An Improved Method For Manufacture Of N [4 (3,4 Dichlorphenyl) 3,4 Dihydro 1(2 H) Naphthalenylidene] Methanamine
Abstract:
Process for preparation of compound of formula (I) by the reaction of compound of formula (III), with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30º C to 80º C and at atmospheric pressure. The solution of methylamine in water has a strength of between 20% to 40% w/v. Methylamine is employed in molar proportions of 2 to 20 moles per mole of compound of formula (III). Also according to the invention there is provided a process for preparation of sertraline hydrochloride of formula (II) by the reduction of compound of formula (I).
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Notices, Deadlines & Correspondence
LUPIN LIMITED, SURVEY NO. 46A/47A, NANDE VILLAGE, TALUKA, MULSHI, PUNE-411 042, MAHARASHTRA, INDIA
3. JAIN, AJINATH MURLIDHAR
LUPIN LIMITED, SURVEY NO. 46A/47A, NANDE VILLAGE, TALUKA, MULSHI, PUNE-411 042, MAHARASHTRA, INDIA
Specification
FORM2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF INVENTION
An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine
2. LUPIN LIMITED, (b) of 159 C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India, (c) an Indian Company
The following specification particularly describes the nature of this invention and the manner
in which it is to be performed
18-8-2005
An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine
FIELD OF THE INVENTION
The present invention relates to an improved method for the manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is a key intermediate for the antidepressant drug, Sertraline hydrochloride.
BACKGROUND OF THE INVENTION
The chemical entity (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride, generically known as sertraline hydrochloride of formula (II), is an antidepressant drug useful for the treatment of panic disorder and obsessive compulsive disorder.
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Many methods have been reported for synthesis of sertraline hydrochlorideMost of the methods utilize N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylideneTmethanamine of formula (I) as an intermediate.
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The synthesis of compound of formula (I) in turn has been achieved in several ways. A summary of the reported methods for synthesis of compound of formula (I) is given hereinbelow.
1. The first method for synthesis of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) was disclosed by Welch et. al. in US Patent No. 4,536,518, which comprises condensation of the tetralone of formula (III) with an appropriate primary amine, viz. methylamine in the presence of an acid catalyst like titanium tetrachloride to give the corresponding imine, viz. N~[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I). The imine thus obtained is subjected to catalytic hydrogenation or reduction with a metal hydride complex to give sertraline as a racemic mixture of cis and trans isomers, from which the desired cis isomer is separated.
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Example 1 of US Patent 4,536,518 describes the method for synthesis of compound (I) wherein a solution of tetralone of formula (III) in tetrahydrofuran is treated with monomethylamine followed by dropwise addition of titanium tetrachloride and the mixture agitated at room temperature for 17 hours under an inert gas atmosphere to give the ketimine compound of formula (I). The product is isolated by distilling off excess methylamine and trituration of the residue with hexane.
However, this method suffers from a serious drawback in that it utilizes titanium tetrachloride, which is not only toxic but also corrosive. It is harmful if swallowed, inhaled or absorbed through the skin. It also causes burns and is very destructive of mucous membranes and can cause permanent damage to the eyes, if splashed into the eyes.
It might be mentioned that compound of formula (I) is a Schiff s base and its method of synthesis from the corresponding ketone compound (III) is an equilibrium reaction wherein the equilibrium has to be shifted to the right side, which is normally achieved by removal of water formed in the reaction through azeotropic distillation or other means.
2. An improvement over the method described in US Patent No. 4,536,518 has been reported in US Patent No. 4,855,500 by Spavins et. al. wherein the Schiff s base formation is carried out by reaction of tetralone of formula (III) with monomethylamine under pressure
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and in presence of molecular sieves, which acts as a dehydrating agent and pushes the equilibrium to the right side.
However, this method also suffers from several drawbacks, viz.
(a) the reaction is carried out under pressure;
(b) utilizes methylamine gas, which is cumbersome to handle;
(c) is specific about the pore size of the molecular sieves used; and
(d) utilizes solvents such as ethers which by virtue of containing peroxides are prone to
explosion as well as solvents like benzene, chloroform, carbon tetrachloride etc. which are not
only carcinogenic but also not recommended for use in an industrial manufacture.
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3. A further improvement in the process was disclosed by Simig et. al. in PCT Application
No. WO 99/57095 wherein the tetralone of formula (III) is treated with methylamine in the
absence of a dehydrating agent and in presence of lower alkanol as solvent.
Even though, this method has advantage in that:
(a) no dehydrating agent is used;
(b) reaction is carried out in an alcoholic jjolvent; and
(c) an alcoholic solution of methylamine rather than a gas is used,
however, a limitation of this process is that the reaction is carried under pressure, which renders the method commercially unattractive.
4. Yet another method for synthesis of compound (I) is disclosed by Thomman et. al. in PCT Application No. WO 00/26181 wherein the tetralone of formula (III) is treated with methylamine in an alcoholic solvent and in the presence of a acid catalyst such as p-toluenesulphonic acid, hydrochloric acid, sulfuric acid etc.
5. In a method described by Colberg et. al. in US Patent No. 6,232,500 the imine of formula (I) has been prepared by reaction of the tetralone of formula (III) with methylamine in an alcoholic solvent having a boiling point under the reaction conditions greater than 55 ° C. This patent claims that the inventive merit lies in selection of a suitable solvent for reaction i.e. an alcohol in which the product formed i.e. (I) has high, solubility which results in shifting the equilibrium to the right hand side.
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However, this method like earlier methods is also associated with the same limitations enumerated hereinearlier.
6. In a method described by Thommen et. al. in PCT Application No. WO 01/36377 wherein,
the imine of formula (I) has been prepared by reaction of tetralone of formula (III) with
methylamine gas in alcoholic solvent under pressure.
This method also suffers from the same limitations associated with US Patent No. 6,232,500.
7. In a method described by Laitinen et. al. in US Patent Application No. 2003/0013768,
wherein imine of formula (I) has been prepared by carrying out the reaction of tetralone of
formula (III) with methylamine in an amide solvent in the presence of acid catalyst such as
formic acid, acetic acid, sulfuric acid, hydrochloric acid, scandium triflate etc.
From the foregoing, it would be evident that the prior art methods for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), suffer from one or more of the following limitations, viz.
i) Utilization of corrosive and toxic chemicals like, titanium tetrachloride;
ii) Requires anhydrous conditions wherein the equilibrium is shifted towards the product through removal of water using dehydrating agents such as molecular sieves, acids etc., which leads to increase in the cost of manufacture;
iii) Requires pressure reactors;
iv) Use of methylamine gas, which is cumbersome to handle in large-scale manufacture;
v) Requires tedious isolation techniques; and
vi)Utilizes solvents such as ethers which by virtue of containing peroxides are prone to
explosion as well as solvents like benzene, chloroform, carbontetrachloride etc.
which are not only carcinogenic but not recommended for use in an industrial
manufacture.
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Thus, there exist a need for an improved method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and avoids use of toxic chemicals and hazardous solvents and is moreover, environmentally harmless.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which overcomes the limitations associated with the prior art methods.
Another object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and environmentally harmless.
Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which avoids utilization of corrosive and toxic chemicals.
A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not utilize any dehydrating agent.
Yet further object of the present invention is to prepare N-[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I) which does not require pressure conditions.
Another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require anhydrous conditions.
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Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require any catalyst and can be carried out in aqueous medium.
A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which which can be isolated by simple and convenient techniques.
In their endeavor to achieve the abovementioned objectives the present inventors have found to their surprise that the tetralone of formula (III) can be reacted with an aqueous solution of methylamine under atmospheric pressure conditions in water or a mixture of water and an organic solvent. While the conversion of the tetralone of formula (III) to the imine compound (I) could be carried out in water as a solvent, however, it was found advantageous to carry out the reaction in a mixture of water and an organic solvent, specially solvents which are miscible with water.
SUMMARY OF THE INVENTION
Thus the present invention relates to a process for the preparation of a compound of formula (I),
comprising reaction of a compound of formula (III),
with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30 ° C to 80 ° C and at atmospheric pressure.
The water-miscible solvents are selected from lower aliphatic alcohols, cyclic ethers, acyclic ethers, aprotic solvents such as amides, nitriles, sulfolane and the like.
The reaction in essence takes place in an aqueous medium or in a medium consisting of a mixture of water and an organic solvent with no added catalyst or agents for removal of water from the reaction mixture.
An advantage of the process of the present invention is that, unlike the prior art methods wherein either methylamine gas or its solution in an alcohol is used, the imine compound (I) can be obtained from the corresponding tetralone (III) through utilization of commercially available and inexpensive aqueous solution of methylamine having strength of between 20-40
% w/v.
The reaction is carried out under atmospheric pressure conditions and most importantly does not require any special technique or addition of any agent to drive out water from the reaction mixture. In particular the reaction is carried out in presence of a substantial amount of water, which contrary to the teachings of the prior art provides compound (I) in high yield and purity.
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In the process of the invention the product i.e. N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) precipitates out from the reaction mixture, which can be easily isolated by filtration.
According an aspect of the present invention there is provided a process for preparation of compound of formula (I),
with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, which is environmentally harmless and avoids use of corrosive, toxic, hazardous and carcinogenic chemicals and solvents.
In another aspect, the present invention provides a simple method for isolation of compound of formula (I),
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with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, and filtering the compound of formula (I) from the reaction mixture.
DETAILED DESCRIPTION OF INVENTION
The starting material for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) viz. the tetralone of formula (III) is a known compound and can be prepared by any one of the methods described in US Patent No. 4,536,518 and US Patent No. 6,054,614.
In a typical embodiment, the tetralone (III) is suspended in water or a mixture of water and water miscible organic solvent at room temperature. To the suspension is added an aqueous
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solution of methylamine whereafter the reaction mixture is agitated at a temperature between 30°Cto80°C till the completion of the reaction.
The aqueous solution of methylamine is available commercially in strengths varying from 20 % to 40 % w/v. A solution of any strength could be used in the process of the present invention.
The methylamine is typically employed in molar proportions in excess of the equimolar quantities. Typically it is employed in molar proportions of between 2 moles to 20 moles per