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 718755Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 718755
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]

Komponenten

9

Edukt 4

HCID 25517Ammonium ChlorideHCID 867223224-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acidHCID 86722332rac-(2'R,4aR,12bR)-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]HCID 178418443HCID 178418443, Verbindung

Produkt 1

HCID 86722336(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

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
-5 °C

Versuchsvorschrift

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)

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag
ord-d535bb80d15144ca88c2e8d8cb8d53da
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09193744B2

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