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

HRID 705312Notes

Reaction equation

HRID 705312 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[N:22]1[CH2:27][C@H:26]([CH3:28])[C@H:25]([N:29]=[N+]=[N-])[C@H:24]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23]1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:48]1[N:53]=[C:52]([C:54](O)=[O:55])[CH:51]=[CH:50][C:49]=1[F:57].[N-]=[N+]=[N-]>CN(C=O)C.O.CC(O)C.[Pd]>[NH2:29][C@H:25]1[C@@H:26]([CH3:28])[CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:54](=[O:55])[C:52]2[CH:51]=[CH:50][C:49]([F:57])=[C:48]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][C:43]=3[F:47])[N:53]=2)[CH2:23][C@H:24]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]

Participants

10

Reactant 5

HCID 111,2-DichloroethaneHCID 33558AzideHCID 181649HOAtHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 86705282tert-butyl ((3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-azido-5-methylpiperidin-3-yl)carbamate

Product 1

HCID 86705281tert-butyl ((3R,4S,5S)-4-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamateYield 58%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 962WaterSolventHCID 3776IsopropanolSolventHCID 6228DimethylformamideSolvent

Procedure

EDC (1.5 equiv.) and HOAt (1.5 equiv.) were added to a solution of tert-butyl ((3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-azido-5-methylpiperidin-3-yl)carbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.3 equiv.) in DMF (0.20 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. To a degassed a solution of the azide (1.0 equiv.) in 2-propanol (0.10 M) was added Pd/C (0.2 equiv.). The mixture was stirred under H2 for 48 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield tert-butyl ((3R,4S,5S)-4-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate in 58% yield). LC/MS (m/z)=557.1 (MH+), Rt=0.69 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. stirringThe mixture was stirred under H2 for 48 hrs
  8. filtrationFilter the mixture over cetlite
  9. washwash the cake with MeOH
  10. concentrationConcentrate the filtrate

Sources & evidence

ORD record
ord-8fd09010743d49e1b29a6c335a3af6c1
Source dataset
uspto-grants-2015_11
Patent number
US09173883B2

Reaction notes

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