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Phosgene → tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-15-(fluoromethyl)-4,17-dimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}isoquinolin-1-yl)carbamate

HRID 708888
ノート
印刷プレビュー

反応式

HRID 708888 の反応式
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:31][CH:30]=[CH:29]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:22][OH:23])[CH2:20][F:21])=[C:15]([CH3:24])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:58](=[O:59])[O:23][CH2:22][C@H:19]([CH2:20][F:21])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:24])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:41])[CH3:40]
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

5

反応物 2

HCID 6371PhosgeneHCID 118098757tert-Butyl N-(6-{[({[5-amino-2-(cyclopropanesulfonyl)phenyl]methyl}(methyl)carbamoyl)({4-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-methylphenyl})methyl]amino}isoquinolin-1-yl)-N-[(tert-butoxy)carbonyl]carbamate

生成物 1

HCID 118098758tert-Butyl N-[(tert-butoxy)carbonyl]-N-(6-{[(2R,15R)-7-(cyclopropanesulfonyl)-15-(fluoromethyl)-4,17-dimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10 (21),16,19-hexaen-2-yl]amino}isoquinolin-1-yl)carbamate
収率 76%

試薬・触媒・溶媒 2

HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒2 回

反応条件

温度
0 °C

実験手順

To a solution of 24E (0.1 g, 0.124 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C., was added phosgene solution (20% in toluene, 0.072 mL, 0.136 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was then added dropwise via syringe pump into a solution of TEA (0.138 mL, 0.993 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. Solvent was removed, and the crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give a mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 24F (38 mg, 76% yield). MS (ESI) (m/z): 831.9 (M+H)+.

後処理

  1. customExtra phosgene was removed
  2. customby bubbling Ar for 20 min
  3. stirringThe solution was stirred at rt over night
  4. customSolvent was removed
  5. customthe crude product was purified by flash chromatography (0-80% EtOAc/hexanes)
  6. customto give
  7. additiona mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield)
  8. customThe diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm)

出典と根拠

ORDレコード
ord-090dd84bae6443b9b0bb2620905ffbf9
出典データセット
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09174974B2

反応ノート

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このページの内容参加物反応条件実験手順後処理出典と根拠反応ノート