Pyridine → HCID 86722390, compound

HRID 718792Notes

Reaction equation

HRID 718792 reaction equation
N1C=CC=CC=1.[CH2:7]([C:9]12[CH2:33][CH2:32][C:31]([C:35]([F:38])([F:37])[F:36])(O)[CH2:30][CH:10]1[CH2:11][CH2:12][CH2:13][C:14]1[C:15]2=[CH:16][C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]=2[CH:22]=1)[CH3:8].S(Cl)(Cl)=O>>[CH2:7]([C:9]12[CH2:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH2:30][CH:10]1[CH2:11][CH2:12][CH2:13][C:14]1[C:15]2=[CH:16][C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]=2[CH:22]=1)[CH3:8].[CH2:7]([C:9]12[CH2:33][CH2:32][C:31]([C:35]([F:37])([F:38])[F:36])=[CH:30][CH:10]1[CH2:11][CH2:12][CH2:13][C:14]1[C:15]2=[CH:16][C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]=2[CH:22]=1)[CH3:8]

Participants

5

Reactant 3

HCID 1049PyridineHCID 24386Thionyl ChlorideHCID 86722391HCID 86722391, compound

Product 2

HCID 86722389HCID 86722389, compoundHCID 86722390HCID 86722390, compoundYield 50%

Conditions

Temperature
80 °C

Procedure

To a vessel containing pyridine (0.886 g, 11.2 mmol) was added rac-(3S,4aS,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]indazol-3-ol (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.100 g, 0.224 mmol), and thionyl chloride (0.480 g, 4.03 mmol). The reaction was warmed to about 80° C. for about 3 h. The reaction was cooled to rt, slowly quenched with sat. aq. NaHCO3 (10 mL) and then extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-30% EtOAc in heptane. The product fractions were concentrated to give about a 2.5:1 mixture of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole and rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole as a colorless oil (0.048 g, 50% yield). LC/MS, method 3, Rt=3.21 min.; MS m/z: 429 (M+H)+. Potassium osmate dihydrate (0.081 g, 0.22 mmol) and 4-methylmorpholine N-oxide (0.771 g, 6.58 mmol) were added sequentially, each in one portion, to a biphasic solution of a mixture of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole and rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (0.940 g, 2.194 mmol), THF (15 mL), and water (7.5 mL). After about 20 h, potassium osmate dihydrate (0.081 g, 0.22 mmol) and 4-methylmorpholine N-oxide (0.771 g, 6.58 mmol) were added sequentially, each in one portion. The reaction was warmed to about 40° C. for about 30 h. The reaction was allowed to cool to rt and after about 3 days at rt, water (300 mL) was added. The solution was extracted with DCM (2×200 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-15% EtOAc in DCM. The product fractions were concentrated under reduced pressure to afford rac-(3R,4S,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-3,4-diol (52, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.520 g, 51% yield) LC/MS, method 3, Rt=2.71 min.; MS m/z: 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.85-7.78 (m, 2H), 7.71 (s, 1H), 7.60 (s, 1H), 7.44-7.37 (m, 2H), 5.48 (s, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.30-3.27 (m, 1H), 3.12-2.98 (m, 2H), 2.46-2.36 (m, 1H), 2.28-2.16 (m, 2H), 2.15-2.04 (m, 1H), 1.96-1.77 (m, 3H), 1.77-1.42 (m, 4H), 0.59 (t, J=7.3 Hz, 3H) and rac-(2R,3S,4aS,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 (51, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.280 g, 27%, yield) LC/MS, method 3, Rt=2.74 min.; MS m/z: 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.87-7.75 (m, 3H), 7.59 (s, 1H), 7.45-7.36 (m, 2H), 5.52 (s, 1H), 4.96 (d, J=6.6 Hz, 1H), 4.11-3.99 (m, 1H), 3.09-2.93 (m, 2H), 2.56-2.51 (m, 1H), 2.35-2.17 (m, 2H), 2.16-2.03 (m, 1H), 1.83-1.71 (m, 1H), 1.71-1.58 (m, 2H), 1.54-1.20 (m, 4H), 0.61 (t, J=7.3 Hz, 3H).

Workup

  1. temperatureThe reaction was cooled to rt
  2. customslowly quenched with sat. aq. NaHCO3 (10 mL)
  3. extractionextracted with EtOAc (3×10 mL)
  4. dry with materialThe combined organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified on silica gel (12 g)
  8. concentrationThe product fractions were concentrated

Sources & evidence

ORD record
ord-13e6d249b4344c93870b76e6e973a02d
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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