An efficient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

Recent progress in enzymatic resolution and desymmetrization of pharmaceuticals and their intermediates.

The literature is surveyed from mid-1998 through to August 2000 for examples of the resolution or desymmetrization of existing/potential pharmaceutical entities and pharmaceutical intermediates, and of chiral building blocks for pharmaceutical manufacture. Examples of commercial interest are included with new developments in the art of resolution.

Efficient pyridinylmethyl functionalization: synthesis of 10, 10-Bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (DMP 543), an acetylcholine release enhancing agent.

2-Fluoro-4-methylpyridine (3) is efficiently functionalized by chlorination, hydrolysis and methanesulfonylation into the novel alkylating agent 7. This mesylate is used for the bisalkylation of anthrone under carefully defined conditions to prepare the cognition enhancer drug candidate 1. This process proceeds in up to 37% overall yield and is adaptable for large scale synthesis.