3,3-Dimethylbutylamine → (2S,3S,4S)-2-(3,3-dimethyl-butylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1052120노트

반응식

HRID 1052120 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]

참가 물질

7

반응물 5

HCID 197093,3-DimethylbutylamineHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68283958(2S,3S,4S)-4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl esterHCID 68284081(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

생성물 1

HCID 90020034(2S,3S,4S)-2-(3,3-dimethyl-butylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 1.14 mmol), 3,3-dimethylbutylamine (115 mg, 1.14 mmol) and HBTU (648 mg, 1.71 mmol) in CH2Cl2 (7 mL) was added DIPEA (0.60 mL, 3.42 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere overnight and concentrated. The crude residue was taken-up in EtOAc, washed with 0.1 N HCl (×2), dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4 in 40 min) to give (2S,3S,4S)-2-(3,3-dimethyl-butylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.5; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (m, 1H), 5.16 (dq, 1H), 4.29-4.37 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.39 (m, 1H), 3.35 (s, 3H), 3.08 (m, 2H), 1.32-1.40 (m, 11H), 0.90 (s, 9H) and (2R,3R,4R)-2-(3,3-dimethyl-butylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.6; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (m, 1H), 5.05 (m, 1H), 4.20 (t, 1H), 4.02 (m, 1H), 3.70 (m, 1H), 3.39 (m, 1H), 3.33 (overlap with DMSO, m, 1H); 3.27 (s, 3H), 3.06 (m, 2H), 1.36-1.43 (m, 11H), 0.89 (s, 9H)

후처리

  1. concentrationconcentrated
  2. washwashed with 0.1 N HCl (×2)
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4 in 40 min)

출처 및 근거

ORD 기록
ord-efc623680b374f91a9f443992361b3b6
출처 데이터셋
uspto-grants-2016_07
특허 번호
US09388199B2

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