N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine → 2-((R)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrile

HRID 1754431Notes

Reaction equation

HRID 1754431 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.[O:21]1[CH2:25][CH2:24][C@@H:23]([O:26][C:27]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:28]=2[C:29]#[N:30])[CH2:22]1>CC(O)C>[NH3:3].[CH3:22][OH:21].[O:21]1[CH2:25][CH2:24][C@@H:23]([O:26][C:27]2[CH:34]=[CH:33][C:32]([NH:35][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:31][C:28]=2[C:29]#[N:30])[CH2:22]1

Participants

5

Reactant 2

HCID 86704443N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amineHCID 867044792-((R)-tetrahydrofuran-3-yloxy)-5-aminobenzonitrile

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 718114812-((R)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrileYield 189%

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), 2-((R)-tetrahydrofuran-3-yloxy)-5-aminobenzonitrile (191 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 2-((R)-tetrahydrofuran-3-yloxy)-5-(5-fluoro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidin-2-ylamino)benzonitrile (Compound 57) (two diastereomers; 295 mg, 95%) 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-f1b727ac31d14965bfe540861e17f353
Source dataset
uspto-grants-2015_10
Patent number
US09169249B2

Reaction notes

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