Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-03-14
2003-04-22
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S304000, C564S428000
Reexamination Certificate
active
06552227
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the novel process of making and purifying (+)-cis-sertraline.
BACKGROUND OF INVENTION
Sertraline hydrochloride, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula
is the active ingredient in Zoloft®, a medication approved by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone. The process for synthesizing sertraline hydrochloride from sertralone comprises two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, sertraline-1-imine.
The imine, or Schiff base, is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 comprises the hydrogenation of sertraline-1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereomers (“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. This hydrogenation step can introduce a number of contaminants, including dechlorinated side-products, if not carefully controlled. One very problematic group of side products are dechlorinated-sertraline derivatives. It is desirable to have a hydrogenation method that reduces the amount of dechlorinated-sertraline side products or eliminates these side products.
The purification of cis-sertraline from (±)-cis/trans-sertraline as described in the '518 patent is relatively complicated and expensive requiring multiple recrystallizations, and the (±)-cis/trans-sertraline so produced has a cis/trans ratios lower than 3:1. It is therefore desirable to have a method of initially making cis/trans-sertraline base from sertraline-1-imine with cis/trans ratios greater than 3:1. It is also desirable to have a simple and cost effective purification of (+)-cis-sertraline from (±)-cis/trans-sertraline base or from (±)-cis/trans-sertraline hydrochloride.
SUMMARY OF THE INVENTION
The present invention relates to a process for making (±)-sertraline having a cis/trans ratio of greater than about 3:1 comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40° C. using a catalyst selected from the group consisting of palladium and platinum. By the processes of the present invention, catalysts include palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO
2
.
The present invention also relates to a process for making (±)-sertraline with a cis/trans ratio between about 8:1 and about 12:1 comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40° C. using a palladium catalyst. By the processes of present invention, suitable catalysts include, palladium on carbon, palladium on graphite, and palladium on carbon paste.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride comprising the step of reacting an optically active selective precipitant with (±)-sertraline base having a cis/trans ratio of greater than 3:1.
The present invention also relates to a process for making (+)-cis-sertraline which is substantially free of dechlorinated side products, comprising the step of catalytically hydrogenating sertraline-1-amine using PtO2 as a catalyst.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride from (±)-sertraline hydrochloride with a cis/trans ratio of greater than 3:1 comprising the steps of: generating (±)-sertraline by addition of an aqueous base to (±)-sertraline hydrochloride with a cis/trans ratio of greater than 3:1; resolving the (±)-sertraline so generated; and isolating (+)-cis-sertraline hydrochloride.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride from (±)-sertraline hydrochloride comprising the steps of: generating (±)-sertraline by addition of a solid base to (±)-sertraline hydrochloride; resolving the (±)-sertraline so generated; and isolating (+)-cis-sertraline hydrochloride.
The present invention also relates to a process for making (+)-cis-sertraline from (±)-sertraline base wherein the (±)-sertraline base has a content of dechlorinated-sertraline side products that is very low, e.g., less than about 1%, or alternatively, wherein the content of dechlorinated-sertraline side products is undetectable by conventional methods, comprising the steps of: generating (±)-sertraline by addition of a solid base to (±)-sertraline hydrochloride; resolving the (±)-sertraline so generated; and isolating (+)-cis-sertraline hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a new process for making (±)-cis/trans-sertraline having a cis/trans ratio greater than about 3:1 by hydrogenation of sertraline-1-imine. It also provides new processes for making sertraline from the Schiff base of sertralone, sertraline-1-imine. The methods provided by the present invention provide high cis/trans ratios of (±)-cis/trans-sertraline. Methods of the present invention are also expected to have fewer impurities and side products than prior art methods. Hydrogenation methods of the present invention also have very low amounts of dechlorinated-sertraline side products.
According to the present invention sertraline is prepared from the Schiff base of sertralone, sertraline-1-imine. The sertraline-1-imine may be made by the process of U.S. Pat. No. 4,536,518, the contents of which are incorporated by reference. The sertraline-1-imine is dissolved in an organic solvent such as t-butyl-methyl ether (MTBE), tetrahydrofuran (THF), toluene, ethanol, isopropanol, n-butanol, ethyl acetate, acetone, methanol, or mixtures thereof, and catalytically hydrogenated in the presence of hydrogen gas with warming. Suitable catalysts include platinum and palladium. In a preferred embodiment of the present invention the catalyst is palladium. Preferably the palladium catalyst is palladium on carbon, palladium on graphite or palladium on carbon paste wherein the metal loading of palladium is about 5 to 10% by dry weight. More preferably, the catalyst is 10% Pd/C by weight. In another preferred embodiment of the present invention the catalyst is platinum. More preferably the platinum catalyst is PtO
2
.
By the methods of the present invention, the reaction is warmed to at least about 40° C. The reaction may be warmed on a heating mantel. Preferably the reaction is warmed to and maintained at about 40° C. to about 80° C. More preferably, the reaction is warmed to and maintained at about 40° C. to about 60° C.
When the reaction is complete, the reaction mixture is filtered, the solvent is removed and the (±)-cis/trans-sertraline isolated. The isolated (±)-cis/trans-sertraline of the present invention has a very low amount of dechlorinated-sertraline side products. Herein, dechlorinated-sertraline side products refers to sertraline derivatives wherein one or both of the 3,4-phenyl chlorine atoms are replaced by hydrogen. In methods of the present invention where palladium is used as the catalyst, the (±)-cis/trans-sertraline isolated has a cis/trans ratio of approximately 8:1 to approximately 12:1, which is a substantial improvement over the cis/trans ratio of about 3:1 reported in the related art. In an embodiment of the present invention where the hydrogenation of sertraline-1-amine uses palladium on graphite as the catalyst in ethanol at about 40° C., the (±)-cis/trans-sertraline isolated has a cis/trans ratio of approximately 12:1. In an embodiment of the present invention where palladium on graphite is used as the catalyst, ethanol is a preferred solvent. In an embodiment of the
Gershon Neomi
Mendelovici Marioara
Nidam Tamar
Pilarsky Gideon
Barts Samuel
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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