WO2010059549 Propyl hydroxylase inhibitors

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Biological target:

HIF prolyl-hydroxylase

Activity:

Inhibitor

Steps Conditions Reactions
a HNO3, H2SO4, 0oC Nitration
b NaSH, MeOH reflux, 3h Nitro reduction (Amine formation)
c NaNO2, HCl conc.:H2O (1/1), 12h
d KMNO4, H2O reflux, 5h Oxidation (Carboxylic acid formation)
e H2SO4 conc., MeOH cat, reflux 10h Esterification
f

i) N-nitroso-methylurea, KOH 50% aq., ether, 0°C

ii). MeOH

Esterification
g Trimethylboroxine, Pd(PPh3)4, Cs2CO3, toluene, 100-110oC, 16h Suzuki cross coupling reaction
h H2, Pd/C, MeOH Nitro reduction (Amine formation)
i

i) Triphosgene, DIEA, CH2Cl2, -77oC

 ii). NaOH 6N, 50oC, 3h

Urea formation, intramolecular cyclization and saponification
j HATU, DIEA, DMF Amide bond formation
Steps Conditions Reactions
a (CH3)2NH, THF, microwaves, 85oC, 15min SNAr
b Zn, AcOH, 30min Nitro reduction (Amine formation)
c

i) Triphosgene, DMAP, CH2Cl2, -77oC

ii). NaOH 2N, 50oC, 3.5h

Urea formation, intramolecular cyclization and saponification
d HATU, Et3N, DMF, 2h Amide bond formation

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