The current process for ziprasidone involves preparation and isolation of the key intermediate 6-chloro-5-(2-chloroethyl)oxindole. An improved process for the synthesis of this intermediate is reported here. The new process involves use of a novel Lewis acidmediated selective deoxygenation of the precursor ketone with tetramethyldisiloxane. The new method affords the desired compound in a one-pot process obviating the need for isolation of the potentially hazardous precursor ketone. This process was successfully scaled up to multikilo scale.

Diastereoselectivity in the reduction of alpha-alkoxy-, alpha-acyloxy-, and alpha-alkylamino-substituted ketones with polymethylhydrosiloxane (PMHS) in the presence of fluoride ion catalysis was investigated. High syn-selectivity was observed in the reduction of alpha-alkoxy, alpha-acyloxy, and alpha-dialkylamino ketones. Reduction of alpha-monoalkylamino ketone proceeded in anti-selective manner with moderate selectivity. The observed selectivity is explained based on Felkin-Anh and Cram-chelate models.

A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an S N Ar reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.

Diastereoselective syntheses Diastereoselective syntheses O 0031Diastereoselectivity in the Reduction of α-Oxyand α-Amino-Substituted Acyclic Ketones by Polymethylhydrosiloxane. -High syn-selectivity is observed in the reduction of α-alkoxy, α-acyloxy, and α-dialkylamino ketones by PMHS in the presence of catalytic amounts of fluoride ions. No epimerization occurs under these conditions. The reduction of α-monoalkylamino ketone (III) proceeds in anti-selective manner with moderate selectivity. The observed diastereoselectivities are explained based on Felkin-Anh and Cram-chelate models. -(NADKARNI*, D.; HALLISSEY, J.; MOJICA, C.; J. Org. Chem. 68 (2003) 2, 594-596; Process Dev. Lab., Pfizer Global Manuf., Groton, CT 06340, USA; Eng.) -Klein 22-031