N-Methylpiperidine → 4,6-Bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide

HRID 2082030Notes

Reaction equation

HRID 2082030 reaction equation
[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](O)=[O:17])[N:6]=1)([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].CN1CCCCC1>ClCCl.CN(C)C=O>[CH3:15][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:4])([CH3:1])[CH3:3])[N:6]=[C:7]([C:16]([N:27]([O:28][CH3:29])[CH3:26])=[O:17])[N:8]=1)([CH3:14])[CH3:13]

Participants

7

Reactant 4

HCID 12291N-MethylpiperidineHCID 65578Oxalyl chlorideHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 152753184,6-Ditert-butyl-5-hydroxy-2-pyrimidinecarboxylic acid

Product 1

HCID 100401704,6-Bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamideYield 58.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a slurry of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid (6.20 g, 24.6 mmol) and N,N-dimethylformamide (0.10 mL, 1.3 mmol) in dichloromethane (200 mL) at ~0° C. under nitrogen atmosphere is added oxalyl chloride (3.30 mL, 37.8 mmol) dropwise. The resulting mixture is stirred 1 hour at 0° C., warmed to room temperature, and stirred an additional 2 hours. The solvent is removed under vacuum and tetrahydrofuran (200 mL) added to the residue. This mixture is cooled to ~0° C. and a solution of N,O-dimethyl-hydroxylamine hydrochloride (2.64 g, 27.1 mmol) and 1-methylpiperidine (3.30 mL, 27.2 mmol) in dichloromethane (100 mL) is added dropwise. After warming to room temperature, the mixture is stirred 16 hours, diluted with dichloromethane (200 mL), and washed with aqueous 0.1N HCl, saturated sodium bicarbonate, and brine solutions. The organic layer is concentrated and the residue recrystallized from ethyl acetate and hexane to give 4.26 g (58%) of the title compound, mp 137°-138° C.

Workup

  1. temperaturewarmed to room temperature
  2. stirringstirred an additional 2 hours
  3. customThe solvent is removed under vacuum and tetrahydrofuran (200 mL)
  4. additionadded to the residue
  5. temperatureThis mixture is cooled to ~0° C.
  6. temperatureAfter warming to room temperature
  7. stirringthe mixture is stirred 16 hours
  8. washwashed with aqueous 0.1N HCl, saturated sodium bicarbonate, and brine solutions
  9. concentrationThe organic layer is concentrated
  10. customthe residue recrystallized from ethyl acetate and hexane

Sources & evidence

ORD record
ord-7c828ef320284f1ca2fecf8494506ff5
Source dataset
uspto-grants-1993_02
Patent number
US05187175

Reaction notes

Loading…