FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
IMPROVED PROCESSES FOR THE
PREPARATION OF 3-ARYLOXY-3-
ARYLPROPYLAMINES AND
INTERMEDIATES THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India


The following specification describes the invention:

IMPROVED PROCESSES FOR THE PREPARATION OF 3-ARYLOXY-3-ARYLPROPYLAMTNES AND INTERMEDIATES THEREOF
FIELD OF THE INVENTION
The invention relates to improved processes for preparing 3-aryloxy-3-arylpropylamines and intermediates thereof.
BACKGROUND OF THE INVENTION
Certain 3-aryloxy-3-arylpropylamines for example, fluoxetine and duloxetine are known to possess central nervous system activity.
Duloxetine hydrochloride is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI, depression, and pain management. Duloxetine hydrochloride is chemically known as (S)-(+)-N-methyl-3 -(1 -naphthyloxy)-3-(2-thienyl) propanamine hydrochloric acid salt and can be depicted structurally as


HCI

Duloxetine base, as well as processes for its preparation, is disclosed in U.S. Patent No. 5,023,269. EP Patent No. 457559 and US Patents Nos. 5,491,243 provide an improved synthetic route for the preparation of duloxetine base. US 5,023,269 describe the preparation of duloxetine base by reacting N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine with fluoronaphtalene (Stage a), followed by demethylation with phenyl chloroformate or trichloroethyl chloroformate (Stage b) and basic hydrolysis (Stage c) according to the following scheme:
2

The conversion of duloxetine base to its hydrochloride salt is described in US 5,491,243 and in Wheeler, W.J., et al, J. Label. Compound. Radiopharm, 1995, 36, 312. In both publications, the conversion reactions are performed in ethyl acetate, and the reported yield for this process in the Wheeler, W.J. et. al. publication is 45 %.
EP 457559 discloses the conversion of N, N-Dimethyl-3-(l- naphthyloxy)-3-(2-thienyl) propanamine oxalate to N, N-Dimethyl-3- (1 -naphthyloxy)-3-(2-thienyl) propanamine with sodium hydroxide.
In US 5,491,243, the process described in Stage b is performed in a phenyl chloroformate/diisopropylethylamine system at 55° C, and, in International Patent
3

Application Publication No. WO 04/056795, this stage is performed in the presence of chloroethyl chloroformate at 60° C.
U.S. Patent No. 5,023,269 and U.S. Patent No. 5,362,886 disclose processes for the reaction of Stage c in which propylene glycol/ sodium hydroxide system and dimethylsulfoxide/sodium hydroxide system, respectively are used.
Fluoxetine hydrochloride is a potent and selective serotonin re-uptake inhibitor. It is used as an efficient antidepressant drug. Fluoxetine hydrochloride is chemically known as N-methyl-3-(2-phenyl)-3-trifluoromethylphenyl propanamine hydrochloric acid salt and can be depicted structurally as CF3

Fluoxetine and a process for the preparation of fluoxetine and its pharmaceutically acceptable addition salts are described in U.S. Pat. No. 4,314,081 and U.S. Pat. No. 4,194,004 respectively and U.S. Pat. No. 4,018,895 describes its use in treating depression.
US 5,225,585 discloses that 3-methylamino- 1-phenyl-1-propanol (formula G) is converted to fluoxetine (formula A) using various known procedures. Thus, by one procedure the anion formed by reacting compound of formula G with sodium hydride in N,N-dimethylacetamide, is reacted with 4-chloro- benzotrifluoride of formula H to give fluoxetine.
4

With compound of formula H

We surprisingly found the improved processes for preparation of the antidepressant compounds and intermediates of antidepressant compounds, the process can be carried out at a comparatively lower temperature, is cost effective and is suitable at large scale production.
SUMMARY OF THE INVENTION
In one aspect, the specification discloses a process for preparing compound of Formula I

I
Wherein R1 and R2 is independently hydrogen or methyl; X is 1-naphthyl, 2-naphthyl or p- trifluoromethylphenyl; Y is 2-thienyl or phenyl
and pharmaceutically acceptable salts thereof, comprising mixing a compound of Formula II
5
wherein Y, R1and R2 are as defined above, with a compound selected from 1-
fluoronaphthalene, 1-chloronaphthalene, 2-fluoronaphthalene, 2-
chloronaphthalene, l-fluoro-4- (trifluoromethyl)benzene or l-chloro-4- (trifluoromethyl)benzene, in a solvent in presence of a base, wherein the process is carried out at a temperature ranging from 50° C. to 85° C.
In another aspect, the specification discloses a process for preparing duloxetine carbamate or pharmaceutically acceptable salts thereof comprising: a. dissolving a salt of compound of Formula IV

IV
having an enantiomeric purity of at least 98 % by HPLC, in an organic solvent;
b. adding an alkyl chloroformate, a halo alkyl chloroformate or aryl
chloroformate, in the presence of base ; and
c. recovering duloxetine carbamate and optionally converting to pharmaceutically
acceptable salts.
In another aspect, the specification discloses a process for preparing duloxetine hydrochloride comprising
6

(a) mixing a compound of Formula

with 1-fluoronaphthalene,
in a solvent, followed by addition of a base; to obtain a compound of Formula IV

wherein the process is carried out at a temperature ranging from 50 ° C. to 85° C;
(b) adding an acid to obtain a salt of compound of Formula IV;
(c) treating the product of step (b) with an alkyl chloroformate, a halo alkyl chloroformate or aryl chloroformate, in the presence of base, in another organic solvent;
(d) recovering duloxetine carbamate; and
(e) converting the duloxetine carbamate to duloxetine hydrochloride.
In another aspect, the specification discloses a compound of formula V, enantiomers and salts thereof.
7

OH

In yet another aspect, the specification discloses a compound of formula VI, enantiomers and salts thereof.

VI
In another aspect, the specification discloses an oxalate salt of the compound of Formula IV

having an enantiomeric purity of at least 98 % by HPLC.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the following terms have the meanings as indicated:

ine term "duloxetme" refers to (+)-N-methyl-3-(2-thienyl)-3-(l-naphthyloxy) propanamine. The term "fluoxetine" refers to N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.. The term "duloxetine carbamate" means S-(+)-N-phenoxycarbonyl -N-methyl -3-(l-naphthyloxy) -3-(2-thienyl) propylamine. The term "pharmaceutically acceptable salt" refers to an acid addition salt using a pharmaceutically-acceptable acid.
In one embodiment, the specification discloses improved processes for preparing 3-aryloxy-3-arylpropylamines, pharmaceutical composition and intermediates thereof. The 3-aryloxy-3-arylpropylamines are preferably duloxetine and fluoxetine. The embodiments of the specification disclose process for preparation of 3-aryloxy-3-arylpropylamines and their intermediates which are substantially pure and novel compounds isolated during the process of preparation of duloxetine.
In one aspect, the specification discloses a process for preparing 3-aryloxy-3-arylpropylamines of formula I

wherein R1 and R2 is independently hydrogen or methyl;
X is 1-naphthyl, 2-naphthyl or p- trifluoromethylphenyl;
Y is 2-thienyl or phenyl and pharmaceutically acceptable salts thereof by;
mixing a 3-hydroxy-3-aryl-propylamine of formula II

II
9

Wherein Y, R1 and R2 are as defined above, with a compound selected from 1-fluoronaphthalene, 1-chloronaphthalene, 2-fluoronaphthalene, 2-chloronaphthalene, 1-fluoro-4-(trifluoromethyl) benzene or l-chloro-4-(trifluoromethyl) benzene, in a solvent in presence of a base.
The process can be carried out in solvents such as, amides, dimethylsulfoxide (DMSO) or water. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
The compound of formula I obtained in the above process may be either racemic or
enantiomeric. The process for preparing compound of formula I, may be carried out at temperatures of from about 50 ° C. to 85° C. and requires about 1-40 hours. For
example, the process for preparing compound of Formula I, may be carried out at a temperature ranging from 65° C. to 70° C. for a period of 24-40 hours.
The bases are selected from; sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide, sodium amide, potassium amide, lithium hydride or lithium N,N-diisopropylamide. In some cases potassium ion in the form of potassium hydroxide can be preferred.
Suitable 3-aryloxy-3-aryl-propylamine of Formula I obtained by the process, includes
N,N-dimethyl-3-(2-thienyl)-3-( 1-naphthyloxy)-propylamine,
(R)- N,N-dimethyl-3-(2-thienyl)-3-( 1 -naphthyloxy)-propylamine,
(S)- N,N-dimethyl-3-(2-thienyl)-3-( 1 -naphthyloxy)-propylamine,
N-methy l-3-(2-thienyl)-3 -(1 -naphthyloxy)-propylamine,
(R)- N-methyl-3-(2-thienyl)-3-( 1 -naphthyloxy)-propylamine,
(S)- N-methyl-3-(2-thienyl)-3-( 1-naphthyloxy)-propylamine,
10

N,N-dimethyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
(R)-N,N-dimethyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
(S)-N,N-dimethyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
N-methyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
(R)-N-methyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
(S)-N-methyl-3-(2-thienyl)-3-(2-naphthyloxy)-propylamine,
N,N -dimethyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine,
(R) -N,N -dimethyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propylamine,
(S) -N,N -dimethyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propylamine,
N-methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propylamine,
(R)- N-methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propylamine and
(S)- N-methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propylamine.
Suitable 3-hydroxy-3-aryl-propylamine of Formula II, includes
N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine,
(R)- N, N- dimethyl - 3- (2- thienyl)- 3-hydroxypropylamine,
(S)-N,N-dimethyl-3-(2-thienyI)-3-hydroxypropylamine,
N-methyl-3-(2-thienyl)-3-hydroxypropylamine,
(R)- N- methyl- 3- (2-thienyl)- 3-hydroxypropylamine,
(S)-N-methyl-3-(2-thienyl)-3-hydroxypropylamine,
N,N-dimethyl-3-phenyl-3-hydroxypropylamine,
(R)- N, N -dimethyl- 3-phenyl- 3-hydroxypropylamine,
(S)- N,N -dimethyl-3-phenyl-3-hydroxypropylamine,
N-methyl-3-phenyl-3-hydroxypropylamine,
(R)- N-methyl-3-phenyl-3-hydroxypropylamine, and
(S)- N-methyl-3-phenyl-3-hydroxypropylamine.
11

Suitable haloaromatics include 1-fluoronaphthalene, 1-chloronaphthalene, 2-
fluoronaphthalene, 2-chloronaphthalene, l-fluoro-4-(trifluoromethyl) benzene and 1-chloro-4-(trifluoromethyl) benzene.
The pharmaceutically acceptable salts of compound of Formula I can be prepared by addition of an acid. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such oxalic acid and maleic acid.
The pharmaceutically acceptable salts thus prepared, have substantially high purity as determined by HPLC (High Performance Liquid Chromatography). If optically active 3-hydroxy-3-arylpropylamines are used for the above process, then enantiomerically enriched products of the above process have purity greater than 90%. For example, an
12

oxalate salt of (+)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthyloxy) propanamine has a purity of at least 98% by HPLC.
The salts obtained by this process can also be used to prepare carbamates of 3-aryloxy-3-arylpropylamines of Formula I. The carbamates of 3-aryl-3-aryloxypropylamines of Formula I can be prepared by contacting salts of 3-aryl-3-aryloxypropylamines with a molar excess of alkyl chloroformate, a halo alkyl chloroformate or aryl chloroformate, such as phenyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, and the like. The reaction can be carried out in the presence of a suitable base, such as triethylamine, pyridine, N,N-diisopropylethylamine, sodium carbonate and the like. For example, the base may be sodium carbonate. The reaction can be carried out in a suitable solvent. The solvent may be an aliphatic hydrocarbon, such as n-hexane, heptane and the like; an aromatic hydrocarbon, such as benzene, toluene, xylene, ethyl benzene, propyl benzene and the like; an ester, such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, benzyl acetate, phenyl acetate and the like; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and the like; or halogenated hydrocarbons such as methylene chloride and the like. Most preferably the organic solvent is toluene. The reaction can be carried out at temperatures from about 0° C. to the refluxing temperature of the solvent and requires about 1-48 hours. For example, the reaction may be carried out at 50-55° C. in toluene for 1-5 hours. The carbamate intermediate can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
The carbamate intermediate can be further converted to the corresponding 3-aryloxy-3-arylpropylamines or salts thereof by processes well-known in the art as per US 5,491,243 which is incorporated herein by reference. For example, the N-methyl-N-phenoxycarbonyl- 3-(l-naphthyloxy)-3-(2-thienyl)propylamine may be converted to
13

N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine. For example, the carbamate intermediate can be then hydrolyzed to give 3-aryloxy-3-arylpropylamine. For example, the carbamate intermediate can be contacted with an excess of sodium hydroxide or potassium hydroxide. The reaction can be carried out in a suitable solvent, such as water, dimethyl sulfoxide, ethanol, dimethyl sulfoxide/water mixtures, and the like. Typically the reaction can be carried out at temperatures of from about 20° C. to about 100° C. and require about 1 hour to 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
In another embodiment, the specification discloses a process for preparing duloxetine hydrochloride comprising steps of:
(a) mixing (S)-(-)N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine with 1-
fluoronaphthalene, in a solvent, followed by addition of a base; to obtain (S)-(+)N, N-
dimethyl- 3-(l-naphthyloxy)-3-(2-thienyl)propanamine wherein the process can be
carried out at a temperature ranging from 50 ° C. to 85° C;
(b) adding an acid to obtain a salt of compound of Formula IV

a*—s% iv ;
(c) treating the product of step (b) with an alkyl chloroformate, a halo alkyl chloroformate or aryl chloroformate, in the presence of a base, in another organic solvent;
(d) recovering duloxetine carbamate; and
(e) converting the duloxetine carbamate to duloxetine hydrochloride.
The process for preparing (S)-(+)- N, N- dimethyl- 3-(l-naphthyloxy)-3-(2-thienyl)propanamine may be carried out at temperatures of from about 50° C. to 85°
14

C. and requires about 1-40 hours. For example, the process for preparing (S)-(+)N, N-
dimethyl- 3-(l-naphthyloxy)-3-(2-thienyl)propanamine, may be carried out at a temperature ranging from 65° C. to 70° C. for a period of 24-40 hours. The process can be carried out in the presence of a suitable base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide, sodium amide, potassium amide, lithium hydride or lithium N,N-diisopropylamide. In some cases potassium ion in the form of potassium hydroxide can be preferred. The process can be carried out in solvents such as, amides, DMSO or water. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
The acid of step (b) can be an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid; or an organic acid such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, or related inorganic and organic acids.
The salts obtained by following the above process may have a high chemical purity and enantiomeric purity. For example, an oxalate salt of (+)-N, N-dimethyl-3-(2-thienyl)-3-(l-naphthyloxy) propanamine has an enantiomeric purity of at least 98% by HPLC.
Duloxetine carbamate may be prepared by contacting salts obtained in step (b) with a slight molar excess of alkyl chloroformate, a halo alkyl chloroformate or aryl chloroformate, such as phenyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, and the like. The reaction can be carried in the presence of a suitable base, such as triethylamine, pyridine, N,N-diisopropylethylamine, sodium carbonate and the like. In some cases, the base sodium carbonate is preferred. The reaction can be carried out in a suitable solvent. The solvent may be an aliphatic hydrocarbon,
15

such as n-hexane, heptane and the like; an aromatic hydrocarbon, such as benzene, toluene, xylene, ethyl benzene, propyl benzene and the like; an ester, such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, benzyl acetate, phenyl acetate and the like; an ether such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and the like; or halogenated hydrocarbons such as methylene chloride and the like. Most preferably the organic solvent is toluene. The reaction can be carried out at temperatures from about 0° C. to the refluxing temperature of the solvent and requires about 1-48 hours. For example, the reaction may be carried out at 50° C. -55° C. in toluene for 1-5 hours. The duloxetine carbamate intermediate can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
The duloxetine carbamate intermediate can be further converted to duloxetine or salts thereof by processes well-known in the art as per US 5,491,243 which is incorporated herein by reference. For example, the duloxetine carbamate may be converted to S-(+)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine. For example, the duloxetine carbamate intermediate can be hydrolyzed to obtain duloxetine. For example, the duloxetine carbamate intermediate can be contacted with an excess of sodium hydroxide or potassium hydroxide. The reaction may be carried out in a suitable solvent, such as water, dimethyl sulfoxide, ethanol, dimethyl sulfoxide/water mixtures, and the like. Typically the reaction can be carried out at temperatures of from about 20° C. to about 100° C. and requires about 1 hour to 48 hours. For example, the duloxetine hydrochloride salts may be prepared from duloxetine using isopropanolic HC1, acetonitrile HC1 and the like. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
16

Duloxetine hydrochloride prepared by the above process may have an HPLC purity of at least about 99%.
In another embodiment, the invention provides a compound of Formula V, enantiomers and salts thereof.

The specification further provides duloxetine HCl containing less than 0.5 % of a compound of the Formula V. For example, duloxetine HCl containing less than 0.1% of a compound of the Formula V.
In another embodiment, the specification discloses a compound of formula VI, enantiomers and salts thereof.

OH H
k. ^CH3
l.
VI
The duloxetine HCl may contain less than 0.5 % of a compound of the Formula VI, preferably, less than 0.1% of a compound of the Formula VI.
17

The pharmaceutical^ acceptable salts of compound of Formulae V or VI can be prepared by addition of an acid. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such oxalic acid and maleic acid.
The compounds of formulae V or VI can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
Duloxetine hydrochloride prepared by the processes of this invention can be used to prepare a pharmaceutical composition as disclosed in US 5508276, which is incorporated by reference herein.
The following examples illustrate certain embodiments in greater detail, and are not intended to limit the scope of the invention.
18

The process for the preparation of duloxetine hydrochloride is depicted in reaction Scheme, as follows:

^s.^
OH
1 -Fluoronaphthalene
CH3 CH7
KOH, DMSO
vJXsllC 3C1Q
(S)-(-)-N,N-Dimethyl-3-hydroxy-3-(2-thenyl)-1 -propanamine

O
j, Phenjl chloro formate
go
o
\_f Nxai,. (cooa\ x^-dasopropjH
etbybmiiie
S(+)- N,>"-dimethyl -3-(l-napbtbalenyloxY) -3-(2-tbienyi)propanamtne oxalate

go
* o
S^N-methji-N-pbenoxycarboiiyl -3~(l-napbtbalenyloxy)-3-{2-tbieoyl) propanamine carbamate

U

o
N:CO6C6H5
Duloxetine carbamate

NaOH
DMSO, 90-95°C
»
Ethyl acetate, Isopropanolic.HCl

,S
•CH
O
?HC1
H
S-(+)-N-methyl-3-(l-naphthalenyloxy)-3 -(2-thienyl)-propanamine hydrochloride

The following examples illustrate certain specific aspects and embodiments of the present invention in greater detail, and are not intended to limit the scope of the invention.
19

COMPARATIVE EXAMPLE 1
a) S-(+)-N, N- DIMETHYL -3- (1-NAPHTHYLOXY)- 3- (2-THIENYL)
PROPANAMINE OXALATE:
25 ml of DMSO and 5.0 g of S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was charged into a reaction flask and stirred. 3.78 g of potassium hydroxide and 3.82 ml of 1-fluoronaphthalene were added at room temperature. The reaction mass was heated to 90 ° C.-950 C. and this temperature was maintained for 6.0 hrs. The completion of the reaction was checked by TLC. The reaction mass was cooled to 15 ° C.-20 ° C. and 125 ml of water was added slowly with stirring. The reaction mass was then extracted with ethyl acetate and the aqueous and organic layers was separated. The organic layer was washed with water, separated from the aqueous layer, dried over sodium sulphate and distilled to to obtain a liquid mass (8.2 g). 8.2 g of liquid mass was added to 130 ml of fresh ethyl acetate and stirred to obtain a clear solution. Activated charcoal was added to the organic layer at room temperature, stirred and filtered. Oxalic acid methanol solution (4.0 g in 8.0ml methanol) was added to the filtrate over a period of 1.0 hour upto a pH of about 3.0. The reaction mass was kept for 30 minutes and then cooled to 0 ° C.-50 C. The reaction mass was maintained for 1 hour at 0 ° C.-50 C. and filtered. The filter cake was washed with 16 ml of ethyl acetate and suck dried. The solid obtained was then dried in hot air oven at 40-45 ° C. for 8.0 hrs. Dry weight of the solid = 8.0 g.
Yield : 73.8%
Chiral purity : 82.78% (S-isomer)
Chemical purity : 100.0%
b) S-(+)-N-METHYL-N-PHENOXYCARBONYL-3-(l-NAPHTHYLOXY)-3-(2-
THIENYL) PROPANAMINE CARBAMATE:
20

7.5 g of S-(+)-N,N-dimethyl -3- (1-naphthyloxy)- 3- (2-thienyl) propanamine oxalate was added to 26 ml of toluene and 75ml of water in a reaction flask and stirred. The reaction mass was cooled to 15 ° C.-200 C. Sodium carbonate solution (5.0 g in 16.6 ml water) was added slowly at a pH of 9.0-9.5 to the reaction mass and maintained for 1.0 hour at room temperature. The aqueous and organic layers were separated and the aqueous layer was again extracted with 11 ml of toluene. The organic layers were combined and washed with water. The organic layer was dried over sodium sulphate and distilled under vacuum to obtain a liquid mass (5.5 g). 5.3 g of this liquid mass was charged to 37.5 ml of toluene in a reaction flask and 0.4 ml of diisopropyl ethylamine was added. The reaction mass was heated to 45 ° C.-500 C. A
solution of phenyl chloroformate and toluene (2.81 ml of phenyl chloroformate in 7.5ml of toluene) was added slowly in 1.5 hours to the reaction mass. The reaction
mass was maintained at this temperature for 3.0 hours. The reaction mass was quenched with 2% sodium bicarbonate solution with stirring. The organic layer was separated and washed with hydrochloric acid solution, sodium bicarbonate solution followed by water. The organic layer was dried over sodium sulfate and distilled to obtain a liquid mass (brown colored residue weight: 6.5 g).
Yield : 83.4%
Chemical purity by HPLC : 95.14%
c) S-(+)-N-METHYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)
PROPANAMINE HYDROCHLORIDE:
6.0 g of S-(+)-N-methyl-N-phenoxycarbonyl-3-(l-naphthyloxy)-3-(2-thienyl) propanamine carbamate was added to 12.0 ml of dimethylsulfoxide and stirred to obtain a clear solution. Sodium hydroxide solution (6.0 g sodium hydroxide in 12.0ml water) was added to the reaction mass. The reaction mass was then heated to 90 ° C-95° C. and maintained at this temperature for 1.0 hour. The completion of the reaction was checked by TLC. The reaction mass was then cooled to room temperature and 30
21

ml of ethyl acetate and 6.0 g of sodium sulfate were added. The reaction mass was filtered after 30 minutes stirring and washed with ethyl acetate. 30 ml of ethyl acetate and 60 ml of water were added to the filtrate and stirred for 20 minutes. The aqueous and organic layers were separated. The aqueous layer was again extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried over sodium sulfate and the clear organic layer was distilled under vacuum to obtain a liquid mass (brown colored liquid; 4.7 g). This 4.7 g of liquid mass was added to 37.6 ml of ethyl acetate in a reaction flask and stirred for 5 minutes. 0.5 g of charcoal was added to the solution and stirred at room temperature for 30 minutes and filtered through hyflow bed. The filtrate was cooled at 0 ° C.-5° C.. Isopropanolic HC1 solution was added upto a pH of about 5.0 over a period of 45 minutes. The reaction mass was then maintained at this temperature for 1.0 hour and filtered. The filter cake was washed with ethyl acetate and suck dried. The compound was then dried in a hot air oven for 8.0 hrs at 40-45° C. (0.95 g).
Yield: 19.8%
Chiral purity 97.30%
EXAMPLE 1
(S)-(+)-N,N-DIMETHYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)-l-PROPANAMINE OXALATE:
In a 100 ml round bottom flask, 25.0 g of S-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxy-propanamine and 19.14 ml 1-fluoronaphthalene were dissolved in 125.0 ml of dimethyl sulfoxide and stirred. 18.91 g of potassium hydroxide was added to the reaction mixture. The reaction mass was heated up to 65° C.-700 C. The reaction mass was stirred at 65° C. to 70°C. temperature for 18 hours. The completion of the reaction was checked by TLC. The reaction mass was cooled to room temperature and stirred for 10 minutes. The reaction mass was dumped in 625 ml chilled water in 2 L four neck round bottom flask and stirred. It was then extracted with 625 ml X 2 of
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ethyl acetate. The aqueous and organic layers were separated by a separating funnel.
The organic layers were combined and washed with 625 ml x 2 of water. The
aqueous and organic layers were separated by separating funnel. The organic layer
was dried with sodium sulfate and filtered it. The filtrate was distilled under vacuum
at 40°C to 45°C. (residue weight = 40.6 g). 320.0 ml ethyl acetate was charged to the
residue and stirred it. 4.0 g activated charcoal was added to the reaction mass and
stirred for 1/2 hour at room temperature. The reaction mass was filtered through
hyflow bed and washed with 40.0 ml x 2 of ethyl acetate. To the filtrate, 85 ml oxalic
acid solution (15.3 g in 85 ml water) was added up to a pH of 2.5-3.5 at room
temperature. The reaction mass was stirred at room temperature for 14 hour and
cooled up to 0° C. to 5°C. The reaction mass was stirred for 1 hour at 0° C. to 5° C,
filtered & washed with 40.0 ml x 2 of chilled ethyl acetate. The residue was suck
dried to obtain a wet solid. Weight of wet residue = 79.0 g. The wet solid was dried
for 8 hours at 40°C to 45°C to obtain an off-white powder (33.5 g.).
Yield : 61.84%
Chemical Purity by HPLC : 98.72%
Chiral purity by HPLC : 95.48%
EXAMPLE 2
(S)- (+)-PHENYL [3-(l-NAPHTHYLOXY)-3-(2-THIENYL) PROPYL]
METHYLCARBAMATE (DULOXETINE CARBAMATE):
105.0 ml toluene and 30.0 g S-(+)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2- thienyl) propanamine oxalate and 300.0 ml water were taken in a 1L round bottom flask and stirred. Sodium carbonate solution [19.8 g sodium carbonate + 45 ml water] was added by addition funnel slowly within 30 minutes at room temperature. The reaction mass was stirred for 30 minutes at room temperature. The reaction mass aqueous and organic layers were separated. The aqueous layer was extracted with 45 ml toluene at room temperature. The reaction mass layers were separated. The organic layers were
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taken in to 1 L round bottom flask. The organic layer was washed with 150 ml x 3
water at room temperature and later separated by separating funnel. The organic layer
was dried using 10.0 g of sodium sulfate and filtered. The filtrate was distilled under
vacuum at 40° C. to 45° C. A liquid mass (23.5 g) was obtained. 150.0 ml toluene
was added to it and stirred. 1.6 ml diisopropyl ethylamine was added to the reaction
mass. The reaction mass was heated upto 50° C. to 55° C. The solution of (11.3 ml
phenyl chloroformate + 30.0 ml toluene) was added to the reaction mass by an
addition funnel within 1.5 hours at 50° C. to 55° C. The addition was completed and
the reaction mass was maintained for 3.0 hours at 50° C. to 55° C. The completion of
the reaction was checked by TLC. The reaction mass was cooled up to 10° C. to 20°
C. and was dumped in to 300 ml of 2% sodium bicarbonate solution and stirred. The
aqueous and organic layers were separated by a separating funnel. The organic layer
was washed with 45 ml X 3 of 5% HC1 solution. The aqueous and organic layers were
separated by a separating funnel. The organic layer was washed with 300 ml 2%
sodium bicarbonate solution. The aqueous and organic layers were separated by a
separating funnel. The organic layer was washed with 150 ml water. The aqueous and
organic layers were separated by a separating funnel and the organic layer was dried
over sodium sulfate and filtered. The filtrate was distilled under vacuum at 40° C. to
45° C. to obtain a light brown coloured liquid mass.
Weight of liquid mass : 30.8 g
Yield : 98.71%
Chemical Purity by HPLC : 93.9%
EXAMPLE 3
(+)-(S)-N-METHYL- 3- (l-NAPHTHYLOXY)-3- (2- THIENYL)
PROPYLAMINE HYDROCHLORIDE (DULOXETINE HCL):
56.0 ml DMSO and 28.0 g of (S)- (+)-phenyl [3-(l-naphthyloxy)-3-(2-thienyl) propyl] methylcarbamate were taken into a round bottom flask and stirred. Sodium
24

hydroxide solution (28 g NaOH flakes + 56 ml water) was added to the reaction mass at room temperature. The reaction mass temperature was taken up to 90° C. to 95° C. The reaction mass temperature was maintained for 1.0 hour at 90° C to 95° C. The completion of reaction was checked by TLC. The reaction mass was cooled up to 15° C. to 20° C. 56.0g of sodium sulfate and 140 ml of ethyl acetate were added to the reaction mass and stirred for 1/2 hour at room temperature. The reaction mass was filtered through hyflow bed and washed with 70 ml of ethyl acetate. The filtrate was taken in a 1000 ml round bottom flask and stirred. 280 ml of water was added to the reaction mass and stirred for 20 minutes. The aqueous and organic layers were separated. The aqueous layer was extracted with 140ml of ethyl acetate. The aqueous and organic layers were separated. Both the organic layer were combined and washed with 140ml x 3 of water. The aqueous and organic layers were separated. The organic layer was collected and dried over sodium sulfate and filtered. The filtrate was distilled under vacuum at 40° C. to 45° C. to obtain a liquid mass (24.8 g). 24.8 g of liquid mass and 198ml of ethyl acetate were stirred at room temperature. 2.48 g of activated charcoal was added at room temperature. The reaction mass was stirred for 30 minutes at room temperature. The reaction mass was filtered through hyflow bed and washed with 24.8ml x 2 of ethyl acetate. The reaction mass filtrate was taken in a 500 ml round bottom flask and stirred. The reaction mass was cooled at 0° C.-5° C. and 15% Isopropanol HC1 solution was added slowly up to a pH 5.0-6.0 at 0° C. -5° C. At pH 5-6 a solid was precipitated. The reaction mass was stirred for 1.0 hour at 0° C.-5° C. and subsequently filtered through a filter paper. The product on filter paper was washed with 25 ml x 2 of chilled ethyl acetate and suck dried. The wet solid was dried for 8.0 hours at 40° C. to 45° C. to obtain duloxetine HC1 crude 11.7 g (light brownish white solid). 70 ml of isopropanol was added to 11.6 g of duloxetine HC1 crude and stirred. The reaction mass was heated upto reflux temperature about 82° C. A clear solution was observed. The reaction mass was cooled to room temperature. A solid was precipitated at 64° C. The reaction mass was further cooled to 0° C. to 5°
C. and stirred for 1.0 hour at 0° C. to 5° C. The reaction mass was filtered through a
25

filter paper and the product on the filter paper was washed with 11.6 ml x 2 of chilled
isopropanol and suck dried to obtain a wet solid (10.5 g). The wet solid was dried for
8.0 hours at 40° C. - 45° C. to obtain duloxetine HC1 in the form of an off-white
powder.
Weight of dry duloxetine HC1 : 9.6 g
Yield : 42.8%
Chemical Purity by HPLC : 99.73%
Chiral purity by HPLC : 100.0%
EXAMPLE 4
S-(+)-N,N-DIMETHYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL) PROPANAMINE OXALATE:
250 ml of dimethylsulfoxide and 50 g of S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propanamine were taken into a reaction flask and stirred. 37.78 g of potassium hydroxide and 38.25 ml of 1-Fluoronaphthalene were added at room temperature. The reaction mass was heated to 65° C. -70° C. and maintained at this temperature for 36.0 hours. The completion of the reaction was checked by TLC. The reaction mass was then cooled to 15 ° C.-200 C. and 1.25 L of water was added slowly under stirring. The reaction mass was then extracted with ethyl acetate, and the aqueous and organic layers were separated. The organic layer was washed with water. The organic layer was separated from aqueous layer and dried over sodium sulphate. Activated charcoal was added to the organic layer at room temperature, stirred and filtered. The filtrate was then distilled under vaccum to obtain a liquid mass (83.0 g). 83.0 g of the liquid mass was added to the 800 ml of fresh ethyl acetate and stirred to obtain clear
solution. 115 ml of oxalic acid acetone solution (30 g of oxalic acid in 100 ml of acetone) was added at 45° C. over a period of 1.0 hour upto a pH of 2.5-3.5. The reaction mass maintained at this temperature for 30 minutes, then cooled to 0 ° C.-50 C. The reaction mass was maintained for 1 hour at 0 ° C.-5 ° C. and filtered. The filter
26

cake was washed with 100ml of chilled ethyl acetate and suck dried. The solid was then dried in hot air oven at 40 ° C.-450 C. for 8.0 hrs to obtain a solid (91.6 g).
Yield : 84.54%
Chiral purity : 93.35%
Chemical Purity : 96.24%
EXAMPLE 5
S-(+)-N,N-DIMETHYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL) PROPANAMINE OXALATE:
50 ml of DMSO and 10 g of S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propanamine were added into a reaction flask and stirred. 5.4 g of sodium hydroxide and 7.65 ml of 1-fluoronaphthalene was added at room temperature. The reaction mass was heated to 65 ° C.-700 C. and maintained at this temperature for
30.0 hours. The completion of the reaction was checked by TLC. The reaction mass was then cooled to 15 °C.-20 °C. and 250 ml of water was added slowly with stirring. The reaction mass was then extracted with ethyl acetate, and the aqueous and organic layers were separated. The organic layer was washed with water, separated from the aqueous layer and dried over sodium sulphate. Activated charcoal was added to the organic layer at room temperature, stirred and filtered. The filtrate was then distilled under vacuum to obtain a liquid mass (16.8 g). 16.8 g of the liquid mass was added to 140 ml of fresh ethyl acetate and stirred to obtain a clear solution. 115 ml of oxalic acid acetone solution (7.5 g of oxalic acid in 30 ml of acetone) was added at 45 ° C. over a period of 1.0 hour upto a pH of 2.5-3.5. The reaction mass maintained at this temperature for 30 minutes and cooled to 0 ° C.-5 ° C. The reaction mass was maintained at this temperature for 1 hour at 0 ° C.-5 ° C. and filtered. The filter cake was washed with 100ml of chilled ethyl acetate and
27

suck dried. The solid obtained was then dried in hot air oven at 40 ° C.-45 ° C. for 8.0 hours. Dry weight of the solid = 15.5 g.
Yield: 71.53%
Chiral purity: 95.24%
EXAMPLE 6
4-[3-(METHYLAMINO)-l-(2-THIENYL)PROPYL]-l-NAPHTHOL:
To 20 g of Duloxetine hydrochloride; 1.0 N aqueous HC1 solution was added. The reaction mass was heated to about 95° C. and stirred for 3.0 hours. The reaction mass
was cooled to 0 ° C. to 5 ° C. and neutralized with 10 % sodium hydroxide solution, ethyl acetate was added and stirred at room temperature. The solid precipitated was filtered and the filtrate was collected. The solid on the filter paper was crystallized from methanol to obtain 4-[3-(methylamino)-l-(2-thienyl)propyl]-l-naphthol.
EXAMPLE 7
2-[3-(METHYLAMINOH-(2-THIENYL)PROPYL]-l-NAPHTHOL:
To 20 g of Duloxetine hydrochloride; 1.0 N aqueous HC1 solution was added. The reaction mass was heated to about 95° C. and stirred for 3.0 hours. The reaction mass was cooled to 0 ° C. to 5 ° C. and neutralized with 10 % sodium hydroxide solution, ethyl acetate was added and stirred at room temperature. The solid precipitated was filtered off and the filtrate was collected. The filtrate collected was transferred into a separating funnel and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined and washed with water. The organic layer was distilled to obtain a residue. The residue was subjected to column chromatography on a silica gel column (100-200) and eluted with methylene chloride and methylene chloride: methanol. The fraction containing 2-[3-(methylamino)-l-(2-thienyl) propyl]-1-naphthol was collected separately by
28

monitoring with TLC. The solvent was distilled off to obtain 2-[3-(methylamino)-l-
(2-thienyl) propyl]-1-naphthol.
EXAMPLE 8
4-[3-(METHYLAMINO)-l-(2-THIENYL) PROPYL]-l-NAPHTHOL AND 2-[3-
(METHYLAMINO)-l-(2-THIENYL)PROPYL]-l-NAPHTHOL:
Mother liquor of duloxetine HC1 was collected after filtration of duloxetine hydrochloride prepared as per Example 3.The mother liquor was distilled to obtain a residue and the residue was subjected to column chromatography on a a silica gel column (100-200) and eluted with methylene chloride and methylene chloride: methanol, fractions containing 4-[3-(methylamino)-l-(2-thienyl)propyl]-1-naphthol and 2-[3-(methylamino)-l-(2-thienyl) propyl]-1-naphthol were collected separately by monitoring with TLC. The solvent was distilled off from the fractions to obtain 4-[3-(methylamino)-1 -(2-thienyl)propyl]-1 -naphthol and 2-[3-(methylamino)-1 -(2-thienyl) propyl]-1-naphthol separately.
Dated this 22nd day of November, 2006
k^l...
for Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi
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ABSTRACT
The invention relates to improved processes for preparing 3-aryloxy-3-arylpropylamines, intermediates or salts thereof having a substantially high purity. The invention also relates to a method for the preparation of Duloxetine HCl.