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

HRID 1811595Notes

Reaction equation

HRID 1811595 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 103.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
7.5 °C

Procedure

A solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (71.0 g, 380 mmol) and 4,6-dichloro-5-methoxypyrimidine (71.6 g, 400 mmol) in anhydrous THF (1 L) was cooled to 5° C. under N2. A solution of potassium t-butoxide (1.0 M in THF, 380 mL, 380 mmol) was added dropwise over 1 h. The reaction temperature was kept under 10° C. during addition. The reaction mixture was stirred at 5-10° C. for 1 h, quenched with saturated NH4Cl (200 mL), and diluted with ether (1 L) and water (1 L). The aqueous phase was separated and discarded. The organic extract was washed with brine (800 mL), dried over MgSO4, and then concentrated. The residue was dissolved in hexane (400 mL) and filtered over Celite™ to remove a small amount of brown solid. The solvent was removed from the filtrate to afford a pale amber oil which gradually crystallized to give the title compound (130 g, 98.6% yield) as a pale amber solid. Exact Mass calculated for C14H20ClN3O4: 329.1. Found: LCMS m/z=330.2 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J=6.2 Hz, 6H), 1.82 (m, 2H), 2.02 (m, 2H), 3.40 (m, 2H), 3.80 (m, 2H), 3.91 (s, 3H), 4.95 (m, 1H), 5.39 (m, 1H), 8.27 (s, 1H).

Workup

  1. additionThe reaction temperature was kept under 10° C. during addition
  2. customquenched with saturated NH4Cl (200 mL)
  3. additiondiluted with ether (1 L) and water (1 L)
  4. customThe aqueous phase was separated
  5. extractionThe organic extract
  6. washwas washed with brine (800 mL)
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in hexane (400 mL)
  10. filtrationfiltered over Celite™
  11. customto remove a small amount of brown solid
  12. customThe solvent was removed from the filtrate
  13. customto afford a pale amber oil which
  14. customgradually crystallized

Sources & evidence

ORD record
ord-3b458d2e4abd457ab7a439f845c173e9
Source dataset
uspto-grants-2013_01
Patent number
US08362248B2

Reaction notes

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