2-Amino-4,6-dichloropyrimidine → 4-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

Temperature

110 °C

(3R)-3-(1-Methylethyl)morpholine HCl salt (3.50 g, 21.1 mmol) and 4,6-dichloro-2-pyrimidinamine (3.81 g, 23.2 mmol, 1.1 equiv) were charged into a 60 mL sealable tube, followed with addition of 20 mL of propionitrile and Hunig's base (11.1 mL, 63.4 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 68 hours. The mixture was concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (150 mL). The aqueous was extracted with another 100 mL of EtOAc. The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo. The foamy residue was taken up in CHCl3 with some EtOAc to give a suspension, which was filtered. The solids collected were mostly starting 4,6-dichloro-2-pyrimidinamine. The filtrate underwent silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3 to afford the title compound (4.36 g) as a glassy foam. LC-MS (ES) m/z=257 [M+H]+.

1. customThe vessel was sealed
2. concentrationThe mixture was concentrated in vacuo
3. customthe residue was partitioned between water (50 mL) and EtOAc (150 mL)
4. extractionThe aqueous was extracted with another 100 mL of EtOAc
5. dry with materialThe combined organic was dried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto give a suspension, which
9. filtrationwas filtered
10. customThe solids collected
11. washelution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3

ORD record

ord-03722c7cdd59441b9f99fed6a915a209

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697685B2