U.S. patent application number 10/485585 was filed with the patent office on 2004-12-09 for process for the preparation of tolterodine.
Invention is credited to Kumar, Yatendra, Misra, Satyananda, Neela, Praveen Kumar, Prasad, Mohan.
Application Number | 20040249211 10/485585 |
Document ID | / |
Family ID | 11097097 |
Filed Date | 2004-12-09 |
United States Patent
Application |
20040249211 |
Kind Code |
A1 |
Kumar, Yatendra ; et
al. |
December 9, 2004 |
PROCESS FOR THE PREPARATION OF TOLTERODINE
Abstract
The present invention relates to a cost effective and
industrially advantageous process for the preparation of
tolterodine and pharmaceutically acceptable salts thereof.
Inventors: |
Kumar, Yatendra; (Gurgaon
Haryana, IN) ; Prasad, Mohan; (Gurgaon Haryana,
IN) ; Neela, Praveen Kumar; (Andhra Pradesh, IN)
; Misra, Satyananda; (Guragaon Haryana, IN) |
Correspondence
Address: |
RANBAXY INC.
600 COLLEGE ROAD EAST
SUITE 2100
PRINCETON
NJ
08540
US
|
Family ID: |
11097097 |
Appl. No.: |
10/485585 |
Filed: |
May 18, 2004 |
PCT Filed: |
August 2, 2002 |
PCT NO: |
PCT/IB02/03012 |
Current U.S.
Class: |
564/397 |
Current CPC
Class: |
C07C 217/62 20130101;
C07C 213/02 20130101; C07C 213/02 20130101 |
Class at
Publication: |
564/397 |
International
Class: |
C07C 29/24 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2001 |
IN |
829/DEL/2001 |
Claims
We claim:
1. A process for the preparation of tolterodine of structural
Formula I, and pharmaceutically acceptable salts thereof,
16comprising: (a) reacting
3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of structural
Formula II 17with dimethyl sulphate in the presence of sodium
hydroxide, and a phase transfer catalyst to obtain
methyl-3-(2-methoxy-5-methylpheny- l)-3-phenyl propionate of
Formula III, 18(b) reducing the ester of Formula III with a
reducing agent in the presence of a Lewis acid to obtain
3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of Formula IV, 19(c)
protecting the hydroxy group of the alcohol of Formula IV to give a
compound of Formula V, 20(d) aminating with diisopropylamine to
give
N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine of
Formula VI, and 21(e) removing the hydroxy protecting group to
obtain
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine of
Formula I.
2. The process according to claim 1 wherein the phase transfer
catalyst used at step a) is selected from the group consisting of
tetrabutylammonium bromide, tetrabutylammonium chloride and
tetrabutylammonium hydrogen sulphate.
3. The process according to claim 2 wherein the phase transfer
catalyst is tetrabutylammonium bromide.
4. The process according to claim 1, wherein the Lewis acid of step
b) is selected from the group consisting of boron trifluoride,
aluminium chloride, ferric chloride, and zinc bromide.
5. The process according to claim 4 wherein the Lewis acid is
aluminium chloride.
6. The process according to claim 1 wherein the reducing agent used
at step b) is sodium borohydride in combination with aluminium
chloride.
7. The process according to claim 1, wherein during step b) the
ester is reduced in the presence of an organic solvent.
8. The process according to claim 7 wherein the organic solvent is
selected from the group consisting of acetone, dioxane,
acetonitrile, chloroform, benzene, methylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine,
monoglyme, diglyme, and mixture(s) thereof.
9. The process according to claim 8 wherein the organic solvent is
monoglyme.
10. The process according to claim 1 wherein the protecting group
used in step c) is p-toluene sulphonyl chloride.
11. The process according to claim 1 wherein the hydroxy protective
group in step e) is removed by aqueous hydrobromic acid in acetic
acid.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a cost effective and
industrially advantageous process for the preparation of
tolterodine, and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
[0002] Tolterodine is a muscarinic receptor antagonist which has
recently been launched for the treatment of urinary urge
incontinence and other symptoms of bladder overactivity.
Chemically, tolterodine is
(+)-(R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenyl
propylamine having structural formula I and was first disclosed in
U.S. Pat. No. 5,382,600. 1
[0003] A process for preparing tolterodine is described in U.S.
Pat. No. 5,382,600. The process involves the reaction of
3,4-dihydro-6-methyl-4-ph- enyl-2H-benzopyran-2-one of structural
Formula II 2
[0004] with methyl iodide and potassium carbonate in refluxing
acetone/methanol to give
methyl-3-(2-methoxy-5-methylphenyl)3-phenyl propionate of Formula
III. 3
[0005] The ester of Formula III is reduced with lithium aluminium
hydride in ether to the corresponding propanol of Formula IV 4
[0006] which is reacted with tosyl chloride and pyridine to yield
the tosylate of Formula V 5
[0007] which on condensation with diisopropylamine in hot
acetonitrile is converted into the tertiary amine of Formula VI.
6
[0008] The compound of Formula VI is treated with boron tribromide
in dichloromethane to give the amine of Formula I as a racemic
mixture, which is resolved with L-(+) tartaric acid. Long reaction
time and low overall yields makes this process very expensive and
less productive. Furthermore, the use of expensive and hazardous
reagents like methyl iodide, lithium aluminum hydride, and boron
tribromide also renders this process unsuitable and hazardous on a
commercial scale.
[0009] U.S. Pat. No. 5,922,914 provides an alternate method for the
preparation of tolterodine. The process involves the cyclization of
trans-cinnamic acid of Formula VIII 7
[0010] with p-cresol of Formula IX 8
[0011] in hot sulfuric acid to give
3,4-dihydro-6-methyl-4-phenyl-2H-benzo- pyran-2-one of Formula II
which is reduced with diisobutyl aluminium hydride (DIBAL) in
toluene to yield 6-methyl-4-phenyl-3,4-dihydro-2H-1-be-
nzopyran-2-ol of Formula X 9
[0012] The reductocondensation of compound of Formula X with
diisopropylamine by means of hydrogen over palladium on charcoal in
methanol affords racemic tolterodine of Formula I which is resolved
with L-tartaric acid. This process is also not commercially
feasible since it makes use of an expensive and hazardous reagent
DIBAL. Although the number of steps are reduced but the cost
incurred to produce tolterodine is high.
[0013] It is, therefore, desirable to solve the problems associated
with the prior art and to provide an efficient process for the
preparation of tolterodine which process improves the economics by
employing less expensive and less hazardous raw materials and is
more productive. The process is convenient to operate on a
commercial scale and gives the desired product in good yield and
quality.
SUMMARY OF THE INVENTION
[0014] The present invention provides a process for the preparation
of tolterodine of structural Formula I, and pharmaceutically
acceptable salts thereof, 10
[0015] comprising:
[0016] (a) reacting
3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of structural
Formula II 11
[0017] with dimetiyl sulphate in the presence of sodium hydroxide,
and a phase transfer catalyst to obtain
methyl-3-(2-methoxy-5-methylphenyl)-3-p- henyl propionate of
Formula III, 12
[0018] (b) reducing the ester of Formula III with a reducing agent
in the presence of a Lewis acid to obtain
3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of Formula IV,
13
[0019] (c) protecting the hydroxy group of the alochol of Formula
IV to give a compound of Formula V, 14
[0020] (d) aminating with diisopropylamine to give
N,N-diisopropylamine-3--
(2-methoxy-5-methylphenyl)-3-phenylpropylamine of Formula VI,
15
[0021] (e) removing the hydroxy protecting group to obtain
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine of
formula I, and
[0022] (f) if desired, converting the compound of formula I into
its pharmaceutically acceptable salts.
[0023] The starting material,
3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-- 2-one of Formula II
is prepared by methods known in the literature (Example 1 of U.S.
Pat. No. 5,922,914).
[0024] The reaction at step a) is performed in the presence of a
phase transfer catalyst to yield the compound of Formula III. The
phase transfer catalyst used is selected from the group consisting
of tetrabutylammonium bromide, tetrabutylammonium chloride, and
tetrabutylammonium hydrogen sulphate.
[0025] The reducing agent used at step b) is a metal hydride such
as sodium borohydride in the presence of a Lewis acid. The Lewis
acid used is selected from the group consisting of boron
trifluoride, aluminium chloride, ferric chloride and zinc bromide.
The solution of the ester of Formula III in an organic solvent is
treated with sodium borohydride in combination with aluminium
chloride at about 25-30.degree. C. for about 2-3 hours. After a
suitable work up 3,3-diphenylpropanol of Formula IV is obtained.
The organic solvent is selected from inert solvents such as
acetone, dioxane, acetonitrile, chloroform, benzene, methylene
chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
pyridine, monoglyme, diglyme, and mixtures thereof.
[0026] The protecting group used in step c) is an arylsulfonyloxy
group such as p-toluene sulphonyl chloride. The reaction of step c)
is performed in methylene chloride at about 10-25.degree. C. for
4-5 hours in the presence of triethylamine. After a suitable work
up, the protected intermediate compound of Formula V is
obtained.
[0027] The amination of compound of Formula V at step d) is carried
out with diisopropylamine in an autoclave to give a compound of
Formula VI. The removal of hydroxy protective groups can be
achieved by treatment with hydrobromic acid, boron tribromide or by
catalytic hydrogenation. It is preferably carried out with aqueous
hydrobromic acid in acetic acid. The reaction of step e) is
performed at about 70-115.degree. C. to afford tolterodine
hydrobromide.
[0028] Tolterodine is an amine and forms acid addition salts both
with organic and inorganic acids. Examples of such salts include
hydrochloride, hydrobromide, sulfate, methane sulfonate, phosphate,
nitrate, benzoate, citrate, tartarate, fumarate and meleate.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In the following section one preferred embodiment is
described by way of example to illustrate the process of this
invention. However, it is not intended in any way to limit the
scope of the present invention.
EXAMPLE
Step a)--Preparation of
methyl-3-(2-methoxy-5-methylphenyl)-3-phenyl propionate (III)
[0030] 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (250 g,
1.05 mol) of Formula II in aqueous sodium hydroxide solution (134.3
g in 1 L water) was heated to 70-80.degree. C. The solution was
cooled to 25-30.degree. C. and methylene chloride and
tetrabutylammonium bromide (TBAB) was added. It was followed by the
slow addition of dimethyl sulfate and the reaction mixture was
further stirred for 2-4 hours. The organic layer was separated,
dried and evaporated to give the titled compound as viscous oil
(301 g); Purity (by HPLC) >99%.
Step b): Preparation of
3-(2-methoxy-5-methylphenyl)-3-phenylpropanol (IV)
[0031] The ester of formula III (295 g, 1.04 mol) was dissolved in
500 ml monoglyme and sodium borohydride (45.4 g, 1.19 mol) was
added at room temperature. The mixture was cooled to 0.degree. C.
and anhydrous aluminium chloride was added slowly. The reaction
mixture was stirred for 2-3 hours at 25-30.degree. C. and then
decomposed by the addition of dilute hydrochloric acid. Monoglyme
was distilled under reduced pressure and the reaction mixture was
filtered to remove the salts. The aqueous layer was extracted with
methylene chloride and evaporated under reduced pressure to give
the titled product as an oil (265 g); Purity ( by HPLC)
>99%.
Step c)--Preparation of
3-(2-methoxy-5-methylphenyl)-3-phenylpropyl-p-tolu- ene sulphonate
(V)
[0032] The propanol of Formula IV (260 g, 1.02 mol) was dissolved
in methylene chloride. The solution was cooled to 0.degree. C. and
triethylamine (158.3 g, 1.56 mol) and p-toluene sulfonyl chloride
(228, 1.19 mol) was added at 0.degree. C. all at once. The reaction
mixture was stirred for 4-5 hours at 10-20.degree. C. It was cooled
to 0.degree. C. and water and concentrated hydrochloric acid were
added. The organic layer was separated and washed with water. The
solvent was removed under reduced pressure and diisopropyl ether
was added. It was cooled to 0.degree. C. and stirred for 3-4 hours.
The product so separated was filtered, washed with diisopropyl
ether and dried under reduced pressure to give the titled product
(358 g) in 86% yield; Purity (by HPLC) >98.78%.
Step d)--Preparation of
N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phe- nylpropyl amine
(VI)
[0033] The tosylate of Formula V (355 g, 0.865 mol) was heated with
acetonitrile and diisopropyl amine (1:1) at 80.degree. C. in a
pressure bottle (autoclave) for 50-55 hours. The solvent was
removed under vacuum and the residue was basified with sodium
hydroxide and extracted with methylene chloride. The extract was
washed with water, the solvent was removed under vacuum and the
residue was dissolved in dilute hydrochloric acid. The solution was
washed with diisopropyl ether, basified and extracted with
methylene chloride. The extract was washed with water, dried and
evaporated to give the titled product as an oil (228.65 g).
Step e)--Preparation of
N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phe- nylpropyl amine
hydrobromide (tolterodine hydrobromide) (I)
[0034] The amine of Formula VI (225 g, 0.663 mol) was heated with
aqueous hydrobromic acid (500 ml) and acetic acid (300 ml) to
reflux temperature (110-115.degree. C.) for 10-12 hours. The
reaction mixture was cooled to room temperature, maintained for 1
hour at room temperature and then filtered. The product so obtained
was washed with water and dried under vacuum to yield the titled
product. (234 g) in 86% yield; Purity (by BPLC) 97.5%.
[0035] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
* * * * *