WO2008065177A1 - Processes for preparing desmethylsertraline or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

The invention relates to processes for preparing desmethylsertraline, or a pharmaceutically acceptable salt thereof, from (+/-) sertraline or from a cis/trans or cis 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine mixture.

Description

 "Processes for preparing desmethylsertraline or a pharmaceutically acceptable salt thereof"

The present invention relates to processes for preparing desmethylsertraline, or a pharmaceutically acceptable salt thereof, from (+/-) - sertralone (4- (3,4-dichloro-phenyl) -3,4- dihydro-2H-naphthalen-l-one).

The present invention also relates to processes for the preparation of desmethylsertraline, or a pharmaceutically acceptable salt thereof, from a cis / trans or cis mixture of 4- (3,4-dichlorophenyl) -1,2, 3,4-tetrahydro-1-naphthylamine.

Desmethylsertraline is the common name for the chemical compound which corresponds to the name 1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine according to the IUPAC nomenclature.

Desmethylsertraline therefore means the stereoisomer (IS, 4S) of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine of formula (I):

The chemical structure (I) of desmethylsertraline can be represented as follows:

Desméthylsertraline La desméthylsertraline est encore appelée deméthylsertraline, ou N- desméthylsertraline ou N-deméthylsertraline ou encore norsertraline. La desméthylsertraline est le principal métabolite de la sertraline chez l'homme. La sertraline est la lS,4S-N-méthyl-4-(3,4-dichlorophényl)-l,2,3,4- tétrahydro-1-naphthy lamine. Le Zoloft® (chlorhydrate de sertraline) est un puissant inhibiteur sélectif de recapture de la sérotonine (SSRI) très bien toléré et très largement utilisé cliniquement pour le traitement d'états dépressifs.

desmethylsertraline Desmethylsertraline is also called demethylsertraline, or N-desmethylsertraline or N-demethylsertraline or norsertraline. Desmethylsertraline is the major metabolite of sertraline in humans. Sertraline is 1S, 4S-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine. Zoloft® (sertraline hydrochloride) is a potent selective serotonin reuptake inhibitor (SSRI) that is highly tolerated and widely used clinically for the treatment of depressive states.

The primary metabolisms of sertraline in humans, dogs, rats and mice are identical and lead to the formation of desmethylsertraline via N-demethylation of the amine. Several studies have shown that the pharmacological properties of desmethylsertraline are significantly different from those of sertraline. Indeed, it has been shown in in vitro studies to quantify the inhibition of serotonin reuptake that desmethylsertraline is ten to twenty times less effective than sertraline (BK Koe et al, Journal of Pharmacology and Experimental Therapeutics 226, (3), 686-700

(1983); MW Welch et al, Journal of Medicinal Chemistry 27, 1508-1515 (1984)).

In addition, unlike sertraline, it could be shown that desmethylsertraline has no significant effect on immobilization time in the Porsolt forced swimming test.

The cis isomer of (I) is intended to mean an equimolar mixture of isomer (IS, 4S) and isomer (IR, 4R) of the compound (I), that is to say an equimolar mixture of desmethylsertraline and 1R, 4R-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine. By trans isomer of (I), is meant an equimolar mixture of isomer (IR, 4S) and isomer (IS, 4R) of the compound (I), that is to say an equimolar mixture of IR, 4S-4- (3,4-dichlorophenyl) -l, 2,3,4-tetrahydro-l-naphthylamine. and 1S, 4R-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine. By cis / trans mixture of (I) is meant an equimolar mixture of cis isomer and trans isomer of the compound (I), that is to say an equimolar mixture of isomer (IS, 4S), isomer (IR, 4R), isomer (IR, 4S) and isomer (IS, 4R) of the compound (I) by 4- (3,4-dichlorophenyl) -1,2,3,4- Tetrahydro-1-naphthylamine is intended to denote a mixture of the isomers (1S, 4S), (1R, 4R), (1S, 4R) and (IR, 4S) in variable proportions of the compound (I).

By (+/-) - sertralone is meant the racemic mixture of the optical isomers of 4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen-1-one corresponding to the chemical structure (II) shown below.

(+/-) sertralone

The term "pharmaceutically acceptable salts" is intended to denote the addition salts which can be obtained by reaction of a compound, such as desmethylsertraline, with an inorganic or organic acid, which are non-toxic and which possess the pharmacological activity. desired parent compound.

The present invention firstly relates to a process for the preparation of desmethylsertraline, or a pharmaceutically acceptable salt thereof, from the cis isomer of 4- (3,4-dichlorophenyl) -1,2,3, 4-Tetrahydro-1-naphthylamine (I), which comprises the following steps:

1) adding an enantiomerically pure chiral organic acid to a solution containing at least one cis isomer of (I); 2) crystallization of the diastereoisomers (IS, 4S) of the salt formed by the addition of this enantiomerically pure chiral organic acid;

3) isolating the isomer (IS, 4S) of the compound (I) in the form of said salt;

4) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of the compound (I) in free base form.

Acid

desméthylsertraline (I¹)we ctive

desmethylsertraline (I ¹ )

The cis isomer of the compound (I) can be obtained from a salt thereof, for example cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydrohydrochloride. 1-naphthylamine, by subjecting this salt to a basic treatment, such as with ammonia in aqueous solution.

Said solution of step 1) is preferably a solution of the cis isomer of the compound (I) or a solution of the cis / trans mixture of the compound (I), as defined above. The solvent is selected so as to allow complete dissolution of the cis isomer of the compound (I). This solvent must be in addition a good crystallization solvent for the diastereoisomer (IS, 4S) of the salt formed by the addition of the enantiomerically pure chiral organic acid. Solvents that meet these criteria are alcohols, chosen for example from ethanol or methoxy ethanol.

The term "enantiomerically pure chiral organic acid" is intended to mean one of the optical isomers of a chiral organic acid, that is to say the levorotatory isomer or the dextrorotatory isomer, with an enantiomeric purity substantially equal to 100%. This chiral organic acid may be chosen from the optical isomers of the acid mandelic acid, tartaric acid, lactic acid or 10-camphorsulfonic acid. The chiral organic acid is preferably L - (+) - tartaric acid.

The addition of the enantiomerically pure chiral organic acid to the cis isomer of the compound (I), that is to say to an equimolar mixture of isomer (IS, 4S) and isomer (IR, 4R) of the compound (I), leads to the formation of a mixture of diastereoisomers of the compound (I) in salt form. Only the diastereoisomer (IS, 4S) will crystallize in the chosen solvent. The stereoselective crystallization of the isomer (IS, 4S) of the compound (I) in salt form can be carried out with stirring and at room temperature. This stereoselective crystallization makes it possible to isolate the isomer (IS, 4S) of the compound (I) of the isomer (IR, 4R) of the compound (I). Its isolation can be effected by filtration for example. An additional step of recrystallization, hot or not, in a suitable solvent can be advantageous. By way of example, ethanol, acetonitrile and methoxyethanol can be mentioned as solvents. Preferably, the crystallization solvent is ethanol and the recrystallization is carried out in methoxyethanol while hot. If it is desired to recover desmethylsertraline in free base form, the salt can be subjected to a basic treatment, such as with aqueous ammonia solution.

The second subject of the present invention is a process for the preparation of desmethylsertraline from (+/-) - sertralone, according to route 1 or route 2.

Lane 1 comprises the preparation of the cis / trans mixture of the compound (I) from (+/-) - sertralone by a reductive amination reaction, followed by the stereoselective crystallization of the (1S, 4S) enantiomer of compound (I), that is to say desmethylsertraline in a salified form with a chiral organic acid, as described above.

More specifically, lane 1 comprises the following steps: 1) reductive animation of the (+/-) sertralone of formula (II) to obtain an equimolar mixture of isomers (IS, 4S), (IR, 4R), (IS, 4R) and (IR, 4S) of the compound (I);

2) preparing a solution containing said equimolar mixture of isomers (IS, 4S), (IR, 4R) (IS, 4R) and (IR, 4S) of the compound (I) obtained in step 1) in a organic solvent;

3) addition of an enantiomerically pure chiral organic acid to the solution prepared in step 2);

4) crystallization of the salt formed by the addition of this enantiomerically pure chiral organic acid;

5) isolating the isomer (IS, 4S) of the compound (I) in the form of said salt;

6) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of the compound (I) in free base form.

The reductive amination reaction of step 1) can be carried out, at room temperature or by heating, from a solution of (+/-) - sertralone (II) in an organic solvent and from a source of ammonia, whether or not in the presence of a dehydrating agent and / or an acid, to conduct an intermediate formation of 4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen ylideneamine (III). The reduction of the compound (III) leads to the cis / trans mixture of the compound (I).

A titre d'exemple de solvant organique, on peut citer le méthanol, l'isopropanol, le dichlorométhane, le chloroforme ou le 1,2-dichloroéthane. De manière préférée, le solvant organique est un alcool comme le méthanol ou l'isopropanol. A titre d'exemple de source d'ammoniaque, on peut citer l'ammoniaque sous la forme de gaz ou bien les sels organiques d'ammonium comme le formiate d'ammonium ou l'acétate d'ammonium. De manière préférée, la source d'ammoniaque est de l'acétate d'ammonium.Reduction

As an example of an organic solvent, mention may be made of methanol, isopropanol, dichloromethane, chloroform or 1,2-dichloroethane. Preferably, the organic solvent is an alcohol such as methanol or isopropanol. As an example of a source of ammonia, mention may be made of ammonia in the form of gases or organic ammonium salts such as ammonium formate or ammonium acetate. Preferably, the source of ammonia is ammonium acetate.

The reduction step may be carried out by adding to the reaction medium a borohydride salt such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Alternatively, the reduction step can be carried out in the presence of hydrogen and a metal catalyst such as Raney nickel, activated palladium on carbon. The hydrogen source may be hydrogen gas added or generated in situ from ammonium formate, for example. Preferably, the reducing agent is sodium borohydride.

The stereoselective crystallization step of the desmethylsertraline can be carried out by adding an enantiomerically pure chiral organic acid to a solution of the cis / trans mixture of the compound (I) in a suitable solvent. An intermediate step of recrystallization, hot or not, in a suitable solvent may be necessary if necessary. The desmethylsertraline can then be isolated in the free base form by a simple basic treatment according to a method known per se.

By way of example of a chiral organic acid, mention may be made of the optical isomers of mandelic acid, the optical isomers of tartaric acid, the optical isomers of lactic acid, and the optical isomers of 10-camphorsulfonic acid. . Preferably, the chiral organic acid is L- (+) - tartaric acid. Route 2 comprises the preparation of desmethylsertraline from (+/-) - sertralone, via imine A and amine cis-B, of the following chemical structures:

Lane 2 comprises the formation of sterically hindered imine of formula A ([4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen-1-ylidene] - (4-methoxy-benzyl) ) -amine)), reducing this imine to amine cis-B ([4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-yl] - (4- methoxy-benzyl) -amine), a debenzylation reaction to lead to the formation of the cis isomer of the compound (I) and finally a step of stereoselective crystallization of the enantiomer (1S, 4S), ie desmethylsertraline in a salified form, with an enantiomerically pure chiral organic acid, as described above. Specifically, route 2 comprises the following steps: 1) adding 4-methoxybenzylamine to a solution of (+/-) sertralone of formula (II) in an organic solvent, optionally in the presence of a dehydrating agent, to obtain the compound of formula A;

2) reduction of the compound of formula A, for example in an organic solvent in the presence of a borohydride salt, or by the action of hydrogen gas in the presence of a metal catalyst such as Raney nickel, palladium activated on carbon, palladium hydroxide or platinum, to obtain the compound of formula cis-B;

3) hydrogenolysis of the NC bond of the compound of formula cis-B, especially under a hydrogen atmosphere in the presence of a metal catalyst, preferably in an acid medium or in the presence of cerium (IV) ammonium nitrate, to obtain an equimolar mixture of isomers (IS, 4S) and (IR, 4R) of the compound

(I);

4) preparing a solution containing said equimolar mixture of isomers (IS, 4S) and (IR, 4R) of the compound (I) obtained in step 4) in an organic solvent;

5) addition of an enantiomerically pure chiral organic acid to the solution prepared in step 5);

6) crystallization of the salt formed by the addition of this enantiomerically pure chiral organic acid;

7) isolating the isomer (IS, 4S) of the compound (I) in the form of said salt;

8) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of the compound (I) in free base form.

The formation of sterically hindered imine A can be carried out at room temperature or by heating by adding 4-methoxybenzylamine to a solution of (+/-) - sertralone (II) in an organic solvent, optionally in the presence of a dehydrating agent. As an example of an organic solvent, mention may be made of toluene, xylene, methanol, isopropanol, dichloromethane, chloroform or 1,2-dichloroethane. Preferably, the organic solvent is toluene.

The reduction of the sterically hindered imine A to the cis-B amine can be carried out for example in an organic solvent, in the presence of a borohydride salt such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Advantageously, the reduction step may be carried out in the presence of hydrogen gas and a metal catalyst such as Raney nickel, activated palladium on carbon, palladium hydroxide or platinum. Preferably, the metal catalyst is Raney nickel. Remarkably, this reduction by hydrogenation catalytic induces stereoselectivity in favor of the predominant formation of the cis-B isomer.

The debenzylation of the cis-B amine to give rise to the formation of the cis isomer of the compound (I) can be carried out by hydrogenolysis of the CN bond, in particular under a hydrogen gas atmosphere, optionally at a pressure greater than 1 atm, and in the presence of a metal catalyst such as palladium activated on charcoal. In order to limit the formation of impurities such as the dechlorination products (loss of one or more chlorine atoms), the debenzylation step may advantageously be carried out in an acidic medium or in the presence of cerium (IV) nitrate. ammonium in one or more solvents. Preferably, the debenzylation step is carried out in an acetonitrile / water mixture in the presence of cerium (IV) ammonium nitrate.

The stereoselective crystallization step of the desmethylsertraline can be carried out by adding an enantiomerically pure chiral organic acid to a solution of the cis isomer of the compound (I) in a suitable solvent, according to the method described above. The present invention also relates to the use of (+/-) sertralone (II) for the preparation of desmethylsertraline.

The subject of the present invention is also the compound of formula cis-B, especially as synthesis intermediate for the preparation of desmethylsertraline. The pharmaceutically acceptable salts of desmethylsertraline can be obtained from desmethylsertraline and a mineral or organic acid in one or more solvents.

Among the salts formed by the addition of an acid, mention may be made of acetates (for example those prepared from acetic or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulphates and borates. , butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrobromic acid) , 2-hydroxyethanesulfonates, lactates, maleates (prepared from maleic acid), methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates , pivalates, propionates, salicylates, succinates, sulfates (for example those prepared by from sulfuric acid), sulphonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates. Preferably, the pharmaceutically acceptable salts of desmethylsertraline are obtained from desmethylsertraline and hydrochloric acid or L - (+) - tartaric acid in one or more solvents.

The examples below are for illustrative purposes only and can not be construed as limiting the teaching of this specification.

EXPERIMENTAL PART

Abbreviations ACN = acetonitrile Bn = benzyl

CDC13 = Deuterated chloroform

DCM = dichloromethane

DMF = dimethylformamide DMSO = dimethylsulfoxide

Eq. = equivalent

Et = ethyl

And ₂ O = diethyl ether or ethyl ether

EtOAc = ethyl acetate EtOH = ethanol

HCl = hydrochloric acid

K ₂ CO ₃ = potassium carbonate

KOH = potassium hydroxide

LAH = lithium aluminum hydride Me = methyl

MeOH = methanol

MgSO ₄ = magnesium sulphate

NaBH ₄ = sodium borohydride

NaBHsCN = sodium cyanoborohydride NaBH (OAc) ₃ = sodium triacetoxyborohydride

NaCl = sodium chloride

Na ₂ CO ₃ = sodium carbonate

NaHCO ₃ = sodium hydrogen carbonate

NaOH = sodium hydroxide Na ₂ SO ₄ = sodium sulphate

NH ₄ Cl = ammonium chloride Ph = phenyl

PI1 ₃ P = triphenylphosphine

TEA = triethylamine

TFA = trifluoroacetic acid THF = tetrahydrofuran

Yield = yield

L = liter (s) mL = milliliter (s) μL = micro liter (s) mM = millimolar μM = micro molar nM = nano molar mmol = millimole (s) μmol = micromole (s) g = gram (s) mg = milligram (s) μg = microgram (s)

TA = ambient temperature

Pf = melting point HPLC = high pressure liquid chromatography

LCMS or HPLC / MS = liquid chromatography coupled to mass spectroscopy

APCI = chemical ionization at atmospheric pressure

Tps ret. = Retention time FM = molecular formula

PM = molecular weight NMR = Nuclear Magnetic Resonance

Procedures and materials used to prepare and characterize chemical molecules

The compounds of the invention were obtained using conventional organic synthesis methods.

The HPLC spectra were carried out on a Varian Prostar device and a 5 μm Xterra MSC18 column (2.1x150 mm) in gradient mode with a mixture ACN / water / TFA (0.05%) as a mobile phase, a flow rate of 0.6 ml / min. and a diode array detector (200-400 nm)

The chiral HPLC spectra were carried out on a Waters Alliance type chain with a CHIRACEL OJ column (4.6x250 mm, 10 μ) in isocratic mode at 30 ^° C. with an Isooctane / EtOH / TFA mixture (97/3 / 0.1) as mobile phase, a flow rate of 1 mL / min and a diode array detector (200-400 nm)

Elemental analyzes were performed on an AE1110 analyzer (EC instrument)

HPLC / MS analyzes were performed on a Plateform spectrometer

LC Micromass (Super ODS gel TSK column 4.6 mm ID x 5 cm, flow rate 2.75 ml / min, gradient: 100% A to 100% B in 3 min, 100% B plateau 1 min, solvent

A = water / 0.05% trifluoroacetic acid and solvent B = acetonitrile / water / trifluoroacetic acid 80/20 / 0.05).

The 1 H NMR spectra were obtained on a BRUCKER Avance 400 pulsed wave spectrometer operating at 400 MHz for proton NMR. Chemical shift values (d) are expressed in parts per million (ppm). The reference used is tetramethylsilane (TMS, d = 0.00 ppm).

In the description of the spectra, the multiplicities of the signals are indicated by means of the following abbreviations: s, d, dd, t, q, m, M meaning singlet, doublet, doublet of doublet, triplet, quadruplet, multiplet and massive, respectively.

Unless otherwise mentioned the products used for the preparation of the compounds of general formula (I) are commercial and have been used without preliminary purification. The experimental protocols described below are in no way limiting and are given by way of illustration.

Example 1: Preparation of [4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen-1-ylidene] - (4-methoxy-benzyl) -amine A

In a 250-mL flask, surmounted by a condenser and a Dean-

Stark (20 mL), 15 g of (+/-) - sertralone (II) (51.5 mmol) and 13.4 mL of A-methoxybenzylamine (103 mmol, 2 eq) are dissolved in 30 mL of toluene. The reaction medium is refluxed for 24 hours and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in isopropanol (35 ml) and heated under reflux of the solvent. The resulting solution is slowly cooled to room temperature and then to 4 ° C resulting in the formation of a precipitate. The solid is filtered off, washed with isopropanol and then with pentane, and then dried to give 19.3 g of [4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen-1-ylidene] (4-methoxy-benzyl) -amine A (Yield: 91%)

FM = C ₂₄ H ₂ ICl ₂ NO; MW = 410.35 g / mol;

¹ H NMR (CDCl ₃ ): 8.37 (1H, dd), 7.32 (5H, M), 7.20 (1H, d), 6.89 (4H, M), 4.63 (2H, dd), 4.17 (1H, m), 3.81 (3H, s), 2.62 (2H, m), 2.30 (1H, m), 2.16 (1H, m);

Example 2 Preparation of cis- [4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-yl] - (4-methoxy-benzyl) -amine of formula cis -B

In a 250 mL three-necked flask, 2 g of [4- (3,4-dichloro-phenyl) -3,4-dihydro-2H-naphthalen-1-ylidene] - (4-methoxy-benzyl) -amine A (4.87 mmol) are put in solution in 20 mL of ethanol. 340 μl of TEA (0.5 eq) and a spatula tip Raney Nickel are added and stirring is continued at room temperature under a hydrogen atmosphere for 7h. The reaction medium is then filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: cyclohexane / EtOAc 95/5) to give 1.69 g of the cis-B [4- (3,4-dichlorophenyl) -1,2 isomer, 3,4-Tetrahydro-naphthalen-1-yl] - (4-methoxy-benzyl) -amine (Yield:

84%)

FM = C ₂₄ H ₂₃ Cl ₂ NO; PM = 412.36 g / mol; ¹ H NMR (CDCl ₃ ): 7.32 (4H, M), 7.25 (1H, d), 7.18 (1H, dd), 7.10 (1H, dd), 6.98 (1H, dd), 6.89 (2H, d), 6.78 (1H, dd), 3.98 (1H, m), 3.78-3.96

(6H, M), 2.15 (1H, m), 2.00 (2H, m), 1.85 (1H, m);

Example 3 Preparation of a cis / trans mixture of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine (I) from (+/-) - sertralone (II)

In a 500 ml flask, 15.8 g of ammonium acetate (206.1 mol, 30 eq.) Are dissolved in 140 ml of isopropanol in the presence of 15 g of Na ₂ SO ₄ . The reaction medium is heated to 80 ^° C. then 2 g of (+/-) - sertralone (II) (6.87 mmol, 1 eq.) Are added in small portions. Stirring is continued at 80 ^° C. for 2 h and then the reaction medium is cooled to ambient temperature. 1.04 g of sodium borohydride (27.5 mmol, 4 eq) are added in portions. Stirring is continued at 80 ^° C. for 16 hours. The reaction medium is filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 50 ml of dichloro-methane and the organic phase is washed with a saturated aqueous solution of NaCl. The organic phase is collected, dried over Na ₂ SO ₄ and concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica (eluent: pentane / EtOAc / NH ₃ , 20/80/2) to give 1.26 g of a cis / trans mixture of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine as a yellowish oil (Y) (Yield: 63%)

FM = Cl ₆ H ₅ Cl ₂ N; MW = 292.21 g / mol;

¹ H NMR (CDCl ₃ ): 7.44 (1H, d), 7.35 (1H, d), 7.22 (2H, M), 7.12 (1H, dd), 6.95 (1H, dd), 6.80 (1H, d), 4.08 (1H, m), 4.02 (1H, m), 2.02 (3H, M), 1.77

(1H, m);

Example 4 Preparation of cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine (cis isomer of (I)) from (+/-) - sertralone (II) In a 500 ml flask, 2.3 g of (+/-) - sertralone (II) (7.9 mmol, 1 eq) and

18 g of ammonium acetate (237 mol, 30 eq.) Are dissolved in 80 ml of isopropanol and then 3.5 g of sodium cyanoborohydride (55.3 mmol, 7 eq.) Are added in portions. Stirring is continued at reflux of the solvent for 8 hours. The reaction medium is filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 100 ml of dichloromethane and the organic phase is washed with a saturated aqueous solution of NaCl. The organic phase is collected, dried over MgSO ₄ and concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica (eluent: pentane / EtOAc / NH ₃ , 20/80/2) to give 423 mg of cis-4- (3,4-dichlorophenyl) -1,2,3-isomer 4-tetrahydro-1-naphthylamine in the form of an oil (Yield: 42%)

FM = Cl ₆ H ₅ Cl ₂ N; MW = 292.21 g / mol;

¹ H NMR (CDCl ₃ ): 7.42 (1H, d), 7.35 (1H, d), 7.22 (2H, M), 7.12 (1H, dd),

6.95 (1H, dd), 6.80 (1H, d), 4.08 (1H, m), 4.02 (1H, m), 2.04 (3H, M), 1.75 (3H, M);

Example 5: Preparation of trans-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine (trans isomer of (I)) from (+/-) - sertralone (II) The trans-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine isomer (210 mg) is isolated in the form of an oil during the purification by gel chromatography. silica described above in Example 4 (yield: 21%)

FM = Cl ₆ H ₅ Cl ₂ N; MW = 292.21 g / mol; ¹ H NMR (CDCl ₃ ): 7.51 (1H, d), 7.33 (1H, d), 7.24 (1H, dd), 7.12 (2H, M),

6.87 (1H, dd), 6.80 (1H, d), 4.10 (2H, M), 2.29 (1H, m), 2.11 (1H, m), 1.79

(1H, m), 1.64 (3H, M);

Example 6: Preparation of cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine (cis isomer of (I)) from cis- [4- (3) 4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-yl] - (4-methoxy-benzyl) -amine of the formula cis-B

In a 100 mL flask, 1 g of cis- [4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-yl] - (4-methoxy-benzyl) - The amine (2.43 mmol) is dissolved in 14 ml of acetonitrile and then 14 ml of an aqueous solution containing 5.32 g of cerium (IV) ammonium nitrate are added dropwise. The reaction medium is stirred at room temperature for 5 h and then diluted with 200 mL of ethyl acetate. The organic phase is collected and then washed successively with 150 ml of a saturated aqueous solution of NaHCO ₃ and then 100 ml of a saturated aqueous solution of NaCl. The organic phase is then dried over Na ₂ SO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent DCM: MeOH / NH ₃ , 98/2 / 0.2) to give 397 mg of cis-4- (3,4-dichlorophenyl) -1,2,3,4 tetrahydro-1-naphthylamine in the form of a translucent oil (Yield: 56%) FM = Cl ₆ H ₅ Cl ₂ N; MW = 292.21 g / mol;

¹ H NMR (CDCl ₃ ): 7.44 (1H, d), 7.35 (1H, d), 7.22 (2H, M), 7.12 (1H, dd), 6.95 (1H, dd), 6.80 (1H, d), 4.08 (1H, m), 4.02 (1H, m), 2.02 (3H, M), 1.77 (1H, m); Example 7 Preparation of desmethylsertraline hydrobromide

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 mL of acetonitrile and 0.5 mL of a solution of acetonitrile containing 0.82 mmol (1.2 eq) of hydrobromic acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered to provide the desmethylsertraline hydrobromide in the form of a white solid (209 mg, Yield: 79%) FM = Cl ₆ Cl ₅ Cl ₂ N, HBr, 0.75H ₂ O; MS = 386.63 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 99.1%;

¹ H NMR (DMSO-d6): 8.4 (3H, br s), 7.6 (3H, M), 7.3 (3H, M), 6.77 (IH, d), 4.56 (IH, m), 4.18 (IH, M ), 2.05 (4H, M);

Elemental Analyzes: Exp.-% C (49.75); % H (4.38); % N (3.70);

Theo-% C (49.71); % H (4.56); % N (3.62);

Example 8 Preparation of Desmethylsertraline Phosphate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 mL of acetonitrile and 0.5 mL of a solution of acetonitrile containing 0.82 mmol (1.2 eq) of phosphoric acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and then recrystallized in hot ethanol to provide the desmethylsertraline phosphate in the form of a white solid (117 mg, yield: 41%)

FM = Ci ₆ Hi ₅ Cl ₂ N, H ₃ PO _4, 1.5 H ₂ O; MS = 417.23 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 100%;

¹ H NMR (DMSO-d 6): 7.62 (1H, d), 7.60 (1H, d), 7.52 (1H, d), 7.25 (2H, M), 7.19 (1H, dd), 6.71 (1H, d); 5.4 (3H, brs), 4.39 (1H, m), 4.12 (1H, M), 2.00 (4H, M); Elemental Analyzes: Exp.-% C (46.05); % H (4.55); % N (3.30);

Theo-C (46.06); % H (5.07); % N (3.36);

Example 9 Preparation of desmethylsertraline methylsulfonate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 mL of ethyl ether and 0.5 mL of a solution of ethyl ether containing 0.82 mmol (1.2 eq) of methanesulfonic acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and then recrystallized from acetonitrile under heat to give desmethylsertraline methylsulphonate in the form of a white solid (150 mg, yield: 56%).

FM = Cl ₆ Cl ₅ Cl ₂ N, CH ₃ SO ₃ H; MS = 388.31 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 99.3%;

¹ H NMR (DMSO-d 6): 8.33 (3H, brs), 7.62 (1H, d), 7.54 (2H, M), 7.28 (3H, M), 6.73 (1H, d), 4.52 (1H, m). ), 4.18 (1H, M), 2.32 (3H, s), 2.00 (4H, M);

Microanalyses: Exp.-% C (52.24); % H (5.02); % N (3.52); % S (8.29) Theo:% C (52.58); % H (4.93); % N (3.61); % S (8.26)

Example 10 Preparation of desmethylsertraline citrate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 ml of ethanol and 0.5 mL of ethanol solution containing 0.82 mmol (1.2 eq) of citric acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and then washed with acetonitrile and then with pentane. The solid is finally recrystallized from hot ethanol to give desmethylsertraline citrate in the form of a white solid (72 mg, yield: 27%). FM = Cl ₆ H ₁₅ Cl ₂ N, 0.5 C ₆ H ₈ O ₇ ; MS = 388.27 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d 6): 7.60 (1H, d), 7.54 (2H, M), 7.21 (3H, M), 6.71 (1H, d), 4.24 (1H, m), 4.12 (1H, M); 2.5 (2H, s), 2.00 (4H, M);

Microanalyses: Exp. -% C (58.64); % H (4.94); % N (3.54); Theo. -% C (58.78); % H (4.93); % N (3.61);

EXAMPLE 11 Preparation of desmethylsertraline malate 200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 mL of acetone and then 0.5 mL of a solution of acetone containing 0.82 mmol (1.2 eq) of malic acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and then recrystallized from methoxyethanol while hot to give desmethylsertraline malate in the form of a white solid (71 mg, yield: 29%).

FM = C ₁₈ H ₁₅ Cl ₂ N, 0.5 C ₄ H ₆ O ₅ ; MS = 359.25 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%; ¹ H NMR (DMSO-d 6): 7.60 (1H, d), 7.54 (2H, M), 7.21 (3H, M), 6.71 (1H, d), 4.21 (1H, m), 4.12 (1H, M); 3.80 (0.5H, dd), 2.39 (1H, dd), 2.00 (4H, M);

Microanalyses: Exp. -% C (59.83); % H (5.11); % N (3.82); Theo. -% C (60.18); % H (5.05); % N (3.90);

Example 12 Preparation of desmethylsertraline succinate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 mL of acetone and 0.5 mL of acetone solution containing 0.82 mmol (1.2 eq) of acid succinic is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered to provide desmethylsertraline succinate in the form of a white solid (182 mg, yield: 65%)

FM = C ₁₈ H ₁₅ Cl ₂ N, C ₄ H ₆ O ₄ ; MP salt = 410.30 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 100%;

¹ H NMR (DMSO-d 6): 7.60 (1H, d), 7.51 (2H, M), 7.23 (3H, M), 6.73 (1H, d), 4.38 (1H, m), 4.14 (1H, M); 2.29 (4H, s), 2.00 (4H, M);

Microanalyses: Exp. % C (58.69); % H (5.17); % N (3.42); Theo. -% C (58.55); % H (5.16); % N (3.41);

EXAMPLE 13 Preparation of Desmethylsertraline fumarate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 ml of ethanol and 0.5 mL of ethanol solution containing 0.82 mmol (1.2 eq) of fumaric acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and recrystallized in hot methoxyethanol to provide desmethylsertraline fumarate as a white solid (22 mg, yield: 9%) FM = Ci ₆ Hi ₅ Cl ₂ N, 0.5 C ₄ H ₄ O ₄ ;

MW salt = 350.25 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d 6): 7.55 (3H, M), 7.21 (2H, M), 7.14 (1H, M), 6.70 (1H, d), 6.40 (1H, s), 4.20 (1H, m). 4.12 (1H, M), 3.40 (3H, brs), 2.00 (4H, M);

Microanalyses: Exp. -% C (61.63); % H (4.94); % N (3.96); Theo. -% C (61.73); % H (4.89); % N (4.00);

EXAMPLE 14 Preparation of desmethylsertraline pamoate 200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 1 ml of pyridine and then 0.5 ml. a solution of pyridine containing 0.82 mmol (1.2 eq) of pamoic acid is added. The medium is concentrated to dryness and then taken up in 5 mL of ethanol. The medium is stirred at room temperature for 3 days. The solid formed is filtered and rinsed with ethanol. The filtrate obtained is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 3 mL of acetonitrile. The solid formed is filtered and rinsed with pentane to provide the desmethylsertraline pamoate in the form of a pinkish solid (143 mg, Yield: 41%) FM = C ₁₈ H ₁₅ Cl ₂ N, 0.5 C ₂₃ H ₁₆ O ₆ , H ₂ O;

MS = 504.41 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 99.2%;

¹ H NMR (DMSO-d6): 8.54 (3H, brs), 8.19 (2H, M), 7.60 (4H, M), 7.31 (3H, M), 7.14 (1H, M), 7.03 (1H, M); 6.76 (1H, d), 4.69 (1H, s), 4.58 (1H, m), 4.17 (1H, M), 2.07 (4H, M);

Microanalyses: Exp. -% C (65.33); % H (4.73); % N (2.77); Theo. -% C (65.48); % H (5.00); % N (2.78);

EXAMPLE 15 Preparation of desmethylsertraline malonate 200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 mL of ethanol then 0.25 mL of an ethanol solution containing 1.02 mmol (1.5 eq) of malonic acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered to provide desmethylsertraline malonate in the form of a white solid (130 mg, Yield: 47%)

FM = C ₁₈ H ₁₅ Cl ₂ N, C ₃ H ₄ O ₄ , 0.08 C ₂ H ₆ O;

MP salt = 399.96 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 99.4%; ¹ H NMR (DMSO-d6): 8.25 (3H, brs), 7.63 (IH, d), 7.53 (2H, M), 7.38 (3H, M), 6.77 (IH, d), 4.52 (IH, m ), 4.18 (1H, M), 2.70 (2H, s), 2.00 (4H, M);

Microanalyses: Exp. -% C (57.67); % H (5.03); % N (3.70); Theo. -% C (57.54); % H (4.91); % N (3.50);

EXAMPLE 16 Preparation of Desmethylsertraline Maleate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 ml of ethanol then 0.35. mL of ethanol solution containing 1.02 mmol (1.5 eq) of malonic acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered to give the desmethylsertraline maleate in the form of a white solid (156 mg, Yield: 55%)

FM = Ci ₆ Hi ₅ Cl ₂ N, C ₄ H ₄ O ₄ 0.06 C ₂ H ₆ O; MS = 411.05 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 100%;

¹ H NMR (DMSO-d6): 8.30 (3H, brs), 7.63 (IH, d), 7.51 (2H, M), 7.28 (3H, M), 6.77 (IH, d), 6.01 (2H, s ), 4.55 (1H, m), 4.16 (1H, M), 2.00 (4H, M); Microanalyses: Exp. % C (58.99); % H (4.78); % N (3.56);

Theo. -% C (58.79); % H (4.75); % N (3.41);

EXAMPLE 17 Preparation of desmethylsertraline nitrate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 ml of ethanol and then 0.25 mL of ethanol solution containing 1.02 mmol (1.5 eq) of nitric acid is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered to provide the desmethylsertraline nitrate in the form of a white solid (138 mg, yield: 56%) FM = Ci ₆ Hi ₅ Cl ₂ N, HNO _3, H ₂ O 0.55; MS = 365.13 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d6): 8.30 (3H, brs), 7.63 (IH, d), 7.52 (2H, M), 7.28 (3H, M), 6.77 (IH, d), 4.55 (IH, m ), 4.18 (1H, M), 2.03 (4H, M);

Microanalyses: Exp. -% C (52.76); % H (4.69); % N (7.67); Theo. -% C (52.63); % H (4.72); % N (7.67);

EXAMPLE 18 Preparation of desmethylsertraline benzensulfonate 200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 mL of ethanol and then 0.32 mL of an ethanol solution containing 1.02 mmol (1.5 eq) of benzensulfonic acid is added. The medium is stirred at ambient temperature for 2 h and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in ether. The insoluble solid is filtered to provide desmethylsertraline benzensulfonate as a white solid (189 mg, yield: 62%)

FM = Ci ₆ Hi ₅ Cl ₂ N, C ₆ H ₆ O ₃ S;

MS = 450.38 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d6): 8.30 (3H, brs), 7.63 (3H, M), 7.52 (2H, M), 7.28 (6H, M), 6.77 (IH, d), 4.55 (IH, m ), 4.18 (1H, M), 2.05 (4H, M); Microanalyses: Exp. -% C (58.70); % H (4.71); % N (3.17); % S (7.08) Theo. -% C (58.67); % H (4.70); % N (3.11); % S

(7.12)

EXAMPLE 19 Preparation of Desmethylsertraline Acetate 200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 ml of ethanol and then 0.32 mL of ethanol solution containing 1.02 mmol (1.5 eq) of acetic acid is added. The medium is stirred at ambient temperature for 2 h and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in pentane. The insoluble solid is filtered to provide desmethylsertraline acetate as a white solid (82 mg, yield: 34

%)

FM = C ₁₈ H ₁₅ Cl ₂ N, C ₂ H ₄ O ₂ . 0.3 H ₂ O; MS = 357.67 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 99.3%;

¹ H NMR (DMSO-d 6): 7.56 (1H, d), 7.49 (1H, d), 7.45 (1H, s), 7.17 (2H, M), 7.09 (1H, dd), 6.67 (1H, d); 4.09 (1H, m), 3.98 (1H, M), 1.80-2.05 (3H, M), 1.88 (3H, s), 1.75 (1H, M); Microanalyses: Exp. -% C (60.90); % H (5.46); % N (3.92);

Theo. -% C (60.45); % H (5.52); % N (3.92);

EXAMPLE 20 Preparation of desmethylsertraline hydrochloride

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 0.4 ml of ethyl ether and then 1 ml of a 2M solution of HCl in ethyl ether is added. The medium is stirred at ambient temperature for 2 h and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in ethyl ether. The insoluble solid is filtered to provide desmethylsertraline hydrochloride in the form of a white solid (79 mg, yield: 34%)

FM = Cl ₆ H ₁₅ Cl ₂ N, HCl, H ₂ O;

MS salt = 346.69 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 95.9%; ¹ H NMR (DMSO-d6): 8.65 (3H, brs), 7.60 (3H, M), 7.28 (3H, M), 6.74 (1H, d), 4.51 (1H, M), 4.15 (1H, M), ), 2.00 (4H, M); Microanalyses: Exp. -% C (55.41); % H (5.12); % N (3.98); Theo. -% C (55.43); % H (5.23); % N (4.04);

EXAMPLE 21 Preparation of desmethylsertraline hydrogen sulphate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 3 ml of acetonitrile and then 1 mL of a 2M solution of sulfuric acid in acetonitrile is added. The medium is stirred at ambient temperature for 2 hours. The solid formed is filtered and washed with acetonitrile to give the desmethylsertraline hydrogen sulfate in the form of a white solid (95 mg, yield: 33%) FM = Cl ₆ Cl ₅ Cl ₂ N, H ₂ SO ₄ , 1.7 H ₂ O; MP salt = 420.91 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d6): 8.65 (3H, brs), 7.63 (1H, d), 7.53 (2H, M), 7.28 (3H, M), 6.76 (1H, d), 4.53 (1H, M); ), 4.16 (1H, M), 2.02 (4H, M); Microanalyses: Exp. -% C (45.72); % H (4.71); % N (3.35); Theo. -% C (45.66); % H (4.89); % N (3.33);

Example 22 Preparation of desmethylsertraline benzoate

200 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 2 ml of ethyl ether and then 83 mg of benzoic acid (0.7 mmol) are added. The medium is stirred at ambient temperature for 2 h and then concentrated to dryness by dry distillation of the solvent under reduced pressure. The residue obtained is taken up in 2 ml of a water / acetonitrile mixture (50/50). The solution obtained is concentrated to dryness by distillation under reduced pressure to give desmethylsertraline benzoate in the form of a white solid (153 mg, yield: 54%). FM = C ₁₈ H ₁₅ Cl ₂ N, C ₇ H ₆ O ₂ ;

PM salt = 414.33 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 100%;

¹ H NMR (DMSO-d 6): 7.91 (2H, d), 7.56 (2H, M), 7.51 (1H, s), 7.46 (1H, m), 7.38 (2H, M), 7.23 (2H, M); 7.15 (1H, dd), 6.70 (1H, d), 4.21 (1H, m),

4.12 (1H, m), 1.98 (4H, M);

Microanalyses: Exp. -% C (66.38); % H (5.13); % N (3.50); Theo. -% C (66.67); % H (5.11); % N (3.38);

Example 23 Preparation of desmethylsertraline (+) - lactate

264 mg of desmethylsertraline (1S, 4S-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (0.7 mmol) are dissolved in 2 ml of acetonitrile and then 112 ml. μL of an 85% aqueous solution of L - (+) - lactic acid are added. The medium is stirred at ambient temperature for 2 h and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in ethyl ether and filtered. The filtered solid is taken up in 2 ml of a water / acetonitrile mixture (50/50). The solution obtained is concentrated to dryness by distillation under reduced pressure to give the desmethylsertraline (+) - lactate in the form of a white solid (21 mg, yield: 6%) FM = C ₁₈ H ₁₅ Cl ₂ N, C ₃ H ₆ O ₃ , 0.9 H ₂ O;

MP salt = 398.50 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 97.6%;

¹ H NMR (DMSO-d 6): 7.52 (3H, M), 7.25 (2H, M), 7.17 (1H, M), 6.71 (1H, d), 4.28 (1H, m), 4.12 (1H, M); 3.74 (1H, q), 2.00 (4H, M), 1.2 (3H, M);

Microanalyses: Exp. -% C (57.28); % H (5.59); % N (3.44); Theo. -% C (57.27); % H (5.77); % N (3.51);

EXAMPLE 24 Preparation of desmethylsertraline (+) - tartrate 500 mg of cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine hydrochloride (cis isomer of (I)) (1.52 mmol) are dissolved in 2 mL of water and then 3 equivalents of ammonia in aqueous solution are added. The medium is extracted with dichloromethane. The organic phase is collected, dried over Na ₂ SO ₄ and concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 5 ml of ethanol and then 228 mg of L - (+) - tartaric acid are added. The medium is stirred at ambient temperature for 24 hours. The solid formed is filtered and then recrystallized under heat in 10 mL of methoxyethanol to give desmethylsertraline (+) - tartrate in the form of a white solid (36 mg, yield: 6%).

FM = C ₁₈ H ₁₅ Cl ₂ N, 0.6 C ₄ H ₆ O ₆ ; MS = 382.26 g / mol; PM excluding salt = 292.21 g / mol; HPLC: purity = 99.51%;

¹ H NMR (DMSO-d6): 7.59 (1H, d), 7.50 (2H, M), 7.25 (2H, M), 7.17 (1H, dd), 6.71 (1H, d), 4.25 (1H, m); 4.12 (1H, M), 2.02 (4H, M);

Microanalyses: Exp. -% C (58.06); % H (4.77); % N (3.80); Theo. -% C (57.81); % H (4.90); % N (3.66);

Alternatively, 1 g of cis / trans-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthylamine) (cis / trans mixture of (I)) are dissolved in 10 ml. mL of methoxyethanol and then 3 mL of a solution of methoxyethanol containing 514 mg of L - (+) - tartaric acid are added. The medium is stirred at ambient temperature for 24 hours. The solid formed is filtered and then recrystallized under heat in 10 mL of methoxyethanol to give desmethylsertraline (+) - tartrate in the form of a white solid (80 mg, yield: 6%, ee: 100%).

FM = C ₁₈ H ₁₅ Cl ₂ N, 0.5 C ₄ H ₆ O ₆ ;

MS = 367.25 g / mol; PM excluding salt = 292.21 g / mol;

HPLC: purity = 100%; ¹ H NMR (DMSO-d6): 7.59 (1H, d), 7.52 (1H, d), 7.49 (1H, s), 7.25 (2H, M), 7.17 (1H, dd), 6.71 (1H, d); 4.25 (1H, m), 4.12 (1H, M), 2.02 (4H, M);

Claims

1. Process for preparing the isomer (IS, 4S) of 4-(3,4-dichlorophenyl)- ^" ,2,3,4-tetrahydro-l-naphthylamine of formula (I):

or one of its pharmaceutically acceptable salts, characterized in that it comprises the following steps: 1) addition of an enantiomerically pure chiral organic acid to a solution containing at least one cis isomer of (I); 2) crystallization of the diastereoisomers (IS, 4S) of the salt formed by the addition of this enantiomerically pure chiral organic acid; 3) isolation of the isomer (IS, 4S) of compound (I) in the form of said salt; 4) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of compound (I) in free base form. 2. Method according to claim 1, characterized in that said solution contains an equimolar mixture of isomers (IS, 4S) and (IR, 4R) of compound (I). 3. Method according to claim 1 or 2, characterized in that said solution contains an equimolar mixture of isomers (IS, 4S), (IR, 4R) (IS, 4R) and (IR, 4S) of compound (I) . 4. Method according to any one of claims 1 to 3, characterized in that the enantiomerically pure chiral organic acid is chosen from one of the optical isomers of mandelic acid, tartaric acid, acid lactic or 10-camphoresulfonic acid. 5. Method according to any one of claims 1 to 4, characterized in that said solution is prepared from an organic solvent chosen from ethanol or methoxy ethanol. 6. Method according to any one of claims 1 to 5, characterized in that the crystallization is carried out with stirring and at room temperature. 7. Method according to any one of claims 2 to 6, characterized in that said equimolar mixture of isomers (IS, 4S) and (IR, 4R) of compound (I) is obtained by a reductive amination of the (+ /-) serralone of formula (II):

8. Method according to claim 7, characterized in that the reductive amination of (+/-) sertralone (II) is carried out by reaction of the latter with ammonia in the form of gas or an organic salt of ammonium, such as ammonium formate or ammonium acetate, in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, hydrogen or a metal catalyst. 9. Method according to any one of claims 2 to 6, characterized in that said equimolar mixture of isomers (IS, 4S) and (IR, 4R) of compound (I) is obtained from the amine of formula cis-B:

by hydrogenolysis of the N-C bond, in particular under a hydrogen atmosphere in the presence of a metal catalyst, preferably in an acidic medium or in the presence of cerium (IV) ammonium nitrate. 10. Method according to claim 9, characterized in that the cis-B amine is obtained from the imine of formula A:

by carrying out a reduction of A, for example in an organic solvent in the presence of a borohydride salt, or by the action of gaseous hydrogen in the presence of a metallic catalyst such as Raney nickel or palladium activated on carbon, palladium, activated on carbon, palladium hydroxide or platinum. 11. Method according to claim 10, characterized in that imine A is obtained from (+/-) sertralone of formula (II):

by addition of 4-methoxybenzylamine to a solution of (+/-) sertralone (II) in an organic solvent, optionally in the presence of a dehydration agent. 12. Use of (+/-) sertralone of formula (II):

for the preparation of the (1S,4S) isomer of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthy lamine of formula (I):

13. Compound of formula cis-B:

4. Process for the preparation of the isomer (IS, 4S) of 4-(3,4-dichlorophenyl)-,2,3,4-tetrahydro-l-naphthylamine of formula (I):

or one of its pharmaceutically acceptable salts, characterized in that it comprises the following steps: 1) reductive amination of (+/-) sertralone of formula (II):

to obtain an equimolar mixture of isomers (IS, 4S), (IR, 4R), (IS, 4R) and (IR, 4S) of compound (I); 2) preparation of a solution containing said equimolar mixture of isomers (IS, 4S), (IR, 4R) (IS, 4R) and (IR, 4S) of the compound (I) obtained in step 1) in an organic solvent; 3) addition of an enantiomerically pure chiral organic acid to the solution prepared in step 2); 4) crystallization of the salt formed by the addition of this enantiomerically pure chiral organic acid; 5) isolation of the isomer (IS, 4S) of compound (I) in the form of said salt; 6) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of compound (I) in free base form. 15. Process for preparing the isomer (IS, 4S) of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthylamine of formula (I):

or one of its pharmaceutically acceptable salts, characterized in that it comprises the following steps: 1) addition of 4-methoxybenzylamine to a solution of (+/-) sertralone of formula (II):

in an organic solvent, optionally in the presence of a dehydration agent, to obtain the compound of formula A:

2) reduction of the compound of formula A, for example in an organic solvent in the presence of a borohydride salt, or by the action of gaseous hydrogen in the presence of a metallic catalyst such as Raney nickel or palladium activated on carbon , palladium hydroxide or platinum, to obtain the compound of formula cis-B:

3) hydrogenolysis of the NC bond of the compound of formula cis-B, in particular under a hydrogen atmosphere in the presence of a metal catalyst, preferably in an acidic medium or in the presence of cerium (IV) ammonium nitrate, to obtain an equimolar mixture of isomers (IS, 4S) and (IR, 4R) of the compound (I); 4) preparation of a solution containing said equimolar mixture of isomers (IS, 4S) and (IR, 4R) of compound (I) obtained in step 4) in an organic solvent; 5) addition of an enantiomerically pure chiral organic acid to the solution prepared in step 5); 6) crystallization of the salt formed by the addition of this enantiomerically pure chiral organic acid; 7) isolation of the isomer (IS, 4S) of compound (I) in the form of said salt; 8) optionally, basic treatment of said salt and isolation of the isomer (IS, 4S) of compound (I) in free base form.