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 2061422ノート

反応式

HRID 2061422 の反応式
[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]

参加物

6

反応物 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

生成物 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-ylcarbamate収率 73%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-5d5a7092e5924db3a69af8686e36c252
出典データセット
uspto-grants-2012_10
特許番号
US08283310B2

反応ノート

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