Sodium Bicarbonate → HCID 86718598, compound

HRID 1480635Notes

Reaction equation

HRID 1480635 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:5]=1[OH:24].[C:25](=[O:28])(O)[O-:26].[Na+].[BH4-].[Na+]>C(OCC)(=O)C>[C:10]([C:8]1[CH:7]=[C:6]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:5]([OH:24])=[C:4]([CH:9]=1)[CH2:3][NH:2][CH:4]([CH3:5])[CH2:3][NH:2][C:25](=[O:28])[O:26][C:8]([CH3:10])([CH3:9])[CH3:7])([CH3:13])([CH3:12])[CH3:11]

Participants

5

Reactant 3

HCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 86718599HCID 86718599, compound

Product 1

HCID 86718598HCID 86718598, compoundYield 67%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

The free base of 2-(aminomethyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (Example 64), was prepared by partitioning the hydrochloride salt (560 mg, 1.55 mmol) between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under reduced pressure. The residue was redissolved in a solution of tert-butyl (2-oxopropyl)carbamate in ethanol (5 mL) and stirred for three days. Sodium borohydride (290 mg, 7.75 mmol) was added portionwise and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous ammonium chloride solution (1 mL) and the reaction mixture partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0-100% ethyl acetate in hexanes to give tert-butyl (2-((5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)amino)propyl)carbamate (500 mg, 67%) as a white solid. The carbamate (500 mg, 1.04 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (10 mL) added and the reaction was stirred for 16 h. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and then redissolved in a 1:1 mixture of methylene chloride and trifluoracetic acid (40 mL) and stirred at room temperature for four hours. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% of (89% methylene chloride, 10% methanol and 1% ammonium hydroxide) in methylene chloride. The purified residue was dissolved in a 1.25 M hydrochloric acid solution in ethanol, the solution stood for 10 minutes, and then the solvent removed under reduced pressure and the residue triturated with diethyl ether to give 2-(((1-aminopropan-2-yl)amino)methyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (150 mg, 32% yield) as a white solid.

Workup

  1. customThe organic phase was separated
  2. dry with materialdried (Na2SO4)
  3. filtrationfiltered
  4. customthe solvent removed under reduced pressure
  5. dissolutionThe residue was redissolved in a solution of tert-butyl (2-oxopropyl)carbamate in ethanol (5 mL)
  6. stirringthe reaction mixture stirred at room temperature for one hour
  7. customThe reaction was quenched with saturated aqueous ammonium chloride solution (1 mL)
  8. customthe reaction mixture partitioned between ethyl acetate
  9. customThe organic phase was separated
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. customthe solvent was removed under reduced pressure
  13. customThe residue was purified

Sources & evidence

ORD record
ord-ebb7037a6d69428abe3a1e0d5c5c6eea
Source dataset
uspto-grants-2016_08
Patent number
US09409893B2

Reaction notes

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