Diisopropylethylamine → ethyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate

HRID 879191Notes

Reaction equation

HRID 879191 reaction equation
[NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.CCN([CH:47]([CH3:49])C)C(C)C.[C:50]([O-])([OH:52])=[O:51].[Na+]>C(Cl)Cl>[NH2:33][C@@H:3]1[CH2:4][C@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:6][C@H:7]([CH3:8])[C@@H:2]1[NH:1][C:50](=[O:51])[O:52][CH2:47][CH3:49]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 86705239tert-butyl (1R,2S,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate

Product 1

HCID 72548918ethyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamateYield 14%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl (1R,2S,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. was added DIEA (3.0 equiv.) and then ETHYL CHLOFORMATE (1.0 equiv.). The homogeneous solution was left standing at 0° C. at for 4 hrs. Neutralize the reaction with sat. NaHCO3 solution. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield ethyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate in 14% yield. LC/MS (m/z)=528.2 (MH+), Rt=0.65 min.

Workup

  1. waitThe homogeneous solution was left
  2. customstanding at 0° C. at for 4 hrs
  3. customThe solution was partitioned between EtOAc and H2O
  4. washThe organic layer was washed with Na2CO3(sat.), NaCl(sat.)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified by ISCO SiO2 chromatography
  9. additionThe Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles
  10. customwere removed in vacuo
  11. dissolutionthe residue was dissolved in DMSO
  12. custompurified by RP-HPLC

Sources & evidence

ORD record
ord-58ac4a8fcf8b4dd89c28afae1883fe90
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Reaction notes

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