Process for recycling amine isomer

A novel 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 is disclosed. The process involves contacting trans-isomeric N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, or a mixture of same with up to about an equal part by weight of the corresponding cis-isomer, with a basic equilibration agent like potassium tert.-butoxide in a reaction-inert polar organic solvent to ultimately afford a cis/trans-mixture wherein the amount of cis-amine present in said mixture achieves a constant value of about 2:1 on a weight-by-weight basis. The aforesaid resultant mixture is useful as an intermediate product that ultimately leads to pure cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline), which is a known antidepressant agent.

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-1-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-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine (sertraline). 
BACKGROUND ART 
There is described in U.S. Pat. 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-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine, 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) -naphthalenylidene]methenamine 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 cis- 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 cis- 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 
cis-(1S)(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 cis-isomer and thereby, in effect, recycle the 
previously unwanted trans-isomer back into the present method of 
production for the desired cis-isomer. Still another and even more 
specific object of the present invention is to convert the previously 
unwanted chiral trans-(1S)(4R)-isomer into the corresponding chiral 
cis-(1S)(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 cis-isomer with a basic equilibration agent, such as 
1,3-diazabicyclo[5.4.0]undec-7-ene or an alkali metal lower alkoxide 
(C.sub.1 -C.sub.4) like potassium tert.-butoxide, in a reaction-inert 
polar organic solvent system at a temperature that is in the range of from 
about 55.degree. C. up to about 125.degree. C. until the amount of the 
desired cis-amine in the resultant cis/trans-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-dichlorophenyl)-1,2,3,4-tetrahydro-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-naphthaleneamin 
e or a 1:1by weight mixture of said trans-isomer with the corresponding 
cis-isomer is converted to about a 2:1 by weight cis/trans-mixture of the 
isomers in a most facile manner. As previously indicated, the latter 2:1 
resultant mixture is useful as an intermediate product that leads to pure 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine (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-naphthalen 
eamine or a 1:1 by weight mixture of said trans-isomer with the 
corresponding cis-isomer (viz., the chiral cis-(1S)(4S)-enantiomer) is 
also converted to about a 2:1 by weight cis/trans-mixture of the isomers 
in a most facile manner. However, in the latter case, the resultant 2:1 
cis/trans-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 (i.e., trans-isomer with up to about an equal part by 
weight of the cis-isomer, etc.) and preferably by using at least 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 1.0:2.0, 
in order to effect the desired conversion of the trans-isomer to the 
cis-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.degree. C. up to about 125.degree. C., and 
preferably one that is in the range of from about 65.degree. C. up to 
about 90.degree. C., until the desired conversion to the constant 2:1 (by 
weight) cis/trans-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.sub.1 
-C.sub.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.sub.1 -C.sub.4) like the alkali metal lower 
alkoxides (C.sub.1 -C.sub.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-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-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 
dichloride, 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) cis/trans-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-naphthaleneamin 
e or a 1:1(by weight) mixture of same with the desired cis-isomer is 
conveniently converted to pure crystalline racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride via the aforesaid 2:1 (by weight) cis/trans-mixture. In like 
manner, the unwanted chiral trans-(1S)(4R)-enantiomer is converted to the 
desired chiral cis-(1S)(4S)-enantiomer, viz., 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine hydrochloride, as previously discussed. 
The pure racemic 
trans-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamin 
e 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 hydrochloride salts in the paper by W. 
M. Welch, Jr., 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 cis- 
and trans-isomers (as the free amine base compounds) in crude form. The 
pure racemic cis-amine hydrochloride is also reported in U.S. Pat. No. 
4,536,518 to W. M. Welch, Jr. et al., along with crude mixtures of the two 
isomers as hydrochloride salts, while the pure racemic trans-amine 
hydrochloride is similarly reported in U.S. Pat. No. 4,556,676, also to W. 
M. Welch, Jr. et al. The pure chiral 
trans-(1S)(4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth 
aleneamine starting material is also reported as a hydrochloride 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) cis/trans-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 
cis-(1S)(4S)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. More 
specifically, when the aforesaid 2:1 (by weight) resultant 
cis/trans-mixture of racemic 
N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
bases is first converted to the corresponding hydrochloride 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 to afford pure racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride, 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 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine (sertraline) as the hydrochloride salt. The corresponding 2:1 (by 
weight) cis/trans-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 hydrochloride 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 cis-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 cis-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-naphthaleneamin 
e [W. M. Welch 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 cis- 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 
hydrochloride salt, while the trans-amine hydrochloride remained in 
solution. In this manner, there were ultimately obtained 3.5 g. (62%) of 
pure racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride (m.p. 275.degree.-277.degree. C.) in the form of the 
recovered crystalline salt. The melting points reported in the literature 
for the pure racemic cis-amine hydrochloride and pure racemic trans-amine 
hydrochloride salts were 275.degree.-277.degree. C. and 
214.degree.-216.degree. C., respectively, according to W. M. Welch 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 
cis-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-naphthaleneamin 
e 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 cis- and 
trans-amines, substantially identical in every respect with the product of 
Example 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 
hydrochloride (m.p. 275.degree.-277.degree. 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 amount of starting material used. 
EXAMPLE 3 
The procedure described in Example 1 is repeated except that 5.0 g. (0.0164 
mole) of a 1:9 (by weight) mixture of pure racemic 
cis-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-naphthaleneamin 
e is the starting material employed in lieu of the corresponding pure 
trans-isomer alone, using the same molar proportions as before. In this 
particular case, the corresponding final product obtained is a 2:1 (by 
weight) mixture of the racemic cis- and trans-amines, substantially 
identical in every respect with the product of Example 1. Pure racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride is then isolated from the aforesaid mixture in the same 
manner as that already described for the identical product in Example 1. 
EXAMPLE 4 
The procedure described in Example 1 is repeated except that 5.0 g. (0.0164 
mole) of a 1:4 (by weight) mixture of pure racemic 
cis-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-naphthaleneamin 
e is the starting material employed in lieu of the corresponding pure 
trans-isomer alone, using the same molar proportions as before. In this 
particular case, the corresponding final product obtained is again a 2:1 
(by weight) mixture of the racemic cis- and trans-amines, substantially 
identical in every respect with the product of Example 1. pure racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride is then isolated from the aforesaid mixture in the same 
manner as that already described for the identical product in Example 1. 
EXAMPLE 5 
The procedure described in Example 1 is repeated except that 5.0 g. (0.0164 
mole) of a 2:3 (by weight) mixture of pure racemic 
cis-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-naphthaleneamin 
e is the starting material employed in lieu of the corresponding pure 
trans-isomer alone, using the same molar proportions as before. In this 
particular case, the corresponding final product obtained is again a 2:1 
(by weight) mixture of the racemic cis- and trans-amines, substantially 
identical in every respect with the product of Example 1. Pure racemic 
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine 
hydrochloride is then isolated from the aforesaid mixture in the same 
manner as that already described for the identical product in Example 1. 
EXAMPLE 6 
The procedure described in Example 1 is repeated except that 5.0 g (0.0164 
mole) of pure chiral 
trans-(1S)(4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth 
aleneamine [W. M. Welch et al., Journal of Medicinal Chemistry, Vol. 27, 
No. 11, p. 1508 (1984)] is the starting material employed in place of the 
pure racemic trans-N-methyl- 
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalene, using the same 
molar proportions as before. In this particular case, the corresponding 
final product obtained is a 2:1 (by weight) mixture of chiral 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine (sertraline) and chiral 
trans-(1S)(4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth 
aleneamine. Pure chiral 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine hydrochloride (sertraline hydrochloride) is then isolated from the 
aforesaid mixture in the same manner as that described previously for the 
corresponding racemic salt reported in Example 1. 
EXAMPLE 7 
The procedure described in Example 6 is repeated except that 5.0 g (0.0164 
mole) of a 1:1 (by weight) mixture of pure chiral 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine and pure chiral 
trans-(1S)(4R)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphth 
aleneamine is 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 is a 2:1 
(by weight) mixture of the chiral cis-(1S)(4S)- and chiral 
trans-(1S)(4R)-amines, substantially identical in every respect with the 
product of Example 6. Pure chiral 
cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal 
eneamine hydrochloride (sertraline hydrochloride) is then isolated from the 
aforesaid mixture in the same manner as that described previously for the 
corresponding racemic salt reported in Example 1.