Technical Field This invention relates to a process for recycling a trans-amine to a cis-amine. More particularly, it is concerned with a novel method for converting trans-isomeric N- methyl-4-(3.4-dichlorophenyl)-1 ,2,3,4-tetrahydro-l-naphthaleneamine to the corresponding cis-isomeric product. The latter material is useful as an intermediate that ultimately leads to the antidepressant agent known as cis-( 1 S)(4S)-N-methyl-4-(3.4- dichlorophenyl)-1 ,2.3,4-tetrahydro-1 -naphthaleneamine (sertraline).

Background Art There is described in U.S. Patent Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry. Vol. 27, No. 11 , p. 1508 (1984), a multi-step method .for synthesizing pure racemic cis-N-methyl-4-(3.4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 - naphthaleneamine, starting from the readily available 3,4-dichlorobenzophenone. in the last step of this synthesis, N-[4-(3.4-dichlorophenyl)-3.4-dihydro-1 (2H)- naphthalenylidenejmethenamine is reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4- tetrahydro-1 -naphthaleneamine, which is actually a mixture of the cjs- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cjs- racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline). Nevertheless, the above described production of pure cjs-(1 S)(4S)-N-methyl-4-

(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine is disadvantageous in that large amounts of the unwanted racemic trans-isomer (which ultimately leads to the unwanted trans-(1S)(4R)-enantiomer) are co-produced and must eventually be discarded, thereby lowering the overall yield of the desired cis-(1S)(4S)-enantiomer and increasing the costs of production. Therefore, it is an object of the present invention to utilize the unwanted trans-isomer that is co-produced in the aforesaid synthesis and so lower the total costs of production. Another and more specific object of the present

invention is to convert the aforesaid trans-racemate free base to the corresponding cjs- isomer and thereby, in effect, recycle the previously unwanted trans-isomer back into the present method of production for the desired cjs-isomer. Still another and even more specific object of the present invention is to convert the previously unwanted chiral trans-(1 S)(4R)-isomer into the corresponding chiral cjs-(1 S)(4S)-isomer which is, of course, sertraline.

Disclosure of the Invention In accordance with the present invention, there is now provided a process for converting trans-isomeric N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1- naphthaleneamine to cis-isomeric N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 - naphthaleneamine, said process comprising contacting trans-isomeric N-methyl-4-(3.4- dichlorophenyl)-1,2.3,4-tetrahydro-1 -naphthaleneamine in the absence or presence of up to about an equal part by weight of the corresponding cjs-isomer with a basic equilibration agent, such as 1 ,3-diazabicyclo[5.4.0]undec-7-ene or an alkali metal lower alkoxide (C^CJ like potassium tert.-butoxide. in a reaction-inert polar organic solvent system at a temperature that is in the range of from about 55 °C up to about 125°C until the amount of the desired cis-amine in the resultant cisΛrans-mixture achieves a constant value of about 2:1 on a weight-by-weight basis. In this connection, it is to be understood that by the use of the term trans-isomeric N-methyl-4-(3,4-dichlorophenyI)- 1 ,2.3,4-tetrahy-dro-1 -naphthaleneamine there is meant to be included not only the racemic trans-compound, but also the corresponding chiral trans-(1S)(4R)-enantiomer which is easily derived from same via resolution with L-(+)-mandelic acid and was first reported by W. M. Welch, Jr. et al. in the aforementioned Journal of Medicinal Chemistry reference article. More specifically, by the use of the process of this invention, a recycled starting material such as pure racemic trans-N-methyl-4-(3.4-dichlorophenyl)-1 ,2,3,4-tetrahydro- 1 -naphthaleneamine or a 1:1 by weight mixture of said trans-isomer with the corresponding cjs-isomer is converted to about a 2:1 by weight cisΛrans-mixture of the isomers in a mostfacile manner. As previously indicated, the latter 2:1 resultant mixture is useful as an intermediate product that leads to pure cis-(1 S)(4S)-N-methyl-4-(3.4- dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine (sertraline), which is a known antidepressant agent. In like manner, chiral trans-(1S)(4R)-N-methyl-4-(3,4- dichlorophenyl)-1 ,2,3,4-tetrahydrophenyl-1-naphthaleneamineora1 :1 by weight mixture

of said trans-isomer with the corresponding cjs-isomer (viz., the chiral cis-(1 S)(4S)- enantiomer) is also converted to about a 2:1 by weight cisΛrans-mixture of the isomers in a most facile manner. However, in the latter case, the resultant 2:1 cisΛrans-mixture of chiral isomers leads directly to sertraline since the resolution step is no longer required.

Detailed Description of the Invention in accordance with the process of this invention, the equilibration reaction is generally carried out by using an excess in moles of the basic equilibration agent with respect to the total amount of N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1- naphthaleneamine starting material employed (i.e., trans-isomer with up to about an equal part by weight of the cjs-isomer, etc.) and preferably by using a starting material/reagent molar ratio ranging from between below and up to about one mole of said starting material per mole of the basic equilibration agent, with the most preferred range being from about 1.0:1.0 to about 1.0:3.0, in order to effect the desired conversion of the trans-isomer to the cjs-isomer as previously discussed. The process is normally conducted in a reaction-inert polar organic solvent system at a temperature that is in the range of from about 55 °C up to about 125°C, and preferably one that is in the range of from about 65°C up to about 90°C, until the desired conversion to the constant 2:1 (by weight) cisΛrans-mixture is substantially complete. Generally, the equilibration reaction will require a time period of at least about four hours, although it is preferable in practice to carry out the reaction for a period of about 40 hours. Preferred reaction-inert polar organic solvents for use in this connection include lower dialkyl (C,-C ₄ ) ethers having a total of at least five carbon atoms such as di-isopropyl ether, di-n-butyl ether, methyl n-butyl ether and ethyl isopropyl ether, cyclic ethers such as tetrahydrofuran and dioxane, alkylated glycols having a total of from four to eight carbon atoms, like 1 ,1-diethoxymethane, 1 ,2-dimethoxyethane, 2-ethoxyethanol, 2-n- butoxyethanol, the dimethyl ether of butylene glycol and the di-n-propyl ether of ethylene glycol, as well as lower N,N-dialkyl lower alkanoamides having a total of up to six carbon atoms (with at least one of said atoms always being present in the N,N- unsubstituted alkanoamide moiety) like dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethylpropionamide and so forth. Preferred basic equilibration agents employed for purposes of the invention process include 1 ,8- diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, 1 ,4-

diazabicyclo [2.2.2] -octane, lithium di-isopropylamide and lithium tetramethylpiperidide, as well as various metal lower alkoxides (C _r C ₄ ) like the alkali metal lower alkoxides (C _r C ₄ ), such as sodium ethoxide and potassium tert.-butoxide. Optimum results are generally obtained when dimethylformamide and like alkanoamide solvents are employed in conjunction with the first-three named basic equilibration agents, and tetrahydrofuran and the other ether-type solvents are used in conjunction with the remaining basic equilibration agents, such as potassium tert.-butoxide and the like. In the latter connection, especially when tetrahydrofuran is employed as the solvent of choice in conjunction with the alkoxide-type equilibration agent, it has often been found most convenient and advantageous in practice to use small amounts of the corresponding lower alkanol in order to "spike" the aforesaid ethereal solvent and so aid in further increasing the solubility of the starting materials and final products that are contained within the selected solvent system. Usually, a minor amount of the alkanol "spike," say, for example, 5% by volume based on the total volume of the ethereal solvent, is sufficient for such purposes.

Upon completion of the equilibration reaction, the desired product, viz., pure racemic cis-N-rnethyl-4-(3.4-dichlorophenvO-1 ,2,3,4-tetrahydro- -naphthaleneamine or the pure chiral cis-(1S)(4S)-enantiomer thereof (as the case may be), is readily recovered from the reaction mixture by conventional means such as, for example, by first removing the solvent via evaporation under reduced pressure and then dissolving the resultant residue in a chlorinated lower hydrocarbon solvent such as methylene chloride, ethylene dichioride, s-tetrachlorethane, chloroform or carbon tetrachloride, followed by successive washing and drying of the resulting solution and subsequent evaporation of the solvent under reduced pressure to afford the previously discussed 2:1 (by weight) cisΛrans-mixture (as detected by such analytical methods as thin layer chromatography, high pressure liquid chromatography, nuclear magnetic resonance spectroscopy, etc.) as the residual oil. When the latter oil is thereafter dissolved in an ethereal solvent such as tetrahydrofuran and treated with a dry hydrohalide gas, like anhydrous hydrogen chloride, the desired cis-amine precipitates from solution as the crystalline hydrohalide salt while the corresponding trans-amine salt remains in solution. In this way, a starting material such as unwanted racemic trans-N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthaleneamine or a 1:1 (by weight) mixture of same with the desired cjs-isomer is conveniently converted to pure crystalline racemic

cis-N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine hydrochioride via the aforesaid 2:1 (by weight) cisΛrans-mixture. In like manner, the unwanted chiral trans-(1 S)(4R)-enantiomer is converted to the desired chiral cjs-(1 S)(4S)-enantiomer, viz., cjs-(1 S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthalene- amine hydrochioride, as previously discussed.

The pure racemic trans-N-methvl-4-(3.4-dichlorophenvl,-1 ,2.3.4-tetrahvdro-1 - naphthaleneamine starting material that may be used for conducting the equilibration process of this invention, as well as the desired pure racemic cis-amine final product are both reported as hydrochioride salts in the paper by W. M. Welch, Jr., et al., as described in the Journal of Medicinal Chemistry. Vol. 27, No. 11 , p. 1508 (1984), along with the corresponding free base compounds and an approximately 1 :1 (by weight) mixture of the racemic cjs- and trans-isomers (as the free amine base compounds) in crude form. The pure racemic cis-amine hydrochioride is also reported in U.S. Patent No. 4,536,518 to W. M. Welch, Jr. et al., along with crude mixtures of the two isomers as hydrochioride salts, while the pure racemic trans-amine hydrochioride is similarly reported in U.S. Patent No. 4,556,676, also to W. M. Welch, Jr. et al. The pure chiral trans-(1 S)(4R)-N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine starting material is also reported as a hydrochioride salt in the previously-mentioned paper by W. M. Welch, Jr. et al., along with the corresponding free amine base compound.

As previously indicated, the 2:1 (by weight) cisΛrans-mixture of racemic N- methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine isomers afforded as a final product of the process of this Invention is valuable as an intermediate product that leads to the antidepressant agent known as sertraline or cjs-(1S)(4S)-N-methyl- 1 ,2,3,4-tetrahydro-1 -naphthaleneamine. More specifically, when the aforesaid 2:1 (by weight) resultant cisΛrans-mixture of racemic N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4- tetrahydro-1 -naphthaleneamine bases is first converted to the corresponding hydrochioride salts in an ethereal solvent system such as pure tetrahydrofuran, the pure crystalline racemic cis-amine salt exclusively separates from solution as a crystalline precipitate. o afford pure racemic cis-N-methvl-4-(3,4-dichlorophenvl)-1.2,3,4-tetrahvdro- 1 -naphthaleneamine hydrochioride, which is then recovered and converted back to the pure racemic cis-amine free base compound and subsequently resolved in a classical manner using the methods described by W. M. Welch, Jr. et al. in the aforesaid prior

art to ultimately yield the desired pure cjs-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1 -naphthaleneamine (sertraline) as the hydrochioride salt. The corresponding 2:1 (by weight) cisΛrans-mixture of chiral N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthaleneamine isomeric bases afforded as a final product of the process of this invention is similarly processed as an intermediate that leads to sertraline, except that the resolution step is not required since the desired pure chiral cis-(1S)(4S)-amine compound (sertraline) is obtained directly after isolation of the crystalline hydrochioride salt.

Hence, the novel process of the present invention now provides a way to convert unwanted trans-isomeric N-methyl-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-1 - naphthaleneamine back to the desired pure cjs-isomer (racemic or chiral) and thus to effectively recycle the previously unwanted trans-isomer back into the present method of production for obtaining said desired cjs-isomer. The latter accomplishment, in turn, represents a major improvement over prior art methods in view of the increased ease and simplicity of operation, and the concomitant decrease in the total costs of production.

EXAMPLE 1

A mixture consisting of 5.0 g. (0.0164 mole) of racemic trans-N-methyl-4-.3.4- dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine [W. M. Welch, Jr. et al., Journal of Medicinal Chemistry. Vol. 27, No. 11 , p. 1508 (1984)] dissolved in 60 ml. of tetrahydrofuran, which also contained 3.09 ml. of tert.-butanol and 3.68 g. (0.0328 mole) of potassium tert.-butoxide. was heated to reflux for a period of 48 hours. Upon completion of this step, the solvent was removed by means of evaporation under reduced pressure and the resulting residue was thereafter taken up in methylene chloride and washed with three-successive 60 ml. portions of water, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a residual oil which proved to be a 2:1 (by weight) mixture of the racemic cjs- and trans-amines, as attested to by nuclear magnetic resonance data. When the latter oil was dissolved in tetrahydrofuran and subsequently treated with anhydrous hydrogen chloride gas, the cis-amine precipitated as the hydrochioride salt, while the trans-amine hydrochioride remained in solution. In this manner, there were ultimately obtained 3.5 g. (62%) of pure racemic cjs-N-methyl-4-(3,4-dichlorophenyl)-

1 ,2,3,4-tetrahydro-1 -naphthaleneamine hydrochioride (m.p. 275-277°C.) in the form of the recovered crystalline salt. The melting points reported in the literature for the pure racemic cjs-amine hydrochioride and pure racemic trans-amine hydrochioride salts were 275-277°C. and 214-216°O, respectively, according to W. M. Welch, Jr. et al. in the Journal of Medicinal Chemistry, Vol. 27. No. 11. p. 1508 (1984).

EXAMPLE 2 The procedure described in Example 1 was repeated except that 5.0 g. (0.0164 mole) of a 1 :1 (by weight) mixture of pure racemic cjs-N-methyl-4-(3,4-dichlorophenyl)- 1 ,2,3,4-tetrahydro-1 -naphthaleneamine and pure racemic trans-N-methyl-4-,3.4- dichlorophenyl)-1 ,2,3,4-tetrahydro-1 -naphthaleneamine was the starting material employed in place of the corresponding pure trans-isomer alone, using the same molar proportions as before. In this particular case, the corresponding final product obtained was a residual oil which proved to be a 2:1 (by weight) mixture of the racemic cjs- and trans-amines, substantially identical in every respect with the product of EΞxample 1 , as attested to by nuclear magnetic resonance data. Pure racemic cis-N-methyl-4-(3,4- dichlorophenyl-1,2,3,4-tetrahydro-1 -naphthaleneamine hydrochioride (m.p. 275-277° C.) was then isolated from the aforesaid mixture in the same manner as that already described for the same product in .Example 1. In this instance, the yield of pure product amounted to 61%, based on the total amount of starting material used.