N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine → HCID 71811483, compound

HRID 1754433Notes

Reaction equation

HRID 1754433 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[CH2:34][O: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[CH2:34][O:33][CH2:32]3)=[C:26]([CH:29]=2)[C:27]#[N:28])=[N:3][CH:4]=1

Participants

5

Reactant 2

HCID 86704443N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amineHCID 86704481HCID 86704481, compound

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 71811483HCID 71811483, compoundYield 107.7%

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; 200 mg, 0.669 mmol, 1 equiv), 5-amino-2-(oxetan-3-yloxy)benzonitrile (178 mg, 0.937 mmol, 1.4 equiv), and PTSA monohydrate (127 mg, 0.669 mmol, 1 equiv) in IPA (7 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-(oxetan-3-yloxy)benzonitrile (Compound 63)(Racemic, single enantiomer; 163 mg, 54%) 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-9bfb488031c648cba1241da53ed35ebe
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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