WO2002096860A1

WO2002096860A1 - Process for preparing sertraline intermediates

Info

Publication number: WO2002096860A1
Application number: PCT/FI2002/000466
Authority: WO
Inventors: Ilpo Laitinen; Pekka PIETIKÄINEN
Original assignee: Orion Corporation Fermion
Priority date: 2001-05-31
Filing date: 2002-05-30
Publication date: 2002-12-05
Also published as: CA2448300A1; EP1397342A1

Abstract

A pharmaceutical intermediate, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, which can be used in the production of sertraline hydrochloride, is conveniently prepared by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone with monomethylamine in a solvent which is an amide solvent with a structure of general formula (IV), wherein R1, R3 are indepen dently hydrogen or C1-6 alkyl, which can be substituted, and R2 is hydrogen.

Description

PROCESS FOR PREPARING SERTRALINE INTERMEDIATES

The present invention relates to a novel method for the production of sertraline. The present invention also relates to a novel process for the preparation of a pharmaceutical intermediate, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphtalenylidene]methanamine.

BACKGROUND OF THE INVENTION

N- [4-(3 ,4-dichlorophenyl)-3 ,4-dihydro- 1 (2H)-naphtalenylidene]- methanamine of formula I

is a well known pharmaceutical intermediate which can be used e.g. in the preparation of sertraline, (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine, which has a structure of formula II

Sertraline is marketed in the form of its hydrochloride for the treatment of depression, obsessive-compulsive disorder and panic disorder.

The synthesis of sertraline is described in U.S. Patent no. 4,536,518. The process described includes a condensation reaction of 4-(3,4-dichlorophenyl)-3,4- dihydro- 1 (2H)-naphtalenone of formula III

with monomethylamine, which is catalyzed by titanium tetrachloride yielding N-[4- (3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenylidene]methanamine. The reaction is an equilibrium reaction, where the equilibrium has to be shifted. This can be done e.g. by using titanium tetrachloride to remove water from the reaction mixture. Titanium tetrachloride, however, is extremely reactive with water and side products formed are hazardous, and therefore other dehydrating agents have been considered.

Another route to N-4-[3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphtalenylidene]methanamine is described in U.S. Patent No. 4,855,500, wherein the dehydration characteristics of appropriate mesh molecular sieves are employed to remove water from the reaction mixture to promote the condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenone and monomethylamine. Molecular sieves are expensive and they must typically be regenerated if they are to be reused.

In a process described in EP 1 059 287 (+) enantiomer of sertraline is prepared by either of the processes described above using (+) enantiomer of 4-(3,4- dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenone as a starting material, so that no resolution of the final product is needed. Still another route to to N-4-[3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphtalenylidene]methanamine is described in the patent application WO 99/36394. In the process described the condensation reaction of 4-(3,4-dichlorophenyl)-3,4- dihydro-l(2H)-naphtalenone with monomethylamine is performed in an alcohol solvent. The solubility of the reaction product to the solvent is such that the equilibrium is favorably enhanced towards the product. No catalysts or dehydrating agents are needed. However, monomethylamine is easily vaporized in reaction temperatures (about 50 deg C or above) and therefore a suitable pressure rated vessel is needed and the reaction is carried out under pressure.

Sertraline hydrochloride is produced by further hydrogenating the N-4-[3,4- dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenylidene]methanamine resulted from processes above and resolving the racemic mixture and finally crystallizing sertraline hydrochloride.

Now we have surprisingly found, that if the solvent for the imination process is selected from the solvents of the invention, the reaction can be performed in atmospheric pressure and ambient temperature. Also the amount of the solvent needed is low, impurities are not formed and the yield is good. Water removal agents like titanium tetrachloride or molecular sieves are not needed.

Another aspect of this invention relates to the process wherein the imine product formed in the process of the invention is hydrogenated to form sertraline which is further resolved by e.g. mandelic acid and finally crystallized as (lS-cis)-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride or some other pharmaceutically suitable salt.

Still another aspect of the invention is a pharmaceutical composition comprising ( 1 S-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 - naphthalenamine or its hydrochloride or some other pharmaceutically suitable salt prepared by the process of the invention. DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides a process for producing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine, by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with monomethylamine in a solvent selected from the a group consisting of amide solvents of general formula IV:

R2

IV

N- ^"R1

R3

wherein Rl and R3 are independently hydrogen or C_1-6 alkyl, which can be substituted, and R2 is hydrogen.

In another embodiment, the present invention provides a process wherein the N-[4-(3,4-dichlorophenyl)-3,4-dihydro- 1 (2H)-naphthalenylidene]methanamine so formed in the process of the invention is hydrogenated to form sertraline which may be further resolved by the use of, e.g., mandelic acid and finally crystallized as (1S- cis)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-N-methyl-l -naphthalenamine hydrochloride or some other pharmaceutically suitable salt.

In still another embodiment, the present invention provides a pharmaceutical composition comprising (lS-cis)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-N- methyl-l -naphthalenamine or its hydrochloride or some other pharmaceutically suitable salt prepared by the process of the invention.

In a preferred embodiment of the present invention the solvent used in the imination step is dimethylformamide or methylformamide, most preferably, the solvent is dimethylformamide. The imination of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with monomethylamine may be performed in the presence of acid catalyst, which can be any suitable organic or inorganic acid, e.g., formic acid, acetic acid, sulfonic acid, or hydrochloric acid. In a preferred embodiment of the invention, formic acid or acetic acid is used as the acid catalyst.

The solubility of the product in the solvent of the invention is low, so that the product is slowly crystallizing out of the reaction mixture and it can be isolated easily by, e.g., filtration. The process has also considerable purification capacity. The reaction can be performed under atmospheric pressure and is typically carried out at a temperature in the range of from about 0 °C to about 50 °C, preferably at ambient temperature, i.e., from about 15 °C to about 25 °C. Of course, the imination may also be carried out under a slight positive pressure of an inert atmosphere, such as nitrogen gas or argon gas.

Suitably, the 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone is added to the solvent in an amount of about 300 g to about 400 g per liter of solvent, preferably about 320 g to about 350 g per liter of solvent. The methylamine is added in an amount of about 4 mole to about 6 mole per mole of 4-(3,4-dichlorophenyl)- 3,4-dihydro-l-(2H)-naphthalenone, preferably about 4.8 mole to about 5.2 mole per mole of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone. When used, the acid catalyst is typically added to the mixture in an amount of about 0.1 mole to about 2.0 mole per mole of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenone, preferably about 0.4 mole to about 0.6 mole per mole of 4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone.

The present method is not constrained to any particular order of addition, and the reaction may be conveniently performed by charging all of the components into a suitable-size vessel at 0 °C and then allowing the reaction mixture to rise to ambient temperature. The reaction mixture is then stirred at ambient temperature for a time of about 10 to about 30 hours, preferably about 20 to about 24 hours. If desired, the progress of the reaction may be monitored by any suitable technique, including chromatography, especially high-pressure liquid chromatography (HPLC) or thin- layer chromatography (TLC). The resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro- l(2H)-naphthalenylidene]methanamine is insoluble in the reaction solvent and exists as a solid precipitate in the reaction mixture at the completion of the reaction. The resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphthalenylidene]methanamine may then be isolated from the reaction mixture by any suitable solid-liquid separation technique, such as filtration, centrifugation, or decantation.

The resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro- l(2H)-naphthalenylidene]methanamine may be further hydrogenated to form cis- ( 1 S)( 1 R)- 4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -naphthalenamine which may then be optically resolved with, e.g., mandelic acid and finally crystallized to afford (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine hydrochloride or some other pharmaceutically suitable salt.

Pharmaceutical compositions comprising (lS-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -naphthalenamine or its pharmaceutically suitable salt prepared by the method of the invention can be prepared by methods well-known in the art.

The following examples are used to illustrate but by no means to limit the scope of the invention, which is defined in the claims.

EXAMPLE 1.

Preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenylidenej-methanamine

4-(3,4-Dichloroρhenyl)-3,4-dihydro-l-(2H)-naphtalenone (100 g), N,N- dimethylformamide (300 ml) and formic acid (6.5 ml) are charged. Methylamine (56.0 g) is added at about 0 °C. The mixture is stirred for 20 hours at room temperature. The mixture is cooled to 10 °C and stirred for 1 hour. The crystalline compound is filtered and washed with methanol. The yield is 97.7 g (93.5 %) as dried. The same process was performed using N-methylformamide as a solvent in the imination step. Yield was 90.1 %.

EXAMPLE 2.

Preparation of (lS-cis)-4-(3 ,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl- 1 -naphthalenamine hydrochloride (sertraline hydrochloride)

N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]- methanamine (50 g) is hydrogenated over palladium on charcoal to yield cis- (lS)(lR)- 4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine. The rasemic compound is resolved by mandelic acid and finally crystallized as sertraline hydrochloride. The total yield from 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphtalenone is 67 % (of the theoretical (+)-enantiomer).

Claims

1. A process for preparing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphthalenylidene]mefhanamine of formula I:

said process comprising:

(1) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone of formula III:

with monomethylamine in a solvent which is selected from the group consisting of amide solvents with a structure of general formula IV: R2-

IV

N— R1

/

R3

wherein Rl and R3 are independently hydrogen or C, ₆ alkyl, which can be substituted and R2 is hydrogen.

2. A process according to claim 1 wherein the solvent is dimethylformamide or methylformamide.

3. A process according to claim 2 wherein the solvent used is dimethylformamide.

4. A process according to any of claims 1 to 3 wherein the reaction is performed in the presence of an acid catalyst.

5. A process according to any of claim 4 wherein the acid catalyst is formic acid or acetic acid.

6. A process according to any of claims 1 to 5 wherein the reaction is performed in the temperature range from about 0 deg C to about 50 deg C.

7. A process for producing (lS-cis)-4-(3 ,4-dichlorophenyl)- 1,2,3, 4- tetrahydro-N-methyl- 1 -naphthalenamine or pharmaceutically acceptable salt thereof, which has the structure of formula II:

said process comprising:

(1) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone of formula HI:

with monomethylamine in a solvent which is selected from the group consisting of amide solvents with a structure of general formula IV:

∞- IV

N— R1

/

R3

wherein Rl and R3 are independently hydrogen or C_{1 6} alkyl, which can be substituted and R2 is hydrogen to obtain N-[4-(3,4-dichlorophenyl)-3,4-dihydro- 1 (2H)-naphthalenylidene]-methanamine of formula I:

(2) hydrogenating said N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphthalenylidene]methanamine of formula I to obtain a mixture of racemic cis sertraline and racemic trans sertraline, and

(3) resolving said mixture of racemic cis sertraline and racemic trans sertraline to obtain said (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1 -naphthalenamine or pharmaceutically acceptable salt thereof.

8. A process according to claim 6 wherein the mixture of racemic cis sertraline and racemic trans sertraline is resolved by mandelic acid.

9. A process of claim 6 or 7 wherein said pharmaceutically acceptable salt is hydrochloride.

10. A pharmaceutical composition comprising (lS-cis)-4-(3,4- dichlorophenyl)- 1 ,2,3,4-tetrahydro-N-methyl- 1 -naphthalenamine hydrochloride prepared by the process of claim 6 or 7.