1,2-Dichloroethane → methyl ((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate

HRID 879220

反応式

HRID 879220 の反応式
C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([CH3:28])[C@H:25]([N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])[C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:23]1.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[C:51]1[N:56]=[C:55]([C:57]([OH:59])=[O:58])[CH:54]=[CH:53][C:52]=1[F:60]>CN(C=O)C.O>[C:39]([O:38][C:36]([NH:35][C@@H:24]1[CH2:23][C@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:57](=[O:58])[C:55]2[CH:54]=[CH:53][C:52]([F:60])=[C:51]([C:45]3[C:44]([F:43])=[CH:49][CH:48]=[CH:47][C:46]=3[F:50])[N:56]=2)[CH2:27][C@H:26]([CH3:28])[C@@H:25]1[N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])=[O:37])([CH3:41])([CH3:40])[CH3:42].[C:39]([O:38][C:36]([NH:35][C@H:24]1[CH2:23][C@@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:57](=[O:59])[C:55]2[CH:54]=[CH:53][C:52]([F:60])=[C:51]([C:45]3[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=3[F:43])[N:56]=2)[CH2:27][C@@H:26]([CH3:28])[C@H:25]1[N:29]([CH3:34])[C:30](=[O:33])[O:31][CH3:32])=[O:37])([CH3:42])([CH3:41])[CH3:40]

参加物

8

反応物 4

HCID 111,2-DichloroethaneHCID 181649HOAtHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 86705269methyl ((1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate

生成物 2

HCID 86705270methyl ((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate収率 15%HCID 86705271methyl ((1R,2S,4S,6R)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate収率 15%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

実験手順

EDC (1.1 equiv.) and HOAt (1.1 equiv.) were added to a solution of (+/−)-methyl ((1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.05 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (40% EtOH, 100 mL/min, IC column) to yield methyl ((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate (15% yield, 99% ee) and methyl ((1R,2S,4S,6R)-2-((tert-butoxycarbonyl)amino)-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)(methyl)carbamate (15% yield, 99% ee). LC/MS (m/z)=628.3 (MH+), Rt=0.89 min.

後処理

  1. extractionextracted with ethyl acetate
  2. washThe combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by ISCO SiO2 chromatography
  7. customPurification

出典と根拠

ORDレコード
ord-d12edd5daef14496bbc8141cac919c3c
出典データセット
uspto-grants-2015_03
特許番号
US08987457B2

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