1,2-Dichloroethane → tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamate

HRID 879214Notes

Reaction equation

HRID 879214 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]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([OH:60])=[O:59])[CH:55]=[CH:54][C:53]=1[F:61]>CN(C=O)C.O>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@@H:22]2[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@H:24]([CH3:43])[CH2:23]2)=[O:59])[CH:55]=[CH:54][C:53]=1[F:61].[F:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([F:44])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@H:22]2[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]2)=[O:60])[CH:55]=[CH:54][C:53]=1[F:61]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 181649HOAtHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 86705263tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexyl)carbamate

Product 2

HCID 90056052tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamateYield 48%HCID 90056064tert-butyl (1S,2R,3R,5S)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamateYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

EDC (2.0 equiv.) and HOAt (2.0 equiv.) were added to a solution of (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.08 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 (50% MeOH, 100 mL/min, IC column) to yield tert-butyl (1S,2R,3R,5S)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (48% yield, 99% ee) and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamate (48% yield, 99% ee). LC/MS (m/z)=663.2 (MH+), Rt=0.88 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.95 (d, J=6.75 Hz, 3H), 1.45 (s, 8H), 1.50-1.84 (m, 5H), 2.80-2.95 (m, 1H), 3.08 (s, 3H), 3.14-3.29 (m, 1H), 3.32-3.45 (m, 1H), 3.56 (br. s., 1H), 3.63-3.77 (m, 1H), 3.95-4.08 (m, 1H), 4.12 (q, J=7.12 Hz, 1H), 5.36 (d, J=8.56 Hz, 1H), 7.04-7.18 (m, 3H), 7.50 (tt, J=8.47, 6.35 Hz, 1H), 7.77 (t, J=8.56 Hz, 1H), 8.33-8.46 (m, 2H), 9.26 (s, 1H), 9.81 (s, 1H).

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-3d6a8d392495456c84c1896536901323
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Reaction notes

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