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 705304Notes

Reaction equation

HRID 705304 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-7d90e868e53647ee85d1d6e2956ef4e9
Source dataset
uspto-grants-2015_11
Patent number
US09173883B2

Reaction notes

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