Tetrahydrofuran → (4S)-5-(4-fluorophenyl)-6-{(R)-hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-3,4-di-hydrospiro[chromen-2,1'-cyclobutan]-4-ol

HRID 1516746Notes

Reaction equation

HRID 1516746 reaction equation
N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:52])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:48])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:51])[CH3:52])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1

Participants

5

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 2725045(1R,2S)-(+)-cis-1-Amino-2-indanolHCID 580029385-(4-Fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1'-cyclobutan]-4(3H)-one

Product 1

HCID 58003031(4S)-5-(4-fluorophenyl)-6-{(R)-hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-3,4-di-hydrospiro[chromen-2,1'-cyclobutan]-4-ol

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Under argon, 1.5 mg (0.01 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 1.5 ml of abs. tetrahydrofuran, 69 μl (0.39 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 50 mg (0.10 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 2 ml of methanol are added, and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 13.5 mg (27% of theory, 78% ee) of Example 38 and 16.5 mg (33% of theory) of Example 39.

Workup

  1. stirringthe mixture is then stirred at room temperature overnight
  2. stirringthe mixture is stirred for 15 min
  3. concentrationconcentrated to dryness
  4. washwashed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution
  5. dry with materialThe organic phase is dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1)

Sources & evidence

ORD record
ord-3bbc83b2593644ddb45b84a0358c2a5d
Source dataset
uspto-grants-2012_07
Patent number
US08227511B2

Reaction notes

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