Triethylamine → (E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate

HRID 563380Notes

Reaction equation

HRID 563380 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](O)=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 8471TriethylamineHCID 8821Ethyl Acrylate2×HCID 67749Trifluoromethanesulfonic anhydrideHCID 592527721-(4-fluorophenyl)-6-methyl-1H-indazol-5-ol

Product 1

HCID 86640303(E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylateYield 54%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalyst2×HCID 1049PyridineSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

(a)(b) 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-ol [(484 mg, 2.0 mmol; prepared as described in Example 105(c)] was dissolved in DCM (20 mL) and pyridine was added (0.16 mL, 2 mmol) followed by triflic anhydride (0.36 mL, 2.1 mmol). After 1 h, the reaction was washed with 1 M HCl and the aqueous layer was dried over MgSO4, filtered, and concentrated. The crude 1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yltrifluoromethanesulfonate was taken up in 20 mL DMF, transferred to a stainless steel pressure bomb, and treated with ethyl acrylate (200 mg, 2 mmol), triethylamine (0.28 mL, 2 mmol), and Pd(PPh3)2Cl2 (160 mg, 0.2 mmol) and heated at 110° C. for 6 h. The reaction was incomplete so additional ethyl acrylate (200 mg, 2 mmol) and Pd(PPh3)2Cl2 (160 mg, 0.2 mmol) was added and the reaction was sealed and heated for 16 h. The reaction was cooled, diluted with EtOAc, washed with brine, and the organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by MPLC using SiO2 and a 1:9 EtOAc/hexane to 1:1 gradient. Obtained 350 mg (54% yield, 2 steps) of (E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate. MS found: (M+H)+=325.

Workup

  1. customprepared
  2. washthe reaction was washed with 1 M HCl
  3. dry with materialthe aqueous layer was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. additionwas added
  7. customthe reaction was sealed
  8. temperatureheated for 16 h
  9. temperatureThe reaction was cooled
  10. washwashed with brine
  11. dry with materialthe organic phase was dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified by MPLC

Sources & evidence

ORD record
ord-830026aadcbc449cb4ac117c1208f06f
Source dataset
uspto-grants-2011_11
Patent number
US08067447B2

Reaction notes

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