Hydrochloric Acid → 6-Fluoro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indazole-3-carboxylic acid

HRID 338495Notes

Reaction equation

HRID 338495 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+].Cl>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].C1(C)C=CC=CC=1.C(O)C>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:25]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:26][CH:27]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 866988305,5-Dimethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxaborinaneHCID 866988325-bromo-6-fluoro-1H-indazole-3-carboxylic acid

Product 1

HCID 866988316-Fluoro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indazole-3-carboxylic acidYield 11%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 5-bromo-6-fluoro-1H-indazole-3-carboxylic acid (793 mg, 3.06 mmol), 5,5-dimethyl-2-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,3,2-dioxaborinane (839 mg, 3.06 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (175 mg, 0.214 mmol) were sealed in a vial and purged with nitrogen. Ethanol (4 mL), toluene (2 mL) and aqueous 2M potassium carbonate (3.67 ml, 7.34 mmol) were added and the mixture was heated at 110° C. for 50 minutes. The cooled reaction mixture was poured into dilute HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give crude material, which was purified using reverse-phase chromatography. The product was crystallized from isopropanol/hexane to give the title compound as a crystalline solid (110 mg, 11% yield). MS (ES−) 339.1 (M−H)−. 1H NMR (500 MHz, CD3OD) δ 8.34 (d, J=7.32 Hz, 1H), 7.54 (d, 2H), 7.35 (d, 2H), 7.27 (d, J=10.25 Hz, 1H), 4.08 (d, J=10.25 Hz, 2H), 3.61 (td, J=10.98, 3.42 Hz, 2H), 2.88 (m, 1H), 1.81-1.90 (m, 4H). m.p.=295° C.

Workup

  1. customwere sealed in a vial and
  2. custompurged with nitrogen
  3. customThe cooled reaction mixture
  4. extractionextracted with ethyl acetate
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give crude material, which
  9. customwas purified
  10. customThe product was crystallized from isopropanol/hexane

Sources & evidence

ORD record
ord-3ef7bc715c314907b5a87b22fed299b1
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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