Patent ID: 6369220
Filing Date: 2002-04-09
Classification: C07D

Abstract:
A method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide having a formula (I): wherein:R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR24, SR15, S(O)R15, SO2R15, and SO3R15; R24 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; R15 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboalkylamino, heteroarylalkyl, heterocyclealkyl, and alkylammoniumalkyl; and R4, R5, R6, R7 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, alkoxy, aryloxy, â€”NO2, and â€”NR9R10; R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, butoxycarbonyl, and carbobenzyloxy; R3 and the hydroxyl at the 4-position of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide are in a syn-conformation with respect to each other; the sulfur at the 1-position of the seven-member ring and the carbons at the 4-position and the 5-position of the seven member ring are chiral centers; wherein the method comprises: (a) oxidizing an aryl-3-hydroxypropylsulfide having a formula (IV): â€ƒwherein R1, R2, R3, R4, R5, R6, and R7 are as described above to produce an enantiomerically-enriched aryl-3-hydroxypropylsulfoxide having a formula (III): â€ƒwherein R1, R2, R3, R4, R5, R6, and R7 are as described above; (b) oxidizing the 3-hydroxyl group of the enantiomerically-enriched aryl-3-hydroxypropyl-sulfoxide of formula (111) to produce an enantiomerically-enriched aryl-3-propanalsulfoxide having a formula (11): â€ƒwherein R1, R2, R3, R4, R5, R6, and R7 are as described above; and (c) cyclizing the enantiomerically-enriched aryl-3-propanalsulfoxide of formula (II) to form the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide of formula (I).