Water → N-(4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide

HRID 334327Notes

Reaction equation

HRID 334327 reaction equation
[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[N:4]=1.C(N(CC)CC)C.[C:27]([CH2:31][C:32](Cl)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>C(OCC)(=O)C.COC(C)(C)C.CCCCCCC>[CH3:11][O:10][C:7]1[C:8]([NH:9][C:32](=[O:33])[CH2:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[N:6]=1

Participants

8

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 815143,3-Dimethylbutanoyl chlorideHCID 666531684,6-Dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-amine

Product 1

HCID 66653331N-(4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamideYield 78.7%

Reagents, catalysts & solvents 3

HCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a solution of 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-amine (36.97 g, 137.8 mmol), triethylamine (15.25 g, 21.0 mL, 150.7 mmol) in ethyl acetate (370 mL) was added tert-butylacetyl chloride (20.26 g, 21.0 mL, 150.5 mmol, 1.1 equiv) dropwise over 15 min. The resulting suspension was stirred overnight at RT, then poured into water, stirred 30 min, and subsequently transferred to a separatory funnel rinsing with ethyl acetate (100 mL). The organic extract was separated and washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to provide yellow-orange solids, which were taken up in 1:1 heptane: methyl tert-butylether (500 mL) and stirred at RT. The resulting suspension was filtered, and the solids were washed with 1:1 heptane: methyl tert-butylether (100 mL) and dried to afford 39.76 g of N-(4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, Example 1, as a white solid. 1H NMR (CDCl3) δ 6.14 (br. s., 1H) 4.23 (ddd, J=14.2, 5.7, 4.5 Hz, 2H) 3.87 (s, 6H) 3.40-3.48 (m, 1H) 3.39 (s, 3H) 3.37 (assumed ddd, J=13.5, 9.2, 3.3 Hz, 2H partially obscured by singlet) 2.20 (s, 2H) 1.83-1.99 (m, 2H) 1.47-1.61 (m, 2H) 1.10 (s, 9H). MS: (ESI) m/z=367.2 (M+1).

Workup

  1. stirringstirred 30 min
  2. customsubsequently transferred to a separatory funnel
  3. washrinsing with ethyl acetate (100 mL)
  4. extractionThe organic extract
  5. customwas separated
  6. washwashed with brine (100 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto provide yellow-orange solids, which
  11. filtrationThe resulting suspension was filtered
  12. washthe solids were washed with 1:1 heptane
  13. dry with materialmethyl tert-butylether (100 mL) and dried

Sources & evidence

ORD record
ord-c0e11c2581b8471fa88dd373dc4477d1
Source dataset
uspto-grants-2014_11
Patent number
US08883812B2

Reaction notes

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