WO2010068262 Processes and intermediates for carbamoylpyridone HIV integrase inhibitors

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Biological target:

HIV integrase

Activity:

Inhibitor

Steps Conditions Reactions
a BnBr, K2CO3, CH3CN, 80oC, 5h

Hydroxyl group protection

(Benzyl protection)
b LiHMDS, THF -60oC, 2h then PhCHO, -60oC, 1h Nucleophilic substitution
c MsCl, Et3N, THF < 30oC, then NMP, DBU < 30oC, 30 min Dehydratation: Mesylate formation (Alcohol activation) and elimination
d

  RuCl3.nH2O, CH3CN, NaIO4 in EtOAc/H2O (1/1) then NaClO2 < 25oC                   

Oxidation              
e EtOH, 65oC, 1h, then 80oC
f MeI, NaHCO3, NMP, 4h Methylation (Esterification)
g NaIO4, AcOH, CH3CN/H2O 1/1, 2h Diol oxidation
h Toluene, AcOH 90oC, 2.5h Intramolecular cyclization
i NBS, NMP, 2h Bromination
j Pd(PPh3)4, iPr2NEt, CO, DMSO, 90oC, 5.5h Aminocarbonylation
k H2, Pd/C, THF/MeOH 9/1, 1h Hydrogenolysis
l 2N NaOH aq, EtOH, 80oC  

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