MXPA00005680A - Process for preparing sertraline from chiral tetralone - Google Patents

Abstract

This invention relates to a novel improved process for preparing the (+) enantiomer of N- 4-(3,4-dichlorophenyl)- 3,4-dihydro-1 (2H)-naphthalenylidenemethanamine by reacting the (+) enantiomer of 4-(3,4-dichlorophenyl) -3,4-dihydro-1 (2H)-naphthalenone with monomethylamine and titanium chloride or molecular sieves.

Description

PROCEDURE FOR PREPARING SERTRALINE FROM TETRALONE QUIRAL BACKGROUND OF THE INVENTION This invention relates to a new and simplified method for preparing a known ketimbin compound. Specifically, it deals with the synthesis of the (+) enantiomer of N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1- (2H) -naphthalenylidenhemetanarnine, a critical intermediate in the production of cis- (1 S) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine (sertraline). Sedalin hydrochloride is the active ingredient in the antidepressant Zoloft®. The most widely used route to date for the commercial preparation of N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenylidenhemetamine, which leads to tis- (1 S) - ( 4S) -N-methyl-4- (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro-1-naphthalenamine (sertraline), involves a condensation reaction of 4- (3,4-dichlorophenyl) - 3,4-dihydro-1 (2H) -naphthalenone with monmethylamine which is catalyzed by titanium tetrachloride, as described by WR Welch, Jr. et al. in U.S. Pat. No. 4,536,518 and in Journal of Medicinal Chemistry, volume 27, No. 1 1, page 1508, 1 .984. In U.S. Pat. r? ° 4.855.500 of J.C. Spavins describes an alternative method to 'produce N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenylidenhemetamine in which the dehydration characteristics of appropriate mesh molecular sieves are employed for activating the condensation ratio between 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone and monomethylamine. Molecular sieves of the appropriate type (specifically those with pores with a size of approximately 30 nm) are contacted in situ with the mixture of 4- (3,4-dichlorophenyl) -3,4-dihydro-1- (2H ) -naphthalenone and monomethylamine and adsorb the water formed in the condensation reaction. Substantial savings can be realized by carrying out procedures similar to those described in the preceding paragraph, using the optically pure (+) enantiomer of the tetralone starting material, or an optically enriched (+) mixture of the (+) and (-) enantiomers of it, instead of the racemic tetralone. The use of the starting chiral material eliminates the need to solve the final product and also eliminates the production of intermediates having the undesired stereochemistry.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a process for preparing the optically pure (+) enantiomer of N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenylidene] methanamine, depicting below (+) or an optically enriched mixture (+) of the above compound of formula II and its opposite enantiomer, which comprises reacting the enantiomer (+) optically pure of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone ("the tetralona"), representing next (+) or an optically enriched mixture (+) of the (+) and (-) enantiomers of tetralone, with menomethylamine and with titanium tetrachloride or molecular sieves in a solvent selected from tetrahydrofuran (THF), methylene chloride and solvents aromatics such as toluene, xylenes and dichlorobenzene, at a temperature from about -20 ° C to about 60 ° C, preferably from about 0 ° C to about 50 ° C. A more specific embodiment of this invention relates to the process described above in that: a) the ketimine product of formula 11 that is formed by said process is hydrogenated to form a mixture of sertraline (+) cis ("sertraline") and sertraline ( -) trans, b) sertraline is optionally separated from said mixture; and c) sertraline is optionally converted to its hydrochloride or mandelate salt. As used herein, both the term "sertraline" and the term "sertraline (+) cis" refer to cis- (1S) - (4S) -N-methyl-4- (3,4-dichlorophenol) -1, 2,3,4-tetrahydro-1-naphthalenamine. As used herein, the expression "sertraline (+) trans" refers to trans- (1R) (4S) -N-methyl-4- (3, 4-dichlorophenyl) -1, 2,3,4-tetrahydro-1-naphthalenamine. As used herein, the expression "sertraline (-) cis" refers to cis (1 R) (4R) -N-methyl-4- (3,4-dichloropheni) -1, 2,3,4-tetrahydro -1-naphthalenamine. As used herein, the expression "sertraline (-) trans" refers to trans- (1 S) (4R) -N-methyl-4- (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro -1-naphthalenamine. As used herein, the term "racemic cis serineralin" refers to an optically inactive mixture of sertraline (+) cis and sertraline (-) cis. As used herein, the term "trans-sertraline trans racemic" refers to an optically inactive mixture of sertraline (+) trans and sertraline (-) trans. As used herein, the term "racemic sertraline" refers to an optically inactive mixture of racemic cis sertraline and trans racemic sertraline.

DETAILED DESCRIPTION OF THE INVENTION The methods of this invention, as well as the use of the ketimine product of said processes in the synthesis of sertraline, are illustrated in the following schemes and are described below.

SCHEME 1 ns SCHEME 2 Sertraline (+) cis Sertraline Hydrochloride (+) cis "Sertraline" "Sertraline Hydrochloride" I I I A I I I B In accordance with the method of this invention, it is combined the starting material, optically pure 4- (3,4-dichlorophenyl) -3,4-dhydro-1 (2H) -naphthalenone (+) or an optically enriched mixture (+) of the (+) enantiomers and ( -) of the same compound, with 1.5 to 25 equivalents of monomethylamine and a solvent selected from methylene chloride, THF and aromatic solvents such as toluene, xylenes and dichlorobenzene. Titanium tetrachloride (0.2 to 1.2 equivalents) or molecular sieves are combined with the reaction mixture and the mixture is allowed to react to a temperature of from about 20 ° C to about 60 ° C, preferably from about 0 ° C to about 50 ° C, during a period of about 1 to about 24 hours. The solid by-products (titanium dioxide and monomethylamine hydrochloride) can be separated from the reaction mixture by filtration and washed with the reaction solvent. To facilitate filtration, an adequate filtering auxiliary agent can be used. Dyeing carbon or an appropriate filtering auxiliary can be added to the solution containing the product, the resulting mixture stirred and filtered, and the filter cake washed with the same solvent. The solution containing the ketimine (+) product of formula II, or an optically enriched mixture (+) of the (+) and (-) enantiomers thereof, can then be concentrated by distillation (either at atmospheric pressure or under pressure reduced), and the solvent can then be essentially replaced by hexane to a final volume of 3-10 liters per kg of starting material. The ketimine product is granulated at a temperature of about -10 ° C to about 30 ° C, separated by filtration and washed with hexanes or heptane. Said product can be used directly, wetted with solvent, in the next operation (ie, the hydrogenation operation) or, if needed for storage, it can be dried under vacuum or at atmospheric pressure, at a maximum temperature of 80 ° C. If THF is used as the reaction solvent for the ketimine formulation reaction, the solution containing the ketimine product can be concentrated by distillation (either at atmospheric pressure or under reduced pressure), and the concentrated solution can be brought directly to the reactor. the next operation. The cetimínico product from the previous operation, dried or wet with solvent, is combined with THF. The solution is hydrogenated in suitable equipment using up to 30% (w / w) of a hydrogenation catalyst, such as palladium on carbon catalyst, wet with water, or palladium catalyst on calcium carbonate, wet with water, or one of the analogous catalysts containing platinum, to produce a mixture of sertraline (+) cis and sertraline (-) trans. The hydrogen pressure for the hydrogenation reaction is from about 101.32 kPa to about 810.60 kPa, preferably from about 101.32 kPa to about 506.63 kPa, and the temperature is from about 0 ° C to about 70 ° C, preferably from about room temperature at approximately 60 ° C. The reaction time is generally from about 1 to about 24 hours. The catalyst is then separated by filtration and washed with the same solvent used for the hydrogenation reaction, and the filtration product is further processed as described below. If toluene is used as a solvent for the ketimine formation reaction, the solution containing the ketimine product can be concentrated by distillation (either at atmospheric pressure or under reduced pressure) and then can be hydrogenated in the manner described above, although using toluene as the hydrogenation solvent, to produce a mixture of sertraline (+ ) cis and sertraline (-) trans. The hydrogenation reaction can also be carried out in other solvents, such as ethanol, diisopropyl ether, methyl t-butyl ether and similar solvents, although, depending on the solvent used for the ketimine formation reaction, it may be It is preferable to isolate the dry ketimine before combining it with the hydrogenation solvent. Once the hydrogenation reaction is complete, a filtration is performed to separate the catalyst. The excess monomethylamine is separated by means of distillation and / or substitution of the original solvent (used for the ketimine formation reaction) by another suitable solvent, such as a lower alkanol, tetrahydrofuran, methyl ethyl ketone or toluene. The preferred temperature range for the hydrogenation reaction is from about 0 ° C to about 70 ° C, and the preferred range of hydrogen pressures is from about 101.32 kPa to about 810.60 kPa. Most preferable temperatures are in the range of about room temperature to about 60 ° C, and most preferable hydrogen pressures are in the range of about 101.32 kPa to about 506.63 kPa. Preferred catalysts for reduction or reductive amination described above include platinum, palladium and other precious metal activators on supports such as carbon, graphite, calcium carbonate and other similar supports, all of which are well known in the catalytic hydrogenation industry. The salt of sertraline hydrochloride can be obtained in the following manner. Hydrogen chloride, either in gaseous form or in the form of an aqueous solution, is combined with the filtration product from the hydrogenation reaction, and the resulting product is subjected to selective crystallization to isolate sertraline (+) cis ("sertraline"). "), granulated at a temperature of about -10 ° C to 30 ° C, separated by filtration and washed with the reaction solvent. The resulting sertraline hydrochloride salt can be used directly, wetted with solvent, in a further processing or, if needed for storage, it can be dried at a temperature lower than 80 ° C, either at atmospheric pressure or under reduced pressure. When toluene is used as the hydrogenation solvent, the mandelate salt of sertraline can be formed by combining the filtration product from the hydrogenation reaction with from 0.9 to 1.5 equivalents of D - (-) - mandelic acid, either directly or in the form of a suspension / solution in ethanol, at a temperature from about 0 ° C to about 80 ° C. The resulting product is the mandelate salt of sertraline (ie, the mandelate salt of sertraline (+) cis), with only minimal amounts of the mandelate of sertraline (-) trans. This is so because D - (-) - mandelic acid converts both sertraline (-) trans and sertraline (-) cis into sertraline (+) cis mandelate ("sertraline mandelate"). The resulting product is then granulated at a temperature of about -10 ° C to about 30 ° C, separated by filtration and washed with ethanol. The sertraline mandelate thus obtained can be used directly, wetted with solvent, in a subsequent processing or it can be dried at a temperature lower than 80 ° C, either at atmospheric pressure or under reduced pressure. The above reaction with D - (-) - mandelic acid can also be carried out in a variety of different solvents (for example, THF, ethanoi, methanol, isopropanol, ethyl acetate, acetone, diisopropyl ether and methyl t-butyl). -ether), although, depending on the hydrogenation solvent used, it may be preferable to isolate the free base of sertraline after the hydrogenation reaction. As an alternative to concentrate and isolate the solid ketimin product from the ketimine formation reaction, the solvent / ketimine mixture from that reaction can be directly processed, without isolation, to the next synthetic operation of sertraline production, whereby the catalytic hydrogenation of the ketimine to form a mixture of sertralines (+) cis and (-) trans is carried out using the same solvent. The hydrogenation can be carried out satisfactorily, either once the formation of the ketimine is completed or simultaneously with the formation of the ketimine, by a reductive amination process. The reductive amination method involves combining the tetralone (+) with monomethylamine (ideally from 2.5 to 3.5 molar equivalents) and a suitable hydrogenation catalyst, such as one of those mentioned above, under an atmosphere of hydrogen in a suitable organic solvent, such as toluene or THF, until the incorporation of hydrogen ceases or, in any case, you see that the reaction has been completed. This reaction is typically carried out at a temperature of from about 20 ° C to about 100 ° C, preferably from about room temperature to about 70 ° C, and at a pressure from about 238.9 kPa to about 790.5 kPa, preferably about 238.9 kPa at approximately 514.7 kPa. Under these conditions, the tetralone (+) is converted into the corresponding ketimine (+) and this is immediately reduced to the desired mixture of sertraline (+) cis and sertraline (-) trans. The following examples illustrate the new methods of this invention, although they do not limit them in their scope.

EXAMPLE 1 Enantiomer (+) of N-r4- (3,4-dichloropheniD-3,4-dihydro-1 (2H) -naphthalenylidenemethanamine) 8.64 g (4.5 equivalents) of monomethylamine were added to 18.0 g of compound I in 18.5 ml of toluene, at -10 ° C and under nitrogen, and the mixture was stirred for 10 minutes. Titanium tetrachloride (4.57 g, 0.56 equivalents) was added dropwise while maintaining the temperature below 15 ° C. The reaction mixture was allowed to warm to room temperature and then the mixture was stirred for 1.5 hours. The reaction mixture was filtered under nitrogen, the filter cake was washed with toluene and most of the toluene was removed by distillation under vacuum. When about 90 ml of toluene remained, the vacuum was removed and 72 ml of hexane was added. This procedure was continued until all the toluene had been removed, hexane added when necessary. Once the distillation was complete, the product was left overnight in the refrigerator and then granulated in 72 ml of hexane for 2 hours at 0 ° C. The resulting mixture was filtered and washed with cold hexane. A light yellow solid having a weight of 15.59 g in the wet state was obtained. The product was dried over the weekend in a vacuum oven, after which 14.96 g of product were obtained. The filtrate was concentrated to dryness, 20 ml of hexane was added and the mixture left in the fridge over the weekend. The mixture was then stirred for 1 hour at 0 ° C and filtered, and washed with cold hexane. The weight of the resulting solid product in the wet state was 1.54 g. The product was dried under vacuum overnight to obtain 1.53 g (88%) of a yellow solid. The nuclear magnetic resonance spectrum corresponded to that of the title compound.

EXAMPLE 2 Sertraline mandelate 14.8 g of compound II and 65 ml of THF were added, under nitrogen, to Pd / C (0.740 g, in the wet state with 50% water). The mixture was hydrogenated at 275.8 kPa for 5 hours. Once the reaction was complete, the mixture was filtered through celite and the catalyst cake was washed with THF. The solvent was removed, ethanol (EtOH, 74 ml) was added to the residue and the solvent was removed. EtOH (74 ml) and D-mandelic acid (7.40 g) were added to the resulting product and the mixture was stirred for 18 hours at room temperature. EtOH (14 ml) was then added and the mixture was stirred for 1 hour. The resulting mixture was filtered and the solid product was washed with EtOH. The weight of the product in the wet state was 21.62 g. The product was dried under vacuum to obtain 17.34 g (78%) of solid. The nuclear magnetic resonance spectrum corresponded to that of sertraline mandelate salt.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing the optically pure (+) enantiomer of N- [4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenylidenhemetanamine, represented below (+) or an optically enriched mixture (+) of the above compound of formula II and its opposite enantiomer, which comprises reacting the enantiomer (+) optically pure of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone ("the tetralona"), represented below (+) or an optically enriched (+) mixture of the (+) and (-) enantiomers of tetralone, with menomethylamine and with titanium tetrachloride or molecular sieves.

2. A process according to claim 1, wherein: a) the ketimine product of formula II which is formed by said process is hydrogenated to form a mixture of sertraline (+) cis ("sertraline") and sertraline (-) trans; b) sertraline is optionally separated from said mixture; and c) sertraline is optionally converted to its hydrochloride or mandelate salt.

3. A process according to claim 1, wherein an excess of monomethylamine is used with respect to the tetralone starting material.

4. A process according to claim 1, wherein the reaction is carried out at a temperature in the range of about -20 ° C to about 60 ° C.

5. A process according to claim 1, wherein the solvent is selected from THF, methylene chloride, xylenes and dichlorobenzene.

6. A process according to claim 1, wherein monomethylamine and titanium chloride are reacted with the tetralone.

7. A process according to claim 1, wherein the tetralone is reacted with monomethylamine and molecular sieves.

8. A process according to claim 1, wherein the ketimine product of formula II, or an optically enriched mixture (+) of said compound and its opposite enantiomer, is hydrogenated in situ in the same solvent in which it was formed. to obtain an optically pure mixture consisting of sertraline (+) cis and sertraline (-) trans, or a mixture consisting of sertraline (+) cis, sertraline (-) cis, sertraline (-) cis and sertraline (-) trans .

9. A process for preparing a mixture of sertraline (+) cis and sertraline (-) trans, which comprises reacting the optically pure (+) enantiomer of 4- (3,4-dicyorophenyl) -3,4-dihydro -1 (2H) -naphthalenone ("the tetralone"), represented below (+) Or an optically enriched (+) mixture of the enantiomers (+) and (-) of the tetralone, with monomethylamine and titanium tetrachloride or molecular sieves, and suitable hydrogenation catalyst in a suitable organic solvent under an atmosphere of hydrogen at a pressure of about 238.9 kPa to about 790.5 kPa, and at a temperature of about • the ambient temperature to about 70 ° C.