Process for preparing sertraline from chiral tetralone

Details Process for preparing sertraline from chiral tetralone Process for preparing sertraline from chiral tetralone

2000-05-30

2003-07-15

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S305000, C564S308000

Reexamination Certificate

active

06593496

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a new, simplified method of preparing a known ketimine compound. Specifically, it is concerned with the synthesis of the (+) enantiomer of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, a critical intermediate in the production of cis-(1S)(4S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline). Sertraline 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)-naphthalenylidene]methanamine, leading to cis-(1S)(4S)-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline), involves a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with monomethylamine, which is catalyzed by titanium tetrachloride, as described by W. R. Welch, Jr. et al. in U.S. Pat. No. 4,536,518 and in Journal of Medicinal Chemistry, Vol. 27, No. 11, p 1508, 1984. An alternative method of producing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene ]methanamine is described in U.S. Pat. No. 4,855,500 to J. C. Spavins, wherein the dehydration characteristics of appropriate mesh molecular sieves are employed to promote the condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenone and monomethylamine. The appropriate type molecular sieves (specifically, those having a pore size of about 3 Angstroms) are contacted in situ with the mixture of 4-(3,4dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine, and adsorb the water formed from the condensation reaction.
Substantial economies can be realized by carrying out similar processes 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 the same, rather than racemic tetralone. Use of the chiral starting material eliminates the need to resolve the final product and also eliminates the production of intermediates having the undesired sterochemistry.
SUMMARY 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]methaneamine, depicted below,
or an optically enriched (+) mixture of the above compound of formula II and its opposite enantiomer, comprising reacting the optically pure (+) enantiomer of 4-(3,4-dichlorophenyl)-3,4dihydro-1(2H)-napthalenone (“the tetralone”), depicted below,
or an optically enriched (+) mixture of the (+) and (−) enantiomers of the tetralone, with monomethylamine and either titanium tetrachloride or molecular sieves in a solvent selected from tetrahydrofuran (“THF”), methylene chloride and aromatic solvents 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, wherein: (a) the ketimine product of formula II that is formed in such process is hydrogenated to form a mixture of cis (+) sertraline (“sertraline”) and trans (−) sertraline; (b) sertraline is optionally separated from such mixture; and (c) sertraline is optionally converted into its hydrochloride or mandelate salt.
The terms “sertraline” and “cis (+) sertraline”, as used herein, both refer to cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term “trans (+) sertraline”, as used herein, refers to trans-(1R) (4S)-N-methyl4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term “cis (−) sertraline”, as used herein, refers to cis-(1R) (4R)-N-methyl-4-(3,4dichlorophenyl)-1,2,3,4-naphthaleneamine.
The term “trans (−) sertraline”, as used herein, refers to trans-(1S) (4R)-N-methyl4-(3,4dichlorophenyl)-1,2,3,4-naphthaleneamine.
The term “racemic cis sertraline”, as used herein, refers to an optically inactive mixture of cis (+) sertraline and cis (−) sertraline.
The term “racemic trans sertraline”, as used herein, refers to an optically inactive mixture of trans (+) sertraline and trans (−) sertraline.
The term “racemic sertraline”, as used herein, refers to an optically inactive mixture of racemic cis sertraline and racemic trans sertraline.
DETAILED DESCRIPTION OF THE INVENTION
The processes of this invention, as well as the use of the ketimine product of such processes in the synthesis of sertraline, are illustrated in the following schemes and described below.
In accordance with the process of this invention, the starting material, optically pure (+) 4(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, or an optically enriched (+) mixture of the (+) and (−) enantiomers of the same compound, is combined with 1.5 to 25 equivalents of monomethylamine and a solvent selected from methylene chloride, THF and aromatic solvents such as toluene, zylenes or dichlorobenzene. Titanium tetrachloride (0.2 to 1.2 equivalents) or molecular sieves is combined with the reaction mixture and reacted at a temperature from about −20° C. to about 60° C., preferably from about 0° C. to about 50° C., for about 1 to about 24 hours. Solid by-products (titanium dioxide and monomethylamine hydrochloride) can be removed from the reaction mixture by filtration and washed with the reaction solvent. A suitable filter aid may be utilized to aid filtration. Decolorizing carbon or a suitable filter aid may be added to the solvent containing product, the resulting mixture stirred and filtered off, and the cake washed with the same solvent.
The solvent containing the (+) ketimine product of formula II, or an optically enriched (+) mixture of the (+) and (−) enantiomers of the same, can then be concentrated by distillation (either atmospherically or under reduced pressure) and then essentially displaced by hexane to a final volume of 3-10 liters per kilogram of starting material. The ketimine product is granulated at a temperature from about at −10° C. to about 30° C., filtered and washed with hexanes or heptane. Such product can be used directly, solvent wet, in the next step (i.e., the hydrogenation step), or, if needed for storage, it can be dried under vacuum or atmospherically at a maximum temperature of 80° C.
If THF is used as the reaction solvent for the ketimine formation reaction, the solvent containing the ketimine product can be concentrated by distillation (either atmospherically or under reduced pressure) and the concentrated solution carried directly into the next step. The dried or solvent wet ketimine product from the above step is combined with THF. The solution is hydrogenated in suitable equipment using up to 30% (weight/weight) of a hydrogenation catalyst such as palladium on carbon water wet catalyst or palladium on calcium carbonate water wet catalyst, or one of the analogous platinum containing catalysts, to produce a mixture of cis (+) sertraline and trans (−) sertraline. The hydrogen pressure for the hydrogenation reaction is from about 1 to about 8 atmospheres, preferably from about 1 to about 5 atmospheres, and the temperature is from about 0° to about 70° C., preferably from about room temperature to about 60° C. The reaction time is generally from about 1 to about 24 hours. The catalyst is then filtered off and washed with the same solvent used for the hydrogenation reaction, and the filtrate is further processed as described below.
If toluene is used as the solvent for the ketimine formation reaction, the solvent containing the ketimine product can be concentrated by distillation (either atmospherically or under reduced pressure) and then hydrogenated, as described above, but using toluene as the hydrogenation solvent, to produce a mixture of cis (+) sertraline an

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