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OTf
MsO
MeO
SO
2
Ph
TBSO
+
TBS O
O
O
OPiv
CH O
122
123
(1.3 equiv per
12 2
)
O
N
NiCl
2
(0.12 equiv per
12 2
)
−
THF
28
−
32 ºC, 2.5 h
23
−
25 ºC
+
CrCl
2
(4.6 equiv
per
122
)
+
Et
3
N
(4.6 equiv
per
122
)
10 to 5 ºC
10
−
16 h
NHMs
(
S
)-
121
(4.6 equiv
per
122
)
MeO
MeO
SO
2
Ph
SO
2
Ph
MeO
TBS O
TBSO
TB SO
TBS O
H
O
O
HO
H
2
N
O
O
KHMDS
(0.5 M in PhMe)
−
20 to
−
15 ºC
65% (2 steps)
O
O
HO
O
H
H
MsO
O
O
O
MsOH
O
O
H
O
O
OPiv
OPi v
125
(1.2 kg)
124
(is olated as THF sol uti on)
20:1 dr
126
MsOH
(INN eribulin mesylate, Halaven)
Scheme 15.26
Synthesis
of Halaven mesylate
(126
MsOH)
via Nozaki-
Hiyama-Kishi coupling.
temperature in the 0-5 1C range. Based on these findings, the process that
was implemented in the plant called for dissolving ligand (S)-121 (4.6 equiv.
per aldehyde 122) in THF and purging the reaction with nitrogen gas until
the oxygen level fell below 200 ppm. CrCl
2
(4.6 equiv. per 122) was then
added and the mixture was warmed to 28-32 1C. After the addition of Et
3
N
(4.6 equiv. per 122) at 30-35 1C, the mixture was stirred at 28-32 1C for at
least 2.5 h. The reaction mixture was then cooled to
10 to 5 1C and NiCl
2
(0.12 equiv. per 122) was added followed by more nitrogen purging.
A solution of aldehyde 122 and triflate 123 in THF was then added and the
resulting mixture was stirred at 23-25 1C for 10-16 h. Following an aqueous
work-up, chiral alcohol 124 was obtained in 20:1 diastereomeric ratio and
isolated as a THF solution that was used in the next step (intramolecular
Williamson ether formation) to afford 1.2 kg of intermediate 125 with a
combined yield of 65%. No information was provided on the level of residual
metal in 124 or final API.
15.2.13 C-H Activation
The design of new methods to activate C-H bonds and transform them into
C-C and C-heteroatom bonds has seen impressive developments in recent
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