Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A

Abstract

A safe, practical and scalable process for manufacture of (−)-huperzine A has been developed and scaled up to manufacture several hundred grams of (−)-huperzine A with chemical and optical purity of >99%. The process consists of 11 chemical stages starting from commercially available materials with only nine isolation steps and no chromatography purification. This process provides a reliable and cost-effective source of synthetic (−)-huperzine A and its derivatives for pharmaceutical and nutraceutical markets.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

“…[53] In their studies towards the antitumora ntibiotic roseophilin (144), Dudley et al also sought to use an annulative allylic alkylation reaction to create ab icyclic ketone (Scheme 33). Further optimizationo ft he reaction parameters precipitated conditions which enabled the synthesis of 133 on 0.7 kilogram scale in 92:8 er,w hich could be upgraded to > 99.5:0.5 er by recrystallization.…”

“…As noted above, the remainder of the synthesis was largely identical to the Kozikowski route (see Scheme30), with minor procedural changes to improves calability.M ost of the steps in the sequence were performed on multi-kilogram scale, and at least 275 grams of (À)-huperzine A(130)w eremanufactured using this process. [53] In their studies towards the antitumora ntibiotic roseophilin (144), Dudley et al also sought to use an annulative allylic alkylation reaction to create ab icyclic ketone (Scheme 33). They initiated their synthesis by annulating the pyrrolidine enamine of cyclododecanone (137)o nto isobutylene dicarbonate 126 c and obtained the desired [9.3.1] bicycle 138 in excellent yield and diastereoselectivity.…”

Hydrazoic Acid and Azides

“…It is also applied to generate acyl azides required for the Curtius rearrangement [87,88]. It can be destroyed by adding acetic acid.…”

“…It can be destroyed by adding acetic acid. Additionally, DPPA serves also as an azide source in Mitsunobu reactions [87].…”

Synthesis of (R)-(+)-4-Methylcyclohex-2-ene-1-one

“…1 (−)-Huperzine A (2) is a candidate for the treatment of a variety of neurological disorders, 2−5 and substantial resources have been devoted toward the development of an economical manufacturing route to 2. 6 The reagent (R)-(+)-4-methylcyclohex-2-ene-1-one (1) has been employed in many synthetic sequences. 7−11 We obtained 1 by a chiral pool approach, developed by Lee et al, 12 which begins with (R)-(+)-pulegone (3).…”