5-amino-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile → 5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile

HRID 633370Notes

Reaction equation

HRID 633370 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:26]([CH:29]=1)[C:27]#[N:28]>CC(O)C>[NH3:3].[CH3:25][OH:30].[F:20][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:26]([CH:29]=2)[C:27]#[N:28])=[N:3][CH:4]=1

Participants

5

Reactant 2

HCID 612971185-amino-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrileHCID 86704443N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 718113925-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrileYield 150.9%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (Racemic, single diastereomer; 150 mg, 0.502 mmol, 1 equiv), 5-amino-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (153 mg, 0.703 mmol, 1.4 equiv), and PTSA monohydrate (95 mg, 0.502 mmol, 1 equiv) in IPA (5 ml) were heated to 70° C. for 3 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness and taken in water, EtOAc, and 1N NaOH. The layers were separated. The organic layer was washed with 1N NaOH (×2), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 96:4 using 1% 2M NH3/MeOH increments to give compound 5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (Compound 41)(Racemic, single diastereomer; 182 mg, 76%) as a solid.

Workup

  1. temperatureAfter cooling to ambient temperature
  2. concentrationthe crude mixture was concentrated to dryness
  3. customThe layers were separated
  4. washThe organic layer was washed with 1N NaOH (×2)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was purified by flash chromatography
  9. washeluted with DCM

Sources & evidence

ORD record
ord-43d9c86a6a9848b4bb2943ef7eab914f
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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