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

HRID 718806Notes

Reaction equation

HRID 718806 reaction equation
C(=[C:8]1/[CH2:9][C@@:10]2([CH2:38][CH3:39])[C:16]3=[CH:17][C:18]4[CH:19]=[N:20][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:22]=4[CH:23]=[C:15]3[CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:31][C@:32]/1([C:34]([F:37])([F:36])[F:35])[OH:33])/C1C=CC=CC=1.C(=[C:47]1/[CH2:48][C@:49]2([CH2:77][CH3:78])[C:55]3=[CH:56][C:57]4[CH:58]=[N:59][N:60]([C:63]5[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=5)[C:61]=4[CH:62]=[C:54]3[CH2:53][CH2:52][CH2:51][C@H:50]2[CH2:70][C@@:71]/1([C:73]([F:76])([F:75])[F:74])[OH:72])/C1C=CC=CC=1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH2:38]([C@:10]12[CH2:9][C:8](=[O:72])[C@@:32]([OH:33])([C:34]([F:36])([F:35])[F:37])[CH2:31][C@@H:11]1[CH2:12][CH2:13][CH2:14][C:15]1[C:16]2=[CH:17][C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:22]=2[CH:23]=1)[CH3:39].[CH2:77]([C@@:49]12[CH2:48][C:47](=[O:33])[C@:71]([OH:72])([C:73]([F:75])([F:74])[F:76])[CH2:70][C@H:50]1[CH2:51][CH2:52][CH2:53][C:54]1[C:55]2=[CH:56][C:57]2[CH:58]=[N:59][N:60]([C:63]3[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=3)[C:61]=2[CH:62]=1)[CH3:78]

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 11776TriphenylphosphineHCID 86722415(2R,4E,5S,7R)-4-benzylidene-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-ol;(2S,4E,5R,7S)-4-benzylidene-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-5-ol

Product 1

HCID 86722412(2R,5S,7R)-2-ethyl-14-(4-fluorophenyl)-5-hydroxy-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-4-one;(2S,5R,7S)-2-ethyl-14-(4-fluorophenyl)-5-hydroxy-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraen-4-oneYield 88%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A solution of (3R,4aS,12bS,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3-ol; compound with (3S,4aR,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3-ol (69, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.489 g, 0.915 mmol), DCM (13.5 mL), and MeOH (1.5 mL) was cooled to −78° C. while purging with O2. After about 10 min, ozone was bubbled through the reaction for about 14 min. The solution was purged with oxygen for about 10 min. Polymer bound triphenylphosphine (3 mmol/g, 0.915 g, 3.50 mmol) was added in one portion. The reaction mixture was allowed to warm to rt over about 30 min. After about 3 h, the mixture was filtered rinsing with DCM. The organic volatiles were removed under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford (3S,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,3,4,4a,5,6,7,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-2(9H)-one; compound with (3R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,3,4,4a,5,6,7,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-2(9H)-one (70, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.371 g, 88% yield) as an ivory solid. LC/MS, method 2, Rt=2.93 min, MS m/z 461 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.86-7.74 (m, 3H), 7.58 (s, 1H), 7.47-7.35 (m, 2H), 6.62 (s, 1H), 3.27-3.19 (m, 1H), 3.18-3.04 (m, 2H), 3.00-2.90 (m, 1H), 2.41-2.18 (m, 3H), 2.06-1.94 (m, 1H), 1.91-1.74 (m, 3H), 1.46-1.16 (m, 2H), 0.41 (t, J=7.3 Hz, 3H).

Workup

  1. customwhile purging with O2
  2. customozone was bubbled through the reaction for about 14 min
  3. customThe solution was purged with oxygen for about 10 min
  4. additionwas added in one portion
  5. waitAfter about 3 h
  6. filtrationthe mixture was filtered
  7. washrinsing with DCM
  8. customThe organic volatiles were removed under reduced pressure
  9. customThe residue was purified on silica gel (40 g)
  10. additionThe fractions containing product
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-fad222a917e04cc38ef066f7740ce7cd
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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