Claims:We claim:
1. (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5).
a.

2. A novel process for preparation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5).
a.

3. Use of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) for synthesis of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6).

4. Use of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) for synthesis of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7).

5. Use of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6) or (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (7) for synthesis of (R)-hydroxy methyl allyl tolterodine (8).

6. Use of (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) for synthesis of (R)-hydroxymethyl tolterodine (1).

7. Use of (R)-allyl tolterodine for synthesis of 5-hydroxymethyl tolterodine and fesoterodine.

8.

9. rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13).

10. A novel process for preparation of rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13).

11. Use of rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) for synthesis of rac-tolterodine (3a).

12. Use of rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) for synthesis for synthesis of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14).

13. Use of rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13)for synthesis of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-
a. phenylpropyl)benzaldehyde (15).
b.

14. Use of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14) or rac- 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15) for synthesis of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (16).

15.

16. Use of rac-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol for synthesis of rac-5-hydroxymethyl tolterodine and rac-fesoterodine.


17.
a. (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5)

b. (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6)

c. (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7)

d. (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8)

e. Methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropanoate (10)

f. 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropan-1-ol (11)

g. 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropyl methanesulfonate

h. 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13)

i. 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14)

j. 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15)

k. (4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (16)

, Description:Field of invention
The present invention relates to novel chiral 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) and racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine () and its use in improved and industrially advantageous process for preparation of chiral and racemic form of 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol also known as 5-hydroxymethyl tolterodine (1) and fesoterodine (2). Further, present invention relates to preparation of the composition containing the same.
Background of invention
Although it is common among older adults, overactive bladder is not a normal part of aging and it negatively affects person’s life. Fesoterodine (2) is one of the widely used drugs for the treatment of overactive bladder with advantage of more flexible dosage than other muscarinic antagonists.
Fesoterodine (2) is designed as a prodrug of 5-hydroxymethyl tolterodine (1).

5-Hydroxymethyl tolterodine (1) is a major active metabolite of tolterodine (3) and chemically, 5-hydroxymethyl fumarate is a 5-hydroxymethyl derivative of tolterodine.

Tolterodine (3) and 5-hydroxymethyl tolterodine (1) are the potent antimuscarinic agents and used as urinary incontinence products for the treatment of overactive bladder. In vitro and in vivo profiles of 5-hydroxymethyl tolterodine are almost identical to tolterodine. 5-Hydroxymethyl tolterodine is responsible for major contribution to the clinical effects.
A prodrug approach is designed to improve systemic bioavailability and to reduce pre-systemic side effects of 5-hydroxy methyl tolterodine. Fesoterodine is selected amongst a series of ester analogues of 5-hydroxymethyl tolterodine because fesoterodine is rapidly de-esterified into its active metabolite, (R)-5-hydroxy methyl tolterodine, a potent and selective muscarinic receptor antagonist.
WO2011145019 & US 20140378699 discloses a process for preparation of fesoterodine and its pharmaceutically acceptable salts.
US 5559269 discloses 3, 3-diphenylpropylamines with method of their preparations, pharmaceutical compositions and method of use.
EP 1496045 discloses process for enantioselective preparation of tolterodine and its active metabolite, 5-hydroxy methyl tolterodine.
WO 2001096279 discloses preparation of 5-hydroxymethyl tolterodine along with other derivative of 3, 3-diarylpropylamines and preparation of pharmaceutical composition for the treatment of incontinence.
WO 2005012227 discloses preparation of 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, an active metabolite of tolterodine.
WO 2007138440 discloses a process for preparation of 5-hydroxymethyl tolterodine.
WO 2007147547 discloses a new process for preparation of 3-(2-hydroxy-5-substituted phenyl)-N, alkyl-3- phenylpropylamines.
There are many processes for preparation of 5-hydroxymethyl tolterodine and fesoterodine in either of the form, chiral form or racemic form.
There is still a need for a short and industrially advantageous method for preparation of 5-hydroxymethyl tolterodine and fesoterodine in both chiral and racemic form. So, present invention provides a novel compound 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine in chiral (5) and racemic form [(compound ()] and its use for synthesis of chiral and racemic form 5-hydroxymethyl tolterodine and fesoterodine, which is further isolated into desired form.

Object of invention
The main object of present invention is to provide a novel compound (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanolin and racemic form of it.
Another object of present invention is to provide the novel and improved process for preparation of both (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)-methanol in chiral (5) and racemic (13) form of it.
Another object of present invention is to provide use of (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol in form and racemic form of it for the synthesis of novel key compounds (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6), (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7), (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8), 5-hydroxymethyl tolterodine (1) and as well as racemic (1a) form of these compounds.
Another object of present invention is to provide novel and improved process for preparation of (R) and racemic 5-hydroxymethyl tolterodine and fesoterodine using (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanolin and racemic form of it.
It is yet another object of present invention is to provide the process for preparation of composition containing suitable form of (R) and racemic 5-hydroxymethyl tolterodine and fesoterodine.

Summary of invention
The object of present invention is to provide a novel (R) and racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine and its use in industrially advantageous process for synthesizing key compounds for further synthesis of (R) and racemic 5-hydroxymethyl tolterodine (1) and fesoterodine (3).
The present invention provides a novel and improved way for synthesis of (R) and racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine.
In one embodiment, present invention provides a process for preparation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5). Method of preparation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) involves conversion of (R)-tolterodine tartarate (4) to (R)-tolterodine (3). Reaction of (R)-tolterodine with allyl bromide leads to formation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5).
In one general aspect, (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) is reacted with copper sulfate and sodium persulfate to produce (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6) and(R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7) depending on reaction conditions. (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6) and (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7 is reduced to (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) using lithium aluminium hydride. Further, (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) is reacted with tetrakis triphenylphosphine palladium (0) to produce (R)-5-hydroxymethyl tolterodine (1) (Scheme-1).

Scheme-1:

In another embodiment, present invention provides process for preparation of 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) and its further use for the preparation of racemic 5-hydroxymethyl tolterodine and fesoterodine.
.
The 6-methly-4-phneyl-chromane-2-one (9) is reacted with allyl bromide under basic condition using potassium carbonate as a base and combination of MeOH/acetone solvent system under refluxing condition to get methyl-3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propionate (10).

The methyl-3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propionate (10) is reduced to 3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propane-1-ol (11) using lithium aluminum hydride. Above synthesized 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propane-1-ol ((11) is reacted with methane sulfonyl chloride and triethylamine base and that produces 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropylmethane sulfonate (12) which is further refluxed with diisopropyl amine that leads to formation of (4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (13).
In one aspect, above synthesized (4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol 913) is reacted with tertakistriphenyl phosphine palladium (0) using sodium borohydride base and methanol solvent which produces 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol (3a) (Scheme-2).

Scheme-2:

In another general aspect, 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) is reacted with copper sulfate and sodium persulfate to produce 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14) and 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15) depending on reaction conditions. Now, 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14) and 4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15) is reduced to (4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (16) using lithium aluminium hydride which upon reaction with tertakistriphenyl phosphine and sodium borohydride gives 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol or racemic 5-hydroxynethyl tolterodine (1a) (Scheme-3).
In another general aspect, rac-5-hydroxymethyl tolterodine is used for the preparation of fesoterodine in racemic form.

Scheme-3:

In one embodiment, present invention relates to the process for preparation of compositions of 5-hydroxymethyl tolterodine and fesoterodine.

Detail description of the invention
Muscarinic receptors are members of G-protein coupled receptors comprising of five receptor sub-types entitled M1, M2, M3, M4, M5 and stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system. These receptors play critical role in maintenance of central and peripheral cholinergic neurotransmission.
It has been established that muscarinic receptors are involved in diseases such as alzheimer’s disease, schizophrenia, Parkinson’s disease, chronic obstructive pulmonary disease, urinary incontinence, irritable bowel syndrome, glaucoma, cerebrovascular insufficiency, rhinitis and chronic cystitis.
Acetylcholine induced stimulation of bladder muscarinic receptor leads to involuntary contraction of detrusor muscle during the filling phase of micturition cycle and these involuntary contractions known as detrusor over activity. 83% of patients with detrusor over activity have symptoms suggestive of overactive bladder.
Overactive bladder is a problem with bladder-storage function that causes a sudden urge to urinate. The urge may be difficult to stop, and overactive bladder may lead to the involuntary loss of urine (incontinence).
Muscarinic receptor antagonists are used for the treatment of overactive bladder. Oxybutynin is widely used for treatment of urge incontinence and other symptoms related to bladder activity. The use of oxybutynin is limited because of antimuscarinic side effects.
A novel tertiary amine series of compounds have proved potent muscarinic (M2)/(M3) receptor antagonistic activity.
The compounds of present invention relates to the class of organic compounds known as diphenylpropylamines. Tolterodine is one of the members of the class of the diphenylpropylamines with a potent and competitive muscarinic receptor antagonistic activity used for urinary incontinence and overactive bladder.
A major metabolite of tolterodine, 5-hydroxymentyl tolterodine is also a potent muscarinic receptor antagonist. 5-hydroxymethyl tolterodine is having same potency as that of tolterodine and gives a major contribution to the clinical effects.
However, because of the additional hydroxy group in tolterodine and its metabolite, 5-hydroxymethyl tolterodine leads to increase hydrophilic property of these compounds and cause pre-systemic side effects. To overcome this disadvantage, prodrug of a metabolite, 5-hydroxymethyl tolterodine is synthesized as fesoterodine.
A series of ester analogues of 5-hydroxymethyl tolterodine has been synthesized and fesoterodine is selected amongst all of those ester analogues of 5-hydroxymethyl tolterodine because fesoterodine is rapidly de-esterified into its active metabolite, (R)-5-hydroxy methyl tolterodine, a potent and selective muscarinic receptor antagonist.
It is an object of present invention is to provide novel compound, (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine in both (R) form and rac form and its use in industrially applicable process for preparation of (R) and rac-5-hydroxymethyl tolterodine and fesoterodine.
According to present invention novel compounds (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5), (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6), (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7) and (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) used in process for preparation of (R)-5-hydroxymethyl tolterodine (1) are represented by following formula:

Also, according to the present invention novel racemic compounds methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propanoate (10), 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropan-1-ol (11), 3-(2-(allyloxy) methylphenyl)-3-phenylpropyl methanesulfonate (12) and 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) used in process for preparation of 5-hydroxymethyl tolterodine (1a) are represented by following formula:

In aspects of present invention, (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) is synthesized from (R)-tolterodine tartarate, while 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) is synthesized from 6-methly-4-phneyl-chromane-2-one (9).
Experimental procedures
1a) (R)-5-hydroxy tolterodine and fesoterodine
1. A process for preparation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5):

a) (R)-tolterodine tartarate (4) is converted into (R)-tolterodine (3) by extracting tolterodine tartarate with sodium bicarbonate and ethyl acetate mixture.
b) (R)-tolterodine (3) is reacted with allyl bromide using solvent system of potassium carbonate and acetone.
c) Reaction mixture is refluxed for 6-8 hours.
d) Synthesized (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) is isolated.

2. Process for preparation of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6):

a) above synthesized (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) is oxidized with copper sulfate and sodium persulfate in a acetonitrile/water solvent system at 78-80 º C and that leads to formation of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6).

3. Process for preparation of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-
phenylpropyl)benzaldehyde (7):

a) Above synthesized (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-
diisopropyl-3-phenylpropan-1-amine (5) is oxidized with copper sulfate and sodium persulfate in a acetonitrile/water/DMSO solvent system at 78-80 ºC and that leads to formation of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-
phenylpropyl)benzaldehyde (7).

4. Process for preparation of (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8):

a) (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) is synthesized from reduction of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6) or ((R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (7) using lithium aluminum hydride.

5. Process for preparation of (R)-hydroxymethyl tolterodine (1):

a) (R)-3-(2-(Allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (8) is reacted with tertakistriphenyl phosphine palladium and sodium borohydride in presence of methanol at room temperature and leads to formation of (R)-5-hydroxy methyl tolterodine.

The use of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) for the preparation of (R)-5-hydroxymethyl tolterodine (1) and (R)-fesoterodine (2) is schematically shown in scheme-1:

1b) rac-5-hydroxy tolterodine (1a) and fesoterodine (2a):
1. Process for preparation of 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13):

a) 6-methly-4-phneyl-chromane-2-one (9) is reacted with allyl bromide that leads to formation of methyl-3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propionate (10).
b) Methyl-3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propionate (10) is reduced to 3-(2-(allyloxy)-5-methyl phenyl)-3-phenyl propane-1-ol (11) using lithium aluminum hydride.
c) 3-(2-(Allyloxy)-5-methylphenyl)-3-phenyl propane-1-ol (11) is reacted with methane sulfonyl chloride and triethylamine base and that leads to formation of 3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropylmethane sulfonate (12).
d) 3-(2-(Allyloxy)-5-methylphenyl)-3-phenylpropylmethane sulfonate (12) is refluxed with diisopropyl amine and leads to formation of 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13).
e) The use of racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) for the preparation of racemic tolterodine (3a) and rac-fesoterodine (2a) is schematically shown in a scheme-2:

2. Process for preparation of rac-tolterodine:

a) rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) is reacted with tertakistriphenyl phosphine palladium (0) using sodium borohydride base and methanol solvent which produces rac-tolterodine (3a).

3. Process for preparation of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14):

a) Above synthesized rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) is oxidized with copper sulfate and sodium persulfate in a acetonitrile/water solvent system at 78-80 ºC and that leads to formation of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14).

4. Process for preparation of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15):

a) Above synthesized rac-3-(2-ethoxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (13) is oxidized with copper sulfate and sodium persulfate in a acetonitrile/water/DMSO solvent system at 78-80 º C and that leads to formation of rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15).

5. Process for preparation of rac-5-hydroxymethyl allyl tolterodine (16):

a) rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (14) or rac-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde (15) is reduced to rac-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol using lithium aluminium hydride (16).

6. Process for preparation of rac-5-hydroxy methyl tolterodine:

a) Reaction of rac-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)- phenyl)methanol (16) with tertakistriphenyl phosphine palladium (0) and sodium borohydride in presence of methanol at room temperature produces rac-5-hydroxymethyl tolterodine (1a).

The use of rac-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)-phenyl)methanol for the preparation of rac-5-hydroxymethyl tolterodine and rac-fesoterodine is schematically shown in a scheme-3:

Above synthesized all racemic compounds can be isolated into (R) form or (S) form. (R) form as well as rac form of tolterodine, (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine, (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid, (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzaldehyde and (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol are isolated into crystalline form. 5-Hydroxymethyl tolterodine and fesoterodine synthesized from (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine are further isolated into crystalline form.
One embodiment of present invention involves use of synthesized 5-hydroxymethyl tolterodine or fesoterodine for preparation of composition containing the same.

Experimental procedure:
Example-1: Preparation of (R)-tolterodine free base (3):
Suspended tolterodine tartrate (1) (10 g) in EtOAc (100 mL) and added saturated solution of sodium bicarbonate (100 mL). Separated the organic layer and washed it with water (100 mL) and distil out solvent under vacuum to get an oily (R)-tolterodine free base (3) (6.9 g).
Example-2: Preparation of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) :
Dissolved (R)-tolterodine free base (5.2 g) in DMSO (35 mL) and added allyl bromide (2.3 g) and KOH (1.8 g) and stir the mixture at 25-30 0C for 3-4 h. After completion of reaction, EtOAc (200 mL) and water (150 mL) were added at once and separated organic layer was washed with water (150 mL) and distil out solvent under vacuum to get (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5.3 g) as a syrupy compound which gets solidified after refrigeration.
Example-3: Preparation of (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (6):
To the solution of (R)-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5.1 g) in acetonitrile (50 mL), added water (50 mL), DMSO (10 mL), copper sulfate (3.8 g) and sodium persulfate (6.6 g) at once and reflux the reaction mixture under stirring for 4-5 h. After completion of reaction, cool the reaction mixture to 25-30 0C and extracted the compound in EtOAc (3 x 50 mL). Combine organic layer and distilled out solvent under vacuum to get crude (R)-4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid (9.2 g) which has been used in the next reaction without further purification.
Example-4: Preparation of (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (8) :

To the suspended mixture of LAH (1.4 g) in THF (130 mL) was added solution of (R)-methanoic acid allyl tolterodine (9.2 g) in THF (30 mL) within 30 minutes while keeping the exotherm below 30-35 0C. Continued the reaction under stirring at 25-30 0C for 1 h. After completion of reaction cool the reaction mixture to 0-5 0C and added saturated solution of sodium sulfate to quench the reaction. Filter off the residue after washing with EtOAc (100 mL). Combined filtrate was washed with water (100 mL) and distil out solvent from the separated organic layer under vacuum to get title compound (4.8 g).
Example-5: Preparation of (R)- 5-Hydroxymethyl tolterodine (1):
Suspended tetrakis(triphenylphosphine) palladium(0) (0.045 g) in the solution of (R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol (4.8 g) in methanol (50 mL). Added sodium borohydride (1.0 g) portion wise over 1 h under stirring at 25-30 0C and kept the reaction mixture under stirring at the same temperature for 1 h. After completion of reaction, filtered the reaction mixture through silica gel and filtrate is concentrated under reduced pressure. The residue is dissolved in EtOAc (50 mL) and washed with water (2 x 30 mL). The organic layer was concentrated under reduced pressure to get crude (R)- 5-hydroxymethyl tolterodine (3.3 g).
Example-6: Preparation of (R)-5-Hydroxymethyl tolterodine fumarate salt (17):

Added a solution of fumaric acid (1.13 g) in acetone (100 mL) to a solution of 5-hydroxymethyl tolterodine (3.3 g) in acetone (100 mL) at 25-30 0C. Stirred the mixture at the same temperature for 1 h. Filtered the precipitated compound, washed with cold acetone (mL) and dried under reduced pressure at 45-50 0C to get 5-hydroxymethyl tolterodine fumarate salt (2.4 g).
Example-7: Preparation of rac-methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propanoate (10):

Into the suspension of rac-6-methyl-4-phenyl chroman-2-one (10 g) in MeOH (30 mL) and acetone (30 mL) was added potassium carbonate (9.4 g) and allyl bromide (7.6 g) at once. Refluxed the reaction mixture under stirring for 5-6 h. After completion of reaction cool the reaction mixture to room temperature and filtered off residual material. Filtrate was concentrated under reduced pressure and added EtOAc (150 mL) and water (100 mL). The separated organic layer was dried over sodium sulfate and solvent was distilled out under reduced pressure to get rac-methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propanoate (11.2 g).
Example-8: Preparation of rac-3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropan-1-ol (11):

Reduction is carried out with the same procedure as that of example-4 instead of using rac-methyl 3-(2-(allyloxy)-5-methylphenyl)-3-phenyl propanoate (11.0 g) to get rac-3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropan-1-ol (9.3 g).

Example-9: Preparation of rac-3-(2-(allyloxy) methylphenyl)-3-phenylpropyl methanesulfonate (12):

Added triethylamine (4.9 g) into the solution of rac-3-(2-(allyloxy)-5-methylphenyl)-3-phenylpropan-1-ol (9.2 g) in DCM (50 mL) and cool the solution to 0-5 0C. To the cold solution was added dropwise methane sulfonyl chloride (4.4 g) over a period of 0.5 h and stirred the reaction mixture at the same temperature for 1-2 h. After completion of reaction, added 10% HCl (30 mL) and separated organic layer washed with water (30 mL). Organic layer was dried over sodium sulfate and distilled out solvent under reduced pressure to get rac-3-(2-(allyloxy) methylphenyl)-3-phenylpropyl methanesulfonate (9.3 g).
Example-10: Preparation of rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3- phenyl-propan-1-amine (rac-tolterodine) (13):

Added potassium iodide (10.3 g) and diisopropylamine (25.2 g) into the solution of rac-3-(2-(allyloxy) methylphenyl)-3-phenylpropyl methanesulfonate (9.0 g) in DMF (55 mL). Heat the reaction mixture under stirring at 100-105 0C for 24-28 h. After completion of reaction, cooled the reaction mixture to room temperature and reaction mixture was added over water (200 mL). Extracted the compound with EtOAc (2 x 200 mL) and wash the combine organic layer with water (300 mL). Dried the organic layer over sodium sulfate and distilled out solvent under reduced pressure to get rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-
diisopropyl-3-phenylpropan-1-amine (7.5 g).
Example-11: Preparation of rac-5-hydroxynethyl tolterodine (3a):

Reaction is carried out as same procedure as that of example 5, while using rac-3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine to get rac-5-hydroxynethyl tolterodine.