Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-03-29
2001-07-17
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S192000, C564S217000, C564S218000, C564S221000, C564S222000, C564S414000
Reexamination Certificate
active
06262308
ABSTRACT:
The present invention relates to a process for the preparation of racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, also known as racemic sertraline, corresponding to formula (I) below:
isolated in salt form.
The S,S enantiomer of sertraline, in the form of the hydrochloride salt, corresponding to the following formula:
has a therapeutic application in the treatment of depression and associated problems, as described, for example, in document EP-0,030,081.
At the present time, the racemic salt from which the abovementioned pharmaceutically active salt is isolated is obtained from 4-(3,4-dichlorophenyl)tetralone of formula (II) below:
In accordance with the synthesis of compound (I) in salt form described in the said document EP-0,030,081, 4-(3,4-dichlorophenyl)tetralone of formula (II) is reacted with anhydrous methylamine, in the presence of a dehydrating reagent, a hydrogenation reaction of the condensation product obtained is carried out over palladium on charcoal and the salt of the racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine is separated out by selective crystallization.
This process has several drawbacks. Firstly, it uses dangerous reagents such as anhydrous methylamine, titanium tetrachloride and gaseous hydrogen chloride. Next, during this process, partial hydrogenolysis of the chloro substituents on the phenyl ring takes place, leading to the formation of monochloro sertraline compounds.
The Applicant has developed a process for obtaining racemic sertraline from 4-(3,4-dichlorophenyl)tetralone which avoids the problems encountered above.
The subject of the present invention is a process for the preparation, in two steps, of racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine (or racemic sertraline) corresponding to formula (I), in salt form, the said process comprising the steps according to which:
(a) 4-(3,4-dichlorophenyl)tetralone of formula (II) described above is reacted with N-methylformamide in the presence of formic acid,
(b) the reaction medium obtained according to (a) is treated with a base, and
(c) the salt of the racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine is separated out by selective crystallization with an acid.
The process of the invention is very advantageous since, starting with the salt which it gives, sertraline can be obtained in a single crystallization step, in virtually pure form.
Preferably, in step (a), the 4-(3,4-dichlorophenyl)tetralone of formula (II) is in a mixture with 4-(2,3-dichlorophenyl)tetralone of formula (III) described below.
This variant of the process of the invention is particularly advantageous for the following reasons:
the pure 4-(3,4-dichlorophenyl)tetralone of formula (II) is obtained in five steps in accordance with the process described in the abovementioned document EP-0,030,081; its synthesis in only one step is also described in EP-0,346,226, by reaction of &agr;-naphthol with ortho-dichlorobenzene in the presence of a Lewis acid such as aluminum chloride; to obtain the tetralone in essentially pure form, according to this second route, two crystallization steps are necessary; the authors of the article Repinskaya, Sib. Khim. Zh. (1993) 73-76 (Chemical Abstracts, 120, 106497) have demonstrated that, under the conditions for obtaining tetralone in a single step (EP-0,346,226), a mixture of the isomers 4-(3,4-dichlorophenyl)tetralone of formula (II) and 4-(2,3-dichlorophenyl)tetralone of formula (III) is in fact obtained in a (II)/(III) ratio of 4.9/1; the variant of the process of the invention proposes to react the mixture of tetralones (II) and (III) directly after reaction of &agr;-naphthol with ortho-dichlorobenzene, without prior purification of the tetralone (II);
the fact that 4-(3,4-dichlorophenyl)tetralone of formula (II) is available as a mixture with 4-(2,3-dichlorophenyl)tetralone of formula (III) does not place a burden on the step for separating out the salt to be obtained.
In the context of the invention, preferred implementations of the process were determined; these are outlined below.
For step (a) the following characteristics can be selected alone; they will advantageously be chosen in combination.
Step (a) is carried out at a temperature ranging from 150° C. to 220° C., preferably ranging from 180° C. to 200° C.
The N-methylformamide is present in a molar ratio ranging from 1.1 to 5 relative to the mixture of the 4-(dichlorophenyl)tetralones of formulae (II) and (III), respectively, and preferably ranging from 2.5 to 3.
Formic acid, which acts as a reducing agent in this reaction, is advantageously introduced in fractions of 10% of the total amount to be added. The latter amount preferably represents a molar ratio ranging from 1.1 to 5, and better still ranging from 1.1 to 2, relative to the abovementioned mixture.
When the 4-(3,4-dichlorophenyl)tetralone of formula (II) is in a mixture with 4-(2,3-dichlorophenyl)tetralone of formula (III), the weight proportion of the 4-(3,4-dichlorophenyl)tetralone in this mixture is at least 80%, that of the 4-(2,3-dichlorophenyl) tetralone being not more than 20%. The mixture is very advantageously obtained by reaction of &agr;-naphthol with ortho-dichlorobenzene, in the presence of aluminum chloride, preferably under the conditions described in document EP-0,346,226. According to the indications described in Chemical Abstracts 120, 106497, the mixture thus obtained contains about 82% of compound of formula (II) and 18% of compound of formula (III).
Similarly, for step (b), it is desirable to select the following characteristics.
The base used in step (b) to deformylate the N-methylformamide-4-(dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamines obtained in step (a) preferably consists of an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, the former being preferred.
This base can be used in pure form or as an aqueous solution.
Step (b) is preferentially carried out in a hydroxylated solvent, such as an alcoholic solvent. This advantageously consists of a C
1
-C
8
alcohol, and preferably consists of 1-butanol. Favorable conditions for the deformylation are a reflux temperature of the solvent and a reaction time of at least three hours.
At the end of step (b), the resulting alkali metal formates are dissolved in the aqueous phase, and the racemic sertraline salt is obtained, in step (c), by selective crystallization by treating the organic phase with an acid, such as a halo acid, preferably hydrochloric acid, an alkylsulfonic acid, preferably methanesulfonic acid, or an arylsulfonic acid, preferably para-toluenesulfonic acid.
The precipitation, isolation and purification of the salt obtained in step (c) are carried out according to standard techniques which are well known to those skilled in the art. According to the preferred acid used, a salt chosen from the methanesulfonate, the para-toluenesulfonate and the hydrochloride is thus obtained.
Starting with the racemic sertraline salt, a person skilled in the art will make use of known methods for separating enantiomers in order to obtain the S,S enantiomer of sertraline hydrochloride, which has therapeutic properties. As an example, this separation can be carried out by crystallization of the salt of an optically active acid or by chromatography on a chiral phase followed by salification with hydrochloric acid.
Another subject of the invention is the compound N-methylformamide-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, which corresponds to formula (IV) below.
This compound is an intermediate in the synthesis of sertraline. It can be obtained by reaction of a mixture of 4-(3,4-dichlorophenyl)tetralone of formula (II) and 4-(2,3-dichlorophenyl)tetralone of formula (III) with N-methylformamide in the presence of formic acid.
The invention also relates to the use of N-methylformamide-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine to obtain racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylam
Catalys
Kumar Shailendra
Oliff & Berridg,e PLC
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