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

HRID 718804Notes

Reaction equation

HRID 718804 reaction equation
[O-]CC.[Na+].[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.[CH:66](=O)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CC(O)=O.CCO>[CH:33](=[C:30]1/[CH2:31][C@:7]2([CH2:5][CH3:6])[C:20]3=[CH:19][C:18]4[CH:17]=[N:16][N:15]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[C:14]=4[CH:13]=[C:12]3[CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:28][C:29]/1=[O:32])/[C:35]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:36]=1.[CH:66](=[C:58]1/[CH2:59][C@@:35]2([CH2:33][CH3:34])[C:48]3=[CH:47][C:46]4[CH:45]=[N:44][N:43]([C:49]5[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=5)[C:42]=4[CH:41]=[C:40]3[CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:56][C:57]/1=[O:60])/[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1

Participants

7

Reactant 4

HCID 240BenzaldehydeHCID 8028TetrahydrofuranHCID 2723922Sodium ethoxide2×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-one

Product 1

HCID 131734190(2R,4E,7R)-4-benzylidene-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,4E,7S)-4-benzylidene-2-ethyl-14-(4-fluorophenyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-oneYield 59%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

Freshly prepared sodium ethoxide (1 M solution in EtOH, 3.00 mL, 3.00 mmol) was added 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]indazol-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 (4aR,12bR)-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) (0.750 g, 1.99 mmol), THF (6.50 mL) and EtOH (13.0 mL) under a nitrogen atmosphere. Benzaldehyde (0.220 mL, 2.17 mmol) was added. After about 3 h, sodium ethoxide (1 M solution in EtOH, 3.00 mL, 3.00 mmol) was added. After about 15 h, the mixture was warmed to about 60° C. After about 30 min, the mixture was allowed to cool to rt. AcOH (0.500 mL) was added. The volatiles were removed under reduced pressure. Water (25 mL) and DCM (50 mL) were added. The layers were separated and the organics were washed with sat. aq. NaCl (25 mL) then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (80 g) using a gradient of 0-25% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford (4aR,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3(2H)-one; compound with (4aS,12bS,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3(2H)-one (68, R1=4-Fluorophenyl, R2=Ethyl) (0.545 g, 59% yield) as an ivory solid. LC/MS, method 3, Rt=3.05 min, MS m/z 465 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.81-7.74 (m, 2H), 7.67-7.62 (m, 2H), 7.62-7.53 (m, 4H), 7.53-7.45 (m, 2H), 7.44-7.35 (m, 2H), 3.37-3.32 (m, 2H), 3.28-3.17 (m, 1H), 2.98-2.87 (m, 1H), 2.62-2.43 (m, 2H), 2.38-2.25 (m, 1H), 2.16-1.89 (m, 3H), 1.75-1.64 (m, 1H), 1.51-1.23 (m, 2H), 0.19 (t, J=7.2 Hz, 3H).

Workup

  1. waitAfter about 15 h
  2. waitAfter about 30 min
  3. temperatureto cool to rt
  4. customThe volatiles were removed under reduced pressure
  5. additionWater (25 mL) and DCM (50 mL) were added
  6. customThe layers were separated
  7. washthe organics were washed with sat. aq. NaCl (25 mL)
  8. dry with materialthen dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified on silica gel (80 g)
  12. additionThe fractions containing product
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f3579d2339bb4ccb96f26377d0da098e
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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