2,6-Difluorobenzoic acid → 5-Amino-N-[2-({[(2,6-difluorophenyl)carbonyl]amino}methyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide

2,6-Difluorobenzoic acid (0.069 mmol) was weighed into a micronic tube. To this O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.069 mmol, 26 mg) was added as a solution in DMF (200 μl). Diisopropylethylamine was then added (0.20 mmol, 36 μl) and the solution shaken for 5 minutes. 5-Amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.069 mmol, 25 mg) was then added as a solution in DMF (200 μl). The solution was then shaken for a further 10 minutes and left to stand overnight at room temperature. LC-MS was taken after this time, the sample (20 μl) was diluted in acetonitrile (100 μl). LC-MS showed product present. The crude mixture was filtered and purified by mass directed HPLC. The products seemed to crash out when introduced to 90% H2O (0.1% TFA)/10% MeCN (0.1% TFA) (of CAT-norm method) resulting in high back pressure. Method Cat-GR was used instead as 70% H2O (0.1% TFA)/30°/0 MeCN (0.1% TFA) ensured no solid crashed out on introduction to column. The collected solution from the purification was transferred to a scintillation vial where MeCN/H2O/TFA was removed in Genevac. The dried compound was then transferred to pre-tared vial. Weight obtained for desired product 22.7 mg.

1. stirringThe solution was then shaken for a further 10 minutes
2. waitleft
3. waitto stand overnight at room temperature
4. filtrationThe crude mixture was filtered
5. custompurified by mass
6. additionintroduced to 90% H2O (0.1% TFA)/10% MeCN (0.1% TFA) (of CAT-norm method)
7. customresulting in high back pressure
8. customThe collected solution from the purification
9. customwas removed in Genevac

ORD 기록

ord-508f69f6565d4ccab7fe4c0a700b46ed

출처 데이터셋

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08247377B2