ABSTRACT
Charles E. Chase,1 Hyeong-wook Choi,1 Atsushi Endo,1 Francis G. Fang,1 and John D. Orr2 1Integrated Chemistry, Eisai, Inc., Andover, Massachusetts 2Analytical Chemistry, Eisai, Inc., Andover, Massachusetts
CONTENTS
17.1 Introduction .......................................................................................................................... 498 17.2 Eribulin Discovery ................................................................................................................ 498 17.3 Eribulin Process Development ............................................................................................. 499
17.3.1 Process Development Challenges ........................................................................... 499 17.3.2 Eribulin Retrosynthetic Analysis ............................................................................502 17.3.3 C.1-C.13 Fragment: L-Mannonolactone (9) Route .................................................503 17.3.4 C.1-C.13 Fragment: D-Gulonolactone (20) Route ..................................................504 17.3.5 C.14-C.26 Fragment: L-Glutamic Acid (28) and L-Arabinose (33) Route ............504 17.3.6 C.14-C.26 Fragment: L-Glutamic Acid (28) and D-Erythrulose (38) Route .........507 17.3.7 C.14-C.26 Fragment via C.19-C.20 Bond Formation: Industrialization of the
NHK Reaction .........................................................................................................507 17.3.8 C.14-C.26 Fragment from D-Quinic Acid: Crystallization-Based Route .............. 510 17.3.9 C.27-C.35 Fragment: L-Arabinose (81) Route ....................................................... 515 17.3.10 C.27-C.35 Fragment from (S)-1,2,4-Butanetriol (91) and 3-Butyn-1-ol (93):
Yamaguchi Coupling Route .................................................................................... 517 17.3.11 C.27-C.35 Fragment: D-Glucuronolactone (99) Route .......................................... 518 17.3.12 C.14-C.35 Fragment via NHK Reaction/ Williamson Ether Cyclization Reaction .... 519 17.3.13 Final Assembly: Construction of Eribulin from C.1-C.13 (5) and C.14-C.35
