Hydrochloric Acid → (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-di-fluoromethoxy-propionic acid benzyl ester

To a solution of the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxypropionic acid (1.15 g, 4.49 mmol) and the compound of Formula V(a), (S)-2-amino-3-difluoromethoxypropionic acid benzyl ester hydrochloride salt (1.15 g, 4.08 mmol), HOBt (0.689 g, 5.10 mmol) and EDCl.HCl (0.867 g, 5.10 mmol) in dichloromethane (20 mL) was added N-methylmorpholine (0.45 mL, 8.16 mmol) dropwise at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then diluted with ethyl acetate and washed successively with water, 1N HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica-gel column chromatography, eluting with 10% to 12.5% ethyl acetate in hexanes, to give the compound of Formula II(a)(ii), (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-di-fluoromethoxy-propionic acid benzyl ester (1.29 g, 65%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.41 (m, 5H), 7.18 (td, 1H), 6.18 (wt, 1H), 6.22 (wt, 1H), 5.25-5.20 (m, 1H), 5.19 (s, 2H), 4.82 (td, 1H), 4.42 (br s, 1H), 4.31 (td, 1H), 4.20-4.15 (m, 2H), 4.01 (dd, 1H), 1.41 (s, 9H).

1. washwashed successively with water, 1N HCl and brine
2. dry with materialThe organic layer was dried over MgSO4
3. concentrationconcentrated
4. customThe crude product was purified by silica-gel column chromatography
5. washeluting with 10% to 12.5% ethyl acetate in hexanes

ORD record

ord-29c31db5892f4c9d8bce00608374965a

Source dataset

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09441012B2