FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - "Novel Process for Preparation of Duloxetine and Intermediates
For Use Therein"
2. Applicant(s)
(a) NAME : ARCH PHARMALABS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri
(East), Mumbai-400 072, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF INVENTION:
The present invention relates to salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine more particularly Lewis acid salts of duloxetine of the formula I.
/
r S / VQ. Lewis acid

Formula-I
The present invention further relates to a process of preparation of salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine, more particularly Lewis acid salts of duloxetine of formula I.
BACKGROUND OF INVENTION:
In general Lewis acid salts of Duloxetine can be represented as:


'S^^ VQ . Lewis acid

NH

Formula-I
e.g. Duloxetine zinc chloride is represented by the compound of formula (la).
/ ~N . ZnCI2
e i H

Formula-(Ia)
's V "o

(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine of the Formula III is known as duloxetine under the International Nonproprietary Name.

Formula III
Duloxetine is a selective inhibitor of serotonin and nor epinephrine uptake in the human body. It is used as antidepressant in the clinical practice. Duloxetine is an efficient active pharmaceutical ingredient, which inhibits the metabolism of serotonin, the decreased level of which is responsible for depression and anxiety. Duloxetine hydrochloride salt of Formula II is most suitable for use in clinical practice as antidepressant

Formula II
US5023269 and US4956388 disclose chemical synthesis of duloxetine. All these syntheses describe the use of optically active precursor of key intermediate or resolution of racemates.
US5491243 discloses a stereospecific process for the synthesis of dimethyl precursor of Duloxetine and isolating it as a phosphoric acid salt (98.1% potency, adjusted yield of 79.6% with EE % 91. The obtained phosphoric acid salt is then


converted into corresponding base followed by demethylation to get duloxetine and isolating it as hydrochloride with potency of 99.8%. However there is no mention of chiral purity
WO2004/056795 discloses resolution of racemic duloxetine using various chiral acids like mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid with preference to di-p-toluyl tartaric acid and conversion of these salts either into free base or other addition salts like hydrochloride as appropriate. It also describes racemisation and recycling of the non-desired enantiomer thereby increasing the economy of the process.
WO 2007/105021 discloses fumarate, citrate or mandelate salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine with organic acids which is essentially devoid of impurity ± methyl-3- (2-thiophenyl)-3-(4-hydroxy-l-naphtyl)-propylamine.
US 2007/0191616 discloses process for obtaining optically pure (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and acid addition salts which also provides for racemic resolution of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine to obtain S-enantiomer with di-para-toluyl-L-tartaric acid.
Thus the prior art discloses that enantiomerically pure duloxetine is obtained by the methods summarized below:
a) Chiral resolution of 3-(Dimethylamino)-l-(2-thienyl)-l-propanol, followed by converting into Duloxetine.
b) Asymmetric reduction of 3-(Dimethylamino)-l-(2-thienyI)-l-propanone to get the corresponding alcohol, followed by converting into Duloxetine.
c) Chiral resolution of 3-methylamino-l-(2-thienyl)-l-propanol, followed by conversion to Duloxetine.
d) Chiral resolution of racemic duloxetine.


The processes for preparation S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine of disclosed in the prior art suffer with disadvantage of requiring racemic resolution with resolving agents like mandelic acid or di p-toluyl tartaric acid to give S- enantiomer. The other disadvantage of the prior art processes is expense which precludes the field scale application. Another disadvantage in the process is the inconsistency, non reproducibility and formation of undesired impurities.
Salt preparation is preferable as a way of purification since salts possess high melting temperature, so the impurities can be removed easily. However, the disadvantage of the methods used in state of art is the high cost of the chiral acids used for isolating the chiral salts of duloxetine or precursors thereby requiring enhanced raw material consumption, conversion of chiral salts into duloxetine base, its isolation and further conversion into addition salts increases unit operation beside the problems like racemisation and yield loss.
Thus there is a need of a process which will be more cost effective and industrially more beneficial.
The present inventors have surprisingly found that the use of salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophen) propanamine more particularly Lewis acid salts renders the invention cost effective and industrially more acceptable.
The present inventors have used salts preferably of Lewis acids, for example salt of zinc chloride. The present invention has following advantages over the existing prior art, namely:
1. Easy availability and low cost material making the process commercially effective.
2. The resultant product thus obtained is of high chiral and chemical purity as required with good yield.


3. There is in-situ conversion of Lewis acid salts e.g. zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine into Duloxetine hydrochloride is achieved by using another simple chemical IPA. HC1. Thus, the total number of steps is reduced as it does not involve the isolation of the duloxetine base.
4. Easy handling of solids isolated as precursors.
5. Enhancement of chiral purity of Duloxetine by using Lewis acid.
In summary, processes disclosed in prior art for the preparation of duloxetine hydrochloride, are tedious, time consuming and operationally difficult at industrial scale. Therefore, there exists a need for improvement in the process which is devoid of the above mentioned drawbacks.
Surprisingly, the present inventors have found an improved process for preparing Duloxetine hydrochloride, which is operationally simple, cost-effective, easy to handle and feasible at commercial scale.
OBJECT OF THE INVENTION:
It is an object of the present invention to provide salts more particularly Lewis
acid salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl)
propanamine.
It is another object of the present invention to provide a process for preparing (+) duloxetine Hydrochloride of high optical purity, almost free from (-)-duloxetine from salts preferably Lewis acid salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.
It is another object of the present invention to provide preparation of salts more particularly Lewis acid salts of (S)-(-)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-


thiophenyl) propanamine which is an important intermediate for preparing duloxetine free base or other acid addition salts as appropriate
It is yet another object of the present invention to enhance the chiral purity of duloxetine or other intermediates thereof by using Lewis acids.
It is yet another object of the present invention to provide the process for preparing duloxetine hydrochloride of the formula II without isolating duloxetine base from salts preferably Lewis acid salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.
It is a further object of the present invention to provide a cost effective process for preparing duloxetine hydrochloride of the formula II.
SUMMARY OF THE INVENTION:
According to an aspect of the present invention there is provided salts more particularly Lewis acid salts of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.
According to another aspect of the present invention there is provided a process for preparation of zinc chloride of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine comprising the step of:
i. Reacting(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl)
propanamine with zinc chloride to form (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine, zinc chloride.
According to yet another aspect of the present invention there is provided a process for preparation of the hydrochloride salt of duloxetine comprising the step of:


i. Adding IPA.HCI to (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-
thiophenyl) propanamine, salt preferably Lewis acid salt to get the required duloxetine hydrochloride without isolating duloxetine base.
DETAILED DESCRIPTION:
Duloxetine required for the purpose can be made from the process available in the prior art.
The present invention uses Lewis acids for making the addition salts of Duloxetine in place of chiral acids.
The present invention uses Lewis acid for the purpose of making salts , for example zinc chloride salt of duloxetine in place of expensive chiral acids. Duloxetine zinc chloride salt is treated with IPA.HC1, where salt of weak base (Duloxetine) and weak acid (Zinc chloride) gets displaced by strong acid (HCl) of IPA.HC1. The resulting bond between duloxetine and HCl is stronger than the existing bond between duloxetine and zinc chloride. This displacement avoids the isolation of duloxetine base. This process not only minimizes the unit operation and cost but also reduces the time cycle making it industrial friendly.
Accordingly the process of the present invention comprises of:
1) Reacting(S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propan- amine with Lewis acid like zinc chloride resulting into (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine. zinc chloride.
2) Adding IPA.HC1 into above salt to get the required Duloxetine Hydrochloride without isolating Duloxetine base.


Schematic representation of the present invention is depicted as below:

SUgtl

o
2-Acetyl thiophene

(HCHO)n; (CH3)2N H.HCI HCI; IPA;70-75-C

VY^N'HCI
o
3-(dimethylamino)-1-(thiophen 2-yl) propan-1-one hydrochloride

SUgtll
Enzyme; 35-38"C

0 3-(dimethylamfno)-1 -(thiophen 2-yl) propan-1-one hydrochloride

OH
S(-)-3-(dimetrtylamino)-1-(thiophen 2-yl) propan-1-ol

Stiff* ///

/ r

S'

OH

o

S(-)-3-{dimethylamino)-1-{thiophen 2-yO propan-1-ol

S(-)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen 2-yl) propan-1-amine

Stage IV

-Sx

r r
o
X ,~

Phenyl chloroformat NaOH/DMSO

O
60

S(-)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen 2-yl) propan-1-amine

S(+)-N-methyl-3-(f)aphthalen-1-yloxy)-3-(thiophen 2-yl) propan-1-amine

Stiff* V

iuTi

N Lewis acid H 0

S{+)-N-methyl-3-(naphthalen-1-yloxy)-3 -(thiophen 2-yl) -propan-1-amine

S(+)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen2-yl) propan-1-amine.ZnCI2

Stage VI
N HCI
I PA .HCI
2

S(+)-N-methyl-3-(naphthalen-1-yioxy)-3-(thiophen 2-yi) propan-1-amine,ZnCI2

S(+}-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen 2-yl) propan-1 -amine .Hydroch loride

The hydroxyl amine used in the present invention can be prepared by any of the process available in the prior art. The Invention can be best understood by the following non limiting examples.


Examples:
Duloxetine base required for the purpose was prepared from the process available in the prior art.
Example -1:
Preparation of (S)(-)-N, N-Dimethyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine
To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged dimethyl sulphoxide (DMSO) (225 ml) and (S)-(-)-3-methylamino-l-(thio[phene-2-yl) propan-1-ol and the colorless solution cooled to 10-15°C. The solution when cooled sodium hydride (12.5 gm, 60% dispersion) was added lot wise over a period of 60 minutes keeping the temperature at 10-20°C and the contents were stirred for 30 minutes at the same temperature. Slowly heat the reaction mixture to 60-65°C and charge drop wise 1-Fluoronaphthalene (50 gm). The solution was stirred at 60°C to 65°C and the progress of the reaction was monitored by TLC. After complete conversion, cooled the reaction mass followed by the reaction mixture was poured into mixture of 10 ml acetic acid in 1000 ml water. Allow the temperature raise to ambient temperature. 10°C to 20°C and stirred for 15 to 20 minutes. Adjust the pH of the reaction mixture to 12 using 30% caustic solution. Extract the reaction mixture with toluene (3 X 150 ml). Combined organic layer washed with water (1 X 50 ml). Dry over anhydrous sodium sulphate. Use the organic layer as such for the next step.
Example -2:
Preparation of (S)-(+)-Methyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-
1-amine, zinc chloride salt
To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux
condenser and calcium chloride drying tube under an atmosphere of nitrogen gas
were charged above toluene layer, diisopropyl ethyl amine (70 ml), and the


colorless solution heated to 50°C. To the solution phenyl chloroformate (105 gm) was added lot wise over a period of 120 minutes keeping the temperature at 50-55°C. The solution was stirred at the same temperature and the progress of the reaction was monitored by TLC. After complete conversion, the reaction mass was cooled to ambient temperature. To the reaction mixture charged caustic solution (700 ml, 10% in water) stirred for 15 to 20 minutes. The layers were separated. Potassium hydroxide (133 gm) was charged to the reaction mixture. The reaction mixture was heated to reflux and maintained for 3 hours. The progress of the reaction was monitored by TLC. After complete conversion, the reaction mass was cooled to ambient temperature. Adjust the pH of the reaction mixture to 12 by using potassium hydroxide (20 ml, 50%). The layers were separated. Washed the organic layer with water (1 x 100 ml). Complete recovery of toluene under vacuum at 45° to 50°C, followed by stripping of toluene (50 ml) provided dark brown colored oil. (83.6 gms) which was dissolved in methanol (400 ml) at 50-60°C. Cooled to ambient temperature followed by to 0°C. To this added a solution of zinc chloride in methanol over a period of 30 mins. The precipitated product was further cooled to 0-5 °C and maintained for one hour. The precipitated solid was filtered, washed with cold methanol (25 ml) and dried at 45 to 50°C for 4 to 6 hours to provide (S)-(+)-Methyl -3-(naphthalene- 1-yloxy)-3-thiophen-2-yl) propan-1-amine, zinc chloride salt as a off white to brown colored powder. DXT-ZnCl2data: IR absorption frequencies in cm-1:
3499, 3477, 3053, 2812, 1680, 1506, 1461, 1396, 1263, 1236, 1094, 1058, 904, 855, 836,
M.P. by DSC- 163-165°C Chemical Purity by HPLC : > 99% Chiral Purity: 99.18%


Example -3:
Preparation of (S)-(+)-Methyl -3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1 -amine, hydrochloride
To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged above zinc chloride salt in IPA. Stirred to suspend. To the suspension charged IPA.HC1 to get clear solution. The clear reaction mixture was stirred for 8 hrs. The precipitated product was further cooled to 0-5°C and maintained for one hour. The precipitated solid was filtered, washed with cold IPA (25 ml) and dried at 45 to 50°C for 4 to 6 hours to provide (S)-(+)-Methyl-3-(naphthalene-l-yloxy)-3-thiophen-2-yl) propan-1-amine, hydrochloride as a off white to white colored powder.