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Br
O
Cl
OSiMe
3
Zn, ClSiMe
3
THF
Cl
3
C
OMe
Cl
OMe
ZnCl
2
,CH
2
Cl
2
92%
HO
HNO
3
H
2
SO
4
NaOH
THF/H
2
O, rt
CO
2
Me
CO
2
Me
Cl
Cl
Cl
Cl
99%
HO
HO
phenylalanine
dehydrogenase
1) pH 7.4 (6 N HCl)
2) NaHCO
3
,85
°
C
CO
2
H
CO
2
H
NADH
NAD
3) HCl, EtOAc
Cl
Cl
O
formate
dehydrogenase
~99%
(2 steps)
37
Ammonium
formate
CO
2
OH
OH
1. Boc
2
O/NaOH
2. i-PrOAc extraction
CO
2
H
CO
2
H
NHBoc
NH
2
78% yield
96 - 99% enantiomeric purity
38
Zn(Et
2
), CH
2
I
2
N
N
39
Boc
Boc
O
NH
2
O
NH
2
Figure 1.11
Development synthesis of the hydroxyadamantylglycine and methano-
proline fragments of saxagliptin.
acid 37;
63
(2) an enzymatic asymmetric reductive amination with ammonia to
give the requisite unnatural amino acid 38;
64
and (3) a continuous flow process
for large-scale diethylzinc-mediated diastereoselective cyclopropanation of a
protected dehydroprolinamide 39.
65
1.13 Saxagliptin Development
Saxagliptin formally entered development at BMS in April of 2001, and the first
human clinical dose was administered to normal healthy volunteers in Decem-
ber of that same year. As highlighted earlier, genetic rodent models of diabetes
proved unsuitable for accurately assessing the chronic ecacy of DPP4 inhi-
bitors, and so the translational leap from acute plasma enzyme inhibition and
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