SYNTHETIC PROCESS FOR PREPARATION OF MACROCYCLIC C1-KETO ANALOGS OF HALICHONDRIN B AND INTERMEDIATES USEFUL THEREIN

摘要

Disclosed is a compound of formula 1, or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, R7, R7′, R8, R9, R10 , R11 , R12 and R13 are as disclosed herein. Also, disclosed is a process for the preparation of the compound of formula 1, or a pharmaceutically acceptable salt thereof, and intermediates used therein. The compound of formula 1 can be used in the preparation of halichondrin analogs, such as Eribulin; and a process for its preparation from the compound of formula 1 is also disclosed.;

主权项

1. A process for preparation of a compound of formula 3, or a pharmaceutically acceptable salt thereof, the process comprising: performing an intramolecular cyclization reaction on a compound of formula 1b to form the compound of formula 3, wherein R1 and R2 each independently is H, a silyl group, an acyl group, a sulfonyl group or an alkoxycarbonyl group; or one of R1 and R2 is absent and the other R1 or R2 together with the nitrogen atom to which it is attached form an azide; R3 is H or an alcohol protecting group; or R3 and one of R1 and R2 together form —C(═O)—, —C(═O)—C(⊚O)— or —C(R14)(R15)—, wherein R14 and R15 each independently is H or a hydrocarbon, the hydrocarbon optionally having one or more heteroatoms; R4 is H, C1-3 alkyl or C1-3 haloalkyl or an alcohol protecting group; R5 is H or —SO2Ar, wherein Ar is an aryl group; R10, R11 and R12 each independently is H or an alcohol protecting group; is a single or double bond; and R13 is ═O or —OR21, wherein R21 is H or an alcohol protecting group.