Methyl iodide → 3-[(2-Chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol

To a solution of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-methyl-4-pyrimidinamine (Example 340, 5.00 g, 15.8 mmol) in DMF (60 mL) was added portionwise NaH (0.95 g, 60% dispersion in mineral oil, 23.7 mmol) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (1.97 mL, 31.7 mmol) was added. After 3 h of stirring at rt, the excess NaH was quenched by the slow addition of a saturated solution of NH4Cl [H2 evolution]. The product was extracted with Et2O. The combined organic layers were then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using a pad of silica gel (3:1 hexanes/EtOAc) and the desired fractions were concentrated under reduced pressure. The resulting silyl derivative was dissolved in a mixture of ethanol (46 mL) and HCl (4.2 mL of a 2 N aqueous solution), and stirred at rt until the reaction was complete (6-10 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes/EtOAc) to yield the title compound (1.22 g, 62%). 1H NMR (400 MHz, CDCl3) δ 1.83 (qt, 2H), 2.32 (s, 3H), 3.19 (s, 3H), 3.56 (t, 2H), 3.69 (t, 2H), 7.70 (s, 1H).

1. stirringAfter 3 h of stirring at rt
2. customthe excess NaH was quenched by the slow addition of a saturated solution of NH4Cl [H2 evolution]
3. extractionThe product was extracted with Et2O
4. dry with materialThe combined organic layers were then dried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customThe residue was purified
8. concentrationthe desired fractions were concentrated under reduced pressure
9. dissolutionThe resulting silyl derivative was dissolved in a mixture of ethanol (46 mL) and HCl (4.2 mL of a 2 N aqueous solution), and
10. stirringstirred at rt until the reaction
11. custom(6-10 h)
12. concentrationThe reaction mixture was then concentrated under reduced pressure
13. additiondiluted with EtOAc
14. washwashed with a saturated solution of NaHCO3 and brine
15. dry with materialThe organic layer was dried (MgSO4)
16. filtrationfiltered
17. concentrationconcentrated under reduced pressure
18. customThe residue was purified by silica gel chromatography (3:1 hexanes/EtOAc)

ORD record

ord-994501b421134d78a3e0e02617d7eaa2

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07906653B2