Cesium fluoride → HCID 86722331, compound
Reaction equation
[CH2:1]([C@:3]12[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=12)[CH:13]=[N:12][N:11]3[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:2].[CH2:29]([C@@:31]12[CH2:55][CH2:54][C:53](=[O:56])[CH2:52][C@H:32]1[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]3[C:42](=[CH:43][C:44]=12)[CH:41]=[N:40][N:39]3[C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[CH3:30].[F-].[Cs+].C[Si](C)(C)[C:61]([F:64])([F:63])[F:62].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([C:61]([F:64])([F:63])[F:62])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=12)[CH:13]=[N:12][N:11]3[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH3:2].[CH2:29]([C@@:31]12[CH2:55][CH2:54][C@:53]([C:61]([F:64])([F:63])[F:62])([OH:56])[CH2:52][C@@H:32]1[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[C:38]3[C:42](=[CH:43][C:44]=12)[CH:41]=[N:40][N:39]3[C:45]1[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=1)[CH3:30]Participants
Conditions
- Temperature
- -50 °C
Procedure
A 3 necked round bottom flask with stir bar, nitrogen line, septum and thermometer was charged with (4aR,12bR)-12b-ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-1,2,4a,5,6,7,9,12b-octahydro-4H-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-one (10, R1=4-Fluorophenyl, R2=Ethyl) (0.41 g, 1.089 mmol) and DME (10 mL). Cesium fluoride (0.025 g, 0.163 mmol) was added, the mixture was stirred for about 10 min at rt, then cooled to an internal temperature of about −50° C. Trimethyl(trifluoromethyl)silane (0.275 g, 1.934 mmol) was added and the mixture was allowed to warm slowly to about 0° C. TBAF (1 M in THF, 1.2 mL, 1.2 mmol) was added and the mixture was warmed to rt. After about 1 h the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (25 mL) and water (35 mL). The organic layer was washed with water (3×25 mL) then brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (3S,4aS,12bR)-12b-Ethyl-9-(4-fluoro-phenyl)-3-trifluoromethyl-1,2,3,4,4a,5,6,7,9,12b-decahydro-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-ol; compound with (3R,4aR,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-3-trifluoromethyl-1,2,3,4,4a,5,6,7,9,12b-decahydro-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (Example 1) (0.395 g, 81%)); LC/MS, method 2, Rt=3.35 min, MS m/z 447 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.84-7.77 (m, 3H), 7.56 (s, 1H), 7.46-7.37 (m, 2H), 5.59 (s, 1H), 3.23-3.03 (m, 1H), 2.97-2.87 (m, 1H), 2.55-2.39 (m, 1H), 2.30-1.94 (m, 4H), 1.91-1.37 (m, 8H), 0.62 (t, J=7.4 Hz, 3H).
Workup
- stirringthe mixture was stirred for about 10 min at rt
- temperatureto warm slowly to about 0° C
- temperaturethe mixture was warmed to rt
- concentrationAfter about 1 h the mixture was concentrated under reduced pressure
- customThe residue was partitioned between EtOAc (25 mL) and water (35 mL)
- washThe organic layer was washed with water (3×25 mL)
- dry with materialbrine (25 mL), dried over MgSO4
- filtrationfiltered
- concentrationconcentrated under reduced pressure
- customThe residue was purified on silica gel (25 g)
- concentrationconcentrated under reduced pressure
Sources & evidence
- ORD record
- ord-4c2c1c52f00d45f99f3cf83539c47a12
- Source dataset
- uspto-grants-2015_11
- Patent number
- US09193744B2
Reaction notes
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