Sito in Italia dove è possibile acquistare la consegna acquisto Viagra a buon mercato e di alta qualità in ogni parte del mondo.

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

Microsoft word - collabservices_wp.doc

Collaborative Service Arrangements: Patterns, Bases, and Perceived Consequences Peter J. May Center for American Politics and Public Policy Søren C. Winter Danish National Centre for Social Research This paper has later been published in Public Management Review 9 (4): 479-502. Acknowledgements Mads Stigaard, Mette F. Sørensen, Ina R. Bøge, Nina Friisberg, Helle N. Jens

Knoblauch

Knoblauch stärkt die Manneskraft und vertreibt die Geister, aber nur die bösen. Für viele mögen das die wichtigsten Eigenschaften des Knoblauchs sein, dabei kann er doch noch so viel mehr! lauben Sie etwa nicht an Geister? Das wäre aber noch schade! «Als Kinder waren wir von ausserirdischen Wesen noch total fasziniert. Die Vorstellung von Geistern und Vampiren, Hexen, Zwergen und Feen ist d

Copyright © 2010-2014 Medicament Inoculation Pdf