Borane → HCID 59458714, compound

HRID 1874263Notes

Reaction equation

HRID 1874263 reaction equation
[NH2:1][CH:2]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[C:3]([NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.B.[H][H].B(F)(F)F.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH:2]([CH2:3][NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:39]([C:44]([F:45])([F:46])[F:47])([OH:48])[C:40]([F:43])([F:42])[F:41]

Participants

7

Reactant 5

HCID 6331BoraneHCID 8000Boron trifluoride etherateHCID 21226445Aluminium lithium hydrideHCID 59458459HCID 59458459, compoundHCID 178418361HCID 178418361, compound2×

Product 1

HCID 59458714HCID 59458714, compoundYield 20%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-amino-4,4,4-trifluoro-N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide, prepared as described in Example 293, (20 mg, 0.028 mmol) in THF (0.5 mL) was added borane (0.2 mL, 1.0 M solution in THF). After hydrogen evolution ceased, the solution was heated in a sealed microwave vial under microwave irradiation at 100° C. for 5 min. The solvents were removed under a stream of nitrogen then THF (0.5 mL) was added to the residue followed by BF3.Et2O (30 mg, 0.21 mmol) and LAH (0.2 mL, 1.0 M solution in THF). After evolution of hydrogen gas had ceased, the sealed microwave vial was heated at 100° C. for 10 min. The solvents were removed under a stream of nitrogen and the residue dissolved in NH4OH (ca. 10 mL). LiCl (10%, ca. 10 mL) was added and the aqueous extracted with DCM (3×10 mL). The combined organic portions were concentrated under reduced pressure and purified by preparative TLC (25×25 mm, silica gel 1 mm elution with hexane:EtOAc 4:1). 3-Amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-ol (Example 327, 5 mg, 20% yield) was isolated as a colorless oil at Rf of 0.5. LCMS: RT=3.88 min [M+H] 693.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.88 min, Purity 91% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 7.05 ppm, 1H, m; 6.86 ppm, 2H, d, J=8.0 Hz; 6.83 ppm, 3H, m; 6.61 ppm, 2H, d, J=8.0 Hz; 5.87 ppm, 1H, t, t, J=52.0 Hz and J=4.0 Hz; 4.41 ppm, 1H, sept, J=8.0 Hz; 3.57 ppm, 1H, d, J=12.0 Hz; 3.48 ppm, 1H, d, J=12.0 Hz; 2.99 ppm, 2H, m; 2.53 ppm, 1H, brt; 1.27 ppm, 3H, d, J=8.0 Hz; 1.25 ppm, 3H, d, J=8.0 Hz.

Workup

  1. customThe solvents were removed under a stream of nitrogen
  2. additionTHF (0.5 mL) was added to the residue
  3. temperaturethe sealed microwave vial was heated at 100° C. for 10 min
  4. customThe solvents were removed under a stream of nitrogen
  5. dissolutionthe residue dissolved in NH4OH (ca. 10 mL)
  6. additionLiCl (10%, ca. 10 mL) was added
  7. extractionthe aqueous extracted with DCM (3×10 mL)
  8. concentrationThe combined organic portions were concentrated under reduced pressure
  9. custompurified by preparative TLC (25×25 mm, silica gel 1 mm elution with hexane:EtOAc 4:1)

Sources & evidence

ORD record
ord-6d39f78ac34f4544873e3f8f733ac3d3
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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