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

HRID 718802Notes

Reaction equation

HRID 718802 reaction equation
[C:1]([Mg]Br)#[CH:2].[CH2:5]([C@:7]12[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][C@H:8]1[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=12)[CH:17]=[N:16][N:15]3[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:6].[CH2:33]([C@@:35]12[CH2:59][CH2:58][C:57](=[O:60])[CH2:56][C@@H:36]1[CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[C:42]3[C:46](=[CH:47][C:48]=12)[CH:45]=[N:44][N:43]3[C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[CH3:34]>C1COCC1>[CH2:5]([C@:7]12[CH2:31][CH2:30][C@:29]([C:1]#[CH:2])([OH:32])[CH2:28][C@@H:8]1[CH2:9][CH2:10][CH2:11][C:12]1[C:20]2=[CH:19][C:18]2[CH:17]=[N:16][N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)[CH3:6].[CH2:33]([C@@:35]12[CH2:59][CH2:58][C@@:57]([C:1]#[CH:2])([OH:60])[CH2:56][C@H:36]1[CH2:37][CH2:38][CH2:39][C:40]1[C:48]2=[CH:47][C:46]2[CH:45]=[N:44][N:43]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:42]=2[CH:41]=1)[CH3:34]

Participants

4

Reactant 2

HCID 86722333(2R,7S)-2-ethyl-14-(4-fluorophenyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-one;(2S,7R)-2-ethyl-14-(4-fluorophenyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-oneHCID 178418486HCID 178418486, compound

Product 1

HCID 86722408(2R,5R,7R)-2-ethyl-5-ethynyl-14-(4-fluorophenyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-ol;(2S,5S,7S)-2-ethyl-5-ethynyl-14-(4-fluorophenyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-olYield 54%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Ethynylmagnesium bromide (0.5 M solution in THF, 6.00 mL, 3.00 mmol) was added dropwise over about 15 min to a mixture of (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3 (2H)-one; compound with (4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.200 g, 0.531 mmol) and THF (2.5 mL) under a nitrogen atmosphere at about 0° C. After about 90 min, the ice bath was removed and the solution was stirred at rt for about 1 h. Sat. aq. NH4Cl (10 mL) and water (10 mL) were added. The solution was extracted with DCM (2×20 mL). The combined organics were dried over Na2SO4 and filtered. Silica gel (2 g) was added and the organic volatiles were removed under reduced pressure. The resulting solid was purified on silica gel (12 g) using a gradient of 0-3% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-12b-ethyl-3-ethynyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol; compound with (3S,4aS,12bS)-12b-ethyl-3-ethynyl-9-(4-fluorophenyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Ethynyl) (0.116 g, 54% yield). LC/MS, method 2, Rt=2.78 min, MS m/z 403 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.7 Hz, 1H), 7.91 (s, 1H), 7.83-7.76 (m, 2H), 7.55 (s, 1H), 7.45-7.36 (m, 2H), 5.48 (s, 1H), 3.24 (s, 1H), 3.22-3.11 (m, 1H), 2.98-2.88 (m, 1H), 2.32-2.23 (m, 1H), 2.20-1.48 (m, 11H), 1.41-1.26 (m, 1H), 0.37 (t, J=7.3 Hz, 3H).

Workup

  1. customthe ice bath was removed
  2. additionSat. aq. NH4Cl (10 mL) and water (10 mL) were added
  3. extractionThe solution was extracted with DCM (2×20 mL)
  4. dry with materialThe combined organics were dried over Na2SO4
  5. filtrationfiltered
  6. additionSilica gel (2 g) was added
  7. customthe organic volatiles were removed under reduced pressure
  8. customThe resulting solid was purified on silica gel (12 g)
  9. additionThe fractions containing product
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-d5bb5ba6f4e14009b102c3fad73c6217
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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