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Sidagliptin.cdx

Sidagliptin (Januvia)
– developed by Merk for the treatment of Type-II diabetes
– inhibits the enzyme DPP-IV, improving glucose regulation
– currently approved and on the market in Australia
– formulated as the H3PO4 salt
key process question: what's the
most efficient way to set the
absolute configuration of the β-
amino amide?
the triazole is not
superphos = hydrated form of
reduced under the
polyphosphoric acid
hydrogenation conditions
First Generation Process Route:
1. 35% NH2NH2/H2O
"superphos"
60–60 °C
49% yield, two steps
1. H2, Pd/C
HCl•HN
2. HCl, IPA
26% yield from 2-chloropiperazine
51% yield, 2 steps
1. (S)-BINAP-RuCl
HBr, 90 psi H2,
BnOHN2•HCl,
MeOH, 80 °C
EDC, LiOH
2. NaOH, MeOH/H
83% yield
NMM = N-methylmorpholine
1. LiOH, THF/H2O
DIAD, PPh
2. EDC, NMM
81% yield
intramolecular
HCl•HN
Mitsunobu rxn
recrystallized from
water to upgrade ee
to >99%
78% yield
over 4 steps
•H3PO4
60% yield over 8 steps
from β-ketoester
Downsides:
– 2 EDC couplings (EDC is expensive!)
– Mitsunobu reaction (DIAD is expensive, and generates waste)

Optimized Process:
t-BuCOCl, DIPEA
cat, DMAP, MeCN
t-Bu
cat. TFA, MeCN, 50 °C
MeCN/MeOH
HCl•HN
82% isolated yield,
3 steps, 1 pot
[RhCl(cod)]
2 (0.15 mol%)
(R,S)-PPF-P(t-Bu) (0.30 mol%)
2, MeOH, 50 °C, 18 h
•H3PO4
isolated in 85% yield and
Sitagliptin
>99.7% ee after one
recrystalizaton
Interesting Notes:
– Merck has prepared 20 MT using this process
Pt-Bu2
– when using D
2 in the hydrogenation, they only see D-incorporation at the β-carbon
– they found that use of 1 mol% NH4Cl during hydrogenation step improved reproducibility
(R,S)-PPF-P(t-Bu)
References:
Org. Proc. Res. Dev.
2005, 634 (1st generation synthesis)
J. Am. Chem. Soc. 2004, 13002 (Meldrum's acid addition)
J. Am. Chem. Soc. 2004, 9918 (free enamine hydrogenation)
J. Med. Chem. 2004, 4135 (DPP-IV as target for diabetes)

Source: http://reismangroup.caltech.edu/242a_Website/2009/Sidagliptin.pdf

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Microsoft word - demsnewsletter 3-21-04.doc

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