3,5-Bis(trifluoromethyl)benzylamine → (+/-)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester

HRID 507075Notes

Reaction equation

HRID 507075 reaction equation
[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]([O:20][C:21]([N:23]1[C:36]2[C:28](=[CH:29][C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=2)[C:27](=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH:17]([O:20][C:21]([N:23]1[C:36]2[C:28](=[CH:29][C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=2)[CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18]

Participants

6

Reactant 3

HCID 5210993,5-Bis(trifluoromethyl)benzylamineHCID 4311764Sodium borohydrideHCID 593791389-oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester

Product 1

HCID 86615658(+/-)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl esterYield 61.1%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolvent

Procedure

Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 mmol) followed by titanium isopropoxide (835 mg, 2.94 mmol) to 9-oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (200 mg, 0.7 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 3 days. Add methanol (3 mL) and sodium borohydride (40 mg, 1.05 mmol) and stir the mixture under nitrogen at room temperature for 16 h. Add sodium bicarbonate saturated solution, filter through Celite® and wash the residue with ethyl acetate. Separate organic layer, extract aqueous with ethyl acetate. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by silica cartridge, eluting with hexanes/ethyl acetate 9:1, to afford (+/−)-isopropyl-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (220 mg).

Workup

  1. filtrationAdd sodium bicarbonate saturated solution, filter through Celite®
  2. washwash the residue with ethyl acetate
  3. extractionSeparate organic layer, extract aqueous with ethyl acetate
  4. dry with materialWash organic layer with brine and dry the organic layers over anhydrous sodium sulfate
  5. filtrationFilter
  6. customremove the solvent under reduced pressure
  7. customPurify the residue by silica cartridge
  8. washeluting with hexanes/ethyl acetate 9:1

Sources & evidence

ORD record
ord-9a2b696be53846d0a2581e29323bd085
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

Loading…