methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate → methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate

HRID 350910Notes

Reaction equation

HRID 350910 reaction equation
[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8](SC)[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1>CN(C)C(=O)C.[Ni]>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1

Participants

4

Reactant 1

HCID 21090186methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate

Product 1

HCID 21090188methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoateYield 81.5%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (87 g, 0.20 mol) was dissolved in N,N-dimethylacetamide (870 mL) and heated to 80° C. Raney Ni was added and slight exotherm and off-gasing were observed. Reaction was complete. Heat and stirring were turned off. Since product had begun to precipitate from the cooled reaction mixture, heat was turned back on to 70° C. and stirring resumed. After redissolving the precipitate, the reaction mixture was allowed to cool for 15 min and then filtered through celite. Rinsed with 50° C. DMA and water, being careful not to let the celite pad go dry. The filtrate was added to 2 L of water and stirred. Product filtered, rinsed with water, and dried in the vacuum oven. When found to still be wet with DMA, slurried with water and stirred 1 h before filtering and redrying. Obtained the product as a white solid (63 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.28 (s, 1H), 8.04 (m, 1H), 7.90 (s, 1H), 7.55 (m, 2H), 6.99 (m, 2H), 5.87 (s, 1H), 5.39 (s, 2H), 3.88 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 387.1195 (M+H calculated for C20H17F2N2O4 requires 387.1151).

Workup

  1. customReaction
  2. temperatureHeat
  3. customto precipitate from the cooled reaction mixture
  4. temperatureheat
  5. customwas turned back on to 70° C.
  6. stirringstirring
  7. dissolutionAfter redissolving the precipitate
  8. temperatureto cool for 15 min
  9. filtrationfiltered through celite
  10. washRinsed with 50° C
  11. customgo dry
  12. additionThe filtrate was added to 2 L of water
  13. stirringstirred
  14. filtrationProduct filtered
  15. washrinsed with water
  16. customdried in the vacuum oven
  17. stirringstirred 1 h
  18. filtrationbefore filtering
  19. customredrying

Sources & evidence

ORD record
ord-fb031777574d471b983cf09a2c350664
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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