Diisopropylethylamine → [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester

The title compound can be synthesized in accordance with any one of the four procedures set forth below. Method A: A flask was charged with N-Cbz-L-valine (1.02 g, 4.04 mmol) and DMF (60 mL) and stirred under nitrogen. To this was added diisopropylethylamine (2.11 mL, 12.1 mmol) followed by TBTU (1.30 g, 4.04 mmol). After stirring for 5 minutes, a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (8.08 mmol) dissolved in DMF (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (300 mL) and the organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as an amber oil. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column to give (1.10 g, 1.97 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.25 (m, 10H), 6.70-6.51 (m, 1H), 5.48-5.35 (m, 1H), 5.18-5.01 (m, 4H), 4.20-3.98 (m, 2H), 3.62-3.42 (m, 1H), 3.38-3.18 (m, 1H), 2.30-2.05 (m, 1H), 2.03-1.60 (m, 10H, 1.38-1.02 (m, 5H), 0.98 (dd, 6H). LCMS m/z: [M+H]+=559.

1. stirringAfter stirring for 5 minutes
2. additionwas added
3. stirringThe reaction mixture was stirred overnight at room temperature
4. washthe organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL)
5. dry with materialThe organic layer was dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto give the crude product as an amber oil
9. customThe crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column

ORD 기록

ord-b60a8744cd5e4f328927b2c722f637ae

출처 데이터셋

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08828974B2