Diisopropylethylamine → benzyl (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-phenyl-propanoate

温度

0 °C

To a stirred solution of benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate hydrochloride (1.65 g, 3.84 mmol), 2-morpholinoacetic acid hydrochloride (768 mg, 4.23 mmol) and HOBt hydrate (648 mg, 4.23 mmol) in DCM (20 mL) was added EDC hydrochloride (811 mg, 4.23 mmol). The resulting mixture was cooled to 0° C. and treated with DIPEA (0.736 mL, 4.23 mmoL), dropwise, warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with saturated sodium bicarbonate (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.72 (m, 1H), 7.35-6.90 (m, 10H), 6.12 (t, J=74 Hz, 1H), 5.14-5.04 (m, 2H), 4.81-4.75 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.20 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.50 (m, 4H), 3.15-2.90 (m, 4H), 2.45-2.35 (m, 4H).

1. temperaturedropwise, warmed to room temperature
2. washwashed with saturated sodium bicarbonate (2×50 mL)
3. dry with materialThe organic phase was dried over anhydrous sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customthen chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes
7. concentrationThe product-containing fractions were concentrated in vacuo
8. customgiving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid

ORDレコード

ord-70173c065afa4076ad30aa6e4a5f3812

出典データセット

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09441012B2