Diisopropylethylamine → (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one

To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

1. stirringAfter stirring at room temperature for 16 hours
2. concentrationthe mixture was concentrated under reduced pressure
3. custompartitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL)
4. extractionThe aqueous layer was extracted with ethyl acetate
5. washthe combined organic phases were washed with brine (20 mL)
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe brown oil was chromatographed (9:1 hexanes/ethyl acetate)

ORD 기록

ord-1883046dd3fd4636b2d75efbcfe18b48

출처 데이터셋

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08324257B2