Sodium Carbonate → HCID 86722396, compound

HRID 718797Notes

Reaction equation

HRID 718797 reaction equation
Br[C:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[C@:18]3([CH2:32][CH3:33])[CH2:26][CH2:25][C@@:24]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:23][C@H:19]3[CH2:20][CH2:21][CH2:22][C:3]=12.[CH3:34]B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH2:32]([C@@:18]12[CH2:26][CH2:25][C@@:24]([C:28]([F:30])([F:31])[F:29])([OH:27])[CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C:3]1[C:4]2=[CH:5][C:6]2[CH:7]=[N:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:10]=2[C:2]=1[CH3:34])[CH3:33]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 139377Methylboronic AcidHCID 86722394HCID 86722394, compound

Product 1

HCID 86722396HCID 86722396, compound

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-CH2Cl2 adduct (0.012 g, 0.015 mmol) was added to a mixture of (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]indazole-3-ol (58, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0393 g, 0.0750 mmol), methylboronic acid (0.0090 g, 0.15 mmol), Na2CO3 (0.020 g, 0.19 mmol), 1,4-dioxane (0.400 mL), and water (0.100 mL) under a nitrogen atmosphere. The reaction vessel was evacuated then back-filled with nitrogen three times. The mixture was warmed to about 80° C. for about 9 h. After cooling to rt, water (2 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Synergy Max-RP column) using a gradient of 10-95% MeCN in aqueous NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-8-methyl-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (59, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0119 g, 34% yield) of a fluffy white solid. LC/MS, method 2, Rt=2.85 mM, MS m/z 461 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 7.70 (s, 1H), 7.56-7.47 (m, 2H), 7.40-7.31 (m, 2H), 5.84 (bs, 1H), 3.23-3.12 (m, 1H), 2.87-2.73 (m, 1H), 2.42-2.26 (m, 1H), 2.22-1.51 (m, 10H), 2.03 (s, 3H), 1.31-1.11 (m, 2H), 0.46 (t, J=7.4 Hz, 3H).

Workup

  1. customThe reaction vessel was evacuated
  2. additionthen back-filled with nitrogen three times
  3. temperatureAfter cooling to rt
  4. additionwater (2 mL) and EtOAc (5 mL) were added
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with EtOAc (5 mL)
  7. dry with materialThe combined organics were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified on silica gel (12 g)
  11. additionThe fractions containing product
  12. concentrationconcentrated under reduced pressure
  13. customThe residue was purified by reverse phase HPLC (Synergy Max-RP column)
  14. additionThe fractions containing product
  15. concentrationconcentrated under reduced pressure
  16. customto remove the organic volatiles
  17. temperatureThe resulting mixture was frozen

Sources & evidence

ORD record
ord-af8bd4560d92498c9f6864d0beda7028
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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