Isopropanol → 5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-(4-isopropylpiperazin-1-yl)benzonitrile

HRID 633451Notes

Reaction equation

HRID 633451 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H: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]([N:30]2[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28].C[CH:40]([OH:42])C>>[NH3:3].[CH3:40][OH:42].[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH:36]([CH3:38])[CH3:37])[CH2:32][CH2:31]4)=[C:26]([CH:29]=3)[C:27]#[N:28])[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2

Participants

5

Reactant 3

HCID 3776IsopropanolHCID 612969195-Amino-2-(4-isopropylpiperazin-1-yl)benzonitrileHCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 867045405-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-(4-isopropylpiperazin-1-yl)benzonitrileYield 71%

Procedure

A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (163 mg, 0.546 mmol, 1.0 equiv), 5-amino-2-(4-isopropylpiperazin-1-yl)benzonitrile (200 mg, 0.819 mmol, 1.5 equiv), and PTSA monohydrate (208 mg, 1.09 mmol, 2.0 equiv) in IPA (5 mL) was heated to reflux for 2 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 1×, 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 95:5 using 1% 2M NH3/MeOH increments to give Compound 138 (195 mg, 71% yield) as a solid.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 2 days
  3. concentrationthe crude mixture was concentrated to dryness
  4. customThe layers were separated
  5. washThe organic layer was washed with 1N NaOH 1×
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe crude product was purified by flash chromatography
  10. washeluted with DCM

Sources & evidence

ORD record
ord-d8c98ba4ec104a079b04b571468b3b11
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

Loading…