Claims:1. A process for resolution of racemic Tolterodine comprising of,
a) Providing a solution of racemic Tolterodine in an alcohol solvent;
b) Adding (S)(+)-BIQOL Phosphoric acid to solution of step (a);
c) Separating the solid formed by the optically pure enantiomer of Tolterodine and Chiral BIQOL Phosphoric acid;
d) Converting the solid obtained in step (c) to optically pure enantiomer of Tolterodine Tartrate;
2. A process for resolution of racemic Tolterodine comprising of,
a) Providing a solution of racemic Tolterodine in an alcohol solvent;
b) Adding (S)(+)-BIQOL Phosphoric acid to solution of step (a);
c) Separating the solid formed by the optically pure enantiomer of Tolterodine and Chiral BIQOL Phosphoric acid;
d) Converting the solid obtained in step (c) to optically pure enantiomer of Tolterodine Tartrate;
e) Recovering the chiral BIQOL Phosphoric acid from step (d).
3. The process according to claim 1 wherein the alcohol in step (a) is methanol
4. The process according to claim 1 wherein the said solid is (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt.
5. The process according to claim 1 wherein the said (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt is converted to (R)-Tolterodine tartrate.
6. The process according to claim 5 for conversion of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt to (R)-Tolterodine tartrate comprising of:
i. Adding ammonia solution to (R)-Tolterodine-(S) (+)-BIQOL Phosphoric acid salt in water; n-Hexane mixture.
ii. Separating n-hexane layer from aqueous layer and concentrating under vacuum;
iii. Adding methanol and L (+) Tartaric acid to the residue from step ii to provide (R)-Tolterodine tartrate.
7. A process according to claim 6 further comprises recovery of (S)-BIQOL Phosphoric acid by adding dilute Hydrochloric acid to aqueous layer.
8. Chiral BIQOL phosphoric acid represented by compound of formula 2.

9. A process for the preparation of (S)(+)-BIQOL Phosphoric Acid, comprising of reacting (S)(+)-BIQOL with Phosphoryl Chloride in pyridine under nitrogen atmosphere at 0-5oC.
10. Enantiomerically pure salts of Tolterodine and BIQOL phosphoric acid represented by compound of formula 3A

, Description:Field of the Invention
The present invention provides a process for preparation of optically pure enantiomer of Tolterodine Tartrate using suitable chiral BIQOL phosphoric acid compound as novel resolving agent and a method for preparation of the same.
Background of the Invention
Tolterodine is a muscarinic receptor antagonist.It is marketed as Tolterodine Tartrate by Pharmacia & Upjohn under the brand name of Detrol® and is indicated for the treatment of urinary incontinence. The chemical name of Tolterodine Tartrate is (R)(+)-2-[3[bis(1-methylethyl)-amino]1-phenylpropyl]-4-methylphenol [R-(R*,R*)]-2,3dihydroxybutanedioate (1:1) (salt). The empirical formula of Tolterodine Tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of Tolterodine Tartrate is represented as compound of formula 1:

Formula 1
(R)-Tolterodine and analogues thereof including the corresponding (S)-enantiomer, as well as the process for preparation thereof were first disclosed in US5,382,600.
US’600 patent discloses a process for the resolution of racemic Tolterodine using L-(+) Tartaric acid as resolving agent. The process involves addition of L-(+) Tartaric acid solution in ethanol to racemic Tolterodine solution in ethanol followed by two times recrystallization from ethanol to yield pure (R)-Tolterodine Tartrate. However, the purity of the final compound is not mentioned in the patent.
JOC, 1998, 63, 8067-8070; discloses asymmetric synthesis of Tolterodine using Oxazolidinone as chiral auxiliary. The process involves copper assisted asymmetric conjugate addition of aryl Grignard reagent to phenylpropanoyl derivative of Oxazolidinone as shown in scheme 1.
Scheme 1

However, this process involves use of expensive chiral auxiliary, harmful chemicals and solvents such as pyridine and benzene.
The methods described in the literature for the resolution of racemic Tolterodine suffer from one or more disadvantages such as low yield, less purity, use of expensive chiral auxiliary and harmful chemicals and solvents and hence does not lead to an industrially feasible process.
Therefore, there exists a need to develop a consistent, cost effective and industrially feasible process for the resolution of racemic Tolterodine.
Summary of the Invention:
The object of the present invention is to provide an improved method for the manufacture of optically pure enantiomer of Tolterodine tartrate thereby resulting in significant economic and technological improvement over the prior art methods.
In one of the aspects, the invention provides a process for resolution of racemic Tolterodine using suitable chiral BIQOL Phosphoric acid, wherein the said process comprises:
a) Providing a solution of racemic Tolterodine in an alcohol solvent;
b) Adding suitable Chiral BIQOL Phosphoric acid to solution of step (a);
c) Separating the solid formed by the optically pure enantiomer of Tolterodine and Chiral BIQOL Phosphoric acid;
d) Converting the solid obtained in step (c) to optically pure enantiomer of Tolterodine Tartrate;
e) Optionally, recovering the chiral BIQOL Phosphoric acid from step (d).
Another aspect of the present invention provides chiral BIQOL Phosphoric acid as a novel resolving agent represented by the compound of formula 2 ((S)(+)-BIQOL Phosphoric acid).

In another aspect, the invention provides a process for the preparation (S)(+)-BIQOL Phosphoric acid.
In yet another aspect, the invention provides novel pair of diastereomeric salts of optically pure enantiomer of Tolterodine and BIQOL phosphoric acid as intermediates represented by compound of formula 3A and 3B.

Brief Description of Drawings:
Fig 1: is IR spectrum of (R)-Tolterodine Tartrate
Fig 2: is NMR spectrum of (R)-Tolterodine Tartrate
Fig 3: is IR spectrum of (S)(+)-BIQOL Phosphoric Acid
Fig 4: is NMR spectrum of (S)(+)-BIQOL Phosphoric Acid
Fig. 5: is IR spectrum of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt
Fig. 6: NMR spectrum of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt
Detailed Description of the Invention:
Reaction of a racemic acid or base with an optically active base or acid gives a pair ofdiastereomeric salts. Members of this pair exhibit different physicochemical properties (e.g. solubility, melting point, boiling point, adsorption, phase distribution) and can be separated owing to these differences. The most widely used method for the separation of enantiomers is the crystallization.

Resolution of racemic Tolterodine using Tartaric acid is known in the literature. In their endeavor to obtain optically pure enantiomer of Tolterodine Tartrate, inventors of the present invention have surprisingly found that resolution of racemic Tolterodine using a novel resolving agent i.e. Chiral BIQOL Phosphoric acid is advantageous in terms of purity and yield in comparison to Tartaric acid.

Hence in the first aspect, the invention provides a process for preparation of optically pure enantiomer of Tolterodine Tartrate using Suitable chiral BIQOL phosphoric acid compound as novel resolving agent wherein the said process comprising of the following steps which is summarized in Scheme 2:
a) Providing a solution of racemic Tolterodine in an alcohol solvent;
b) Adding suitable Chiral BIQOL Phosphoric acid to solution of step (a) at 55-60oC and reaction mixture was allowed to stir for 3 hours;
c) Separating the solid formed by the optically pure enantiomer of Tolterodine and Chiral BIQOL Phosphoric acid;
d) Converting the solid obtained in step (c) to optically pure enantiomer of Tolterodine Tartrate;
e) Optionally, recovering the chiral BIQOL Phosphoric acid from step (d).
Suitable chiral BIQOL phosphoric acid compound include (S)(+)-BIQOL Phosphoric acid.
As used herein “optical pure enantiomer” refers to a single enantiomer having optical purity at least 95%.
By mixing the chiral BIQOL phosphoric acid with racemic Tolterodine in alcohol solvent and gentle warming to about 55-60oC, the chiral BIQOL phosphoric acid forms a salt with enantiomers of Tolterodine. One pair of diastereomeric salt crystallizes out as solid compound, which is separated out.
By these operations, the process achieves the physical separation of the two enantiomers of Tolterodine, one pair of diastereomeric salt crystallizes out and other salt pair remains in the solution.
In a preferred aspect the present invention provides a process for preparation of (R)-Tolterodine Tartrate wherein the said process comprises:
a) Providing a solution of racemic Tolterodine in an alcohol solvent;
b) Adding (S)(+)-BIQOL Phosphoric acid to solution of step (a) at 55-60oC and reaction mixture was allowed to stir for 3 hours.
c) Separating (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt
d) Converting (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt to (R)-Tolterodine Tartrate
e) Optionally, recovering the(S)(+)-BIQOL Phosphoric acid from step (d).
Wherein, in step (a) the alcohol is selected from methanol, ethanol, propanol, and/or mixture thereof, more preferably methanol.

Scheme 2

Wherein, the step (d), conversion of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt to (R)-Tolterodine Tartrate,comprising of,
i. Addition of ammonia solution to (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt in water; n-hexane mixture;
ii. Separation of n-hexane layer from aqueous layer and concentrating under vacuum;
iii. Addition of methanol and L-(+)-Tartaric acid to the residue from step ii to yield enantiomerically pure Tolterodine Tartrate.

Wherein, the step (e), recovery of chiral BIQOL Phosphoric acid, involves addition of dilute hydrochloric acid to the aqueous layer from step ii.
The process for the conversion of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt to (R)-Tolterodine Tartrate and recovery of (S)-BIQOL Phosphoric acid from reaction mixture is summarized in scheme 3

Scheme 3

The present method addresses the drawbacks of the resolution using Tartaric acid. A comparative study on Tolterodine resolution using Tartaric acid and BIQOL phosphoric acid is summarized in Table 1.
Table 1
Parameters L-Tartaric acid Chiral BIQOL phosphoric acid
Moles of reagent required 1.5 1.1
Solvents Ethanol Ethanol, IPA, Methanol
Temperature 65-70oC 55-60oC
‘ee’ in first isolation 60 to 70 % 75-80%
‘ee’ in first purification 90 to 95% =99%
‘ee’ in second purification =99% Not required
Overall yield (optically pure or optically enriched Tolterodine Tartrate from racemic Tolterodine) 0.40 to 0.45 w/w 0.50 to 0.58 w/w

In an another aspect the present invention provides chiral BIQOL Phosphoric acid as a novel resolving agent represented by the compound of formula 2 ((S)(+)-BIQOL Phosphoric acid).

In another aspect, the invention provides a process for preparation (S)(+)-BIQOL Phosphoric acid as illustrated in scheme 4. The aforementioned process comprises reacting (S)(+)-BIQOL with Phosphoryl Chloride in pyridine under nitrogen atmosphere at 0-5oC, to yield (S)(+)-BIQOL Phosphoric Acid. Thus obtained (S)(+)-BIQOL Phosphoric Acid is characterized by Mass, IR, NMR and specific optical rotation.

Scheme 4

Yet in another aspect, the invention provides novel pairs of diastereomeric salts of Tolterodine and BIQOL phosphoric acid as intermediates represented by compound of formula 3A and 3B.

Present invention is further illustrated with the following non-limiting example
Examples
Example 1: Synthesis of (S)(+)-BIQOL Phosphoric acid (Formula 2)
To a stirred solution of 0.5 gm of (S)(+)-BIQOL (0.00173 moles) in 3.81 ml pyridine, 0.584 gm of POCl3 was added slowly under nitrogen atmosphere at 0-5oC. The reaction mass was stirred and monitored by TLC. After completion of the reaction, pyridine was distilled off under vacuum and water (5ml) was added. Aqueous layer was washed with DCM (2.5 ml X 3). pH of the aqueous layer was adjusted to 7 to 7.5 and stirred for 30 min at room temperature. Solid obtained was filtered and dried under vacuum at 40oC.
Dry Weight – 0.32 gm

Characterization data – MS 351.0414 (M+1); IR: 2811.78 cm-1(medium), 1H NMR (MeOD): 7.318 to 7.350 (m) 2H, 7.417 to 7.449 (d) 2H, 8.227 to 8.249 (d) 2H and 8.808 to 8.816 (d) 2H; [a]D: +316.332o at 25oC and c=1.35% in methanol.

Example 2: Resolution of racemic Tolterodine using (S) (+)-BIQOL Phosphoric acid

To a solution of racemic Tolterodine (10 gm, 0.0307 moles) in methanol (50 ml), (S)(+)-BIQOL Phosphoric acid (12.34 gm, 0.0353 moles) was added at 55-60oC. The reaction mixture was stirred for 3 hr. Slurry was cooled to ambient temperature. Precipitated solid was isolated by filtration and washed with methanol (10 ml).
Wet cake was then taken in methanol (100 ml) and heated to reflux temperature. The reaction mixture was stirred for 3 hr and then cooled to 0-5oC. Precipitated solid was filtered and washed with methanol (10 ml). Solid was dried under vacuum at 40oC to yield 7.78 gm of (R)-Tolterodine-(S)(+)-BIQOL Phosphoric acid salt (Formula 3A). Yield: 75%; ee: 99%.

Characterization data – MS 326 (M+1) and 351.0414 (M+1);
IR: 3392 cm-1, 2990 cm-1, 1259cm-1, 1099cm-1
1H NMR (MeOD): 1.17-1.40 (m) 14H, 2.16 (s) 3H, 2.36-2.48 (m) 2H, 2.91-3.03 (m) 2H, 3.59-3.99 (m) 3H, 4.35-4.39 (t) 1H, 6.67-8.84 (m) 18H.

Example 3: Synthesis of (R)-Tolterodine Tartrate

7.78 gm of R-Tolterodine-S-BIQOL Phosphoric acid salt (Formula 3A) was taken in water (40 ml) and n-Hexane (40 ml). Ammonia solution was added to the reaction mixture at 25-30oC till reaction mixture attain pH 10-12. The reaction mixture was stirred and then allowed to settle followed by layer separation. n-Hexane layer was concentrated under vacuum at 40oC to yield residue. The residue was taken in methanol and heated at 55-60oC. L (+)-Tartaric acid was added to reaction mixture and allowed to stir for 60 min. Methanol distillation under vacuum at 45oC yielded 5.46 gm of R-Tolterodine Tartrate as white solid.

Characterization data – MS 326 (M+1); IR: 3573 cm-1, 1596 cm-1; 1H NMR (MeOD): 1.27-1.32 (m) 12H, 2.19 (s) 3H, 2.43-2.57 (m) 2H, 3.01-3.06 (m) 2H, 3.64-3.71 (m) 2H, 4.37-4.41 (m) 2H, 6.69-7.38 (m) 8H.

Example 4: Recovery of (S)(+)-BIQOL Phosphoric acid (Formula 2)
To the water layer from example 3, dilute hydrochloric acid was added to adjust the pH to 6.5-7 and allowed to stir. Solid obtained was isolated by filtration and dried under vacuum to yield 4.83 gm of S(+)-BIQOL Phosphoric acid.