Tetrahydrofuran → (2R,4R,5S,7R)-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraene-4,5-diol;(2S,4S,5R,7S)-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraene-4,5-diol

HRID 718808Notes

Reaction equation

HRID 718808 reaction equation
[BH4-].[Na+].[CH2:3]([C@:5]12[CH2:29][C:28](=[O:30])[C@@:27]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:26][C@@H:6]1[CH2:7][CH2:8][CH2:9][C:10]1[C:11]2=[CH:12][C:13]2[CH:14]=[N:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17]=2[CH:18]=1)[CH3:4].[CH2:36]([C@@:38]12[CH2:62][C:61](=[O:63])[C@:60]([OH:68])([C:64]([F:67])([F:66])[F:65])[CH2:59][C@H:39]1[CH2:40][CH2:41][CH2:42][C:43]1[C:44]2=[CH:45][C:46]2[CH:47]=[N:48][N:49]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[C:50]=2[CH:51]=1)[CH3:37].C1COCC1>CO>[CH2:3]([C@:5]12[CH2:29][C@H:28]([OH:30])[C@:27]([C:31]([F:34])([F:33])[F:32])([OH:35])[CH2:26][C@@H:6]1[CH2:7][CH2:8][CH2:9][C:10]1[C:11]2=[CH:12][C:13]2[CH:14]=[N:15][N:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:17]=2[CH:18]=1)[CH3:4].[CH2:36]([C@@:38]12[CH2:62][C@@H:61]([OH:63])[C@@:60]([C:64]([F:67])([F:66])[F:65])([OH:68])[CH2:59][C@H:39]1[CH2:40][CH2:41][CH2:42][C:43]1[C:44]2=[CH:45][C:46]2[CH:47]=[N:48][N:49]([C:52]3[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=3)[C:50]=2[CH:51]=1)[CH3:37]

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 4311764Sodium borohydrideHCID 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-one

Product 1

HCID 86722418(2R,4R,5S,7R)-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraene-4,5-diol;(2S,4S,5R,7S)-2-ethyl-14-(4-fluorophenyl)-5-(trifluoromethyl)-14,15-diazatetracyclo[9.7.0.02,7.013,17]octadeca-1(11),12,15,17-tetraene-4,5-diolYield 54%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

NaBH4 (0.060 g, 1.6 mmol) was added in one portion to a solution of (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) (0.500 g, 1.09 mmol), THF (4.0 mL), and MeOH (8.0 mL). After about 30 min, the volatiles were removed under reduced pressure. Sat. aq. NH4Cl (20 mL), water (20 mL) and DCM (50 mL) were added. 2 M aq. HCl was added dropwise to adjust to about pH 1. After stirring vigorously for about 15 min, the layers were separated and the organic layer was washed with 40 mL of sat. aq. NaCl (40 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (80 g) using a gradient of 10-50% EtOAc in heptane. The fractions containing the first eluting diastereomer were combined and concentrated under reduced pressure to afford (2R,3S,4aR,12bR)-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-2,3-diol; compound with (2S,3R,4aS,12bS)-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-2,3-diol (71, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl, R3′=Hydroxyl, R3″═H) (0.270 g, 54% yield) as an ivory solid. LC/MS, method 2, Rt=2.84 min, MS m/z 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.28 (d, J=0.7 Hz, 1H), 7.84 (s, 1H), 7.84-7.76 (m, 2H), 7.60 (s, 1H), 7.46-7.35 (m, 2H), 5.37 (d, J=5.3 Hz, 1H), 5.30 (s, 1H), 3.99-3.90 (m, 1H), 3.38-3.23 (m, 1H), 2.96-2.85 (m, 1H), 2.46-2.29 (m, 2H), 2.07-1.73 (m, 4H), 1.73-1.63 (m, 1H), 1.63-1.45 (m, 3H), 1.44-1.27 (m, 1H), 0.53 (t, J=7.3 Hz, 3H). The fractions containing the second eluting diastereomer were combined and concentrated under reduced pressure to afford (2S,3 S,4aR,12bR)-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-2,3-diol; compound with (2R,3R,4aS,12bS)-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-2,3-diol (71, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl, R3′═H, R3″=Hydroxyl) (0.171 g, 34% yield) as an ivory solid. LC/MS, method 2, Rt=2.61 min, MS m/z 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.30 (d, J=0.8 Hz, 1H), 7.82 (s, 1H), 7.89-7.75 (m, 2H), 7.55 (s, 1H), 7.46-7.35 (m, 2H), 5.82 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.89-3.78 (m, 1H), 3.21-3.08 (m, 1H), 2.99-2.88 (m, 1H), 2.36-2.26 (m, 1H), 2.21-2.08 (m, 2H), 2.03-1.93 (m, 1H), 1.89-1.58 (m, 6H), 1.43-1.25 (m, 1H), 0.45 (t, J=7.3 Hz, 3H).

Workup

  1. customthe volatiles were removed under reduced pressure
  2. additionSat. aq. NH4Cl (20 mL), water (20 mL) and DCM (50 mL) were added
  3. addition2 M aq. HCl was added dropwise
  4. customthe layers were separated
  5. washthe organic layer was washed with 40 mL of sat. aq. NaCl (40 mL)
  6. dry with materialThe combined organics were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified on silica gel (80 g)
  10. additionThe fractions containing the first eluting diastereomer
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-0826216b969c40989fb1d4c977995f4c
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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