4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine → (2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

HRID 1398610Notes

Reaction equation

HRID 1398610 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>N1CCCCC1.C(#N)C.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>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C@:26]([C:23]4[N:22]=[C:21]([CH3:20])[O:25][N:24]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1

Participants

7

Reactant 2

HCID 681818784-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amineHCID 86669593(R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol2×

Product 1

HCID 60164849(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6342AcetonitrileSolventHCID 8082PiperidineSolvent

Conditions

Temperature
66 °C

Procedure

To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.

Workup

  1. temperaturewarming
  2. temperatureFollowing cooling to RT
  3. concentrationthe reaction mixture was concentrated in vacuo, DCM (10 mL)
  4. additionwas added
  5. customthe solution re-evaporated to dryness in vacuo (
  6. customre-evaporation process
  7. customPurification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol)
  8. customfurnished a brown oil which
  9. concentrationconcentrated in vacuo
  10. additionwas introduced acetonitrile until a fine cream precipitate
  11. customresulted
  12. filtrationFiltration

Sources & evidence

ORD record
ord-934c481953864fa9ab67e7cd22cfca12
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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