Water → (S)-1-tert-Butyl 4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl) 2-((tert-butoxycarbonyl)amino)succinate

HRID 716094노트

반응식

HRID 716094 반응식
[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34](=[O:48])[C@@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C:37](O)=[O:38])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([O:43][C:41]([NH:40][C@@H:35]([CH2:36][C:37]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:38])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])=[O:42])([CH3:47])([CH3:46])[CH3:45]

참가 물질

7

반응물 4

HCID 962WaterHCID 10868DicyclohexylcarbodiimideHCID 7010517(3S)-4-(tert-butoxy)-3-{[(tert-butoxy)carbonyl]amino}-4-oxobutanoic acidHCID 91820646(3R)-3-[(3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl]-1-[(4-methylphenyl)methyl]pyrrolidin-2-one

생성물 1

HCID 118207674(S)-1-tert-Butyl 4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl) 2-((tert-butoxycarbonyl)amino)succinate수율 72.6%

시약·촉매·용매 2

HCID 142844-(Dimethylamino)pyridine촉매HCID 6344Dichloromethane용매

실험 절차

To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol) in DCM (5 mL) was added (S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (0.118 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction was stirred at rt for 18 hours. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 25% ethyl acetate in petroleum ether to provide the purified product (37 mg, 68%) as an off-white semi solid. LC-MS (Method A) RT=2.55 min, (M+H)+=654.4. 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.34 (m, 2H), 7.20-6.98 (m, 6H), 4.82-4.53 (m, 1H), 4.43-4.24 (m, 2H), 4.11 (d, J=14.1 Hz, 1H), 3.58 (t, J=8.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.22-3.07 (m, 3H), 3.02 (dd, J=16.1, 6.5 Hz, 1H), 2.87 (dd, J=15.8, 7.8 Hz, 1H), 2.78-2.63 (m, 2H), 2.38-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.03 (m, 1H), 1.98-1.86 (m, 1H), 1.78 (br. s., 1H), 1.74-1.58 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.

후처리

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted with DCM (3×15 mL)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated to a crude product
  5. customThe crude product was purified by preparative TLC
  6. washeluting with 25% ethyl acetate in petroleum ether

출처 및 근거

ORD 기록
ord-43fdd3e876de43488e13adb28c2aa17b
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09187506B2

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