Triethylamine → (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester

HRID 1261499노트

반응식

HRID 1261499 반응식
Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH2:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([N:13]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])[C:17]1=[O:16])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1

참가 물질

6

반응물 3

HCID 8471TriethylamineHCID 19788116Methyl 2-(bromomethyl)-3-fluorobenzoateHCID 22861687methyl (2S)-2-amino-3-cyclohexylpropanoate hydrochloride

생성물 1

HCID 70945620(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester수율 57.2%

시약·촉매·용매 2

HCID 962Water용매HCID 6342Acetonitrile용매

반응 조건

온도
82 °C

실험 절차

A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).

후처리

  1. temperatureThe reaction mixture was then heated
  2. concentrationconcentrated in vacuo
  3. customto remove the acetonitrile
  4. additionThe remaining material was then diluted with another portion of water (10 mL)
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe combined organic layers were then dried over magnesium sulfate
  7. filtrationfiltered
  8. customto remove the drying agent
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe crude material was purified

출처 및 근거

ORD 기록
ord-4dd8cb7d8f6442eb90de73b58a2f1873
출처 데이터셋
uspto-grants-2013_06
특허 번호
US08470866B2

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