Potassium Carbonate → 5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-4-[4-(1H-indazol-6-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525189Notes

Reaction equation

HRID 525189 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][N:36]=[CH:35]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:40]5[CH:39]=[C:38]6[C:34]([CH:35]=[N:36][NH:37]6)=[CH:33][CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 177504691H-Indazole-5-boronic acid pinacol esterHCID 67355143HCID 67355143, compound

Product 1

HCID 673758655-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-4-[4-(1H-indazol-6-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 26%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.186 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 9.80 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (50 mg, 0.205 mmol)) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.7 mL, 1.400 mmol) was stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was adjusted to pH˜6-6.5 using 1N aq HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-90% acetonitrile/water+0.1% NH4OH) provided the title compound as a white solid (20 mg, 26%). MS(ES)+ m/e 415.2 [M+H]+.

Workup

  1. customIn a microwave vial purged with nitrogen
  2. customThe layers were separated
  3. extractionThe aqueous layer was extracted with ethyl acetate (2×30 mL)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customPurification of the residue by reverse phase HPLC (10-90% acetonitrile/water+0.1% NH4OH)

Sources & evidence

ORD record
ord-730c2beee8174cafa73a16135579f875
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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