Molecule in Review

Brendan Kelly (Lambert) Synthesis Literacy Group

26Jun2009 Columbia University Chemistry
Januvia (Sitagliptin):
Through the Pipeline
Outline
Kelly 2 - CU Synthesis Lit Group - Januvia
Introduction
Kelly 3 - CU Synthesis Lit Group - Januvia
Merck gained FDA approval to market Januvia in November 2006
Januvia (Sitagliptin) is a DPP-4 inhibitor for the treatment of Type II diabetes
In the US, 23.6 million people have diabetes (90% of those suffer from type II)
N
O NH
2
N
N
N
F
F
F
CF
3
H
3
PO
4
DPP-4 breaks down hormones essential to glycaemic control
Sitagliptin competively binds to DPP-4, inhibiting that degradation pathway
Review: Drucker, Cell Metab., 2006, 3, 153
image: http://en.wikipedia.org/wiki/Dipeptidyl_peptidase-4_inhibitors
By inhibiting the degradation of these hormones, glucose levels can be controlled
Mode of Action (DPP-4 Inhibitor)
Kelly 4 - CU Synthesis Lit Group - Januvia
Mode of Action (DPP-4 Inhibitor)
Kelly 5 - CU Synthesis Lit Group - Januvia
DPP-4 breaks down hormones essential to glycaemic control
Sitagliptin competively binds to DPP-4, inhibiting that degradation pathway
Review: Drucker, Cell Metab., 2006, 3, 153
image: http://en.wikipedia.org/wiki/Dipeptidyl_peptidase-4_inhibitors
By inhibiting the degradation of these hormones, glucose levels can be controlled
x
Medicinal Chemistry Synthesis
Kelly 6 - CU Synthesis Lit Group - Januvia
Retrosynthesis of 1st published Medicinal Chemistry route to Sitagliptin
Key stereocenter installed from chiral Schollkopf reagent
N
O NH
2
N
N
N
F
F
F
CF
3
O NH
F
F
F
OH
HN
N
N
N
CF
3
N
N
Cl
OH
NH
2
F
F
F
Boc
O
N
N Me
Me
F
F
F OMe
OMe
N
N Me
Me OMe
OMe
Medicinal Chemistry Synthesis
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Medicinal Chemistry Synthesis
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Medicinal Chemistry Synthesis
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Medicinal Chemistry Synthesis
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First Process Chemistry Synthesis
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First Process Chemistry Synthesis
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OMe
O O
F
F
F
Chiral center introduced by asymmetric hydrogenation of -keto ester using Noyori's catalyst
1) (S)-BinapRuCl
2
, H
2
2) NaOH
OH
O OH
F
F
F
83% Yield (94% ee)
OH
O OH
F
F
F
N
H
O OH
F
F
F
F
F
F
N
O
BnO
OBn
BnONH
2
HCl
EDC DIAD, PPh
3
F
F
F
N
O
BnO
O NH
F
F
F
OH
81%
(over 2 steps)
LiOH
BnO
Hansen et. al., Org. Process Res. Dev., 2005, 9, 634
First Process Chemistry Synthesis
Kelly 13 - CU Synthesis Lit Group - Januvia
First Process Chemistry Synthesis
Kelly 14 - CU Synthesis Lit Group - Januvia
52% vs 17% overall yield
No chiral auxiliary to control stereochemistry
Removed Arndt-Eistert homologation
Two peptide couplings ($$$)
Mitsunobu and peptide couplings waste
Pros Cons
Retrosynthesis of 1st Process Chemistry route to Sitagliptin
N
O NH
2
N
N
N
F
F
F
CF
3
O NH
F
F
F
OH
HN
N
N
N
CF
3
N
N
Cl
F
F
F
N
O
BnO
OMe
O O
F
F
F
BnO
Second Process Chemistry Synthesis
Kelly 15 - CU Synthesis Lit Group - Januvia
Retrosynthesis of 2nd Process Chemistry route to Sitagliptin
N
O NH
2
N
N
N
F
F
F
CF
3
OH
O
F
F
F
N
O NH
N
N
N
F
F
F
CF
3
HN
N
N
N
CF
3
R
Second Process Chemistry Synthesis
Kelly 16 - CU Synthesis Lit Group - Januvia
One-pot, three-component reaction to key -enamino amide intermediate
OH
O
F
F
F
O
O
O
O
Me
Me
Cl
O
O-tBu
i-Pr
2
NEt, DMAP
O
F
F
F
i-Pr
2
NHEt
O
O
O
O
Me
Me
N
O NH
2
N
N
N
F
F
F
CF
3
N
O O
N
N
N
F
F
F
CF
3
NH
4
OAc
MeOH/MeCN
H
2
N
N
N
N
CF
3
Cl
CF
3
CO
2
H (0.3 eq)
82%
(over 3 steps)
Hansen et. al., J. Am. Chem. Soc., 2009, ASAP
Second Process Chemistry Synthesis
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Second Process Chemistry Synthesis
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Proposed mechanism of the amination reaction
O
O
O
O
Me
Me
O
F
F
F
i-Pr
2
NHEt
CF
3
CO
2
H
(0.3 eq)
O
O
O
O
Me
Me
O
F
F
F
H
O
F
F
F
C
O
H
+
H
2
N
N
N
N
CF
3
Cl
N
O O
N
N
N
F
F
F
CF
3
Xu et. al., J. Am. Chem. Soc., 2004, 126, 13002
CO
2
+
Me Me
O
Second Process Chemistry Synthesis
Kelly 19 - CU Synthesis Lit Group - Januvia
Substrate-controlled diastereoselective hydrogenation using chiral auxillary (PGA)
N
O HN
N
N
N
F
F
F
CF
3
H
2
, PtO
2
(acid washed)
92% yield
(97% de)
CONH
2
Ph
N
O HN
N
N
N
F
F
F
CF
3
CONH
2
Ph
Ikemoto et. al., J. Am. Chem. Soc., 2004, 126, 3048
Second Process Chemistry Synthesis
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Second Process Chemistry Synthesis
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Second Process Chemistry Synthesis
Kelly 22 - CU Synthesis Lit Group - Januvia
Deuterium was incorporated in the -position only
N
O
N
N
N
F
F
F
CF
3
N
O NH
2
N
N
N
F
F
F
CF
3
[Rh(COD)
2
Cl]
2
ligand
D
2
, MeOH
Fe
P(Ph)
2
P(t-Bu)
2
Me
ligand
N
O HN
N
N
N
F
F
F
CF
3
[Rh]
Rh
D
2
N
O
N
N
N
F
F
F
CF
3
HN
D
D
+ MeOH
- MeOD
H
2
N D
Hansen et. al., J. Am. Chem. Soc., 2009, ASAP
Second Process Chemistry Synthesis
Kelly 23 - CU Synthesis Lit Group - Januvia
65% vs 52% overall yield
Eliminated Mitsunobu reaction
Minimized coupling reactions
Propietary ligand ($$$)
Pros Cons
F
F
F
R
O
N
O NH
2
N
N
N
F
F
F
CF
3
N
O NH
N
N
N
F
F
F
CF
3
BnO
N
O NH
2
N
N
N
F
F
F
CF
3
Three steps
(one-pot)
Six steps
New Process route
Old Process route
Rh catalyst
H
2
Pd/C
H
2
Sitagliptin
Unprotected enamine
Protected amine
Conclusions
Kelly 24 - CU Synthesis Lit Group - Januvia
0.668
1.4
2.6
0
0.5
1
1.5
2
2.5
3
$

(
i
n

b
i
l
l
i
o
n
s
)
2007 2008 2009
(projected)
Annual Sales
Questions
Kelly 25 - CU Synthesis Lit Group - Januvia
August 29
th
, 1958 - June 25
th
2009