Acetic Acid → Methyl 1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclopentanecarboxylate

HRID 1615790Notes

Reaction equation

HRID 1615790 reaction equation
[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([NH:7][C:8]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:11])[CH2:9][NH:21][C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 231225Methyl 1-amino-1-cyclopentanecarboxylate (H-Ac5c-OMe)HCID 5003444Sodium cyanoborohydrideHCID 86616399tert-butyl N-[2-(3,5-difluorophenyl)-1-oxopropan-2-yl]carbamate

Product 1

HCID 66865198Methyl 1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclopentanecarboxylate

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolvent

Procedure

To tert-butyl[1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate (28.9 g, 101 mmol) were added methyl 1-aminocyclopentanecarboxylate (43.4 g, 303 mmol) followed by titanium(IV) isopropoxide (44.5 mL, 152 mmol) and the reaction mixture was stirred at ambient temperature for 90 min, diluted with MeOH (130 mL), and cooled in an ice-water bath. To this stirred mixture were added AcOH (29 mL, 507 mmol) followed by NaCNBH3 (7.64 g, 122 mmol), portionwise, over 5 min. Stirring was continued for 5 min, then the ice-water bath was removed, and stirring was continued for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 L) and extracted with EtOAc (3×1.5 L). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 50:50, to give a mixture of the title compound and the corresponding isopropyl ester. MS: m/z=413 (M+1).

Workup

  1. temperaturecooled in an ice-water bath
  2. waitportionwise, over 5 min
  3. stirringStirring
  4. waitwas continued for 5 min
  5. customthe ice-water bath was removed
  6. stirringstirring
  7. waitwas continued for 30 min
  8. customThe reaction mixture was quenched with saturated aqueous NaHCO3 (1 L)
  9. extractionextracted with EtOAc (3×1.5 L)
  10. washThe combined organic extracts were washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe crude product was purified by silica gel chromatography
  15. washeluting with hexane
  16. customEtOAc—100:0 to 50:50, to give

Sources & evidence

ORD record
ord-1626eaf157414fafa16cbde4e8dc994c
Source dataset
uspto-grants-2014_07
Patent number
US08765759B2

Reaction notes

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