Hydrochloric Acid → HCID 86722447, compound

HRID 718838Notes

Reaction equation

HRID 718838 reaction equation
[Br:1][C:2]1[C:3]([OH:18])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.Br[CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O.C1COCC1>[Br:1][C:2]1[C:3]([O:18][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 115533-Bromopropionic acid2×HCID 14798Sodium Hydroxide5×HCID 136348393HCID 136348393, compound

Product 1

HCID 86722447HCID 86722447, compoundYield 141.3%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

THF (100 mL) was added to a mixture of 7-bromo-1-(4-fluorophenyl)-1H-indazol-6-ol (4.54 g, 14.8 mmol) (97, R1=4-Fluorophenyl) and 3-bromopropionic acid (34.0 g, 222 mmol). The mixture was cooled to about 0° C. NaOH (2 M aqueous solution, 150 mL, 300 mmol) was added over about 15 min. The ice bath was removed. After about 15 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. 3-Bromopropanoic acid (6.00 g, 39.2 mmol) was added in portions over about 5 min. After about 6 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 14 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 2 h, NaOH (2 M aq. solution, 20.0 mL, 40.0 mmol) was added over about 5 min. After about 15 h, the solution was cooled to about 0° C. 2 M aq. HCl (250 mL) and EtOAc (400 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were washed with water (400 mL) and sat. aq. NaCl (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (220 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford a light tan solid. DCM (50 mL) was added. The solid was collected by filtration rinsing with 2×10 mL DCM (2×10 mL) then dried under reduced pressure to afford 3-((7-bromo-1-(4 fluorophenyl)-1H-indazol-6-yl)oxy)propanoic acid (98, R1=4-Fluorophenyl) (7.93 g, 30% yield) as an ivory solid. LC/MS, method 3, Rt=1.97 min, MS m/z 379 and 381 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.56-7.46 (m, 2H), 7.39-7.30 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 4.34 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H).

Workup

  1. customThe ice bath was removed
  2. waitAfter about 6 h
  3. waitAfter about 14 h
  4. waitAfter about 2 h
  5. waitAfter about 15 h
  6. temperaturethe solution was cooled to about 0° C
  7. customThe layers were separated
  8. extractionthe aqueous layer was extracted with EtOAc (100 mL)
  9. washThe combined organics were washed with water (400 mL) and sat. aq. NaCl (400 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe residue was purified on silica gel (220 g)
  14. additionThe fractions containing the product
  15. concentrationconcentrated under reduced pressure
  16. customto afford a light tan solid
  17. filtrationThe solid was collected by filtration
  18. washrinsing with 2×10 mL DCM (2×10 mL)
  19. customthen dried under reduced pressure

Sources & evidence

ORD record
ord-34a68a48ebbd42b79ee1c615941be3b2
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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