3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol → (2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(3,3-difluoro-2-hydroxy-2-methylpropyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

HRID 1398615Notes

Reaction equation

HRID 1398615 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH2:18][C:19]([CH3:24])([OH:23])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:27]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:34]#[C:33][C@:31]([C:28]4[N:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:15]=3)[C:10]([CH2:18][C:19]([OH:23])([CH3:24])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

6

Reactant 2

HCID 681817953-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-olHCID 86669593(R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol2×

Product 1

HCID 68181626(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(3,3-difluoro-2-hydroxy-2-methylpropyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 178418397HCID 178418397, compoundCatalyst2×HCID 8082PiperidineSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of 3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol (75 mg, 0.19 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for 1.5 hr under an atmosphere of nitrogen. After cooling to RT, the reaction mixture was re-treated with additional tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for a further 3 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, eluent 9:1 DCM/MeOH) furnished a partially purified product. Further purification by reverse phase preparative HPLC gave the title compound as a brown solid: 1H NMR (500 MHz, DMSO) delta 1.17 (3H, s), 1.90 (3H, s), 2.63 (3H, s), 3.09 (1H, d, J 14.2), 3.21 (1H, d, J 14.2), 5.50 (1H, s), 5.92 (1H, t, J 56.1), 6.78 (1H, s), 7.01 (2H, s), 7.08 (1H, d, J 5.5), 7.36 (1H, dd, J 8.3, 1.2), 7.94 (1H, d, J 8.3), 8.29 (1H, d, J 5.5), 8.89 (1H, s); LC-MS: m/z=+470.05 (M+H)+.

Workup

  1. temperatureAfter cooling to RT
  2. temperatureThe reaction mixture was warmed to 65° C. for a further 3 hr
  3. temperatureAfter cooling to RT
  4. concentrationthe reaction mixture was concentrated in vacuo
  5. customPurification of the residue by flash chromatography (Biotage, eluent 9:1 DCM/MeOH)
  6. customfurnished a partially purified product
  7. customFurther purification by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-7938184648434f16a7e368bb7ea9fc97
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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