CZ2001708A3 - Process for preparing sertraline - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing sertraline by reducing amination of a racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenone. The preparation process is carried out in a single reaction vessel without isolation of intermediates, in the form of pure cis and trans geometric isomers being separated from each other. Disclosed is also a conversion process of trans isomer to cis-isomer, as well as preparation process of cis isomer polymorph 1S from any other polymorph.

Description

Technical field

The invention relates to a process for the preparation of sertraline by reductive amination of racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalenone in the form of pure, separated geometric cis and trans isomers, the conversion of the trans isomer to the cis isomer and the preparation of the cis isomer polymorph.

BACKGROUND OF THE INVENTION

Several methods for the preparation of 4- (3,4-dichlorophenyl) 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, known under the generic name sertraline, are effective as an antidepressant (a serotonin blocker) in the patent literature (i.e. 5-hydroxytryptamine). For example, condensation of naphthalenone with methylamine in the presence of TiCl ₄ (J. Med. Chem. 1984, 27, 1508-1515 or US 4 * 855,500) and subsequent reduction of the resulting ketimine with sodium borohydride have been described. Alternatively, a molecular sieve was used as a condensation agent and the reduction was performed by catalytic hydrogenation on a palladium catalyst (US 4,855 * 500).

Also described is the preparation of the amine oxide from naphthalenone by reaction with N-methylhydroxylamine and hydrogenation of the reaction product on Raney nickel (US 6,034 * 274). Catalytic hydrogenation gives a higher yield of cis isomer than hydrogenation in a homogeneous phase, but requires a special hydrogenation apparatus and, in addition, there is a risk of contamination of the final product with heavy metals. In addition, the whole process is a two-step process with an unstable intermediate and the isolation of the end product is relatively complex.

In patent application EP 0947499, for the preparation of the starting compound for the preparation of racemic sertraline, 4- (3,4-dichlorophenyl-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine from 3,4-dichlorophenyl-1- tetralone using the procedure cited in US Patent 5,442,116 (Cervinka et al., Coll. Czech. Chem. Commun., vol. 38, p. 1156 (1973)) for tetralone unsubstituted at the 4-position. -dichlorophenyl) -3,4-dihydro-1- (2H) naphthalenone in this case is contaminated with up to 20% of 4 (2,3-dichlorophenyl) -1-tetralone, which causes problems in the next steps and reduces the overall yield of racemic sertraline to to around 22%, an unacceptably low value.

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In accordance with EP 0947499, in the first step, the reaction of a mixture of 4- (3,4-dichlorophenyl) tetralone and 4- (2,3-dichlorophenyl) tetralone with N-methylformamide in the presence of formic acid gives N-methyl-N-1. 2,3,4-tetrahydro-1-naphthylformamide. This is hydrolyzed and isolated as the racemic N-methyl-1,2,3,4-tetrahydro-1-naphthylamine salt from the base by selective acid crystallization. The reaction proceeds at temperatures between 150 ° C and 220 ° C.

The process claimed in the patent for reacting 1-naphthol with 1,2-dichlorobenzene under AlCl 3 catalysis is not new. Hydrolysis of the product is accomplished by refluxing in a mixture of C1-C8 alcohols with water in an alkaline medium, e.g. butanol with potassium hydroxide.

In the case of TiCl ₄ catalysis, the catalyst presents a safety risk (stormy water decomposition, aggressiveness of decomposition products). Reducing hydrides in turn increases the difficulty of isolation and gives relatively low yields. The asymmetric synthesis of the intermediate for sertraline is also not preferred because they are multistage, have low overall yield and use expensive raw materials.

SUMMARY OF THE INVENTION

The process for preparing sertraline, 4 (3,4, dichlorophenyl) 1,2,3,4 tetrahydro-N-methyl-1-naphthalenamine hydrochloride (IIa, IIb), according to the invention is relatively simple.

Ha cis (1S, 4S + 1R, 4R) lb trans (1S, 4R + 1R, 4S)

The catalysts based on metal compounds are not used in this process, they are operated without pressure and dehydrating agents. The preparation proceeds without isolation of the intermediates and gives a very high yield without the formation of impurities that would have to be removed and without the formation of dark colored tarry fractions, as is usual in this type of reaction.

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The precursor for the preparation of sertraline according to the invention, racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalenone (I), is prepared by a method analogous to that of

published in literature (see: Žur. Org. Chimii, vol.7, p. 2398 (1971), Žur. Org. Chimii vol. 18, no. 4, p. 870-878 (1982), Houben-Weyl, vol. It was prepared by the reaction of 1,2-dichlorobenzene and α-naphthol in the presence of anhydrous aluminum chloride.

Its preparation was optimized for the highest yield compared to the available data and was conducted at low temperatures to minimize the formation of undesirable isomers that would interfere with the next preparation step. This gives a crude beige crystalline product with a yield of 85% (based on α-naphthol), m.p. 99/101 ° C. For reductive amination, precursor (I) must be free of impurities, especially isomeric impurities.

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The reductive amination of 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) -naphthalenone (I) according to the invention is carried out in the presence of methylamine salts and alkali formate, where the active methylammonium formate is formed "in situ" in the environment N-methylformamide and / or

CH ₃ NH ₃ X, HCOO M hconhch ₃

lla, lib

1,2-dichlorobenzene. Salts of formula M _and Xb, which partially dissolve in the reaction medium and increase the ionic strength, are added. The M ⁺ cation must have a relatively small diameter, such as lithium, beryllium, magnesium or aluminum. The anion X may be a halogen, a sulfate, and the like. Salts of said metals are added to increase the yield and reduce the content of impurities resulting from side reactions. Alternatively, reductive amination can be performed directly with methylammonium formate in the same medium as above, instead of a mixture of methylammonium chloride or methylammonium sulfate with sodium formate.

After completion of the reaction, the solvent and salts were extracted once with water and the product was extracted into chloroform or ethyl acetate. The organic layer was washed with water, dried and evaporated on a rotary evaporator. The residue was dissolved in ethanol and to the solution was added half volume of HCl (1: 1, i.e. 5.5 M) by volume and the reaction mixture was refluxed. After completion of the reaction, the trans isomer hydrochloride IIb remains in solution, while the cis hydrochloride hydrochloride IIa, which precipitates in crystalline form, is isolated, washed and air dried. Ethyl acetate was added to the filtrate which was evaporated to near dryness and crystallized at reduced temperature. The yield of both isomers is 96.5%, the fraction of the cis isomer containing 98.1% of the cis isomer and 1.8% of the trans isomer. The trans isomer fraction contains 92.5% trans and 7.2% cis isomer (HPLC). The melting point is identical to that reported in J. Med. Chem. 1984, 27, 1508-1515. Hydrolysis of both N-formyl isomers as part of this step (i.e., without isolation of intermediates) using a mixture of C 1 -C ₄ aliphatic alcohols

-5 in an alcohol / water ratio of 1: 4 to 4: 1, acidified with HCl so that the final concentration of HCl, based on water, is in the range of 1.0 to 6.0 M, thus obtaining isomers Ha and IIb directly with purity 98% and 92% respectively, the remainder up to 99.6% being the other of the two geometric isomers.

Alternatively, the reductive amination of naphthalenone (I) can also be carried out by reacting naphthalenone (I) with a mixture of methyl ammonium formate with triethylammonium formate in N-methylformamide to catalyze said salts M _and Xt>. Under these conditions, it is possible to reduce the reaction temperature by 20 to 30 ° C.

By converting IIb of the geometric isomer to Ha, a further increase in the yield of the desired 1S, 4S enantiomer can be achieved. The reductive amination product, consisting of 92% trans and 8% cis isomer, is converted by adding dry triethylamine to the hydrochloride suspension in tetrahydrofuran while stirring. The suspension is filtered, washed with tetrahydrofuran and filtered off with suction. To the filtrate was added sodium hydride as a 60% suspension in oil and a finely powdered potassium tertiary butylate, which was prepared by evaporating a solution of tertiary butylate in tertiary butanol. Potassium tertiary butylate provides the highest yields of basic catalysts. The flask was placed under a by-pass reflux condenser for nitrogen inlet and under a nitrogen atmosphere and rapidly heated to 50 ° C with vigorous stirring. However, it has been found that the reaction does not take 4 ^ 8 hours at an optimal temperature in the range between 55 ^ 125 ° C, as disclosed in U.S. Pat. No. 5,882,870, but equilibrating takes only 4/10 minutes to dissolve the catalyst. briefly heated to 50 ° C. The low reaction order, less than 1, and the low activation energy of the reaction result in the catalyst amount and temperature having little effect on equilibrium rate. Thus, in less than 5 minutes, the potassium tertiary butylate more or less dissolves and after a further 5 minutes the equilibrium is complete. The solution was allowed to cool under nitrogen and then 250 ml of water and 50 g of NaCl were added, the layers were separated and the organic layer was evaporated in vacuo on a rotary evaporator. Since tetrahydrofuran is in contact with a strong alkali when hot, there is no need to worry about the accumulation of organic peroxides during evaporation. If it is not possible to evaporate the tetrahydrofuran immediately after the extraction, it is better avoided by using 750 ml instead of 250 ml of water, add 250 ml of chloroform and separate the layers. The chloroform phase is washed with water and, after drying over Na 2 SO 4, evaporated to dryness and continued in the same manner as described for the reductive amination treatment of the product. A light oil was obtained which was dissolved in ethanol and an equal volume of 5.5 M HCl solution was added to the solution. The precipitated cis derivative (60%) is recrystallized and combined with the product obtained directly from the synthesis, the mother liquor of the trans-derivative batch having the same concentration as the original and therefore can be coupled to it in the next batch, thereby allowing lossless utilization of the cis and trans isomer.

The desired 1S, 4S enantiomer is isolated by a known procedure for crystallizing a base salt with an optically active acid, in this case D (-) mandel. Isolation of 1S cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methylnaphthalenamine base and polymorph preparation is accomplished by shaking the mandelate slurry in ethyl acetate with 1 q% aq. until completely dissolved. The layers were separated and the organic phase was dried and evaporated. Acquired

The colorless oil is stirred in isopropanol and precipitated with a 1.25 molar excess

isopropanolic HCl. Slow addition of the acid results in a very viscous, thick gel, and after two hours of stirring diisopropyl ether is added and vigorous stirring forces rapid recrystallization. Alternatively, any polymorph can be converted to polymorph FII by dissolving the dried hydrochloride product in three times (w / v) Ν, Ν-dimethylformamide p.a. heating to 8 DEG-90 DEG C., after dissolution, the solution is allowed to cool spontaneously to about 70 DEG C. and acetone p.a. is slowly added with vigorous stirring. The precipitated crystalline product is initially again gelled and dense, but with shorter stirring, recrystallization occurs. The polymorph is aspirated on a frit S3 or S4 and dried at 50-60 ° C in a vacuum oven.

The process according to the invention is so cheap and technologically cheap and feasible that, despite the loss of approximately 50% of the undesired enantiomer, the cost balance is more favorable than in the enantioselective (asymmetric) processes disclosed in the patents, which are technologically incomparably complex and more expensive.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of cis and trans isomer of 4 (3,4, dichlorophenyl) 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride (racemic sertraline and its trans geometric isomer) from racemic naphthalenone of the invention is described in the following examples. .

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-7 Example 1

Preparation of racemic 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) naphthalenone

1450 ml 1,2-dichlorobenzene and 192 g α-naphthol (approx. 1,33 M) are placed in a three-necked flask equipped with a thermometer, stirrer and air cooler with a chlorine-calcium cap. Stirring is started and 420 g of anhydrous aluminum chloride is introduced in portions over 3¾ minutes. The temperature reaches 45 DEG -48 DEG C. in a short time, the suspension thickens strongly and is difficult to stir. After an additional 15 minutes the catalyst complex slurry, liquefied and further stirred easily. The temperature is maintained at a temperature of 4 ° / 48 ° C with stirring for 24 hours. If, for reasons of technology, it is necessary to shorten the reaction, the mixture can be heated to 75 ° C for 2 hours with stirring. The product is isolated in the same way but will contain about 50% more impurities. After 24 hours, the reaction is complete and the mixture is allowed to cool to 25 ° C. It is then poured onto ice and 35 ml of concentrated (11 M) HCl and 900 ml of chloroform are added. The layers were separated in a separatory funnel and the aqueous layer was extracted several times with a small amount of chloroform. The combined organic extracts were washed 2x with water, the organic phase is dried over Na ₂ SO ₄ and then under atmospheric pressure, chloroform was distilled off. Excess 1,2-dichlorobenzene is distilled off on the boiling water bath and under the vacuum of the water pump, which is recovered and can be reused in another batch. After evaporating the 1,2-dichlorobenzene to constant weight, the oily residue (ca. 405 g) is allowed to cool and a 3-fold volume of 96% Mhel of ethanol is added based on the volume of the product. Stirring (preferably under ultrasound) crystallizes completely. The crude crystalline product was allowed to stand for about 8 hours and sucked off on a frit S2 and then washed with 2 times a small amount of cold ethanol. After drying in air (or in an oven up to 60 ° C), 330 g of a crude beige crystalline product (yield 85% based on α-naphthol) with a ferrite of melting point 99/0101 ° C is obtained.

Example 2

The ratio of isomer in naphthalenone (I) is determined by HPLC with UV detection. The analysis is performed on a Zorbax SB C-18 column, 250 x 4.6 mm. A methanol / water mixture (67:33) was used as the mobile phase at a flow rate of 1 ml / min. The column temperature is 40 ° C. The substances are detected at 230 nm. The isomer ratio is evaluated from the peak area ratio of the two most frequently represented isomers of naphthalenone (I). The response factors of the two isomers are approximately the same at the wavelength used.

Adrian et al. (US 5 J191935) discloses the GLC purity of naphthalenone (I), obtained under similar conditions at 98/99%. We do not consider this result correct, as we have found that over a wide temperature range (40 / Ό5 ° C) and a wide reactant ratio, the ratio of the resulting isomers changes little and the resulting purity of the crude crystallizate after complete separation of both isomers will not exceed 95%.

Example 3

Purification of the crude 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) naphthalenone (I) crystallizate

Purification of the crude crystalline product I for reductive amination is accomplished by dissolving the dry crude crystalline product in six times (w / v) acetone hot (just below Bedeo) acetone boiling and adding 8% activated carbon (e.g. the percentage is based on the weight). Allow to stand for 10 minutes with occasional stirring and filter the still hot solution through a thick pleated filter. After filtration, the filtrate remains only slightly yellowish. Evaporation of acetone on a vacuum rotary evaporator yields (colorless crystalline product having a melting point of 100 DEG-102 DEG C. and a yield of 94.5%. It is free of non-polar impurities but the content of isomeric impurity remains more or less unchanged. Half of the crystalline product is dissolved in six times the weight of ethanol at boiling and allowed to crystallize by slow cooling, seeded with a small amount of crystals when the solution temperature drops to about 60 DEG C. After standing for 6 hours, the crystalline product is suction filtered. The second half of the crude product is added to the mother liquor after crystallization and recrystallized in the same manner, after aspiration and washing, the two halves of the combined product are dried and dried, and the crystallization is repeated two more times to give an isomer content of 102 / -104 ° C. All mother liquors join The crystalline product precipitated on the next day is filtered off with suction, dried and added to another crude batch, which corresponds to its purity.

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-9 Example 4

Reductive amination of 4- (3,4-dichlorophenyl) 3,4-dihydro-1- (2H) naphthalenone (I)

105 g of 4- (3,4-chlorophenyl) 3,4-dihydro-1 (2H) -naphthalenone (I) purified by recrystallization, containing an isomeric 2,3-dichloro derivative of not more than 0,16%, are placed in a two-necked 1 l flask equipped with Dissolve in 230 ml N-methylformamide and add 4.5 g lithium chloride, 49.5 g anhydrous potassium formate and 49.5 g methylammonium hydrochloride. The mixture was heated to 145 ° C and held at 145/155 ° C for 10 hours. The reaction can be interrupted at any time by cooling below 100 ° C and continued after heating. After completion of the reaction, allow the mixture to cool; if the temperature is above 100 ° C, the reaction mixture is covered with a stream of nitrogen.

The solvent and salts are rinsed once with about 700 ml of water, the product is shaken into about 700 ml of chloroform or ethyl acetate, the aqueous and organic layers are separated and then washed with a small amount of water. The organic layer was further dried over Na ₂ SO ₄ and evaporated in a rotary evaporator, the residue was dissolved in 480 mL of ethanol and half an aqueous HCl solution (240 mL) was added to give a final HCl concentration of 5.5 M While stirring, the mixture was refluxed for 12 hours. After completion of the reaction, the trans isomer hydrochloride IIb remains in solution. The cis isomer hydrochloride IIa precipitates in crystalline form, is suctioned off on a frit S2, washed twice with acetone and air-dried. The filtrate was evaporated almost to the ear and 450 ml of ethyl acetate were added thereto and allowed to crystallize at 5/10 ° C. After 4 hours the precipitated trans isomer is filtered off with suction and washed twice with ethyl acetate. The yield is 57 g of the cis isomer and 62.5 g of the trans isomer in the hydrochloride form (i.e. 96.5%), the cis isomer fraction containing 98.1% cis and 1.8% of the trans isomer. , 5% trans and 7.2% cis isomer (HPLC method). The biophyses are identical to those reported in J. Med. Chem. 1984, 27, 1508-1515.

Example 5

Reductive amination of naphthalenone (I)

Alternatively, the reductive amination of naphthalenone (I) can be accomplished by adding 105g of 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) naphthalenone to a two-necked flask equipped with a thermometer and an air cooler with an inert gas inlet. (I) 58.5 g of methyl 10 ammonium formate, 6 g _MgSO4, 28 g of triethylammonium formate and 200 ml of N-methylformamide. The mixture was heated to 125 ° C and then slowly raised to 145 ° C over two hours and maintained at this temperature for an additional 14 hours. After completion of the reaction, the inert gas is introduced until the temperature falls below 100 ° C. After evaporation, the residue is dissolved in 400 ml of isopropanol, to which 150 ml of HCl (1: 1, i.e. 5.5 M) are added and refluxed for 6 hours. The further processing of the product is identical to that of Example 4.

Example 6

Conversion of the geometric isomers lb to 11a g of the Ha product with lb (containing 92% trans and 8% cis isomer from reductive amination) was converted by adding 30 ml of triethylamine dried with molecular sieves A3 to a suspension of hydrochloride in 500 ml of tetrahydrofuran. and stirred for 0.5 to 1 hour. The suspension is filtered, washed twice with a small amount of tetrahydrofuran on the filter and sucked off rapidly. To the filtrate was added 3.8 g of sodium hydride as a 60% solid suspension in mineral oil and 18 g of finely powdered potassium tertiary butylate, which was prepared by evaporating a solution of tertiary butylate in tertiary butanol and still containing about 25-30% tertiary butanol.

The flask is placed under a by-pass reflux condenser for nitrogen inlet and is rapidly heated to 50 ° C under vigorous stirring under nitrogen. Within less than 5 minutes the potassium tertiary butylate more or less dissolves and after another 5 minutes the equilibrium is complete. The solution was allowed to cool freely under nitrogen, 250 ml of water and 50 ml of NaCl were added, the layers were separated and the organic layer was evaporated in vacuo on a rotary evaporator. Since tetrahydrofuran is in contact with strong alkali when hot, there is no danger of organic peroxides accumulating and exploding on evaporation. If it is not possible to evaporate the tetrahydrofuran immediately after the extraction, it is better avoided by diluting the reaction mixture with 750 ml of water instead of 250 ml, adding 250 ml of chloroform and separating the layers. The chloroform phase was washed 2 more times with water and, after drying over Na 2 SO ₄ evaporated to dryness. 50 g of a light oil are obtained, which is dissolved in 200 ml of ethanol and 200 ml of 5 .mu.M HCl are added. A thick crystalline mass of the cis derivative precipitated immediately and was stirred for 2 hours. The cis derivative (60%, 36 g) was recrystallized as in Example 4 and combined with the directly obtained from the synthesis. The mother liquor with the 4C ||% residue of the trans derivative feed has the same concentration as the original and therefore can be coupled to it in the next feed, allowing lossless utilization of the cis and trans derivative.

Example 7

Preparation 1 S-cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine mandelate and hydrochloride

26.8 g of the Qis-racemate hydrochloride of compound IIIa prepared according to Example 3 are converted on a base by stirring in a mixture of 100 ml of aqueous 5M NaOH and 220 ml of ethyl acetate until dissolved. The layers were separated, the organic layer was dried over Na ₂ SO ₄ and evaporated on a rotary evaporator. 23.8 g of the residue of the base are obtained in the form of an oil which is taken to the next step in 200 ml of ethyl alcohol distilled under vacuum at 100 tons and then 12 g of D (-) mandelic acid are added. The mixture was warmed to 60 ° C when all components were completely dissolved and allowed to crystallize at room temperature overnight

10 ° C. The crystallized mandelate is suctioned off sharply, washed with a small amount of diethyl ether and air-dried (yield 16 g, m.p. 187 + 189 ° C). The mandelate was converted on a base in a manner similar to that of racemic hydrochloride IIIa, but using 200 ml of 2.5 M NaOH and 500 ml of ethyl acetate. The organic layer was dried and evaporated, the residue was dissolved in a mixture of isopropanol and diisopropyl ether (7: 3 v / v) and precipitated with hydrogen chloride gas. Excess hydrogen chloride is stripped with nitrogen. The resulting pH should be approximately 2 (on wet universal paper). A thick gel precipitated and was stirred overnight until crystallized. The product is suction filtered on frit S3 and washed with diisopropyl ether. Dry under vacuum at 60 ° C to constant weight. The residual solvent content is checked by chromatography.

Example 8

Preparation of polymorph

1S-cis-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methylnaphthalenamine base (48 g), prepared from D (-) mandelic acid salt, was stirred in 400 ml of isopropanol and precipitates 1.25 mol. isopropanolic HCl. Slow addition of the acid results in a very viscous, dense hydrochloride gel. After stirring for two hours, it was added

the same volume of diisopropyl ether (400 mL) was stirred vigorously for two hours to force rapid recrystallization. The crystalline product is suction filtered on frit S3, washed with diisopropyl ether and air dried. The product has an FII polymorphism according to DSC and X-ray diffraction spectra. In case of uncertainty or other precipitation method, the product is dissolved in three times (w / v) of Ν, Ν-dimethylformamide p.a. by heating to

80 DEG-90 DEG. After dissolution, the solution is allowed to cool spontaneously to about 70 ° C and acetone p.a. is slowly added with vigorous stirring. (^4 times by volume to dimethylformamide). The precipitated crystalline product is initially again gelled and dense, after shorter stirring (2/4 hours) crystallization occurs. The product is aspirated on a frit S3 and dried for 5 hours at 50 and 60 ° C in a vacuum oven. The X-ray diffraction spectrum is identical to the published as well as the DSC record for the FII polymorph. By this procedure any polymorph can be converted to F II without conversion based on precipitation and precipitation as the hydrochloride.

Industrial applicability

The method is industrially useful in the production of sertraline, which is effective as an antidepressant, a serotonin blocker.

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Claims (10)

PATENT CLAIMS A process for the preparation of a trans and cis isomer of sertraline, characterized in that racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalenone-4 is reductively aminated with methylammonium formate in the presence of at least one inorganic lithium salt or beryllium or magnesium or aluminum in N-methylformamide and / or 1,2-dichlorobenzene in an inert atmosphere and the product obtained is hydrolysed directly to the cis and trans isomer of 4 (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride in an acidic, aqueous-alcoholic medium, which are isolated separately, with a minimum content of the second geometric isomer. 2. The process of claim 1 wherein the reductive amination of the racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone was used as a mixture of 4-thylammonium formate with N-triethylammonium formate. 3. The process according to claim 1, wherein the reductive amination of racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone is carried out using an " in situ " methylamine with an alkali formate. 4. The process of claim 3 wherein the methylamine salts are methylammonium halide or methylammonium sulfate. The process according to any one of claims 1 to 4, wherein the aqueous-alcoholic medium for the hydrolysis of the reductive amination product is a mixture of water and a C 1 -C ₄ alcohol acidified with HCl, the alcohol to water ratio being 1: 4 to 4: 1 and molar concentration. The HCl relative to water is in the range of 1.0 to 6.0 M. A process according to any one of claims 1 to 5, characterized in that the reductive amination of racemic 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalenone, hydrolysis of the resulting formamides, preparation and isolation of sertraline hydrochloride and its The trans geometric isomers are performed in the same reaction vessel without isolation of the intermediates. )>)> 7. A process according to claim 1, wherein the conversion of the trans isomer of sertraline to the cis isomer is effected by treatment of the trans isomer of sertraline with a base-reacting compound, and the resulting base isomerized at 50 DEG C. to 55 DEG C. ° C to the cis isomer of sertraline. 8. The process of claim 7 wherein the basic reacting compound is triethylamine, wherein the alkali hydride is sodium hydride and the alkali metal alcoholate is potassium butylate. Process according to any one of claims 1 to 8, characterized in that a polymorph F111S, 4S-enantiomer of sertraline is prepared from an isopropanolic solution of the cis isomer of sertraline by precipitation with an isopropanolic HCl solution and addition of diisopropyl ether. A process according to any one of claims 1 to 9, characterized in that by eliminating sertraline from its solution in the N, N-di (C 1 to C ₂ ) alkylamide Ο _Ί to C ₄ aliphatic acid with an aliphatic C ₃ to C ₈ ketone, The polymorph is prepared by the polymorph F111S, 4S-enantiomer of sertraline.