Pyrimidine → 4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester

HRID 1159442Notes

Reaction equation

HRID 1159442 reaction equation
Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])[CH3:11].CC(C)([O-])C.[K+].N1C=CC=NC=1>O1CCCC1>[CH:10]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([O:22][C:2]2[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])[CH3:11]

Participants

6

Reactant 4

HCID 9260PyrimidineHCID 8188604,6-Dichloro-5-methylpyrimidineHCID 16745126Isopropyl 4-Hydroxypiperidine-1-carboxylateHCID 23665647Potassium tert-butoxide2×

Product 1

HCID 114933574-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl esterYield 96.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-12.5 °C

Procedure

4,6-Dichloro-5-methylpyrimidine (1) (2.4235 Kg, 1.000 equivalents) and 4-hydroxypiperidine-1-carboxylic acid isopropyl ester (2) (2.8182 Kg, 1.012 equivalents) were dissolved in tetrahydrofuran (THF, 25.0028 Kg), and the resulting solution was cooled to −15 to −10° C. To the cold solution, potassium-tert-butoxide in tetrahydrofuran (1 M, 12.6051 Kg, 0.9399 equivalents) was added at a rate sufficiently slow to maintain the reaction mixture below 0° C. with reactor jacket cooling. The reaction mixture was then stirred at about −5° C. for about 2 hours before an additional portion of potassium-tert-butoxide in tetrahydrofuran (1 M, 0.5692 Kg, 0.0424 equivalents) was added to achieve >97% conversion of the pyrimidine after an additional hour of stirring at about −5° C. Most of the solvent was then removed by distillation at 30-65° C., ≦80 torr. Addition of water (19.9681 Kg) to the evaporation residue precipitated the product. Distillative removal of THF was then completed at 30-65° C., ≦80 torr, and the resulting stirred slurry was cooled to 0° C. for an hour. The solids were then collected by suction filtration, washed with water (8.011 Kg, 4° C.), and vacuum dried to constant weight at 50° C., ≦40 torr to provide product (3) (4.491 Kg, 96.3% yield).

Workup

  1. temperatureto maintain the reaction mixture below 0° C. with reactor jacket
  2. temperaturecooling
  3. additionwas added
  4. customMost of the solvent was then removed by distillation at 30-65° C.
  5. additionAddition of water (19.9681 Kg) to the evaporation residue
  6. customprecipitated the product
  7. customDistillative removal of THF
  8. customwas then completed at 30-65° C.
  9. stirring≦80 torr, and the resulting stirred slurry
  10. temperaturewas cooled to 0° C. for an hour
  11. filtrationThe solids were then collected by suction filtration
  12. washwashed with water (8.011 Kg, 4° C.), and vacuum
  13. customdried to constant weight at 50° C.

Sources & evidence

ORD record
ord-9e3da39ece9d42a9838e5af8ce7aaf72
Source dataset
uspto-grants-2010_10
Patent number
US07812159B2

Reaction notes

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