Ammonium Chloride → Tert-butyl 4-(3-amino-6-(4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate

HRID 595958Notes

Reaction equation

HRID 595958 reaction equation
[NH2:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1

Participants

6

Reactant 3

HCID 25517Ammonium ChlorideHCID 4311764Sodium borohydrideHCID 118045455Tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate

Product 1

HCID 118045335Tert-butyl 4-(3-amino-6-(4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoateYield 98.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (9 g, 23.35 mmol) in methanol (125 mL) and THF (125 mL) was cooled down to −78° C., and then NaBH4 (2.297 g, 60.7 mmol) was added portion wise. The reaction mixture was then stirred at −78° C. for 40 min, and LCMS indicated the reaction was completed. Some over-reduction product was observed. The ratio of trans to cis was about 8:1. 100 mL of sat. NH4Cl was added slowly at −78° C., and then the mixture was warmed up gradually to room temperature. The reaction mixture was quenched by sat. NaHCO3, and extracted by EtOAc (2×200 mL). The organic layers were combined, dried over Na2SO4, filtered off, concentrated and dried under high vacuum to provide tert-butyl 4-(3-amino-6-(4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (8.9 g, 22.97 mmol, 98%), which was used in next step without further purification. LCMS (m/z): 388.2 (MH+), 0.86 min.

Workup

  1. temperaturethe mixture was warmed up gradually to room temperature
  2. customThe reaction mixture was quenched by sat. NaHCO3
  3. extractionextracted by EtOAc (2×200 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered off
  6. concentrationconcentrated
  7. customdried under high vacuum

Sources & evidence

ORD record
ord-fde81ca3ceda4ca6963a8c187d537b82
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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