Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates.
[formula: see text] The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps involved the enantioselective transfer hydrogenation of imine 8 employing Noyori's catalyst, the stereoselective crystallization and methanolysis of trans-bataines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14. The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.
Samano
V
V
Department of Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. vs43467@glaxowellcome.com
Ray
J A
JA
Thompson
J B
JB
Mook
R A
RA
Jung
D K
DK
Koble
C S
CS
Martin
M T
MT
Bigham
E C
EC
Regitz
C S
CS
Feldman
P L
PL
Boros
E E
EE
D003460:Crystallization; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D000432:Methanol; D009466:Neuromuscular Blocking Agents / Q000138:chemical synthesis*; D013237:Stereoisomerism
C410428:GW 0430; D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D000432:Methanol