure of 5-5.5 kg/cm2 was applied at 25-35o C. for about 3-6 hours. Filtered the reaction mass and washed the solids with 100 ml of methanol. Distilled out methanol completely and added ethanol (60ml). Heated the reaction mixture at 60 o C for 10-15 minutes and then added mixture of L (+) tartaric acid (19.2g) in ethanol (192ml) at 60±5°C within 30-45 minutes. The reaction mixture was stirred at 80±5°C for 60-90 minutes. Then again it was stirred at 25±5°C for 60-90 minutes and then at 5±3°C for 60-90 minutes. Filtered the solid and washed with ethanol to give crude tolterodine Tartrate. This was further purified by recrystallising in ethanol.

Claims
1. A process for preparing Tolterodine or its enantiomer  or a salt thereof  comprising a step of obtaining a compound of formula IV(a) or formula IV(b) or a salt there of 
IV (a) IV (b)
Wherein Bn is benzyl group  by the resolution of the corresponding racemic compound of formula (III):
III
2. A process according to claim 1  wherein resolution of racemic compound of formula (III) through formation of the diastereomeric salt thereof with an optically active acid.
3. A process according to claim 2  wherein an optically active acid is an optically active carboxylic acid or sulphonic acid.
4. A process according to claim 3  wherein an optically active acid is selected from (+) tartaric acid  (-) tartaric acid  (+) 2 3-dibenzoyl-D-tartaric acid  (-) 2 3-dibenzoyl-L-tartaric acid  mandelic acid  3-chloro mandelic acid  abietic acid  S-(+)-camphorsulfonic acid   di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid.
5. A process according to claim 4  wherein an optically active acid is di-p-tolyl D-tartaric acid.
6. A process according to claim 1  wherein the resolution of racemic compound of formula (III) is carried out in a solvent selected from water  a dipolar aprotic solvent  a C3-C8 ketone  a cyclic or acyclic ether  an ester  a chlorinated solvent and a polar protic solvent  or a mixture of two or more  typically two  of said solvents.
7. A process according to claim 1  wherein the resolution of racemic compound of formula (III) is carried out in a isopropyl alcohol
8. A process for preparing Tolterodine or its enantiomer  or a salt thereof  comprises a step of crystallizing the compound of formula II in isopropanol.
II
Wherein Bn is benzyl group.
9. A process for preparation of Tolterodine or it’s a physiologically acceptable salt comprising the steps of: reducing the compound of formula II to III using sodium borohydride and boron trifluoride etherate.

Wherein Bn is benzyl group.
10. A process for preparation of Tolterodine tartrate of formula I:

characterized by the steps of:
a. Reacting N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl- propane amide of formula (II) with reducing agent in the presence of a lewis acid to give N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III);
b. Resolving compound of formula (III) using a suitable optically active acid to give (R) N  N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula IV(a);
c. Debenzylation of the compound of formula IV (a) to obtain Tolterodine;
d. converting tolterodine into tolterodine tartarate.

11. The process of claim 10  wherein the reducing agent used in step (a) is a metal hydride  selected from the group comprising lithium aluminum hydride  sodium borohydride  potassium borohydride and sodium cyano borohydride; wherein the Lewis acid is selected from the group comprising aluminium chloride  calcium chloride  boron trifluoride and zinc chloride.
12. The process according to claim 11  wherein the reducing agent used in step (a) is sodium borohydride and the Lewis acid is boron trifluoride.
13. The process of claim 10  wherein the resolution agent used in step (b) is selected from (+) tartaric acid  (-) tartaric acid  (+) 2 3-dibenzoyl-D-tartaric acid  (-) 2 3-dibenzoyl-L-tartaric acid  mandelic acid  3-chloro mandelic acid  abietic acid  S-(+)-camphorsulfonic acid   di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid.
14. The process according to claim 13  wherein the resolution agent used in step (b) is di-p-tolyl-D-tartaric acid.
15. The process of claim 10  wherein the debenzylation is carried out by hydrogenation of compound of formula (V) by using a hydrogen gas and hydrogenation catalyst selected from Raney Ni  palladium on carbon  palladium acetate  platinum oxide  platinum black  platinum oxide adsorbed on carbon  rhodium on carbon  ruthenium and its salts adsorbed on solid support.
16. The process according to claim 15  wherein the hydrogenation catalyst used in step (d) is Raney Nickel.

Dated this 05th day of Jan 2012

Dr. Alpesh Pathak
Applicant’s Agent