Dimethylformamide → HCID 86722394, compound

HRID 718796Notes

Reaction equation

HRID 718796 reaction equation
C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C@@:11]12[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][CH2:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10].CN(C=O)C.C([O-])(O)=O.[Na+]>CC#N.O.CCOC(C)=O>[Br:8][C:24]1[C:23]2[N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:21]=[CH:20][C:19]=2[CH:18]=[C:17]2[C@:11]3([CH2:9][CH3:10])[CH2:35][CH2:34][C@@:33]([C:37]([F:40])([F:39])[F:38])([OH:36])[CH2:32][C@H:12]3[CH2:13][CH2:14][CH2:15][C:16]=12

Participants

8

Reactant 4

HCID 6228Dimethylformamide3×HCID 67184N-bromobutanimide3×HCID 516892Sodium BicarbonateHCID 86722395HCID 86722395, compound

Product 1

HCID 86722394HCID 86722394, compoundYield 69%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

NBS (0.052 g, 0.29 mmol) was added in one portion to a solution of (3R,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]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.100 g, 0.224 mmol) and DMF (2.20 mL) under a nitrogen atmosphere. The solution was warmed to about 60° C. for about 2 h. A solution of NBS (0.0040 g, 0.022 mmol) and DMF (0.10 mL) was added. After about 1 h, a solution of NBS (0.0040 g, 0.022 mmol) and DMF (0.10 mL) was added. After about 30 min, the light yellow solution was allowed to cool to rt. Sat. aq. NaHCO3 (5 mL), water (5 mL), and EtOAc (10 mL) were added. The layers were separated and the organics were washed with water (10 mL) and sat. aq. NaCl (10 mL). The aqueous layers were extracted with EtOAc (10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (12 g) using a gradient of 0-7% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford a sticky ivory solid. The residue was dissolved in MeCN, treated with water, and concentrated under reduced pressure to remove MeCN. The mixture was frozen then lyophilized to afford (3R,4aR,12bR)-8-bromo-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 (58, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0809 g, 69% yield) as a fluffy white solid. LC/MS, method 2, Rt=3.00 min, MS m/z 525 and 527 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.91 (s, 1H), 7.55-7.48 (m, 2H), 7.37-7.29 (m, 2H), 5.87 (s, 1H), 3.73-3.63 (m, 1H), 3.04-2.90 (m, 1H), 2.42-2.27 (m, 1H), 2.22-1.52 (m, 11H), 1.29-1.10 (m, 1H), 0.46 (t, J=7.3 Hz, 3H).

Workup

  1. waitAfter about 30 min
  2. temperatureto cool to rt
  3. customThe layers were separated
  4. washthe organics were washed with water (10 mL) and sat. aq. NaCl (10 mL)
  5. extractionThe aqueous layers were extracted with EtOAc (10 mL)
  6. dry with materialThe combined organics were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified on silica gel (12 g)
  10. additionThe fractions containing product
  11. concentrationconcentrated under reduced pressure
  12. customto afford a sticky ivory solid
  13. concentrationconcentrated under reduced pressure
  14. customto remove MeCN
  15. temperatureThe mixture was frozen

Sources & evidence

ORD record
ord-cd05cd4c68ff423aba096e9221ba76ad
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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