Method of isolating (R)-tofisopam
The present invention is directed to a process for the isolation of (R)-tofisopam with high enantiomeric purity and high overall yields from a mixture of tofisopam enantiomers by means of a non-steady state continuous chromatographic process.
1 . A method for separating (R)-tofisopam, substantially free of the (S)-enantiomer of tofisopam, from a mixture of tofisopam enantiomers comprising:
introducing a feedstock solution of a mixture of tofisopam enantiomers into a non-simulated moving bed system comprising a chiral separation medium; and
isolating (R)-tofisopam in an eluant from said chiral separation medium.
2 . A method according to claim 1 , wherein the method comprises the steps of:
a) forming a feedstock solution of a mixture of tofisopam enantiomers;
b) introducing said feedstock solution of racemic tofisopam into a non-simulated moving bed system maintained at a substantially constant temperature, said system comprising a plurality of chromatographic columns, each column containing an adsorbent, wherein said columns are arranged in series and in a loop, said loop comprising a feedstock inlet point, a raffinate outlet point, a solvent inlet point, and an extract outlet point, the portion of the loop between an inlet point and an outlet point defining a chromatographic zone;
c) introducing an solvent into said system at said solvent inlet point;
d) shifting the location of said inlet points and said outlet points, wherein shifting said inlet points occurs at a substantially different time than shifting of said outlet points;
e) removing (R)-(−)-tofisopam, (S)-(+)-tofisopam, and (S)-(−)-tofisopam from said loop at said raffinate draw-off point; and
f) collecting (R)-tofisopam from said extract outlet point.
3 . The method of claim 1 wherein said adsorbent comprises a chiral stationary phase comprised of at least one sugar derivative.
4 . The method of claim 3 wherein said adsorbent comprises a chiral stationary phase selected from the group consisting of cellulose tris 4-methylbenzoate; cellulose tricinnamate; amylose tris [(S)-α-methyl benzylcarbamate]; and amylose tris-(3,5-dimethylphenyl) carbamate.
5 . The method of claim 4 wherein said adsorbent comprises a chiral stationary phase of amylose tris (3,5-dimethylphenyl) carbamate.
6 . The method of claim 1 wherein said solvent is selected from the group consisting of C1-C10 alkanes, C1-C6 alcohols, acetates of C1-C6 alcohols, propionates of C1-C6 alcohols, C1-C10 ketones, C1-C10 ethers, halogenated C1-C10 hydrocarbons, trifluoroacetic acid, dimethylformamide, dimethylacetamide, acetonitrile and combinations thereof.
7 . The method of claim 6 wherein said solvent is selected from the group consisting of hexane, heptane, methanol, ethanol, propanol, isopropanol, butanol, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, acetone, butanone, isopropyl methylketone, diethyl ether, diisopropyl ether, tertbutylmethyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, chlorobenzene, trifluoroacetic acid, dimethylformamide, dimethylacetamide, acetonitrile and combinations therein.
8 . The method of claim 7 wherein the solvent is a mixture of acetonitrile and methanol.
9 . The method of claim 7 wherein the solvent is acetonitrile.
10 . The method of claim 2 wherein the solvent is selected from the group consisting of acetonitrile, methanol, and mixtures thereof, and the chiral stationary phase is selected from the group consisting of cellulose tris 4-methylbenzoate; cellulose tricinnamate; amylose tris [(S)-α-methyl benzylcarbamate]; and amylose tris (3,5-dimethylphenyl) carbamate.
11 . The method of claim 10 wherein the solvent is acetonitrile and the chiral stationary phase is amylose tris (3,5-dimethylphenyl) carbamate.
12 . The method of claim 2 wherein the (R)-enantiomer of tofisopam is recovered in at least 95% enantiomeric excess.
13 . The method of claim 2 wherein the (R)-enantiomer of tofisopam is recovered in at least 98% enantiomeric excess.
14 . The method of claim 2 wherein the (R)-enantiomer of tofisopam is recovered in at least 99% enantiomeric excess.
15 . The method of claim 2 wherein said substantially constant temperature is from about 0° C. to about 60° C.
16 . The method of claim 2 wherein said substantially constant temperature is from about 25° C. to about 45° C.
17 . The method of claim 11 wherein said substantially constant temperature is about 40° C.