Tetrahydrofuran → (4S)-5-(4-Fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-3,4-dihydrospiro[chromen-2,1'-cyclobutan]-4-ol

HRID 1516747Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1516747
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]([F: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]([CH:37]([F: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

Komponenten

5

Edukt 3

HCID 8028Tetrahydrofuran2×HCID 2725045(1R,2S)-(+)-cis-1-Amino-2-indanolHCID 580029745-(4-Fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1'-cyclobutan]-4(3H)-one

Produkt 1

HCID 58002989(4S)-5-(4-Fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-3,4-dihydrospiro[chromen-2,1'-cyclobutan]-4-ol

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Versuchsvorschrift

Under argon, 0.6 mg (0.004 mmol) of (1R,2S)-1-aminoindan-2-ol is dissolved in 0.5 ml of abs. tetrahydrofuran, 27.5 μl (0.15 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 20 mg (0.04 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 59A), dissolved in 1 ml of abs. tetrahydrofuran, are then added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 3 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 thick-layer chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This is followed by further purification by preparative HPLC. This gives 5.3 mg (26% of theory) of the title compound as a mixture of diastereomers.

Aufarbeitung

  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 thick-layer chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1)
  9. customThis is followed by further purification by preparative HPLC
  10. additionThis gives 5.3 mg (26% of theory) of the title compound as a mixture of diastereomers

Quellen und Nachweise

ORD-Eintrag
ord-1233189df13c42dcba432c879d347a28
Quelldatensatz
uspto-grants-2012_07
Patentnummer
US08227511B2

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