4,6-Dichloro-5-methoxypyrimidine → Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate

HRID 1811546Notes

Reaction equation

HRID 1811546 reaction equation
[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([O:21][CH3:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:19]2[C:20]([O:21][CH3:22])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 787204,6-Dichloro-5-methoxypyrimidineHCID 16745126Isopropyl 4-Hydroxypiperidine-1-carboxylateHCID 23665647Potassium tert-butoxide

Product 1

HCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylateYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (3.15 g, 17 mmol) and 4,6-dichloro-5-methoxy-pyrimidine (3.00 mg, 17 mmol) in 15 ml of THF, IM potassium-t-butoxide in THF (18.4 ml, 18.4 mmol) was added dropwise at 0° C. After 45 min, the crude mixture was extracted with CH2Cl2 and brine. Organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1→1:1 v/v) to provide 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (4.7 g, 85%). 1HNMR (CDCl3, 400 MHz) δ 1.24-1.28 (d, 6H), 1.80-1.84 (m, 2H), 2.00-2.05 (m, 2H), 3.37-3.44 (m, 2H), 3.77-3.81 (m, 2H), 3.91 (s, 3H), 4.92-4.95 (m, 1H), 5.38-5.40 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C14H20ClN3O4 329.11. found 330.1 (MH+).

Workup

  1. extractionthe crude mixture was extracted with CH2Cl2 and brine
  2. dry with materialOrganic phase was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1→1:1 v/v)

Sources & evidence

ORD record
ord-ed7c7aa687284a49987a67215eaf2f6e
Source dataset
uspto-grants-2013_01
Patent number
US08362248B2

Reaction notes

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