FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
A PROCESS FOR THE PREPARATION OF (-)-TRANS-4-(4-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]PIPERIDINE
SUN PHARMACEUTICAL INDUSTRIES LIMITED

A company incorporated under the laws of India having their office at ACME
PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

A PROCESS FOR THE PREPARATION OF (-)-TRANS-4-(p-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL]PIPERIDINE
The present invention relates to a process for the preparation of a process for the
preparation of (-)-trans-4-(4-fluorophenyl)-3-[[3,4-
(methylenedioxy)phenoxy]methyl]piperidine, compound of formula I, and its pharmaceutically acceptable salts. Compound of formula 1, commonly known as paroxetine, is used in the treatment of depression, obsessive compulsive disorder (OCD) and panic.
F
X JCX>
N l
H
formula I BACKGROUND OF THE INVENTION
formula II
2
United States Patent No. 4007196 discloses hydrolysis of compound of formula II, wherein R is phenyl, with solid potassium hydroxide in methylcellosolve (2-methoxyethanol). The use of 2-methoxyethanol produces undesired transesterified carbamate impurity which is difficult to hydrolyze and remove from the reaction mixture.


United States Patent No. 4721723 (assigned to GlaxoSmithKline) prepares compound of formula I by basic hydrolysis of compound of formula II in large volumes of toluene. This process is not commercially viable as this method results in formation of an
insoluble complex mass resulting in incomplete conversion, besides requiring large volumes of solvent (>14 volumes with respect to carbamate).
European Patent No. 810225 (assigned to Asahi Glass Company) exemplifies hydrolysis of compound of formula II, wherein R is not phenyl; with potassium hydroxide in ethanol and mixture of ethanol/toluene as the solvent system. However, the reaction is reported to take two/three days for completion, rendering it commercially.
In United States Patent No. 6686473 (assigned to Synthon) the hydrolysis of compound of formula II, wherein R is phenyl, is carried out with potassium hydroxide in n-butanol/toluene solvent system to yield compound of formula I. However, this process too, results in compound of formula I containing undesired transesterified carbamate impurity viz. the n-butyl carbamate derivative, which is difficult to remove from the reaction mixture.
United States Patent Publication No. 2003/0187269 (assigned to Beecham) discloses the preparation of compound of formula I by making a sulfonate derivative of compound of formula III to obtain compound of formula IV, coupling with sesamol in dimethylformamide solvent to obtain compound of formula V, followed by N-dealkylation-carbamoylation to yield compound of formula II. Finally hydrolysis of compound of formula II yields compound of formula I.
3


^
,x^\ .
^OH

OS02R"

o
,^\.

0
>
o

formula III

formula IV

formula V

wherein, R' and R" may be selected from halo substituted or unsubstituted linear or branched alkyl, alkylaryl, arylalkyl.
OBJECT OF THE INVENTION
The object of the present invention is to provide a commercially viable process for the preparation of (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl)]-piperidine, compound of formula I, without the formation of unwanted impurities.
SUMMARY OF THE INVENTION
A process for preparing (-)-trans-4-(4-fluorophenyl)-3-[[3,4-
(methylenedioxy)phenoxy]methyl)]piperidine, compound of formula I or pharmaceutically acceptable salts thereof, said process comprising



II}
.*\.
O
formula I

4

hydrolyzing compound of formula II, wherein R may be selected from halo substituted or unsubstituted linear or branched alkyl, alkyl aryl and aryl alkyl; with base in solvent
system selected from amides, sulfoxides, nitriles, ethers, acyclic or cyclic polyethers and their mixtures with organic solvent(s).
DESCRIPTION OF THE INVENTION
It is our endeavor to synthesize compound of formula I in high yield, by a commercially viable process that would avoid the formation of undesired side products, including transesterified carbamate impurities.
According to one embodiment of the process of the present invention, the compound of formula II may be hydrolyzed to compound of formula I by base in a solvent system selected from amides, sulfoxides, nitriles, acyclic or cyclic ethers or polyethers, esters and its mixtures with organic solvent(s).



H
formula I formula II
The base may be selected from an organic or inorganic base. Organic base may be selected from quaternary ammonium hydroxides, such as Triton B. Inorganic base may be selected from hydroxides, carbonates or bicarbonates of sodium, potassium or lithium, preferably potassium hydroxide.
5

The solvent system may be selected from amides such as dimethylformamide, diethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide, and the like; nitriles such as acetonitrile, propionitrile, and the like; acyclic or cyclic ethers or polyethers used in the present invention may be selected from 1,2-dimethoxyethane, 1,4-dimethoxybutane, diglyme, tetrahydrofuran, 1,4-dioxane, crown ethers, dialkylated poly(alkylene glycol)s such as diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, tetraethylene glycol dimethyl ether (tetraglyme), poly(ethylene glycol) dimethyl ether 250 & the like; esters such as t-butyl acetate and the like; and its mixtures with organic solvent(s).
The organic solvent(s) may be selected from amides, sulfoxides, nitriles, ethers, acyclic or cyclic polyethers, esters and hydrocarbons.
The hydrocarbons may be selected from alkyl or aryl hydrocarbon such as hexane, heptane, cyclohexane, toluene, xylene and the like.
Preferably, the solvent system is dimethyl sulfoxide or dimethyl sulfoxide-toluene mixture in volume ratios ranging from about 1:99 to 99:1.
Hydrolysis of compound of formula II may be carried out at a suitable temperature, preferably at temperature greater than 50°C.
According to another embodiment of the process of the present invention compound of formula II may be prepared by (a) reacting compound of formula III with p-toluenesulfonyl chloride to give compound of formula IV; and (b) converting compound of formula IV to compound of formula I.
6

«'*^OH r>^*^OS02R»
formula III formula IV
Preferably, compound of formula IV may be prepared by reacting compound of formula III with p-toluenesulfonyl chloride, treating the reaction mixture with an acid followed by isolation of compound of formula IV. The acid(s) may be selected from inorganic or an organic acid, preferably an organic acid.
The inorganic acid may be selected from hydrochloric acid, sulfuric acid, nitric acid and the like. The organic acid may be selected from a an alkyl or arylcarboxylic acid such as acetic acid, citric acid, succinic acid, maleic acid, fumaric acid, oxalic acid, benzoic acid and the like, or an alkyl or arylsulfonic acid such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid and the like, preferably methanesulfonic acid.
For instance, compound of formula IV may be prepared by reacting compound of formula III with p-toluenesulfonyl chloride in organic solvent, in presence of a base, followed by adding acid(s) to the reaction mixture after completion of reaction. The treatment of the reaction mixture with an acid after the reaction, prior to processing, protonates the nitrogen centre in formula IV and prevents possible intramolecular or intermolecular nucleophilic attack of the basic nitrogen at the electrophilic carbon bearing the tosyl group in the piperidnyl system system. Thus the possibility of isomerization or quaternization of the product of formula IV is averted, and the product is isolated with high purity and yield.
7

Compound of formula IV may be then converted to compound of formula I by using prior known methods such as reacting with sesamol to give compound of formula V; dealkylating-carbamoylating with haloformate ROCOX, wherein R is selected from halo substituted or unsubstituted linear, branched alkyl, alkylaryl and arylalkyl & X is halo.
F

formula V
The invention is illustrated but not restricted by the description in the following examples.

Examples
Example 1: Preparation of compound of formula IV
To a stirred solution of trans-(-)-paroxol (100g), compound of formula III, (wherein R' is
methyl) in dichloromethane (500ml) was added triethylamine (75 ml), and cooled to -5 to -15°C. p-Toluenesulfonyl chloride (120g) was slowly added and stirred for lhr at -5 to -15°C. Methanesulfonic acid (44ml) was then added gradually and the mixture concentrated at about 50°C at atmospheric pressure. The residue was taken up in toluene, water was added, stirred for 30min. and the top toluene layer separated. The pH of the aqueous layer was then adjusted to 9.0 to 9.5 with saturated NaHC03 solution, the product filtered, washed with water and dried to yield compound of formula IV (138.0g), as white to off-white solid, purity >99.0%.
Example 2: Preparation of N-methylparoxetine, compound of formula V (wherein R' is methyl).
To a stirred solution of sesamol (27.5g) in N,N-dimethylacetamide (150ml) was added potassium tertiary butoxide (18.5g), followed by compound of formula IV (wherein R' is methyl and R" is p-tolyl) (50 g). The mixture was heated for 2hrs under stirring at 55 to 60°C, cooled to 10-15°C, and quenched with aqueous sodium hydroxide. The product was filtered, washed with water and dried till constant weight to obtain N-methylparoxetine as a white solid, purity >99.0%.
Example 3: Preparation of 3-(benzo[l,3]dioxo-5-yloxymethyI)-4-(4-fluorophenyl)-piperidine-1-carboxylic acid phenyl ester, compound of formula II, wherein R is phenyl.
To a stirred solution of N-methylparoxetine (formula V, R'=CH3)) (50g) in toluene (250ml) was slowly introduced phenyl chloroformate (37ml) at reflux temperature and stirring continued under reflux for 3hrs. Diisopropylethylamine (5ml) was then added to the mixture and reflux continued for an additional hour. The mixture was then cooled to
25-30°C and quenched by addition of water. The upper toluene layer was separated,
9

washed with water and concentrated. The resulting solid is recrystallized from 2-propanol, filtered and dried till constant weight, to obtain compound of formula II as white solid, purity >99.0%.
Example 4a: Preparation of compound of formula I
A mixture of compound of formula II (50g), toluene (250ml), dimethyl sulfoxide (50ml) and potassium hydroxide (30g) is heated to 80-85°C for 4hrs, cooled to 30-35°C and then quenched by addition of water (150ml) at 30-35°C. The upper toluene layer was separated and the aqueous layer extracted with toluene (100ml). The combined toluene layer were washed subsequently with water and saturated aqueous sodium chloride solution, charcoalized and acidified with cone, hydrochloric acid. After stirring at 20-25°C for 2hrs the product was filtered and washed with toluene followed by water. The crude product was recrystallized from 2-propanol and dried until water content was within the range of 2.3 to 2.7%, to yield paroxetine hydrochloride, as white crystalline solid, purity >99.5%.
Example 4b: Preparation of compound of formula I
A mixture of compound of formula II (5g), toluene (25ml), N,N-dimethylacetamide (5ml) and potassium hydroxide (3g) was heated to 80-85°C for 4hrs, cooled to 30-35°C and quenched by addition of water (15ml) at 30-35°C. The upper toluene layer was separated and the aqueous layer was extracted once with toluene. The combined toluene layer was washed with water and saturated aqueous sodium chloride solution, charcoalized and acidified with cone, hydrochloric acid. After stirring at 20-25°C for 2hrs the product was filtered, washed with toluene followed by water. The crude product was recrystallized from 2-propanol, filtered and dried until water content is with in the range of 2.3 to 2.7%, to yield paroxetine hydrochloride, as white crystalline solid, purity >99.5%.
10

Example 4c: Preparation of compound of formula I
The experiment was carried out in the same manner as in Example 4b, but by replacing N,N-dimethylacetamide with polyethylene glycol) dimethyl ether 250 (5ml), to yield paroxetine hydrochloride with purity >99.5%.
Comparative Example (as per United States Patent No. 6686473)
To a pre-heated mixture of potassium hydroxide (3.7g) in 1-butanol (14ml) at 80°C, was added a solution of (3S,4R)-3-[(l,3-benzodioxol-5-yloxy)methyl)]4-(4-fluorophenyl)piperidine-l-carboxylic acid phenyl ester (compound of formula II, wherein R is phenyl), (5g) in toluene (8.5ml) and 1-butanol (10ml) under stirring. Exothermic reaction was observed upon addition. The mixture was stirred under reflux for 2hrs, cooled to 90-95°C and then quenched by addition of water (14ml). After stirring for 30min the upper toluene layer was separated and washed sequentially with 30% aqueous NaOH solution (6ml) and 16% aqueous NaCl solution (6ml), charcoalised and evaporated at reduced pressure at 50-60°C to give paroxetine free base as a pale yellow syrupy base. Analysis by HPLC showed purity of paroxetine free base to be 95.66%, with (3S,4R)-3-[(l,3-benzodioxol-5-yloxy)methyl)]4-(4-fluorophenyl)piperidine-l-carboxylic acid n-butyl ester, compound of formula II (wherein R is n-butyl) as a major impurity (3.64%), characterized by LC-MS characterized by LC-MS (mol. ion. at 430.3 [M+l]+).
11

We Claim:
1. A process for preparing (-)-trans-4-(4-fluorophenyl)-3-[[3,4-
(methylenedioxy)phenoxy]methyl)]piperidine, compound of formula I or
pharmaceutically acceptable salts thereof, said process comprising

formula I formula II
hydrolyzing compound of formula II, wherein R may be selected from halo substituted or unsubstituted linear or branched alkyl, alkylaryl, arylalkyl, with base in solvent system selected from amides, sulfoxides, nitriles, acyclic or cyclic ethers or polyethers, esters and their mixtures with organic solvent(s).
2. A process as claimed in claim 1 wherein the organic solvent(s) is selected from amides, sulfoxides, nitriles, ethers, acyclic or cyclic polyether, esters and hydrocarbons.
3. A process as claimed in claim 1 wherein the solvent system is mixture of dimethyl sulfoxide or dimethyl sulfoxide-toluene mixture.
12

4. A process as claimed in claims 1 to 3, wherein compound of formula II is
prepared by
a. reacting compound of formula III with p-toluenesulfonyl chloride to give
compound of formula IV; and
b. converting compound of formula IV to compound of formula I.
5. A process as claimed in claim 4 wherein the reaction mixture of step (a) is treated with an acid and compound of formula IV isolated.
6. A process as claimed in claim 5 wherein the acid is methanesulfonic acid.
7. A process for the preparation of compound of formula 1 as claimed in claims 1 to 6 substantially as herein described and illustrated by examples 1 to 4.
Dated this 25th day of April, 2005

SWATI VEERA
PATENT ATTORNEY (IN-HOUSE)
SUN PHARMACEUTICAL INDUSTRIES LTD.
13

ABSTRACT
A process for preparing (-)-trans-4-(4-fluorophenyl)-3-[[3,4-
(methylenedioxy)phenoxy]methyl)]piperidine, compound of formula I or pharmaceutically acceptable salts thereof, said process comprising

formula I formula II
hydrolyzing compound of formula II, wherein R may be selected from halo substituted or unsubstituted linear or branched alkyl, alkylaryl, arylalkyl, with base in solvent system selected from amides, sulfoxides, nitriles, acyclic or cyclic ethers or polyethers, esters and their mixtures with organic solvent(s).
To
The Controller of Patents, The Patent Office, Mumbai-400 013.
14