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In tetrahydrofuran; diethyl ether; at -30℃; for 4h;Inert atmosphere;
Mixture of compound 15 (2.0 g, 10.6 mmol) in anhydrous THF (20 mL) was added to a solution of methyl magnesium bromide (14 mL, 42 mmol, 3.0 M in Et20) at -30 C under a nitrogen atmosphere. The mixture was stirred at -30 C for 4 h, and then quenched by addition of water (40 mL) and aq. HC1 (50 mL, 1 M) with stirring at 0 C. The mixture was separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried, filtered and concentrated under vacuum to give the crude intermediate 16 (2.1 g, 100% crude) as a colorless oil, which was used directly in next step without purification. 1H NMR: (CDC13): delta 4.97 (br, 1H), 3.10 (s, 2H), 2.17 (br, 1H), 1.44 (s, 9H), 1.20 (s, 6H).
In tetrahydrofuran; diethyl ether; at -30℃; for 4h;Inert atmosphere;
A mixture of intermediate 21 (2.0 g, 10.6 mmol) in anhydrous THF (20 mL) was added to methyl magnesium bromide (14 mL, 42 mmol, 3.0 M in Et2O) at -30 C. under a N2 atmosphere. The mixture was stirred at -30 C. for 4 h, and then quenched by addition of H2O (40 mL) and aqueous HCl (1 M, 50 mL) with stirring at 0 C. The mixture was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried, filtered and concentrated under vacuum to give the crude intermediate 22 (2.1 g), which was used directly in the next step without purification.1H NMR: (CDCl3): delta 4.97 (br, 1H), 3.10 (s, 2H), 2.17 (br, 1H), 1.44 (s, 9H), 1.20 (s, 6H).
To a solution of BOC glycine methyl ester (J. Med. Chem. 2001, 44, 8, 1192-1201) (19.2 g, 101.5 mmol) in THF at 0° C. was added dropwise ethyl acrylate (11 mL, 101.5 mmol) over 10 minutes. The solution was stirred for 20 minutes, then KOtBu (111.65 mL, 111.65 mmol) was added over 45 minutes. The solution was allowed to warm to 25° C. overnight. The resulting solution concentrated in vacuo and portioned between ethyl acetate and water containing 5 mL of acetic acid. The ethyl acetate layer was removed and aqueous layer extracted with 2*200 mL of ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. MS (DCI/NH4) m/z=258 (M+H)+, 275 (M+NH4)+.
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