FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
PROVISIONAL SPECIFICATION (See section 10; rule 13)
A PROCESS FOR PREPARATION OF AN ANTIDEPRESSANT COMPOUND


SUN PHARMACEUTICAL INDUSTRIES LTD.

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 describes the nature of this invention

A PROCESS FOR PREPARATION OF AN ANTIDEPRESSANT COMPOUND
The present invention provides (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, a compound of formula 1, and acid addition salt thereof in high optical purity and a process for preparation thereof.

Formula 1
Duloxetine is the INN for the hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, a pharmaceutical under approval as an anti¬depressant.
The present invention also provides (S)-isomer of intermediate compounds like (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a key intermediate for duloxetine in high optical purity and a process for preparation thereof.
In another aspect the present invention provides a process for preparation of (±)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine comprising racemization of (R)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine by treatment with a base.
In another aspect the present invention provides a process for preparation of (±)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, comprising racemization of (R)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, by treatment with a base.
In another aspect the present invention provides a process for preparation of an acid addition salt of duloxetine, particularly duloxetine hydrochloride.

2
The aryloxypropanamine compounds like the compound of formula 1 and a process for preparation thereof (see Scheme I) are disclosed in United States Patent Nos., 4956388 and 5023269 (product patent, equivalent Indian references not available). Process for preparation of racemic aryloxypropanamine compounds has been exemplified therein, however, the process for obtaining the optically active isomers is not detailed. The description provides that the optically active isomers may be prepared from optically active precursors or may be resolved from the racemic aryloxypropanamine compounds. These patents however, do not teach the method of obtaining the optically active precursor. For resolution of the aryloxypropanamine compounds, particularly useful resolving agents mentioned are, dibenzoyl-d- and -1-tartaric acid. However, we have found that dibenzoyl-d- and -1-tartaric acid is a poor resolving agent for compound of formula 1 or for the key intermediate thereof, namely, N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine.

Scheme I
As depicted in Scheme I, in the product patent route 2-acetylthiophene is converted to 2-thienyl-2-dimethylaminoethyl ketone, a compound of formula 2 under Mannich reaction condition. The ketone of formula 2 is reduced to obtain the compound of formula 3, viz., N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine. The compound of formula 3 is converted to the aryl ether intermediate, a compound of formula 4 (wherein R\ and R2
3

both are methyl), viz., N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, by reacting with 1-fluoronaphthalene in presence of sodium hydride (NaH). The aryl ether intermediate is converted to the carbamate intermediate, a compound of formula 5, which when hydrolysed, yields the N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1, the hydrochloride salt of the S-isomer thereof, namely, (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine known as duloxetine is of interest for use as an antidepressant.
The asymmetric synthesis of duloxetine involving use of lithium aluminum hydride complexed with a chiral ligand, to synthesize the compound of formula 3 in enantiomeric form has been discussed by Deeter et al in Tetrahedron Letters, 31(49), 7101-04, (1990). It is mentioned that this asymmetric synthesis typically provided duloxetine of >98% enantiomeric excess.
United States Patent No. 5362886 (the '886 patent, equivalent Indian reference not available) teaches an improved process for preparation of duloxetine, wherein the racemic hydroxy compound of formula 3 is resolved by using optically active (S)-(+)-mandelic acid to obtain the S-isomer of compound of formula 3, namely, (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine. Thereafter 'Step c' has been carried out in presence of a potassium compound such as potassium benzoate or potassium acetate to obtain the S-isomer of the aryl ether intermediate (the compound of formula 4, wherein Ri and R2 both are methyl), namely, (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine. The S-isomer of this aryl ether intermediate, has been exemplified in Example 1 and isolated as phosphoric acid salt thereof with 91% enantiomeric excess (ee). In Example 2 duloxetine hydrochloride (duloxetine HC1) is prepared in ethyl acetate using concentrated HC1 and then adding seed crystal.
Although '886 patent does not specifically disclose the ee of duloxetine HC1 obtained in 'Preparation 2' from the salt of S-isomer of compound of formula 4 (wherein Ri and R2 both are methyl) having 91% ee, we have observed that it yields duloxetine HC1 with an ee of about 98% with poor yield. To achieve further higher ee one needs to purify the
4

compound of formula 4 and then convert it to duloxetine HCl or purify duloxetien HCl repeatedly to improve its enantiomeric excess.
Moreover, when we repeated this example on higher scale, we have found it to be non-reproducible and also that dulxetine base would invariably undergo disintegration during treatment with concentrated HCl in ethyl acetate, as is evident from the low yield reported in the Example 2 of the '886 patent, of overall yield of about 27% only. Duloxetine has a 2-thienylmethyl-l-naphthyl ether component making it susceptible to cleavage under acidic conditions. Thus it would be advantageous to have a scaled-up, consistent, reproducible process for preparation of duloxetine HCl, free of undesired impurities.
As discussed hereinbefore it was important that one started with a compound of formula 4 with a higher enantiomeric purity so as to avoid multiple purifications either at intermediate stage or that of duloxetine HCl to achieve further higher enatiomeric purity of duloxetine HCl in high yields. Moreover use of aryl ether intermediate with ee of about 90% leads to optically impure final product. Hence there is a need for developing a process, which consistently yields high purity aryl ether intermediate in terms of chemical and chiral purity.
The chiral intermediate compound of formula 3 is used in the prior art to prepare the aryl ether intermediate in chiral form, a compound of formula 4 (wherein R\ and R.2 both are methyl). It means one needs to handle chiral intermediates at three stages in the process, Step c, Step d and Step e, and particularly one could envisage racemization during the ether formation step wherein compound of formula 4 could racemize in presence of a strong base like NaH, leading to lower enantiomeric purity of the intermediate.
PCT publication WO 03/070720 discloses a different synthetic route using thiophene compounds containing a carbamate group for preparation of intermediate compound of formula 3. Examples 9 an 11 exemplify resolution of compound of formula 3 to obtain the S-enantiomer thereof by using L-(+)-mandelic acid as a resolving agent.
5

PCT publication WO 03/062219 teaches preparation of intermediate compound of formula 6 by subjecting the corresponding racemic compound to resolution with,

Formula 6
(S)-(-)-2-Pyrrolidone-5-carboxylic acid or 2,3,4,6-Di-0-isopropyIidene-2-keto-L-guIonic acid.
PCT publication WO 04/005307 teaches a process for preparation of enantiomerically enriched intermediate compound of formula 6 by subjecting the enantiomeric mixture thereof to resolution with 2,3,4,6-Di-0-isopropylidene-2-keto-L-gulonic acid.
The prior art processes are able to provide duloxetine in about 98% enantiomeric excess. None of the prior art processes exemplify resolution of the aryl ether intermediate, a compound of formula 4 or the resolution of N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, compound of formula 1.
The present invention provides for use of Di-p-toluloyl tartaric acid (referred to as DPTTA herein) as an effective resolution agent for obtaining a compound of formula 4 (wherein Ri and R2 both are methyl or R\ is methyl and R2 is benzyl or substituted benzyl group); or the compound of formula 1 in an enantiomerically enriched form, with optical purity of greater than 98% (ee).
The resolution process of the present invention obviates the need of processing the optically active compound of formula 3 to obtain optically active compound of formula 4 in presence of a hazardous and highly reactive base like NaH, which could lead to potential problems of racemization. Further, it provides a convenient alternative to use of
6

unnatural derivatives of sugar like 2,3,4,6-Di-0-isopropylidene-2-keto-L-gulonic acid as resolving agent, which itself could be sensitive to moisture and acidic conditions.
In our experience, it was observed that optically active resolving agents routinely used on commercial scale such as tartaric acid, mandelic acid, camphor sulphonic acid etc did not work efficiently to resolve either N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 4 (wherein Ri and R2 both are methyl) or the N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1. Also, optically active dibenzoyl-tartaric acid were ineffective in resolving the compound of formula 4 or the compound of formula 1.
However, surprisingly optically active Di-para-toluoyl-tartaric acid was found to be an
effective resolution agent for compound of formula 4 (wherein R\ and R2 both are methyl
or Ri is methyl and R2 is benzyl or substituted benzyl group) and compound of formula 1.
Di-para-toluoyl-L-tartaric acid works as an efficient resolving agent for preparation of
(S)-isomer of compound of formula 4 for example, (S)-(+)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl)propanamine, and (S)-(+)-N-methyl-3-( 1 -
naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1.

Formula 4
For the compound of formula 4, R\ and R2 both are methyl or Ri is methyl and R2 is benzyl or substituted benzyl group. Examples of substituted benzyl group are phenyl ring of the benzyl group substituted with one or more halogen, alkoxy or haloalkoxy group such as -OCF3 group and the like.
For obtaining the other isomer of the compound of formula 4 for example, (R)-(-)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine or the compound of formula
7

1, namely, (R)-(-)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, Di-para-toluoyl-D-tartaric acid can be used as a resolving agent.
In the process of the present invention, any base like potassium tert-butoxide, sodium methoxide, sodium hydroxide can be used in preparation of the racemic aryl ether intermediate of formula 4, from a racemic compound of the formula 3, and the racemic aryl ether intermediate can then be resolved with resolving agent, namely, Di-para-toluloyl-L-tartaricacid to isolate (S)-isomer of compound of formula 4.
In one aspect the present invention provides a process for preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 4 (wherein Ri and R2 both are methyl), comprising the steps of:

Formula 4
a) reacting a mixture of R and S enantiomers of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of (S)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid; and
b) converting the said precipitated salt to (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine.
Further the (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 4 (wherein R| and R2 both are methyl) can be converted to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1 and optionally further converted to a pharmaceutically acceptable salt thereof.
8

The compound of formula 4, wherein R\ is methyl and R2 is benzyl or substituted benzyl can be prepared starting from 2-acetylfhiophene, resolved to obtain the (S)-isomer thereof by reacting with Di-para-toluoyl-L-tartaric acid. The resultant (S)-isomer compound of formula 4 can be isolated and converted to (S)-(+)-N-mefhyl-3-(l-naphfhaleneoxy)-3-(2-thienyl)propanamine, a compound of formula 1 by subjecting to debenzylation reaction for example, by catalytic hydrogenation (outlined in Scheme II below).

Scheme II
A suitable alcohol, ketone, nitrile, ester solvent may be used in the resolution process for preparation of isomers of compound of formula 4 or compound of formula 1. Preferably an ester solvent like ethyl acetate.
The ratio of the compound of formula 4 to the Di-para-toluoyl-L-tartaric acid is preferably from about 1:0.4 to 1:1 mole/mole, more preferably 1:0.48 mole/mole. To accelerate crystallization the solution may be optionally seeded with crystal of the desired
isomer.
9

The desired S-isomer of compound of formula 4, for example, (S)-(+)-N,N-dimethyl-3-
(l-naphthalenyloxy)-3-(2-thienyl)propanamine can be obtained from its Di-para-toluloyl
tartaric acid salt by treatment with any suitable organic or inorganic base, followed by the
subsequent conversion steps leading to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine, which can be converted
to a hydrochloride salt thereof, if desired. If required, the enantiomerically enriched Di-para-toluloyl-L-tartaric acid salt of the (S)-isomer of compound of formula 4 can be subjected to purification from a suitable solvent to obtain desired enantiomeric excess.
The process of the present invention provides (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with greater than 98% enantiomeric excess.
The present invention also provides a process for preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1, comprising the steps of:

Formula 1
a) reacting a mixture of R and S enantiomers of N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of (S)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-L-tartaric acid; and
b) converting the said precipitated salt to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine and optionally further converting to a pharmaceutically acceptable salt thereof.
10

The ratio of N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine to the Di-para-toluoyl-L-tartaric acid is preferably from about 1:0.4 to 1:1 mole/mole, more preferably 1:0.48 mole/mole. To accelerate crystallization the solution may be optionally seeded with crystal of the desired isomer.
The desired (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine can be obtained from its Di-para-toluloyl-L-tartaric acid salt by treatment with any suitable inorganic or organic base and then converted in to a hydrochloride salt thereof, if desired.
In another aspect the present invention provides acid addition salt of (S)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-L-tartaric acid and acid addition salt of (R)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-D-tartaric acid.
The present invention also provides acid addition salt of (S)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-L-tartaric acid and acid addition salt of (R)- N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-D-tartaric acid.
In another aspect the present invention provides a process for preparation of (±)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine comprising racemization of (R)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine by treatment with a base.
In another aspect the present invention provides a process for preparation of (±)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, comprising racemization of (R)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, by treatment with a base.
Any suitable organic base like an alkali metal alkoxide for example, potassium tert-butoxide and the like or inorganic base like alkali or alkaline earth metal salts, for example, sodium hydroxide, potassium carbonate and the like in a suitable protic or
11

aprotic solvents, preferably aprotic solvents like dimethylsulfoxide may be employed for
carrying out the racemization of the unwanted (R)-isomer of N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl)propanamine or the unwanted (R)-isomer of N-methyl-3-
(l-naphthaleneoxy)-3-(2-thienyl)propanamine, generated during resolution of the R and S
enantiomers thereof. It is advantageous to perform the racemization reaction for
converting the unwanted (R)-isomer in to the racemic forms thereof by treatment with
potassium tert-butoxide in dimethyl sulfoxide solvent. Use of 0.5 equivalent of potassium
tert-butoxide with respect to the R-isomer in the form of a free base, is sufficient to carry
out the racemization of the unwanted (R)-isomer. The resultant racemized N,N-dimethyl-
3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine or racemized N-methyl-3-(l-
naphthaleneoxy)-3-(2-thienyl)propanamine then can be recycled to generate the desired (S)-isomers of the respective compounds, thereby increasing the yield of the desired isomer.
The process of resolution of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluloyl-L-tartaric acid yields the aryl ether intermediate viz. (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine a compound of formula 4 in high optical purity (greater than 98% ee) which can be further converted to the desired (S-enantiomer) duloxetine or its HC1 salt with greater than 99% ee, preferably greater than 99.5% ee.
The process of the present invention employing Di-para-toluoyl-L-tartaric acid as a resolution agent provides desired (S-enantiomer) duloxetine HC1 in greater than 99% ee, preferably greater than 99.5% ee.
In another aspect, the present invention provides a process for preparation of hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine, a compound of formula 1, i.e. duloxetine hydrochloride (dulxetine HC1).
12

As discussed hereinbefore, we have observed that in preparation of duloxetine HC1, the use of mineral acid is highly detrimental. The present invention provides an alternative process.
The present invention provides a process for preparation of an acid addition salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1A,

Formula 1A
comprising reacting a compound of formula 1 in the form of free base with a compound represented by formula BHX in a protic solvent, wherein B represents a base and HX represents an acid.
In a preferred embodiment BHX is selected from a group consisting of ammonium chloride, anilinium chloride, trialkylamine hydrochloride, diarylamine hydrochloride and pyridine or substituted pyridine hydrochloride. The most preferred is ammonium chloride. The protic solvent may be any suitable solvent such as an alcohol, water or aqueous alcohol.
In preferred embodiment BHX is ammonium chloride and the protic solvent is an alcohol like methanol.
A salt like ammonium chloride provides a safe and efficient alternative to use of mineral acid in preparation of duloxetine HC1 from a free base thereof, practically without formation of any undesired side-products. Apparently, duloxetine base having a stronger basic character is able to deprotonate ammonium chloride and in turn it gets protonated in
13

presence of a protic solvent to afford duloxetine HCl in higher yields (about 50%) and practically no undesired side products. The duloxetine HCl thus obtained exhibits greater than 99.9% ee and assay greater than 99%.
The process of the present invention provides hydrochloride salt of (S)-N-methyl-3-(l-naphthalenyl-oxy)-3-(2-thienyl) propanamine with greater than 99 % ee.
In a preferred embodiment the hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is prepared by a process comprising,
a) reacting a mixture of R and S enantiomers of N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of
(S)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-
toluoyl-L-tartaric acid;
b) converting the said precipitated salt to (S)-(+)-N-methyl-3-(l-naphfhalenyloxy)-3-(2-
thienyl)propanamine;
c) further treating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine in the form of free base with ammonium chloride in a protic
solvent; and
d) isolating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
hydrochloride salt.
In another preferred embodiment the hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is prepared by a process comprising,
a) reacting a mixture of R and S enantiomers of N,N-dimethyl-3-(l-naphfhalenyloxy)-3-
(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of
(S)-N,N-dimethyl-3-(l -naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-
toluoyl-L-tartaric acid;
b) converting the said precipitated salt to (S)-(+)-N,N-dimefhyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine;
c) further converting (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine to (S)-(+)-N-methyl-3-(1 -naphthalenyloxy)-3-(2-thienyl)propanamine;
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The advantages of the process involving use of a biphasic system over prior art system is that excess HCl would remain in the aqueous phase whereas duloxetine would be in organic phase thereby contact of excess HCl that may be present in the system with the duloxetine would be avoided. Thus the possibility of degradation of dulxetine in presence of HCl is reduced. The water immiscible organic solvent for example, dichloromethane being practically immiscible with water unlike ethyl acetate, is advantageously used in the biphasic system of the present invention for preparation of duloxetine HCl. Another practical advantage is that duloxetine HCl can be prepared conveniently at ambient conditions using the biphasic system of the process of the present invention.
The present invention provides crude (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride (duloxetine hydrochloride) with an enantiomeric purity greater than 99%, preferably greater than 99.5% ee.
Crude duloxetine hydrochloride is the product present in the reaction mixture when duloxetine base is converted to dulxetine hydrochloride salt.
Examples of the water immiscible organic solvents useful for the biphasic system are chlorinated hydrocarbons like dichloromethane, dichloroethane; aromatic hydrocarbons like toluene, xylene; cyclic and acyclic hydrocarbons like hexane, heptane, cyclohexane, petroleum ether fractions; ethers like diethylether. The preferred being chlorinated hydrocarbons, more preferably dichloromethane.
In a preferred embodiment the hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is prepared by a process comprising,
a) reacting a mixture of R and S enantiomers of N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of (S)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with Di-para-toluoyl-L-tartaric acid;
b) converting the said precipitated salt to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine;
16

d) further treating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine in the form of free base with ammonium chloride in a protic
solvent;
e) isolating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
hydrochloride salt.
In prior art duloxetine HCl has been prepared from duloxetine base by treatment with HCl in ethyl acetate solvent. As discussed herein, when we repeated this example on higher scale, we have found it to be non-reproducible and also that dulxetine base would invariably undergo decomposition during treatment with con HCl in ethyl acetate, as is evident from the low yield reported in the Example 2 of the '886 patent, of overall yield of about 27% only. Duloxetine has a 2-thienylmethyl-l-naphthyl ether component making it susceptible to cleavage under acidic conditions. The miscibility of ethyl acetate in water being such that the excess HCl present in the reaction system remains in contact with duloxetine thereby inducing the formation of undesired side-products and lowering the yield of duloxetine.
We further report a novel process for preparation of acid addition salt of duloxetine using a mineral acid in a biphasic system. Particularly of interest is duloxeine HCl.
The present invention provides a process for preparation of hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a compound of formula 1,

Formula 1
comprising treating a compound of formula 1 in the form of free base with HCl in a biphasic system consisting of aqueous phase and water immiscible organic solvent.
15

c) further treating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine in the form of free base with HC1 in a biphasic system
consisting of aqueous phase and water immiscible organic solvent; and
d) isolating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
hydrochloride salt.
In another preferred embodiment the hydrochloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is prepared by a process comprising, a) reacting a mixture of R and S enantiomers of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid to precipitate the salt of (S)-N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thienyl)propanamine with Di-para-toluoyl-L-tartaric acid;
c) converting the said precipitated salt to (S)-(+)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl)propanamine;
d) further converting (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-
propanamine to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine;
d) further treating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine in the form of free base with HC1 in a biphasic system
consisting of aqueous phase and water immiscible organic solvent;
e) isolating (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
hydrochloride salt.
The following examples are given by way of illustration only and not to be construed as limiting.
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EXAMPLES
Example 1
Preparation of (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine
To 170 ml ethyl acetate is added 13 g (0.034 moles) of Di-para-toluoyl-L-tartaric acid and the resultant solution cooled to about 25°C. To this is added a solution of 21 g (0.070 moles) of racemic N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine in 40 ml ethyl acetate. The resultant clear solution is stirred at room temperature for 24 hrs so as to crystallise the acid addition salt of the desired enantiomer of N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine. The product is filtered, washed with ethyl acetate and dried at 50-55°C. Yield:12 g, Specific optical rotation = -11° (C=l in methanol at 25°C , on as is basis).
The above acid addition salt, Di-para-toluoyl-L-tartarate salt of (S)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is then converted to its free base with alkali treatment to obtain S-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine free base followed by conversion to its hydrochloride salt by a process as described in the Example 4 below, to yield S(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride with 99.99% ee
Example 2
Preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthaleneoxy)-3-(2-
thienyl)propanamine
To 120 ml ethyl acetate is added 10 g (0.032 moles) of racemic N,N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, followed by 5.95 g (0.015 moles) of Di-para-toluoyl-L-tartaric acid at 25°C-28°C. The resultant clear solution is stirred at room temperature for about 2-3 hrs so as to crystallise the acid addition salt of the desired enantiomer of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine. The product is filtered, washed with 100 ml ethyl acetate and dried at 60-70°C. Yield: 7.8 g, enantiomeric purity of about 98% ee.
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Example 3
Preparation of (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine
free base from Di-para-toluoyl-L-tartarate salt of (S)-(+)-N,N-dimethyl-3-(l-
naphthaleneoxy)-3-(2-thienyl)propanamine
To (777ml) of DM water is added Di-para-toluoyl-L-tartarate salt of (S)-(+)-N,N-dimethyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine (111 gm) at 25-30°C, toluene (300ml) is added, stirred for about 30 minutes, followed by addition of ammonia solution (about 25%, 100 ml) to the pH of about 9. The layers are separated, and aqueous layer is extracted with toluene (300ml). The layers are separated and the aqueous layer is extracted with toluene (200ml). The combined toluene extract is washed with water (2x100ml) and aqueous NaCl (10%), dried over sodium sulfate. About 100ml toluene is distilled out under vacuum at 60-65°C and then cooled to 40-45°C. Toluene (100ml) is added, followed by addition of diisoprpylethylamine (2 ml) and the reaction mixture is raised to 60-65°C, phenylchloroformate (31.2gm) is added dropwise over about 30 minutes, then temperature is raised to 70-75°C and maintained for 6 hours. The reaction mixture is cooled to 35-40°C and worked up by treatment with aq NaHCC>3, HC1 acid (1 .ON), again with NaHCCb solution, followed by water and NaCl solution and dried over sodium sulfate. Toluene is distilled out under vacuum at 55-60°C and residual mass is degassed under high vacuum (70gm).
To the above residual mass, dimethylsulfoxide (360ml) is added and heated to 40°C, followed by addition of NaOH flakes (20gm) and water (60ml). The temperature is gradually raised to 85-90°C and stirred for 18 hours. The reaction mixture is cooled to 20-25°C and quenched by adding water (650 ml) under stirring. The pH is adjusted to 5.5-6 by adding aq acetic acid (50%, about 80 ml) under stirring at 25-30°C and stirred for 10-15 minutes. The reaction mixture is filtered thro hyflo, washed with hexane (210ml). The product enriched aqueous layer is basified by adding slowly aq NaOH (25%) to pH of about 10.5 at 25-30°C. It is extracted with ethyl acetate (2x300ml), the combined ethyl acetate layer is washed with water, dried, concentrated. The residual mass is degassed under high vacuum at 45-50°C for 1 hour to obtain (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine free base (38gm).
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Example 4
Preparation of duloxetine HC1 salt from (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-
(2-thienyI)propanamine free base
To (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine free base (65gm) prepared as above, methanol (520ml) is added under stirring. To the clear solution at 20-25°C, ammonium chloride (12.3gm) is added under stirring. The reaction mixture is stirred at 20-25°C for 1.5 hours. The solution is heated to 40-45°C and methanol is distilled out under vacuum, residue is degassed. Isopropanol (520 ml) is added to it and charcolized at 40-45°C, filtered through Hyflo bed. The solvent is distilled out completely at 40-45°C under vacuum. To the residue, acetone (650ml) is added under stirring, cooled to 20-25°C, the slurry is stirred for 30 minutes. Then it is heated to 50-55°C to dissolve. The clear solution is gradually cooled to 5-10°C and maintained for 1-2 hours. The product is filtered and washed with acetone (100 ml), dried in air oven at 65-70°C for 2-3 hours.
To duloxetine HC1 obtained above, isopropanol (600ml) is added under stirring and heated to 60°C to get a clear solution, which is gradually cooled to 5-10°C. The solid is filtered and washed with acetone and dried at 60°C to obtain pure duloxetine HC1 (37gm, 100% ee).
Preparation of duloxetine HCI salt from (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine free base: exemplifies preparation of pure duloxetine HCI without crystallization of the salt
To (S)-(+)-N-methyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine free base (65gm) prepared as above, methanol (520ml) is added under stirring. To the clear solution at 20-25°C, ammonium chloride (12.3gm) is added under stirring. The reaction mixture is stirred at 20-25°C for 1.5 hours. The solution is heated to 40-45°C and methanol is distilled out under vacuum, residue is degassed. To the residue, dichloromethane (650ml) is added under stirring, at 25-30°C and the clear solution is stirred for 30 minutes. Then
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dichloromethane layer is washed with D.M Water (2x130 ml). Organic layer (dichloromethane layer) is charcoalised at 25-30°C, filtered through Hyflo bed and dried over sodium sulfate. Dichloromethane is distilled out under vacuum at 40-45°C and residual mass is degassed under vacuum. Acetone (195 ml) is added to the residual mass at 25-30°C to get a slurry and the resultant slurry is gradually cooled to 5-10°C and maintained for 1-2 hours. The product is filtered and washed with acetone (100 ml), dried in air oven at 65-70°C for 2-3 hours to obtain pure duloxetine HC1 (35g, 100% ee).
Example 5
Preparation of (±)-N,N-dimethyl-3-(l-naphthaleneoxy)-3-(2-thienyl)propanamine
oxalate salt by racemization of the (R)-N,N-dimethyl-3-(l-naphthaleneoxy)-3-(2-
thienyI)propanamine
The ethyl acetate filtrate containing the unwanted (R)-isomer as a major component generated during resolution of (±)-N,N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine in a similar manner as in Example 2 is subjected to racemization as below.
To the ethyl acetate filtrate (100ml) containing (R)-N,N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, water (300ml) is added and stirred. The reaction mixture is basified to pH of 8.5-10 by addition of aqueous ammonia solution (~20ml, -23%) at 25-30°C and stirred for 15-20 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate (100ml). The combined product enriched organic layers are washed with water (50ml), aqueous sodium chloride solution (50ml, ~15%w/v) and dried and the solvent distilled out to under vacuum and degassed.
To the residual mass (lOOgm) obtained, dimethyl sulfoxide (400ml) is added and stirred at 25-30°C, cooled to 15-20°C and slowly powdered potassium tert-butoxide (18gm) is added and the suspension is stirred for about 20 minutes at 20-25°C. The reaction mixture is gradually heated to about 80°C and maintained under stirring for 4.5 to 5 hours. It is cooled to about 25°C and water (1200ml) is added and stirred for 15 minutes. The
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reaction mixture is extracted with ethyl acetate (2x400ml). The product enriched ethyl acetate layers are washed with water (200ml) and 10% aqueous sodium chloride solution (200ml), dried. To the product enriched ethyl acetate solution oxalic acid (45gm) and methanol (100ml) are added under stirring at 20-25°C. The slurry is cooled to 15-20 □ 8c and maintained for 1 to 2 hours. The resultant product is filtered and washed with ethyl acetate (2x50ml) and suck dried under vacuum (80gm).
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The present invention particularly relates to:
A] A process for preparation of (±)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine, comprising racemization of (R)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl)propanamine by treatment with a base.
B] The process as described in 'A' above, wherein the racemization is carried out by
treatment with potassium tert-butoxide in dimethylsulfoxide.
C] A process for preparation of (±)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thienyl)propanamine, comprising racemization of (R)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl)propanamine by treatment with a base.
D] The process as described in 'C above, wherein the racemization is carried out by
treatment with potassium tert-butoxide in dimethylsulfoxide.
E] (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine with greater
than 98% enantiomeric excess.
F] (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride with
greater than 99% enantiomeric excess.
G] (S)-(+)-N-methyl-3-( 1 -naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride
with greater than 99.5% enantiomeric excess.
H] Crude (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine
hydrochloride with greater than 99% enantiomeric excess.
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I] Crude (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine
hydrochloride with greater than 99.5% enantiomeric excess.
Dated this 10th day of February 2005
DILIP SHANGHVI
CHAIRMAN AND MANAGING DIRECTOR
SUN PHARMACEUTICAL INDUSTRIES LIMITED