Propionitrile → 4-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

HRID 2367506Notes

Reaction equation

HRID 2367506 reaction equation
Cl.[CH3:2][CH:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1.C(#N)CC.CCN(C(C)C)C(C)C>>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][C@H:5]2[CH:3]([CH3:4])[CH3:2])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1

Participants

5

Reactant 4

HCID 7854PropionitrileHCID 81531DiisopropylethylamineHCID 2598804,6-Dichloro-n-methylpyrimidin-2-amineHCID 66990572(3R)-3-(propan-2-yl)morpholine hydrochloride

Product 1

HCID 585044624-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamineYield 44.3%

Conditions

Temperature
110 °C

Procedure

(3R)-3-(1-Methylethyl)morpholine hydrochloride salt (3.0 g, 18.11 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (3.22 g, 18.11 mmol, 1 equiv) were charged into a 60 mL sealable tube, followed with addition of propionitrile (25 mL) and Hunig's base (9.49 mL, 54.3 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 96 hours. The mixture was concentrated in vacuo. The residue was partitioned between cold 2N HCl (100 mL) and EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The acidic aqueous phase was basified with 6N NaOH to pH=10, followed by extraction with EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark brownish oil. Both samples were purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3. The combined fractions were concentrated in vacuo. The residue was dried under vacuum at room temperature for 7 hours to give the title compound (2.17 g). LC-MS (ES) m/z=271 [M+H]+.

Workup

  1. customThe vessel was sealed
  2. concentrationThe mixture was concentrated in vacuo
  3. customThe residue was partitioned between cold 2N HCl (100 mL) and EtOAc (2×100 mL)
  4. dry with materialThe organic was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. extractionfollowed by extraction with EtOAc (2×100 mL)
  8. dry with materialThe organic was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto give a dark brownish oil
  12. customBoth samples were purified by silica gel column chromatography
  13. washelution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3
  14. concentrationThe combined fractions were concentrated in vacuo
  15. customThe residue was dried under vacuum at room temperature for 7 hours

Sources & evidence

ORD record
ord-211e0c9326ac4c82aea843fc35e13029
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

Loading…