WO2010084459A2

WO2010084459A2 - Improved process for preparing an intermediate of sertraline

Info

Publication number: WO2010084459A2
Application number: PCT/IB2010/050250
Authority: WO
Inventors: Vilas Vasant Pandit; Rajesh Naik; Pravin Karnik; Nitin Pawar; Pranay Shah
Original assignee: Piramal Healthcare Limited
Priority date: 2009-01-21
Filing date: 2010-01-20
Publication date: 2010-07-29
Also published as: WO2010084459A3

Abstract

The present invention provides an improved process for preparation of N-[4-(3,4- dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]methanamine (ketimine) comprising condensation of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (sertralone) with monomethyl amine gas in the presence of a dehydrating agent and an aprotic solvent.

Description

IMPROVED PROCESS FOR PREPARING AN INTERMEDIATE OF

SERTRALINE

FIELD OF INVENTION

The present invention relates to a process for the preparation of N-[4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]methanamine (ketimine). More particularly, the invention relates to an improved process for the preparation of ketimine, a key intermediate in the production of an antidepressant agent, cis-(lS,4S)-4-(3,4- dichlorophenyl)-N-methyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine (Sertraline).

BACKGROUND OF THE INVENTION

The compound, N- [4-(3 ,4-dichlorophenyl)-3 ,4-dihydro- 1 -(2H)-naphthalenylidene] methanamine also known as ketimine, is a key intermediate in the production of sertraline which is an antidepressant. Sertraline hydrochloride is an active ingredient of Zoloft®. There are several methods known in the art for the preparation of ketimine from 4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone (sertralone).

US Patent No. 4,536,518 describes a process for the preparation of ketimine by condensation of sertralone with monomethyl amine using titanium tetrachloride (TiCl₄) as a dehydrating agent in the presence of tetrahydrofuran, as the solvent. When titanium tetrachloride is used as the dehydrating agent, the reaction is very expansive. Also the other drawback of using TiCl₄ as the dehydrating agent is that it forms titanium dioxide in the presence of water, which requires various perilous waste disposal techniques. Moreover, TiCl₄ reacts exothermically with donor solvents such as tetrahydrofuran to give hexacoordinated adducts.

US Patent No. 4,855,500 describes condensation of sertralone with monomethyl amine using hydratable molecular sieves as the dehydrating agent, in the presence of an inert- aprotic solvent to obtain ketimine, wherein appropriate type of molecular sieves (particularly those having a pore size at least about 3 Angstrom units in diameter) absorbs water formed during the condensation of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenone (sertralone) with monomethyl amine. Once the desired condensation reaction is essentially complete, the water saturated molecular sieves are removed by filtration prior to the isolation of ketimine. Further the water saturated molecular sieves need to be recycled for reuse.

US Patent No. 6,593,496 teaches condensation of optically pure (+) enantiomer of sertralone with monomethyl amine involving either using titanium tetrachloride (TiCl₄) or molecular sieves as a dehydrating agent, in the presence of a solvent to yield optically pure cis-(+) enantiomer of sertraline. The process is disadvantageous as it uses titanium tetrachloride as the dehydrating agent and also the process for isolation of the product is very tedious.

International Patent Application No. WO 01/36378 describes reaction of sertralone with monomethyl amine either in the presence Of Ci-C₂₄ amine or C₁-C₁₂ nitrile as a solvent or in the presence of sulfonic acid as a catalyst and a non-alcoholic solvent to obtain ketimine. However, the product obtained using this process may contain traces of sulfur (due to sulfonic acid), which can poison the hydrogenation catalyst during subsequent catalytic reduction of the ketimine to the corresponding amine.

International Patent Application No. WO 99/36394 discloses a process for the preparation of ketimine involving reaction of sertralone with monomethyl amine in the presence of an alcohol, as the solvent. Moreover, the ketimine obtained in this process is hydrogenated in situ to yield a mixture of racemic sertraline, cis sertraline and trans sertraline. However, this process for the preparation of ketimine is carried out at a high reaction temperature of about 100⁰C. Also the time period for said preparation of ketimine is 12 hours. Use of such high temperature and longer reaction time are certainly drawbacks for industrial application of the process. Accordingly, there is a need to develop a process for the preparation of ketimine which is efficient and can substantially eliminate the drawbacks of the existing processes. The inventors of the present invention have surprisingly found a simple and efficient process for the preparation of ketimine from sertralone using inexpensive, non-hazardous and easily available dehydrating agents.

OBJECTS OF THE INVENTION

The basic object of the present invention is to provide an improved process for preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenylidene]methanamine (ketimine) from 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone (sertralone).

Another object of the present invention is to provide an improved process for the preparation of ketimine with better yield and purity >98%.

Yet another object of the present invention is to provide an improved process for the preparation of ketimine using non-hazardous dehydrating agent.

Yet another object of the present invention is to provide an improved process for the preparation of ketimine which is efficient and simple.

Yet another object of the present invention is to provide an improved process for the preparation of ketimine which is cost-effective.

STATEMENT OF THE INVENTION

In accordance with the objects of the present invention, there is provided an improved process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenylidene]methanamine (ketimine) of formula I from 4-(3,4-dichlorophenyl)- 3,4-dihydro-l-(2H)-naphthalenone (sertralone) of formula II, involving reaction of sertralone with monomethyl amine using a dehydrating agent in the presence of an aprotic solvent, with a proviso that the dehydrating agent is not titanium tetrachloride, sulfonic acid or molecular sieves.

The process of the present invention is depicted in the following scheme,

Monomethyl amine

Dehydrating agent Aprotic solvent

Formula II

(Sertralone)

In accordance with another aspect of the present invention, the ketimine prepared in good yield > 92% and better purity >98%.

In accordance with yet another aspect of the present invention, the process of the invention overcomes the disadvantages associated with the processes disclosed in the cited prior art, which concerns with the use of titanium tetrachloride, molecular sieves and sulfonic acid as the dehydrating agent.

In accordance with yet another aspect of the present invention, the dehydrating agents used in the reaction such as aluminum chloride and ferric chloride are inexpensive, non- hazardous and commercially available, hence making the process for preparation of ketimine simple, efficient, cost-effective and non-hazardous. DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for preparing N-[4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]methanamine (ketimine) comprising reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone (sertralone) with monomethyl amine in the presence of a dehydrating agent and an aprotic solvent.

In one embodiment of the present invention the dehydrating agent used in the reaction is selected from the group consisting of an acid catalyst such as aluminum chloride, ferric chloride, zinc chloride and calcium chloride. The dehydrating agent is preferably selected from aluminum chloride and ferric chloride. The dehydrating agents used in the reaction are inexpensive, commercially available and non-hazardous in nature. Aluminum chloride in the presence of water partially hydrolyzes to form hydrochloric acid gas, hence isolation of product is easier.

According to the process of the present invention, dehydrating agents such as titanium tetrachloride, sulfonic acid and molecular sieves are excluded from the scope of the dehydrating agents.

The dehydrating agent, particularly when the dehydrating agent is selected from aluminum chloride or ferric chloride, is used in an amount from 0.4 to 1.0 molar equivalents based on the compound of formula II, 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone (sertralone).

In another embodiment of the present invention, the reaction is carried out in the presence of an aprotic solvent selected from benzene, toluene or xylene. In accordance with the present invention, the reaction is preferably carried out using toluene as the solvent.

The solvent used in the reaction, is about 5 to 15 volume with respect to the compound of formula II, 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone (sertralone), preferably using 8 to 12 volume of solvent with respect to the compound of formula II, 4- (3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone (sertralone).

In another embodiment of the present invention, monomethyl amine used in the reaction, is in the gaseous form. Monomethyl amine gas is used in an amount from 4 to 8 molar equivalents based on the compound of formula II, 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenone (sertralone).

In another embodiment of the present invention, the formation of ketimine according to the process of the present invention is carried out at a temperature ranging from 0⁰C to

70⁰C.

In accordance with the present invention, the starting material sertralone, 4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone is dissolved in an aprotic solvent such as toluene and the temperature of reaction is lowered to about 0°C-5°C. Further the monomethyl amine gas is passed through the reaction mass slowly at about 0°C-5°C, and then the dehydrating agent selected from anhydrous aluminum chloride or ferric chloride is added slowly to the reaction mass. During addition of the dehydrating agent exotherm is observed and the temperature of the reaction rises to room temperature i.e. to about 30⁰C. The reaction mixture is then slowly heated to the temperature ranging from about 65°C-70°C within one hour time duration. At this temperature reaction is maintained further for 5 to 6 hours. At this stage the reaction shows approximately 97% conversion of sertralone to ketimine. (GC analysis, sertralone content NMT 3%). The reaction mixture is then cooled to room temperature. The inorganic salts formed in the reaction can be removed from the reaction solvent using a suitable filtering aid, and then the product is washed with solvent, preferably washed with the same solvent; such as toluene. Thereafter the product is isolated from the reaction solvent by means of evaporation under reduced pressure, to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphthalenylidene]methanamine (ketimine) of formula II, having purity >98%. The starting material of the process, 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenone (sertralone) is a known compound and can be prepared by a person skilled in the art by following the methods described in the literature. For example, sertralone can be prepared by employing the method described in US Patent No. 4,536,518 or the Journal of Medicinal Chemistry, 1984, Vol. 27, No. 11, Page No. 1508, which is incorporated herein by reference.

As previously discussed, the compound of formula I, N-[4-(3,4-dichlorophenyl)-3,4- dihydro-l-(2H)-naphthalenylidene]methanamine (ketimine), product of the present invention is finally converted to sertraline, cis-(lS,4S)-4-(3,4-dichlorophenyl)-N-methyl- 1, 2,3, 4-tetrahydronaphthalen-l -amine, an anti-depressant agent. The ketimine as obtained by the process of the present invention can be converted to sertraline by following the process described in the prior art, US Patent No. 4,536,518. Mainly, N-[4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenylidene]methanamine (ketimine) undergoes catalytic reduction to yield racemic cis-N-[4-(3,4-dichlorophenyl)-3,4- dihydro-l-(2H)-naphthalenylidene]methanamine, thereafter the racemic product is resolved by means of appropriate resolving agents, for example D(-)mandelic acid to obtain sertraline.

The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be construed in anyway to limit the scope of this invention.

EXAMPLES

Example-1: (using aluminum chloride as a dehydrating agent)

In a round bottom flask, sertralone (lOOgm, 0.34mole) was dissolved in toluene (1000ml) and then cooled to 0°C-5°C. The monomethyl amine gas (53.3gm, 1.72mole) was slowly passed through the reaction mixture at 0°C-5°C. Then anhydrous aluminum chloride (22.9gm, 0.17mole) was slowly added at 0°C-5°C. Exotherm was observed during the addition of aluminum chloride and the temperature of the reaction rose to 30⁰C. The flask was slowly heated to 65°C-70°C for 1 hour and the temperature of the flask was maintained for 5-6 hours. The reaction mixture was allowed to cool to room temperature and the inorganic salts precipitated were filtered out. The cake was washed with toluene

(100ml) and then the toluene was removed completely under vacuum to obtain ketimine

(96.6gm).

Yield 92.9%, purity 98% (GC analysis)

Example-2: (using ferric chloride as a dehydrating agent)

In a round bottom flask, sertralone (25gm, 0.086mole) was dissolved in toluene (250ml) and then cooled to 0°C-5°C. The monomethyl amine gas (18gm, 0.58mole) was slowly passed through the reaction mixture at 0°C-5°C. Then ferric chloride (13.8gm, 0.08mole) was slowly added at 0°C-5°C. Exotherm was observed during the addition of ferric chloride and the temperature of the reaction rose to 30⁰C. The flask was slowly heated to 65°C-70°C for 1 hour and the temperature of the flask was maintained for 5-6 hours. The reaction mixture was allowed to cool to room temperature and the inorganic salts precipitated were filtered out. The cake was washed with toluene (25ml) and then the toluene was removed completely under vacuum to obtain ketimine (24gm). Yield 92%, Purity 98% (GC analysis).

Experimental details for Gas Chromatography (GC) analysis

Instrument: Agilent GC 7890A

Column: DB- 17, 30m X 0.53mm I.D.X lμ film thickness Part No. 125-1732

Oven temperature: 200⁰C (hold 1 min) → 260⁰C @ 2°C / min. (hold 9 mins)

Injector temperature: 250⁰C

Detector temperature: 280⁰C

Carrier gas: Helium

Flow rate: 9 ml/min

Split ratio: 1:10

Injection volume: lμl

Claims

WE CLAIM:

1. A process for the preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenylidene]methanamine (ketimine) of formula I,

Formula I

comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone (sertralone) of formula II,

Formula II

with monomethyl amine gas in the presence of a dehydrating agent using an aprotic solvent at a temperature ranging from 0⁰C to 70⁰C, with a proviso that said dehydrating agent is not titanium tetrachloride, sulfonic acid or molecular sieves.

2. The process as claimed in claim 1, wherein the dehydrating agent is selected from a group consisting of aluminum chloride, ferric chloride, zinc chloride and calcium chloride.

3. The process as claimed in claim 2, wherein said dehydrating agent is aluminum chloride or ferric chloride.

4. The process as claimed in claim 1 , wherein said aprotic solvent is selected from a group consisting of benzene, toluene and xylene.

5. The process as claimed in claim 4, wherein said aprotic solvent is toluene.

6. The process as claimed in claim 1, wherein the dehydrating agent is used in amount of 0.4 to 1.0 molar equivalents based on the sertralone of formula II.

7. The process as claimed in claim 1, wherein monomethyl amine gas is used in an amount of 4 to 8 molar equivalents based on the sertralone of formula II.