Tetrahydrofuran → HCID 57705999, compound
Reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH:18]([OH:23])[C:19]([CH3:21])([CH3:20])[CH3:22]Participants
Procedure
To a stirred solution of 1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanone T4.5 (2.00 g, 6.3 mmol) in THF (63 mL, 6.3 mmol) at 0° C. was added LAH (1.0 M in THF, 13 mL, 13 mmol). The reaction was then stirred for 2 hours. 1N NaOH (aq) was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to afford 1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol T4.6 (1.50 g, 75% yield) as a white solid. MS ESI (pos.) m/e: 336.2 (M+H2O)+. Chiral separation of T.4.6 was accomplished on a CHIRALCEL® OD column (4% IPA in hexane) to provide T4.7 and T4.8. Both enantiomers were used to synthesize example compounds, and both enantiomers gave active example compounds. However, the enantiomer corresponding to peak 2 (T4.8) provided the most active example compounds. Analytical column (CHIRALCEL® OD column (4% IPA in hexane, 45 min run) Peak 1-18.5 mins, Peak 2-24.5 mins).1
Workup
- extractionthe resulting mixture was extracted with EtOAc
- dry with materialdried over MgSO4
- filtrationfiltered
- concentrationconcentrated in vacuo
- customThe residue was purified by silica gel flash chromatography (0-30% EtOAc/hexane)
Sources & evidence
- ORD record
- ord-cf2ae176ed404f76964eeea159e4672e
- Source dataset
- uspto-grants-2014_06
- Patent number
- US08748462B2
Reaction notes
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