Water → 4-(3,5-DI-Tert-butyl-4-hydroxyphenyl)-2-methoxy-N-methylpyrimidine-5-carboxamide

HRID 2039752Notes

Reaction equation

HRID 2039752 reaction equation
S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[CH3:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15].[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[K+].O.[CH3:24][CH:25]([OH:27])[CH3:26]>C(O)(C)(C)C.ClCCl.C(OCC)(=O)C>[CH3:11][NH:12][C:13]([C:14]1[C:17]([C:18]2[CH:21]=[C:26]([C:18]([CH3:21])([CH3:19])[CH3:17])[C:25]([OH:27])=[C:24]([C:18]([CH3:21])([CH3:19])[CH3:17])[CH:19]=2)=[N:10][C:8]([O:7][CH3:6])=[N:9][CH:15]=1)=[O:16]

Participants

9

Reactant 5

HCID 962WaterHCID 3776IsopropanolHCID 14470N-MethylpropanamideHCID 169039Carbamimidic acid, methyl ester, sulfate (1:1)HCID 23665647Potassium tert-butoxide

Product 1

HCID 1360590354-(3,5-DI-Tert-butyl-4-hydroxyphenyl)-2-methoxy-N-methylpyrimidine-5-carboxamideYield 32.8%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

O-methylisourea hydrogensulfate (3.44 g, 20 mmol) was added to a solution of 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-3-oxo-2-(dimethylamino)methylene]-propanoic acid methyl amide (3.55 g, 9.84 mmol) in 2-propanol (37.5 mL). The suspension was stirred at room temperature for 10 min then a 1 M solution of potassium tert. butoxide in tert. butanol (37.5 mL) was added and the mixture was immersed into a bath maintained at 80° C. and stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then distributed between dichloromethane (150 mL) and water (75 mL). The organic layer was washed with water (2×50 mL), once with brine (10 mL), dried over magnesium sulfate and evaporated. The residue obtained was dissolved in dichloromethane and flash-chromatographed using DCM, 1:19, 1:9, and 1:3 ethyl acetate-dichloromethane, followed by ethyl acetate as mobile phases. Early fraction eluted 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl amide, which is the solvolysis product of the starting material; the title compound was eluted using 1:3 ethyl acetate-dichloromethane. The fractions containing the product were evaporated; the residue redissolved in hot DCM, diluted with cyclohexane then heated to remove some DCM and allowed to crystallize. The solids obtained were redissolved in ethyl acetate, the solution filtered, concentrated, diluted with cyclohexane and allowed to crystallize to give white crystals. The solids were filtered off, washed with cyclohexane and hexane, and dried to constant weight at 55° C. and 20 torr to afford 1.20 g of the title compound (32.8% yield). TLC (ethyl acetate), Rf 0.68, 1H-NMR (300 MHz, DMSO-d6) δ 1.40 (9H, s), 2.75 (3H, d, J=3.9 Hz), 3.98 (3H, s), 7.55 (1H, s), 7.69 (2H, s), 8.44 (1H br s), 8.49 (1H, s).

Workup

  1. customthe mixture was immersed into a bath
  2. temperaturemaintained at 80° C.
  3. stirringstirred for 4 hours
  4. temperatureto cool to ambient temperature
  5. washThe organic layer was washed with water (2×50 mL), once with brine (10 mL)
  6. dry with materialdried over magnesium sulfate
  7. customevaporated
  8. customThe residue obtained
  9. customflash-chromatographed
  10. washEarly fraction eluted 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl amide, which
  11. washthe title compound was eluted
  12. additionThe fractions containing the product
  13. customwere evaporated
  14. dissolutionthe residue redissolved in hot DCM
  15. additiondiluted with cyclohexane
  16. temperaturethen heated
  17. customto remove some DCM
  18. customto crystallize
  19. customThe solids obtained
  20. filtrationthe solution filtered
  21. concentrationconcentrated
  22. additiondiluted with cyclohexane
  23. customto crystallize
  24. customto give white crystals
  25. filtrationThe solids were filtered off
  26. washwashed with cyclohexane and hexane
  27. customdried to constant weight at 55° C.

Sources & evidence

ORD record
ord-2225563a1d2646a9a1d1a9a910f617d8
Source dataset
uspto-grants-2013_11
Patent number
US08580805B2

Reaction notes

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