AU1152500A

AU1152500A - Method of producing ketimines

Info

Publication number: AU1152500A
Application number: AU11525/00A
Authority: AU
Inventors: Peter Herold; Marc Thommen
Original assignee: Ciba Spezialitaetenchemie Holding AG; Ciba SC Holding AG
Current assignee: BASF Schweiz AG
Priority date: 1998-10-30
Filing date: 1999-10-19
Publication date: 2000-05-22
Anticipated expiration: 2019-10-19
Also published as: HUP0104323A3; WO2000026181A1; DE59910149D1; TW588034B; ATE272611T1; ES2226501T3; AR021005A1; IL142367A0; CA2346900A1; PT1124792E; JP2002528528A; TR200100942T2; AU767324B2; HUP0104323A2; EP1124792A1; CN1325381A; EP1124792B1; ZA200103323B

Description

I-11-/ -4 i O O-/ Method of producing ketimines The present invention relates to a process for the preparation of ketimines suitable as starting materials for the preparation of pharmaceutical active ingredients such as, for example, sertraline having antidepressant properties. The best processes hitherto for the preparation of ketimines are described, for example, in US-A-4 536 518 or US-A-4 855 500. In the process for the preparation of ketimines disclosed in US-A-4 536 518 (columns 9/10, Example 1(F)), the ketone is reacted, with cooling, in an aprotic solvent, for example tetra hydrofuran, with methylamine in the presence of titanium tetrachloride. That process has the disadvantage that it is necessary to work with tetrahydrofuran, which is readily combustible, and with titanium tetrachloride, which is not free of ecological concern. In addition, the process is expensive to perform, because the reaction is carried out with cooling. A further disadvantage of that process relates to the working-up. The product has to be precipitated with additional hexane. In the process for the preparation of ketimines disclosed in US-A-4 855 500 (columns 5/6, claim 1), the ketone is reacted, with cooling, in an aprotic solvent, for example methylene chloride, toluene or tetrahydrofuran, with anhydrous methylamine in the presence of a molecular sieve. That process too has the disadvantage that it is necessary to work under anhydrous conditions with solvents that are not free of ecological concern, for example methylene chloride, or with readily combustible solvents, for example tetrahydrofuran. The molecular sieve used is expensive and has to be recycled again in an additional step. A further disadvantage of that process is that the molecular sieve has to be separated off and the product has to be precipitated with additional hexane. There is therefore still a need to find an efficient process for the preparation of ketimines that does not have the disadvantages mentioned above and that works especially in protic solvents, for example alcohols. The present invention accordingly relates to a process for the preparation of compounds of formula -2 N CH3 (1) , wherein R3 R2

R

1 , R 2 and R 3 are each independently of the others hydrogen, halogen, trifluoromethyl or C1-C 4 alkoxy, in which process (a) a compound of formula 0 (2) wherein R3 R 2

R

1 , R 2 and R 3 are as defined for formula (1), is reacted with methylamine in a protic solvent, and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation and/or reaction step (a) is carried out in the presence of a catalyst. Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred. Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred. According to the invention, preference is given to a process wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation; or a process wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1).

-3 Very special preference is given to a process wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1), and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation. Of interest is a process for the preparation of compounds of formula (1) wherein

R

1 is hydrogen or chlorine. Also of interest is a process for the preparation of compounds of formula (1) wherein

R

2 and R 3 are each independently of the other hydrogen, chlorine or bromine. Of special interest is a process for the preparation of compounds of formula (1) wherein

R

1 is hydrogen and

R

2 and R 3 are chlorine. Particularly of special interest is a process for the preparation of compounds of formula (1) wherein the protic solvent is an a-hydric alcohol wherein a is the number 1, 2, 3 or 4. Preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is a compound of formula (3) X(OH)a wherein a is 1, 2, 3 or 4, and when a is 1, X is C 1

-C

8 alkyl, C 5

-C

8 cycloalkyl or -CH 2

CH

2

(OCH

2

CH

2 )bR 4 , b is 0, 1 or 2, and

R

4 is C 1

-C

4 alkoxy, or when a is 2, X is C 2

-C

8 alkylene or -CH 2

CH

2

(OCH

2

CH

2 )b-, wherein b is as defined above, or when a is 3, X is C 3

-C

8 alkanetriyl or N(CH 2

CH

2

-)

3 , or when a is 4, X is C 4

-C

8 alkanetetrayl.

-4 Alkyl having up to 8 carbon atoms is a branched or unbranched hydrocarbon radical, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl or isooctyl.

C

5

-C

8 Cycloalkyl is, for example, cyclopentyl, cycloheptyl or especially cyclohexyl. Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.

C

2

-C

8 Alkylene is a branched or unbranched radical, for example ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octa methylene. Alkanetriyl having from 3 to 8 carbon atoms is derived from an alkane having from 3 to 8 carbon atoms wherein 3 hydrogen atoms are absent and is, for example, -CHF-CH-CH2-- , -OCH-CH-CH-CH- , -CH-CHi-CH--CHjCH2- or -CHi-H-CH2-CH-CH-CH-CH- . Glyceryl is preferred. Alkanetetrayl having from 4 to 8 carbon atoms is derived from an alkane having from 4 to 8 carbon atoms wherein 3 hydrogen atoms are absent and is, for example,

CHI

I I I I -CH2-C---H , -CH2-CH-CH-CH2- , -Hr-H--H-H-H- or CHi I I -HHgCOH-CHgCOH-CHCH2- . Pentaerythrityl is preferred. A preferred meaning of X (for a = 1) is, for example, C 1

-C

6 alkyl, especially C 1

-C

4 alkyl, e.g. ethyl or isopropyl. A preferred meaning of X (for a = 2) is, for example, C 2

-C

6 alkylene, especially C 2

-C

4 alkylene, e.g. ethylene.

-5 Of special interest is a process for the preparation of compounds of formula (1) wherein the protic solvent is a compound of formula (3) X(OH)a wherein a is 1 or 2, and when a is 1, X is C1-C 4 alkyl or C 5

-C

6 cycloalkyl, or when a is 2, X is C 2

-C

4 alkylene. Special preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is methanol, ethanol, isoproponanol, n-butanol, ethylene glycol, methyl Cellosolve, cyclohexanol, diethylene glycol or triethanolamine. Special preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is ethanol or isopropanol. The starting compounds of formula (2) are known or can be prepared analogously to the processes described in US-4 536 518. Preferred reaction conditions for the process according to the invention (reaction step (a)) are as follows: The reaction can be carried out at room temperature or at elevated temperature, especially temperatures of from 20 to I 00 0 C, e.g. from 25 to 65 0 C, optionally under slight pressure. The reaction is especially carried out with a large molar excess of methylamine. Special preference is therefore given to a process for the preparation of compounds of formula (1) wherein the relative molar proportion of the compound of formula (2) to methylamine is from 1:1 to 1:100, especially from 1:1.05 to 1:50, e.g. from 1:1.5 to 1:15. The methylamine can be used in the form of methylamine gas or in the form of a solution in an alcohol, for example ethanol.

-6 Preferred catalysts for the process for the preparation of compounds of formula (1) are protonic acids, Lewis acids, aluminium silicates, ion exchange resins, zeolites, naturally occurring layer silicates or modified layer silicates. Suitable protonic acids are, for example, acids of inorganic or organic salts, e.g. hydrochloric acid; sulfuric acid; phosphoric acid or sulfonic acids, for example methanesulfonic acid, p toluenesulfonic acid or camphor-1 0-sulfonic acid. A suitable Lewis acid is, for example, scandium tristriflate [Sc(OTf) 3 1. Suitable aluminium silicates are, for example, those widely used in the petrochemical industry and also known as amorphous aluminium silicates. Such compounds contain about 10-30 % silicon oxide and 70-90 % aluminium oxide. Suitable ion exchange resins are, for example, styrene/divinyl benzene resins that also carry sulfonic acid groups, e.g. Amberlie 200* and Amberlyst* from Rohm and Haas or Dowex 50* from Dow Chemicals; perfluorinated ion exchange resins, e.g. NafionH* from DuPont; or other superacidic ion exchange resins such as those described by T. Yamaguchi, Applied Catalysis, 61, 1-25 (1990) or M. Hino et al., J. Chem. Soc. Chem. Commun. 1980, 851-852. Suitable zeolites are, for example, those widely used as cracking catalysts in the petro chemical industry and known as crystalline silicon-aluminium oxides having different crystal structures. Special preference is given to the faujasites from Union Carbide, e.g. Zeolith X* Zeolith Y* and ultrastable Zeolith Y*; Zeolith Beta* and Zeolith ZSM-12* from Mobil Oil Co.; and Zeolith Mordenit* from Norton. Suitable naturally occurring layer silicates are also known as "acid earths" and are, for example, bentonites or montmorillonites, which are mined on a large scale, ground, treated with mineral acids and calcined. Especially suitable naturally occurring layer silicates are the Fulcato types from Laporte Adsorbents Co., e.g. Fulcat 22A*, Fulcat 22B*, Fulcat 20*, Fulcat 30* or Fulcat 40*; or the Fulmont* types from Laporte Adsorbents Co., e.g. Fulmont XMP-3* or Fulmont XMP-4*. An especially preferred catalyst for the process according to the invention is Fulcat 22B®, but the other Fulcat* types and Fulmont* types are also to be included in this preferred class, because there are only very slight differences between the individual types, for example in the number of acidic centres. Modified layer silicates are also known as "pillared clays" and are derived from the naturally occurring layer silicates described above in that they also contain, between the silicate -7 layers, oxides of, for example, zirconium, iron, zinc, nickel, chromium, cobalt or magnesium. That type of catalyst is widely known in the literature, as described e.g. by J. Clark et al., J. Chem. Soc. Chem. Commun. 1989, 1353-1354, but is produced by only very few companies. Especially preferred modified layer silicates are, for example, Envirocat EPZ-10*, Envirocat EPZG* or Envirocat EPIC from Contract Chemicals. Special preference is also given to a process for the preparation of compounds of formula, wherein the catalyst is a sulfonic acid, especially p-toluenesulfonic acid, methanesulfonic acid or camphor-1 0-sulfonic acid. The relative molar proportion of the catalyst used to methylamine used is advantageously from 0.001:1 to 1:1, especially from 0.01:1 to 0.5:1, e.g. from 0.05:1 to 0.1:1. The relative molar proportion of the catalyst to methylamine of 1:1 also means that the methylamine can also be used in the process according to the invention in the form of a salt, for example in the form of the methylamine hydrochloride. Also of particular interest is a process for the preparation of compounds of formula (1) wherein the compound of formula (1) is continuously crystallised out of the reaction medium during preparation and then filtered off. Also of special interest is a process for the preparation of compounds of formula (1) wherein the filtrate is used for a further reaction for the preparation of compounds of formula (1), the consumed amounts of compound of formula (2) and methylamine being replaced. The filtrate is preferably recycled from 2 to 10 times. The present process according to the invention is accordingly also suitable as a continuous process for the preparation of the compounds of formula (1). The water formed during the process can optionally be bound with an additional water binder, for example molecular sieves or orthoesters, e.g. orthoformic acid trimethyl ester. The purification step (b) is carried out in a protic solvent, especially an alcoholic solvent. Especially preferred alcohols correspond to formula (3), especially ethanol or isopropanol. In an especially preferred embodiment, the purification step (b) is carried out in the same solvent as reaction step (a). In a preferred process variant, the purification is carried out by recrystallisation of sertraline imine (compound of formula (1)) under reflux. For that purpose, the isomerically pure -8 sertraline-imine, which is usually contaminated with from 2 to 10 % sertralone and from 0.01 to 0.3 % sulfonic acid, in a suitable alcohol is introduced into a suitable reaction vessel having a stirrer and reflux condenser. The reaction mass is heated, with stirring, at reflux temperature in an inert gas atmosphere until a clear solution is obtained. The solution is cooled to the appropriate isolation temperature, the product slowly precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried. The yield of imine is from 80 to 90 %, with a sertralone content of from 0.1 to 0.3 % (HPLC), catalyst contamination of s 0.001 % and a water content of from 0.1 to 0.3 %. In a further process variant, the recrystallisation of sertraline-imine is carried out under pressure. For that purpose, the crude sertraline-imine and the solvent are introduced into a suitable pressurised reactor having a stirrer. The reactor is rendered inert with nitrogen and sealed. The stirrer is started and the reaction mixture is heated at the desired reaction temperature until a clear solution is obtained. The solution is cooled to the appropriate isolation temperature, the product slowly precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried. The dissolution temperatures in the chosen alcohols are in the range of from 50 to 150 0 C, preferably in the range of from 70 to 140 0 C. According to the boiling points of the solvents indicated, the dissolving experiments can be carried out under normal pressure or elevated pressure, but normally under reflux. For dissolving temperatures above the boiling point, the dissolving experiments can be carried out under pressure, normally in the range of from 0 to 10 bar excess pressure, preferably in the range of from 0 to 3 bar excess pressure. The cooling gradients are in the range of from 0.05 to 10*C/min, preferably from 0.1 to 1*C/min. The isolation temperatures are in the range of from -20 to 400C, preferably from 0 to 25*C. The concentrations of crude sertraline-imine in the clear solution are in the range of from 5 to 40 % by weight, preferably from 15 to 20 % by weight. During the process, in order to remove discolouring impurities it is possible to add adsorbents such as activated carbon or adsorber resins. They are added to the clear -9 solution in amounts of from 1 to 10 % and are removed while hot by filtration prior to the crystallisation process. The present invention relates also to a process for the preparation of optically pure (cis) and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and (trans)-sertraline. The process comprises the following reaction steps (I)-(III): (1) reaction of pure sertraline-ketone of formula (2) to form the sertraline-imine of formula (1) in accordance with the process of claim 1, (1l) subsequent cis-selective hydrogenation using noble metal catalysts or further copper- or nickel-based catalysts to form cis-sertraline-enriched mixtures of racemic cis- and trans sertraline, (lll) subsequent racemate cleavage using mandelic acid for the selective preparation of the desired enantiomerically pure cis-isomer. Starting from pure setraline-ketone, sertraline-imine is prepared in accordance with the process described in claim 1. In a subsequent cis-selective hydrogenation with noble metal catalysts or further copper- or nickel-based catalysts of a wide variety of supports, e.g. carbon, alox, silica, calcium carbonate, barium carbonate, barium sulfate etc., the imine is converted into cis-sertraline-enriched mixtures of racemic cis- and trans-sertraline. In a subsequent racemate cleavage using mandelic acid, the desired enantiomerically pure cis-isomer can be crystallised selectively. The optically pure amine is freed with sodium hydroxide solution and converted in hydro chloride form in suitable solvents into the desired polymorphous form. The following Examples further illustrate the invention. Parts or percentages relate to weight.

- 10 Example 1: Preparation of the compound of formula (101) without catalyst and without water-binder N CH 3 (101) CI CI 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 3.16 g (34.4 mmol) of a 33 % ethanolic methylamine solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone (prepared in accordance with US-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 600C in a preheated oil bath. After about 30 minutes, a clear solution is observed for 1 to 4 minutes. The product of formula (101) then begins to crystallise. After about 40 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed three times using 25 ml of ethanol each time and then dried in a vacuum drying cabinet at about 700C/0.1-0.2 mbar. 4.41 g (84 %) of the compound of formula (101) are obtained. M.p. 145-1470C. Example 2: Preparation of the compound of formula (101) usinq p-toluenesulfonic acid as catalyst 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 0.60 g (3.44 mmol) of dried p-toluenesulfonic acid (dried at 100 110 C and 100-200 mbar), 3.16 g (34.4 mmol) of a 33 % ethanolic methylamine solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60'C in a preheated oil bath. After about 30 minutes, a clear solution is observed for 1 to 4 minutes. The product of formula (101) then begins to crystallise. After about 3 hours, a conversion of more than 95 % has been achieved (HPLC).

The reaction mixture is cooled and filtered. The residue is washed three times using 25 ml of ethanol each time and then dried in a vacuum drying cabinet at about 70 0 C/0.1-0.2 mbar. 14.57 g (87 %) of the compound of formula (101) are obtained. M.p.: 145-147 0 C. Example 3: Preparation of the compound of formula (101) re-usinq the filtrate (recycling method) and using p-toluenesulfonic acid as catalyst 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 0.6 g (3.44 mmol) of dried p-toluenesulfonic acid (dried at 100-110*C and 100-200 mbar), 12.9 g (140.2 mmol) of a 33 % ethanolic methylamine solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 30 0 C in a preheated oil bath. At that temp erature at no time is a clear solution observed. After about 5 hours and 40 minutes, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed once with 33 % ethanolic methylamine solution. 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone [prepared in accordance with US 4 536 518, Example 1(E)] is again added to the filtrate (reaction medium) and the mixture is subjected to a further reaction cycle as described above. After three further reaction cycles the residues are combined, washed three times with ethanol and then dried in a vacuum drying cabinet at about 70*C/0.1-0.2 mbar. 22.5 g (86 %) of the compound of formula (101), m.p. 145-147 0 C, are obtained. Example 4: Preparation of the compound of formula (101) using scandium tristriflate as catalyst and montmorillonite as water-binder 60 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 14.2 g (155 mmol) of a 33 % ethanolic methylamine solution, 3.0 g of dried G62 montmorillonite (water-binder), 50 mg (0.3 %, 0.13 mmol) of Sc(OTf) 3 (scandium tristriflate) and 15.0 g (55 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H) naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round- - 12 bottomed flask is then sealed tightly with a stopper and heated at 60 0 C in a preheated oil bath. After about 20 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is taken up in tetrahydrofuran. The insoluble montmorillonite is filtered off and washed with tetrahydrofuran. The filtrate is concentrated using a vacuum rotary evaporator. The residue yields 13.5 g (86 %) of the compound of formula (101). M.p.: 145-1470C. Example 5: Preparation of the compound of formula (101) using scandium tristriflate as catalyst and using orthoformic acid trimethyl ester as water-binder 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine solution, 2.55 g of -orthoformic acid trimethyl ester (water-binder), 100 mg (2.0 %, 0.26 mmol) of Sc(OTf) 3 [scandium tristriflate] and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro 1(2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60 0 C in a preheated oil bath. After about 6 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed three times using 4 ml of ethanol each time and then dried in a vacuum drying cabinet at about 70*C/0.1-0.2 mbar. 4.5 g (86 %) of the compound of formula (101) are obtained. M.p.: 145-147 0 C. Example 6: Preparation of the compound of formula (101) without catalyst, but using ortho formic acid trimethyl ester as water-binder 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine solution, 2.55 g of orthoformic acid trimethyl ester (water-binder) and 5.0 g (17.2 mmol) of 4-(3,4 dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60 0 C in a preheated oil bath. After about 7 hours, a conversion of - 13 more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed three times using 4 ml of ethanol each time and then dried in a vacuum drying cabinet at about 70*C/0.1-0.2 mbar. 4.5 g (86 %) of the compound of formula (101) are obtained. M.p.: 145-147*C. Examples 7 to 14: Preparation of sertraline-imine using various solvent/catalyst combinations 20 g of solvent (a) are introduced into a 50 ml round-bottomed flask. 0.33 equivalent (relative to the ketone used) of catalyst (b) are added to 2.9 g of a 33 % ethanolic methylamine solution. Heating is carried out for 4 hours at the temperature indicated. An HPLC sample is taken, heating is carried out for a further 16 hours and the solid product of formula (101) is filtered. Finally, HPLC samples of both the product and the mother liquor are taken. The experiment parameters and results are given in Table 1: - 14 Table 1: Example Temp. Solvent (a) Catalyst (b) Yield Isolated yield rel. imine l*ci after 4 h %]/ concentra [%] contaminated tion in the HPLC with % mother liquor ketone [%1, HPLC 7 60 Ethanol - 76 74/2.5 17 8 60 Isopropanol p-TsOH 93 81/4.5 <1 9 30 Ethanol Methane- 46 84/3.2 6 sulfonic acid 10 30 Isopropanol Methane- 29 86/8.5 6 sulfonic acid 11 60 Triethanol- p-TsOH 92 77/4.0 28 amine } 12 60 Ethylene p-TsOH 93 84/3.8 <20 glycol 13 60 Cyclo- p-TsOH 81 64/12 18 hexanol 14 30 Ethanol Camphor- 49 80/2.9 17 sulfonic acid Example 15: Preparation of sertraline-imine using methanesulfonic acid as catalyst Sertralone (240.0 g; 0.825 mol) is introduced with ethanolabs (800 ml) into a suitable reaction vessel equipped with a stirrer and gas inlet line.

-15 The suspension is cooled to 0*C and methylamine (55.0 g; 1.762 mol) is introduced under the level, i.e. below the surface, of the solvent. Methanesulfonic acid (10 ml) is then fed in over a period of 5 minutes using a syringe. The reaction mass is heated and stirred for 3 hours at 50*C and for 1 hour at 70*C in order to obtain conversion into the imine (> 94 %). The reaction mixture is then cooled to 10*C, filtered and washed with cold ethanol (2 x 250 ml). The crude filter cake is dried overnight in vacuo and yields 213 g of dry N-methyl-sertraline-imine. Quality and yield of the resulting imine (determined by means of HPLC): 88 % yield of sertraline. The imine contains: 1.8 % sertralone 0.1 %water. 0.05 % methanesulfonic acid (determined using CE) Example 16: Purification of sertraline-imine by recrystallisation from ethanol: 12 g of sertraline-imine from Example 15 are introduced into 200 ml of ethanol in a suitable reaction vessel having a stirrer, nitrogen inlet line and reflux condenser. The stirrer is started and the reaction mixture is heated at reflux temperature until a clear solution is obtained. The solution is slowly cooled to 200C, the product crystallising out. The suspension is filtered, the filter cake is washed with the solvent and dried. 10.6 g of sertraline-imine having the following composition (HPLC) are obtained: 88 % yield of sertraline-imine The imine contains: 0.2 % sertralone < 0.05 % water < 0.001 % methanesulfonic acid (determined using CE). By means of the recrystallisation it is possible both to improve product purity and to remove troublesome impurities such as water or catalyst residues.

- 16 Example 17: Preparation of sertraline-imine without catalyst (see Example 1) Quality and yield of the imine (determined by means of HPLC): 84 % yield of sertraline-imine The imine contains: 5 % sertralone 0.1 %water Example 18: Recrysallisation of sertraline-imine from catalyst-free preparation The recrystallisation of imine from Example 16 is carried out with the addition of 480 mg of activated carbon. 1 hour at reflux is followed by hot (at T>70*C) clarifying filtration and subsequent cooling. The following results are obtained: 88 % yield of sertraline-imine The imine contains: 0.2 % sertralone <0.05 % water Example 19: Recrystallisation of sertraline-imine in ethanol at temperatures above the boiling point (under pressure) 10 g of sertraline-imine from Example 18 are introduced into 20 ml of ethanol in a suitable pressurised reaction vessel having a stirrer. The reaction mixture is heated, with stirring, at from 11 0*C to 115*C (pressure range from 2 to 5 bar) until a clear solution is obtained. The solution is slowly cooled to 20 0 C, the product precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried. 8.6 g of sertraline-imine of the following composition (HPLC) are obtained: 86 % yield of sertraline-imine The imine contains: 0.9 % sertralone < 0.05 % water 0.001 % methanesulfonic acid (determined using CE)

Claims

1. A process for the preparation of compounds of formula N-CH3 R, (1) R3 R2 wherein R 1 , R 2 and R 3 are each independently of the others hydrogen, halogen, trifluoromethyl or C-C 4 alkoxy, in which process (a) a compound of formula 0 (2) wherein Ri R 3 R2 R 1 , R 2 and R 3 are as defined for formula (1), is reacted with methylamine in a protic solvent, and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation and/or reaction step (a) is carried out in the presence of a catalyst.

2. A process according to claim 1, wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation.

3. A process according to claim 1, wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1).

4. A process according to claim 1, wherein - 18 (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1), and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation.

5. A process according to any one of claims 1 to 4, wherein R 1 is hydrogen or chlorine.

6. A process according to any one of claims 1 to 5, wherein R 2 and R 3 are each independently of the other hydrogen, chlorine or bromine.

7. A process according to any one of claims 1 to 6, wherein R 1 is hydrogen and R 2 and R 3 are chlorine.

8. A process according to any one of claims 1 to 7, wherein the protic solvent is an a-hydric alcohol wherein a is the number 1, 2, 3 or 4.

9. A process according to claim 8, wherein the protic solvent is a compound of formula (3) X(OH)a wherein a is 1, 2, 3 or 4, and when a is 1, X is C 1 -C 8 alkyl, C 5 -C 8 cycloalkyl or -CH 2 CH 2 (OCH 2 CH 2 )bR 4 , b is 0, 1 or 2, and R 4 is C 1 -C 4 alkoxy, or when a is 2, X is C 2 -C 8 alkylene or -CH 2 CH 2 (OCH 2 CH 2 )b-, wherein b is as defined above, or when a is 3, X is C 3 -C 8 alkanetriyl or N(CH 2 CH 2 -) 3 , or when a is 4, X is C 4 -C 8 alkanetetrayl. - 19

10. A process according to claim 9, wherein the protic solvent is methanol, ethanol, isoproponanol, n-butanol, ethylene glycol, methyl Cellosolve, cyclohexanol, diethylene glycol or triethanolamine.

11. A process according to claim 10, wherein the protic solvent is ethanol or isopropanol.

12. A process according to claim 1 or any one of claims 3 to 11, wherein the catalyst is a protonic acid, a Lewis acid, an aluminium silicate, an ion exchange resin, a zeolite, a naturally occurring layer silicate or a modified layer silicate.

13. A process according to claim 12, wherein the catalyst is a sulfonic acid.

14. A process according to claim 13, wherein the catalyst is p-toluenesulfonic acid, methanesulfonic acid or camphor-1 0-sulfonic acid.

15. A process according to any one of claims 1 to 14, wherein the compound of formula (1) is continuously crystallised out of the reaction medium during preparation and then filtered off.

16. A process according to claim 15, wherein the filtrate is used for a further reaction for the preparation of the compound of formula (1).

17. A process according to any one of claims 1 to 16, wherein the relative molar proportion of the compound of formula (2) to methylamine is from 1:1 to 1:100.

18. A process according to claim 1, 2 or any one of claims 4 to 17, wherein the purification step (b) is carried out in a protic solvent.

19. A process according to claim 18, wherein the protic solvent is a compound of formula (3).

20. A process according to claim 19, wherein the protic solvent is ethanol or isopropanol.

21. A process according to claim 1, 2 or any one of claims 4 to 20, wherein purification step (b) is carried out in the same solvent as reaction step (a).

22. A process according to claim 1, 2 or any one of claims 4 to 21 21, wherein purification step (b) is carried out under reflux.

23. A process according to claim 1, 2 or any one of claims 4 to 21, wherein purification step (b) is carried out under elevated pressure. -20

24. A process according to claim 1, 2 or any one of claims 4 to 23, wherein purification step (b) is carried out at a temperature of from 50 to 15000.

25. A process according to any one of claims 1 to 24, wherein the compound of formula (1) is isomerically pure and prior to purification step (b) is contaminated with from 2 to 10 % compound of formula (2) and from 0.01 to 0.3 % sulfonic acid.

26. A process for the preparation of optically pure (cis)- and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and (trans)-sertraline, which process comprises the following reaction steps (1)-(111): (1) reaction of pure sertraline-ketone of formula (2) to form the sertraline-imine of formula (1) in accordance with the process of claim 1, (II) subsequent cis-selective hydrogenation using noble metal catalysts or further copper- or nickel-based catalysts to form cis-sertraline-enriched mixtures of racemic cis- and trans sertraline, and (Ill) subsequent racemate cleavage using mandelic acid for the selective preparation of the desired enantiomerically pure cis-isomer.