Ammonium Chloride → (2S,5R,7S)-2-ethyl-14-(4-fluorophenyl)-5-propyl-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-ol;(2R,5S,7R)-2-ethyl-14-(4-fluorophenyl)-5-propyl-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-ol

HRID 718755Notes

Reaction equation

F[C:2]1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=C[CH:3]=1.[CH2:23]([C:25]12[CH2:51][CH2:50][C:47]3([CH2:49][O:48]3)[CH2:46][CH:26]1[CH2:27][CH2:28][CH2:29][C:30]1[C:31]2=[CH:32][C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH:38]=1)[CH3:24].[CH2:52]([Mg]Br)[CH3:53].[NH4+].[Cl-]>[Cu]I.CCOC(C)=O.O.C1COCC1>[CH2:23]([C@:25]12[CH2:51][CH2:50][C@@:47]([CH2:49][CH2:2][CH3:3])([OH:48])[CH2:46][C@@H:26]1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[C:37]3[C:33](=[CH:32][C:31]=12)[CH:34]=[N:35][N:36]3[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH3:24].[CH2:23]([C@@:25]12[CH2:51][CH2:50][C@:47]([CH2:49][CH2:52][CH3:53])([OH:48])[CH2:46][C@H:26]1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[C:37]3[C:33](=[CH:32][C:31]=12)[CH:34]=[N:35][N:36]3[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH3:24]

Participants

Conditions

Temperature: -5 °C

Procedure

A 50 mL 3 necked round bottom flask with stir bar, nitrogen line, septum and thermometer was charged with rac-(2′R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane](14, R1=4-Fluorophenyl, R2=Ethyl) (0.225 g, 0.576 mmol), THF (10 mL) and copper(I) iodide (0.016 g, 0.086 mmol). The mixture was stirred for about 10 min then cooled to about −5° C. Ethylmagnesium bromide (3 M in ether, 0.576 mL, 1.73 mmol) was added keeping the internal temperature below about 0° C. After about 15 min sat. aqueous NH4Cl (3 mL), water (25 mL) and EtOAc (25 mL) were added to the mixture. The layers were separated then the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (3S,4aR,12bR)-12b-Ethyl-9-(4-fluoro-phenyl)-3-propyl-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,4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-3-propyl-1,2,3,4,4a,5,6,7,9,12b-decahydro-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-ol (16, R1=4-Fluorophenyl, R2=Ethyl, R3=Propyl) (Example 4) (0.187 g, 77%); LC/MS, method 2, Rt=3.84 min, MS m/z 421 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=0.6 Hz, 1H), 7.92 (s, 1H), 7.83-7.77 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 3.83 (s, 1H), 3.22-3.15 (m, 1H), 2.95-2.89 (m, 1H), 2.22-2.14 m, 1H), 2.12-1.93 (m, 3H), 1.88-1.71 (m, 2H), 1.68-1.59 (m, 1H), 1.56-1.48 (m, 2H), 1.44-1.24 (m, 8H), 0.88 (t, J=6.6 Hz, 3H), 0.35 (t, J=7.3 Hz, 3H)

Workup

customthe internal temperature below about 0° C
customThe layers were separated
dry with materialthe organic solution was dried over MgSO4
filtrationfiltered
concentrationconcentrated under reduced pressure
customThe residue was purified on silica gel (12 g)
concentrationconcentrated under reduced pressure

Sources & evidence

ORD record: ord-d535bb80d15144ca88c2e8d8cb8d53da
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09193744B2

Reaction notes

Loading…