1H-Indazole-6-boronic acid → 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

HRID 1854801Notes

Reaction equation

HRID 1854801 reaction equation
Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B(O)O)[CH:27]=2)[CH:22]=[N:21]1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(Cl)Cl.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>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[CH:27]=2)[CH:22]=[N:21]1

Participants

8

Reactant 2

HCID 247286171H-Indazole-6-boronic acidHCID 866424656-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine

Product 1

HCID 462396696-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amineYield 39.1%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
135 °C

Procedure

A mixture of impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (195 mg), from above, and 1H-indazol-6-ylboronic acid (159 mg, 0.650 mmol) in 1 M aqueous sodium carbonate (1.3 mL) and 1,4-dioxane (3.5 mL) was sparged with nitrogen while stirring for 5 min. Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol) was then added and the resulting mixture heated under microwave irradiation at 135° C. for 30 min. After this time, the reaction was diluted with methylene chloride (30 mL) and water (20 mL), and filtered through diatomaceous earth. The filtrate layers were separated and the aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol), then trituration with acetonitrile to afford 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (5) (85 mg, 35%) as a yellow solid: mp >250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.75 (dd, J=8.7, 1.2 Hz, 1H), 7.62 (s, 1H), 4.52 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); ESI MS m/z 359.4 [M+H]+; HPLC, 5.37 min, >99% (AUC).

Workup

  1. filtrationfiltered through diatomaceous earth
  2. customThe filtrate layers were separated
  3. extractionthe aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL)
  4. concentrationThe combined organic layers were concentrated under reduced pressure
  5. customthe resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol)

Sources & evidence

ORD record
ord-41d7cac932c245c3b26a2457681d966a
Source dataset
uspto-grants-2015_02
Patent number
US08962835B2

Reaction notes

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