Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-09-18
2004-01-27
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S315000, C568S316000, C568S321000, C564S222000, C564S308000
Reexamination Certificate
active
06683220
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a chromatographic process for obtaining optically pure tetralone as an intermediate in the preparation of optically pure sertraline. Sertraline is used in the synthesis of Zoloft, a drug currently marketed for the treatment of depression, as discussed in the U.S. Pat. Nos. 4,536,518, 5,196,607, 5,442,116 and 4,777,288, all incorporated by reference. Various processes for preparing Sertraline are described in the above patents. Typically, there is a resolution of a racemic mixture of sertraline at the later stages of the process which has the disadvantage of requiring an undesired enantiomer to be carried through several of the processing steps. It is preferred and would be a significant advantage if an enantiomerically pure tetralone were used as a starting material in the preparation of optically pure sertraline to substantially limit the production of the undesirable enantiomer of sertraline, thus avoiding a final separation step.
To produce Zoloft (sertraline hydrochloride) in an efficient way, separation of the cis-(1S, 4S) enantiomer from cis-(1R, 4R) enantiomer of sertraline-tetralone is required. In PCT publication number WO99/57089, a process for producing an enantiomerically pure or optically enriched sertraline-tetralone is described utilizing continuous chromatography. Key to the processing is the utilization of a derivitized polysaccharide solid chiral stationary phase and a liquid mobile phase preferably containing acetonitrile.
While an available route to achieving optically pure sertraline, the process utilizes a solid chiral stationary phase which has limited utility at temperatures above 40° C. Acetonitrile is an expensive solvent, that is also environmentally undesirable to use due to its' toxicity. The cost of production utilizing such a process is thus high, and may not be sufficiently economically attractive so as to find utilization in the preparation of optically pure tetralone. Consequently the search continues for processes for producing optically pure or enriched sertraline at low cost and with optimized productivity.
SUMMARY OF THE INVENTION
A process for chromatographically obtaining substantially enantiomerically pure chiral tetralone from a mixture of two tetralone enantiomers comprises providing a liquid mobile phase comprising at least one solvent; providing a solid stationary chiral phase comprising an inorganic carrier loaded with an optically pure metal-organic complex; and, chromatographically separating the mixture to obtain at least one substantially enantiomerically pure tetralone. The solvent used may be selected from the group consisting of lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol; acetates and propionates of these alcohols; ketones such as acetone, butanone, isopropyl-methylketone; ethers, such as diethyl ether, diispropyl ether, tertbutylmethyl ether; tetrahydrofuran; dioxane; alkanes such as pentane, hexane, heptane, cyclohexane, cycloheptane, benzene, toluene, xylene; halogenated lower alkanes such as methylene chloride, chloroform, chlorobenzene, fluorinated lower alkanes, acetonitrile, and combinations of these. The solvent is preferably a mixture of methanol and methyl acetate. The separation of the mixture is preferably conducted at a temperature of from about 40EC to about 80EC. In the inorganic carrier material (silica gel, clay, etc.), the metal complexing cations are selected from metals from the group consisting of nickel, osmium, ruthenium, platinum, cobalt, iron, copper and chromium, with ruthenium complexing cations preferred. The organic part of the metal-organic complex consists of aromatic nitrogen-containing heterocycles which confer chirality to the complex. Such complexes can be obtained in optically pure form from their racemates by known methods. The preferred heterocycles are 2,3-bipyridines and 1,10-phenanthrolines. The inorganic carrier is preferably a spherical clay material. The inorganic carrier may have a particle size of from about 5 to 30 &mgr;m, and also may be hydrophobically treated. In one embodiment, the liquid mobile phase used is a supercritical fluid, such as supercritical CO
2
, and a polar solvent selected from the group consisting of methanol, ethanol, THF, dichloroethane, acetone, methyl acetate and ethyl acetate. The chromatographic process may use single column chromatography, or multicolumn chromatography such as simulated moving bed chromatography, or non-steady state continuous chromatography. In one embodiment, at least one substantially pure tetralone enantiomer is a preferred enantiomer and a second of the two enantiomers in the mixture is an undesired enantiomer, the solid stationary phase having a chiral orientation for retaining the undesired enantiomer.
Using a mobile phase preferably free of acetonitrile and containing methanol reduces cost and eases environmental concerns. The use of a clay carrier having an interlayer of optically active metal-organic complex cations therein, enables processing at higher temperatures, of from about 40 to 80° C., which leads to higher solubility and higher productivity without detrimentally affecting the enantiomer separation. According to the present invention, optically pure or enriched tetralone can be obtained in an environmentally acceptable fashion at higher yield with reduced cost, as compared to the prior art, enabling the production of optically pure sertraline with less process steps.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention can utilize any continuous chromatographic method for separating racemic tetralone so as to produce optically pure or enriched tetralone for the production of sertraline, such as single column chromatography or simulated moving bed (SMB) chromatography. While a simulated moving bed process may be used, a preferred chromatographic method is described in U.S. Pat. No. 6,136,198, where a non-steady state continuous separation process can be used which varies the length of given zones represented by column sections during the chromatographic separation to increase efficiency.
In either case, the process for obtaining enantiomerically pure or optically enriched tetralone utilizes one or more columns packed with a solid stationary chiral phase which preferentially absorbs a first enantiomer (the more strongly retained enantiomer) from a feed containing the enantiomer mixture. Ports are provided for introducing the feed mixture, for introducing a desorbant liquid mobile phase, for removing a raffinate containing the second enantiomer (the less strongly retained enantiomer) and for removing an extract which contains the desorbed more strongly retained enantiomer. Multiple columns are preferably used and connected to each other from a feed end to an outlet end. While the outlet end could be connected to the feed end to provide a continuous recycle, recycle is unnecessary in the preferred process of the invention.
The liquid mobile phase is selected from lower alcohols such as methanol, ethanol, propanol, proponal, isopropanol, butanol; acetates, and propionates of these alcohols; ketones such as acetone, butanone, isopropyl-methylketone, ethers, such as diethyl ether, diispropyl ether, tertbutylmethyl ether; tetrahydrofuran; dioxane; alkane such as pentane, hexane, heptane, cyclohexane, cycloheptane, benzene, toluene, xylene; halogenated lower alkanes such as methylene chloride, chloroform, chlorobenzene, fluorinated lower alkanes, and combinations of these. While acetonitrile may be used, in certain circumstances, it is generally not a preferred solvent.
Of the various solvents, a methyl acetate based liquid mobile phase is preferred which may comprise methyl acetate alone or methyl acetate in combination with one or more of the solvents listed above. More preferably, methyl acetate or a methanol/methyl acetate mixture is used. The most preferred liquid mobile phase is methanol/methyl acetate having a ratio in the range of 0 to 100, more preferably 70 to 30 and most preferably 85 to 15.
This particu
Berger Laurent
Duval Raphael
Taillasson Philippe
Weber Ingo
Wick Alexander
Coleman Sudol Sapone P.C.
Pfizer Inc.
Richter Johann
Sapone William J.
Witherspoon Sikarl A.
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