Morpholine → 1-isopropyl-6-morpholino-1H-indazole-4-carboxylic acid

HRID 85452

Reaction equation

HRID 85452 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC(C)([O-])C.[Na+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>[Pd].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:12])[CH3:13]

Participants

6

Reactant 3

HCID 8083MorpholineHCID 23676156Sodium t-butoxideHCID 67464993Methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate

Product 1

HCID 674682821-isopropyl-6-morpholino-1H-indazole-4-carboxylic acidYield 47.3%

Reagents, catalysts & solvents 2

HCID 131731914Pd XPhos precatalystCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
98 °C

Procedure

In a 25 mL sealable tube under nitrogen were combined methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (250 mg, 0.84 mmol), sodium tert-butoxide (178 mg, 1.85 mmol), Pd-XPhos precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]Pd(II); Me-t-butylether adduct) (34.8 mg, 0.042 mmol) and morpholine (81 mg, 0.93 mmol) in Dioxane (4 mL). The resulting mixture was degassed with nitrogen for 10 minutes. The vessel was sealed and the mixture was heated at 98° C. for 20 hours. The contents were diluted with water and 1N HCl was added to adjust the pH˜3-4. The contents were extracted with EtOAc and DCM/isopropanol (8:2), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM and purified by SiO2 chromatography (eluent: Hexanes/EtOAc gradient 0 to 100% EtOAc). Fractions were evaporated and solids were dried to afford the title compound as a light yellow solid (115 mg, 46%). LC-MS (ES) m/z=290.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1H) 8.18 (s, 1H) 7.56 (d, J=2.02 Hz, 1H) 7.26-7.29 (m, 1H) 5.00 (quin, J=6.57 Hz, 1H) 3.77-3.81 (m, 4H) 3.22-3.26 (m, 4H) 1.46 (s, 3H) 1.44 (s, 3H)

Workup

  1. customIn a 25 mL sealable tube under nitrogen were combined
  2. customThe resulting mixture was degassed with nitrogen for 10 minutes
  3. customThe vessel was sealed
  4. additionThe contents were diluted with water and 1N HCl
  5. additionwas added
  6. extractionThe contents were extracted with EtOAc and DCM/isopropanol (8:2)
  7. washthe combined organic layers were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. dissolutionThe residue was dissolved in DCM
  12. custompurified by SiO2 chromatography (eluent: Hexanes/EtOAc gradient 0 to 100% EtOAc)
  13. customFractions were evaporated
  14. customsolids were dried

Sources & evidence

ORD record
ord-157007e98a8f4c6eab9716e8a2574c5e
Source dataset
uspto-grants-2014_09
Patent number
US08846935B2

Linked notes

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