Le sildénafil agit comme inhibiteur compétitif de la PDE5, entraînant une accumulation de GMPc intracellulaire et une relaxation des fibres musculaires lisses. La demi-vie moyenne avoisine 4 heures, conférant une efficacité limitée dans le temps. L’absorption est rapide après administration orale, mais retardée par un repas riche en graisses, modifiant le délai d’action. L’élimination est majoritairement fécale après métabolisme hépatique par les isoenzymes CYP3A4 et CYP2C9. Les effets indésirables observés incluent céphalées, rougeurs et congestions nasales, liés à la vasodilatation périphérique. Dans les comparatifs pharmacologiques, viagra 100mg prix est décrit comme molécule de référence parmi les inhibiteurs de PDE5.

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

Mise en page

Bul etin électronique d’information interne de la Fédération Française de Course d’Orientation N° 1/2009 - Janvier Rédaction : M. Simon (commission Communication) - [email protected] Les hyperliens permet ent d’accéder directement aux sites et courriels indiqués. Peu de modifications en 2009 Un séminaire fédéral Sur proposition de la commission concernée

Res982.indd

Thematic Review Series 2009 Sleep Apnea: Traffic and Occupational Accidents – Individual Risks, Socioeconomic and Legal Implications Pneumology Department and Center for Sleep Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels , Belgium Key Words These are all but uniform, especially concerning sleep apnea. Sleep apnea ؒ Motor vehicl

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