Hydrochloric Acid → 4-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochloride

HRID 422043Notes

Reaction equation

HRID 422043 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[C:18]([CH3:30])[CH:17]=1)=O.[NH2:32][C:33]([NH2:35])=[O:34].[ClH:36].O1CCOCC1>C(O)C>[ClH:36].[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])[NH:35][C:33](=[O:34])[N:32]=2)=[CH:17][C:18]=1[CH3:30]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 1176UreaHCID 312751,4-DioxaneHCID 666727301-(2-{[2-(Methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione

Product 1

HCID 1363568074-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochlorideYield 19%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione (0.24 g, 0.56 mmol), urea (0.34 g, 5.6 mmol), 4.0M hydrochloric acid in dioxane (1.4 mL, 5.6 mmol) in ethanol (2 mL) was heated in a 110° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (10% methanol) and aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This crude mixture was taken up in 2.0 mL trifluoroacetic acid and heated in an 80° C. oil bath for 1 hour then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid), followed by concentration in vacuo, treatment with methanol and 4.0 M hydrochloric acid in dioxane, and lyophilization gave the title compound 4-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochloride (0.037 g, 19%). 1H NMR (400 MHz, d6-DMSO): 11.07 (s, 1H), 8.01 (d, 1H), 7.92 (dd, 1H), 7.74 (dd, 1H), 7.63 (dt, 1H), 7.47 (s, 1H), 7.29 (d, 1H), 7.19 (dt, 1H), 7.10 (d, 1H), 4.29 (m, 2H), 3.71 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H). MS (EI) for C20H20N2O4: 352 (MH+).

Workup

  1. concentrationwas concentrated in vacuo
  2. customThe residue was partitioned between ethyl acetate (10% methanol) and aqueous saturated sodium bicarbonate
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (2×)
  5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. temperatureheated in an 80° C. oil bath for 1 hour
  9. concentrationthen concentrated
  10. customPurification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid)
  11. concentrationfollowed by concentration in vacuo, treatment with methanol and 4.0 M hydrochloric acid in dioxane, and lyophilization

Sources & evidence

ORD record
ord-fa993180b3eb4355b195e0f93064df74
Source dataset
uspto-grants-2012_01
Patent number
US08101625B2

Reaction notes

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