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 879220Notes

Reaction equation

HRID 879220 reaction equation
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]

Participants

8

Reactant 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

Product 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)carbamateYield 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)carbamateYield 15%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-d12edd5daef14496bbc8141cac919c3c
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Reaction notes

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