Potassium Phosphate, Tribasic → 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(5-isopropyl-1H-indazol-4-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine

HRID 80827Notes

Reaction equation

HRID 80827 reaction equation
Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][N:7]([C:13]3[N:17]([CH3:18])[N:16]=[C:15]([CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:22]([C:25]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2)([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Cl-].[Na+].O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([C:15]2[CH:14]=[C:13]([N:7]3[CH2:6][CH2:5][C:4]4[N:3]=[C:2]([C:26]5[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:33][CH:32]=[C:31]6[C:27]=5[CH:28]=[N:29][NH:30]6)[CH:11]=[C:10]([CH3:12])[C:9]=4[CH2:8]3)[N:17]([CH3:18])[N:16]=2)[CH2:21][CH2:20]1

Participants

9

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 712406515-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleHCID 866902762-chloro-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine

Product 1

HCID 712405116-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(5-isopropyl-1H-indazol-4-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

Microwave was used to irradiated a solution of 2-chloro-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (30 mg, 0.099 mmol), crude 5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (38.2 mg, 0.119 mmol), Pd(PPh3)4 (11.45 mg, 9.91 μmol) and K3PO4 (42.1 mg, 0.198 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.05 mL) at 130° C. for 1 h under nitrogen. Additional Pd(PPh3)4 (22.90 mg, 0.020 mmol) was added to the mixture. Microwave was irradiated to the mixture at 130° C. for further 2 h under nitrogen. The mixture was diluted with brine and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/MeOH=100:0 to 10:1) to give 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(5-isopropyl-1H-indazol-4-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine: 1H NMR (400 MHz, CDCl3) δ ppm 9.98 (br s, 1 H), 7.76 (d, J=0.76 Hz, 1H), 7.45-7.51 (m, 2 H), 7.12 (s, 1 H), 5.65 (s, 1 H), 4.11 (s, 2 H), 3.75 (s, 3 H), 3.30-3.33 (app t, 2 H), 3.15-3.24 (m, 3 H), 2.30 (s, 3 H), 1.87-1.94 (m, 1 H), 1.25 (d, J=7.07 Hz, 6 H), 0.89-0.94 (m, 2 H), 0.72-0.76 (m, 2 H); MS (ESI+) m/z 427.33 (M+H)+.

Workup

  1. customMicrowave was irradiated to the mixture at 130° C. for further 2 h under nitrogen
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/MeOH=100:0 to 10:1)

Sources & evidence

ORD record
ord-ccc514d6341a460db714794252b03abd
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Reaction notes

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