| 摘要 |
Enantiomers of 1-(4-chloro-2-hydroxy phenyl)-2-(4-(4-fluoro phenyl) methyl)piperidin-1-yl) ethanol (I) are separated from racemic (I) by conversion to the 2-methoxy methyl ether, reaction with an enantiomer of 1-phenyl ethyl isocyanate, separation of the resultant carbamates, and release of (I). USE - (I) is known (FR 91.01088) to be useful in the treatment of degenerative cerebral disorders. In an example, 4.15g racemic (I) was stirred with 100ml dichloromethane, 100ml water, 5ml NaOH (d = 1.33), 2 spatulasful of tetrabutyl ammonium hydrogen sulphate and 870 microlitres chloromethyl methyl ester (II). After 1 hour 10 minutes a further 500 microlitres of (II) was added, then, after 50 minutes, a further 500 microlitres (II). The product (III) was extracted into chloroform and dried. 4.57g (III) 250ml toluene, and 1.6ml S(-) 1-phenyl ethyl isocyanate were heated together for 7 hours at 100 deg.C. A further 1ml of the isocyanate was added and heating continued for a further 7 hours. This gave 9g crude product which was purified by chromatography on silica gel to give 1.15g diastereoisomer A and 3g mixture of diastereoisomers A and B. Recrystallisation from ethanol gave 630mg diastereoisomer A. 1.8g Diastereoisomer A, 100ml DMF and 1.8g sodium methane thiolate were heated at 100 deg C for 31/2 hours then purified to give 520mg of pure (+) (I), specific rotation (D line, 25 deg C) = +4 deg (c = 0.5; DMF).
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