Diisopropylethylamine → tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2061422노트

반응식

HRID 2061422 반응식
[CH2:1]([S:4][C@:5]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([OH:27])=O)[CH2:6]1)[CH:2]=[CH2:3].[NH2:40][C@:41]1([C:47]([NH:49][S:50]([C:53]2([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:43][C@H:42]1[CH:44]([F:46])[F:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([S:4][C@:5]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](=[O:27])[NH:40][C@:41]2([C:47](=[O:48])[NH:49][S:50]([C:53]3([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:54][CH2:55]3)(=[O:52])=[O:51])[CH2:43][C@H:42]2[CH:44]([F:46])[F:45])[CH2:6]1)[CH:2]=[CH2:3]

참가 물질

6

반응물 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57998012(2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acidHCID 59366237(1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide

생성물 1

HCID 59366238tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate수율 73%

시약·촉매·용매 1

HCID 6344Dichloromethane용매2회

실험 절차

To a slurry of (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (55.3 mg, 0.10 mmol), (1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide (38.7 mg, 0.10 mmol) and HATU (57.0 mg, 0.150 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.087 mL, 0.500 mmol). The formed solution was stirred at room temperature overnight. Diluted with DCM, washed with 1M HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜30% Acetone-Hexane to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (65 mg, 0.073 mmol, 73% yield) as a white foam. 1H NMR (400 MHz, MeOD) ppm 0.81-0.88 (m, 2 H) 1.07 (s, 9 H) 1.21-1.61 (m, 17 H) 1.64-1.80 (m, 1 H) 1.81-2.12 (m, 6 H) 2.37 (t, J=11.42 Hz, 1 H) 2.91-3.05 (m, 3 H) 3.91 (dd, J=10.29, 6.53 Hz, 1 H) 3.98 (d, J=11.04 Hz, 1 H) 4.48 (d, J=9.79 Hz, 1 H) 4.86-5.13 (m, 5 H) 5.66-6.14 (m, 3 H) 7.36 (t, J=7.28 Hz, 1 H) 7.45 (t, J=7.53 Hz, 2 H) 7.52-7.76 (m, 6 H). LC-MS (retention time: 3.39 min, Method B), MS m/z 885 (M+H).

후처리

  1. washwashed with 1M HCl and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by Biotage column
  6. washeluted with gradient 5%˜30% Acetone-Hexane

출처 및 근거

ORD 기록
ord-5d5a7092e5924db3a69af8686e36c252
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08283310B2

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