Process for preparing a ketimine

Details Process for preparing a ketimine Process for preparing a ketimine

1999-09-02

2001-05-15

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S270000

Reexamination Certificate

active

06232500

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 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-methyl4(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. However, the safety concerns (due to extreme reactivity with water) and hazardous by-products (namely, titanium dioxide monomethylamine hydrochloride) associated with use of titanium tetrachloride, have prompted evaluation of alternative dehydrating agents that would eliminate the formation of hazardous by-products. The advantages associated with elimination of solid by-product formation include not only improved safety, but also improved productivity associated with elimination of the need for filtration of the by-product from the reaction medium. The process of filtering titanium dioxide monomethylamine hydrochloride on common commercially available isolation devices is very time consuming.
An alternative route to N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenyl-idene-]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-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine, and adsorb the water formed from the condensation reaction. Once the desired condensation reaction is essentially complete, forming N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine, the water saturated molecular sieves must be removed from the product containing solution by filtration prior to isolation of the ketimine product. Furthermore, used sieves must typically be regenerated if they are to be reused.
The process of this invention provides a novel and useful synthetic route to N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine, known to be a useful intermediate in the synthesis of sertraline. This novel route involves a condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and monomethylamine in a solvent such as an alkanol or a mixture of two or more alkanols. The nature of the solvent and the solubility of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenylidene-]methanamine in the solvent are such that reaction equilibrium is favorably enhanced towards the ketimine product, namely N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine. The desired ketimine is thus produced in acceptable purity and high yield without requiring the addition of a heterogeneous catalyst, such as, for example, molecular sieves. This novel, one step approach to the synthesis of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene-]methanamine from 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone therefore avoids the above described disadvantages associated with the titanium tetrachloride route. Moreover, the need for addition of a dehydration agent (es, titanium tetrachloride or molecular sieves or another such dehydration promoting additive) is eliminated, as is the associated need for removal of by-products or spent sieves from the completed reaction mixture.
SUMMARY OF THE INVENTION
This invention relates to a process for preparing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenylidene]methaneamine, depicted below,
comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone, depicted below and also referred to herein as “tetralone”,
with monomethylamine in an alcohol solvent selected from primary, secondary and tertiary straight or branched (C
1
-C
6
) alkanols, and other alcohols having a boiling point, under reaction conditions, that is greater than about 55° C., and in which monomethylamine is soluble.
Examples of suitable solvents for use in the processes of this invention are benzyl alcohol, phenol, ethanol, n-propanol, isopropanol, t-butanol, isobutanol, n-butanol and methanol.
Preferred solvents for use in the processes of this invention are alcohols, as defined above, having a vapor pressure that is about 1 atmosphere or lower under reaction conditions.
A more specific embodiment of this invention relates to the process described above, wherein the ketimine product of formula II that is formed in such process is hydrogenated to form a mixture of racemic cis sertraline and racemic trans sertraline.
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-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term “cis (−) sertraline”, as used herein, refers to cis-(1R) (4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.
The term “trans (−) sertraline”, as used herein, refers to trans-(1S) (4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-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.
This invention also relates to a process for preparing the optically pure (+) enantiomer of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenylidene]methaneamine, depicted below,
or an optically enriched (+) mixture of the (+) and (−) enantiomers of the same, respectively;
comprising reacting the optically pure (+) enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone, depicted below,
or an optically enriched (+) mixture of the (+) and (−) enantiomers of the same, respectively,
with monomethylamine in an alcohol solvent selected from primary, secondary and tertiary straight or branched (C
1
-C
6
) alkanols, and other alcohols having a boiling point, under reaction conditions, that is greater than about 55° C., and in which monomethylamine is soluble.
A more specific embodiment of this invention relates to the process described immediately above, wherein the optically pure or optically enriched (+) ketimine product of formula II′ that is formed in such process is hydrogenated to form an optically pure (+) mixture of cis (+) sertraline and trans (+) sertraline, or an optically enriched (+) mixture of cis (+) sertraline, trans (+) sertraline, cis (−) sertraline and trans (−) sertraline.
This invention also relates to a process for preparing a mixture of racemic cis sertraline and racemic trans sertraline, comprising reacting a compound of the formula I, as depicted above, with monomethylamine, hydrogen gas (i.e., under a hydrogen atmos

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