FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
TITLE: An improved process for preparation of O-desmethylvenlafaxine
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor, Chinubhai Centre. Ashram Road, Ahmedabad 380009 Gujarat. India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of O-des methyl venlafaxine.
BACKGROUND OF THE INVENTION
O-desmethylvenlafaxine chemically named l-[2-(dimethylamino)-l-(4-
phenol)ethyl]-cyclohexanol was exemplified as a fumarate salt in U.S. Pat. No. 4,535,186 has the following formula (I).

Klamerus, K.J. et al. (J. Clin. Pharmacol. 32:716-724), mentions that O-Desmethylvenlafaxine is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake.
U.S. Patent No. 6,689,912 describes a process for preparation of O-desmethylvenlafaxine, where venlafaxine is treated with a high molecular weight alkane or arene thiolate anion in an alcohol, ethylene glycol, ether of ethylene glycol or mixture.
U.S. Patent No. 7,026,508 describes a process for preparation of O-desmethylvenlafaxine, which involves demethylating venlafaxine or a salt thereof with an alkali metal salt of a trialkylborohydride.

PCT Patent Publication No. WO 00/59851 describes a process for preparation of O-desmethyl venlafaxine, which involves contacting venlafaxine with lithium diphenylphosphide for a time and at a temperature sufficient to form O-desmethylvenlafaxine.
PCT Patent Publication No. WO 2007/071404 describes a process for preparation of O-desmethylvenlafaxine, which comprises combining metal sulfide, venlafaxine, and optionally selenium in a solvent and heating it sufficiently to obtain O-desmethylvenlafaxine.
PCT Patent Publication No. WO 2007/120923 describes aprocess for preparation of O-desmethylvenlafaxine, which comprises combining venlafaxine, an organic solvent and a reagent selected from the group consisting of thiophenol, sodium sulfide and a C1-C8 alkyl thiolate, heating the mixture and recovering O-desmethyl venlafaxine.
The above processes involve use of hazardous, toxic, costly and highly difflcult-to-use reagents, which are not desirable on production scale. Also the yield and purity appear to be relatively low.
There is a need for cost effective, non hazardous and efficient process for preparing O-desmethylvenlafaxine, particularly those suitable for use on industrial scale.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel and industrially feasible process for the preparation of O-desmethylvenlafaxine.

Another object of the present invention is to provide cost effective, non hazardous and efficient process for preparing O-desmethyl venlafaxine.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for the preparation of O-desmethylvenlafaxine from Venlafaxine or its pharmaceutically acceptable salt, by using mercapto carboxylic acids in the presence of suitable solvents under alkaline conditions.
DETAILED DESCRIPTION
The present process for preparation of O-desmethylvenlafaxine of formula- CD involves demethylation of venlafaxine (II) or it's salt in presence of mercapto carboxylic acid and can be depicted by following scheme:

The mercapto carboxylic acids used as demethylating agent in present process can be selected from thioglycollic acid, 3-mercaptopropionic acid, thiomaleic acid, 4-mercapto benzoic acid, 4-mercapto phenylacetic acid or cysteine.
The salt of venlafaxine used in present invention can be any salt, preferably, hydrochloride salt.

The above reaction is carried out in presence of suitable solvent and base. The solvent can be any organic solvent but preferably are selected from polar solvents such as dimethyl formamide, dimethyl acetamide or N-methyl pyrrolidone or mixture thereof. Preferably strong base such as sodium hydroxide or potassium hydroxide is used in present process.
The O-demethylation of present invention is carried out at high temperature; the reaction temperature may range from 100°C to the reflux temperature of the solvent. However, the preferred temperature ranges from 120° to 165°C. The duration of reaction may vary form 10-25 hrs, more specifically 15-24 hrs, The reaction can be monitored by HPLC.
The O-desmethyl venlafaxine free base of formula (II) can be isolated from reaction mixture by following process:
i. adjusting the pH of reaction mixture to about 8-10; ii. isolating desmethylvenlafaxine free base.
For isolation of O-desmethylvenlafaxine the pH of highly alkaline reaction mixture is adjusted towards lower range i.e. lower than 13. The product can be isolated at pH in range of 8-10, preferably product is isolated at pH 9.5.
Alternatively O-desmethylvenlafaxine can be isolated from the reaction mixture by a process comprising steps of:
i. adjusting the pH of reaction mixture to about 5.0;
ii. increasing the pH to about 8-10;
iii. isolating desmethylvenlafaxine free base.

Any organic or inorganic acid can be used for pH adjustment, preferably hydrochloric acid is used.
The demethylating reagents used in present invention are safe to handle on large scale. Major advantage is the high boiling range of present reagents, which enables to" carryout reaction at high temperature without loss of the reagents. This reduction in loss of demethylating reagents eventually leads to better yield.
Further advantage is presence of carboxylic group in demethylating agents which facilitate its removal in the basic condition after completion of reaction this simplifies the work up and also allows an odorless workup.
As a result we are able to obtain O-desmethylvenlafaxine having HPLC purity of about 99.5% and any single impurity is not more than 0.1%. If desired the product can be further recrystallised / purified by any organic solvent. The solvent used in the present process is methanol.
The O-desmethylvenlafaxine thus obtained can be converted to its pharmaceutically acceptable salts by methods known in the art.
Venlafaxine or its salts employed in present invention can be prepared by process disclosed in US 4,535,186.
EXAMPLES
The process of the present invention is in the following illustrated by examples that should not be construed to limit the scope of the invention in any manner:

Example 1: Preparation of O-desmethylvenlafaxine free base by using Thioglycollic acid
A 1.0 litre, 4 neck flask equipped with thermometer and mechanical stirrer was charged with 50 g of Venlafaxine hydrochloride and 250 ml N-methyl pyrrolidone. Then, 45.93 g NaOH was added to it. 55.09 g thioglycolic acid (80 %) was added within 40-45 minutes. The temprature of reaction was raised 155-160 °C and it was stirred at the same for 15-20 hours. After completion of reaction the pH was adjusted to 9.5-10 with conc. HC1. The solid thus separated was filtered purified by methanol and then dried to obtain 30 g of title compound. HPLC purity-99.5%
Example 2: Preparation of O-desmethylvenlafaxine free base by using L-Cysteine
A 1.0 litre, 4 neck flask equipped with thermometer and mechanical stirrer was charged with 50 g of Venlafaxine hydrochloride and 250 ml N-methyl pyrrolidone. Then, 45.93 g NaOH was added in it. 57.9 g L-Cysteine was added within 40-45 minutes. The temperature of reaction was raised to 155-160 °C and reaction mixture was stirred at the same for 15-20 hours. After completion of reaction the pH of reaction mixture was adjusted to 9-9.5 with conc. HCI. The product thus separated was filtered and then purified with methanol. The wet product was dried to obtain 28 g of title compound.
HPLC purity-99.6%

Example 3: Preparation of O-desmethylvenlafaxine free base by using Thioglycollic acid
A 5.0 litre, 4 neck flask equipped with thermometer and mechanical stirrer was charged with the 500 g of Venlafaxine hydrochloride and 2.5 litre N-methyl pyrrolidone. Then, 458.8 g NaOH was added to it. 550.3 g thioglycollic acid (80 %) was added within 40-45 minutes. Reaction was heated at 160-165°C for 20-24 hours. The reaction was monitored by HPLC. The reaction was quenched with water and pH was adjusted to 5.5 to 6.0 with acetic acid to get clear solution. Activated charcoal was added! stirred for 30 minutes and filtered through celite bed. The pH of filtrate was adjusted 9.5-10 with aqueous NaOH solution. Separated solid was. filtered and then purified by methanol. The wet product was filtered to obtain 302 g of title compound.
HPLC purity - 99.5 %

We claim:

comprising O-demethylation of venlafaxine (II)

1. A process for preparation of O-desmethylvenlafaxine of formula (I)
or its salt in presence of mercapto carboxyiic acid.
2. The process according to claim 1, wherein the mercapto carboxyiic acid is selected from the group comprising thioglycollic acid, 3~mercaptopropionic acid, thiomaleic acid, 4-mercapto benzoic acid, 4-mercapto phenylacetic acid and cysteine.
3. The process as claimed in claim 1, wherein O-demethylation of venlafaxine (II) or its salt comprises:
a. reacting venlafaxine (II) or its salt and mercapto carboxyiic acid, in the
presence of a organic solvent and a base;
b. isolating O-desmethylvenlafaxine (I) from reaction mixture.

4. The process as claimed in claim 3, wherein the solvent selected from dimethyl formamide, N-methyl pyrrolidone, N,N-dimethyl acetamide or mixture thereof.
5. The process according to claim 3, wherein the base is selected from sodium hydroxide or potassium hydroxide.
6. The process according to claim 3, wherein the isolation of O-desmethylvenlafaxine from reaction mixture comprises:
a. adjusting the pH of reaction mixture to about 8-9.5;
b. isolating O-desmethyl venlafaxine; and
c. optionally purifying O-desmethylvenlafaxine.
7. The process according to claim 3 wherein isolation of O-desmethylvenlafaxine
comprises
a. adjusting the pH of reaction mixture to about 5;
b. adding base to adjust pH about 8-10
c. isolating O-desmethyl venlafaxine; and
d. optionally purifying O-desmethylvenlafaxine.
8. The processes claimed in claim 7, wherein pH of reaction mixture is adjusted by using an acid selected from acetic acid and hydrochloric acid.
9. The process according to claim 8, wherein pH in step (b) is adjusted by using sodium hydroxide

10. The novel process for the preparation of O-desmethylvenlafaxine as herein described with foregoing description and examples.