Hydroxylamine → HCID 87209522, compound

Temperature

70 °C

(S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl) phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.030 g, 0.067 mmol) was dissolved in EtOH (1 mL) in a 2 dram vial. NH2OH (1 mL, 50% solution in water) was added and the sealed screw capped vial was heated to 70° C. for 3 h. The cooled solution was diluted with DCM (10 mL) and transferred to a separation funnel. The organic layer was separated and the aqueous portion was washed further with DCM (5 mL). The combined organic portions were dried, decanted and concentrated yielding (R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N′-hydroxy-3-((S)-2-methylpropan-2-ylsulfinamido)propanamidine as a tan oil (0.032 mg, quantitative yield). LCMS: 1.50 min [M+1] 481.1 (2 min gradient, MeOH/H2O 0.1% TFA). The crude oil was dissolved in dry DCM (1 mL), cooled to 0° C. and TEA (25pL) was added followed by acetic anhydride (11 μL). The reaction mixture was allowed to reach room temperature with stirring over 18 h. The solution was diluted with DCM (10 mL), transferred to a separation funnel, washed with sat. NaCl (10 mL), dried, decanted and concentrated yielding a white solid. LCMS: 1.87 min [M+1] 523.1 (2 min gradient, MeOH/H2O 0.1% TFA). The intermediate N-((R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(hydroxyimino)-3-((S)-2-methylpropan-2-ylsulfinamido)propyl)acetamide was redissolved in anhydrous THF (2 mL) and anhydrous Cs2CO3 was added (0.063 g). The solution was heated to 105° C. for 3 h whereupon the solvent evaporated leaving a pale brown solid which was dissolved in MeOH (1 mL) and purified by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA) yielding (S)-N-((R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a colorless oil (0.015 g, 44% yield over 3 steps). LCMS: 1.96 min [M+1] 505.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.80 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 96%.

1. customthe sealed screw capped vial
2. customtransferred to a separation funnel
3. customThe organic layer was separated
4. washthe aqueous portion was washed further with DCM (5 mL)
5. customThe combined organic portions were dried
6. customdecanted
7. concentrationconcentrated

ORD record

ord-6a86d041d96a4fd1b23c0d494f9dfb03

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07888376B2