Acetic Acid → 5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

HRID 1617437Notes

Reaction equation

HRID 1617437 reaction equation
[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](F)(F)F)[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9](I)[C:8](=[O:13])[NH:7][C:6]1=[O:14].[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.[OH-].[Na+].C(O)(=O)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:9]1[C:8](=[O:13])[NH:7][C:6](=[O:14])[N:5]([CH2:4][C:3]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:10]=1[CH3:11]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 426062771-[2-fluoro-6-(trifluoromethyl)benzyl]-5-iodo-6-methylpyrimidine-2,4(1H,3H)-dioneHCID 450369072-(2-Chloro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Product 1

HCID 582393035-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dioneYield 70%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
45 °C

Procedure

Compound 1b (80 g, 0.19 mol), 7a (60.22 g, 0.22 mol), HP(t-Bu)3BF4 (13.01 g, 44.85 mmol), and Pd2(dba)3 (13.69 g, 14.95 mmol) were charged to the reaction vessel and purged with an inert atmosphere. Degassed THF (560 mL) was added followed by NaOH (31.45 g, 0.56 mol) in degassed water (128.8 mL) and the reaction warmed to 45° C. After 2 hours acetic acid (56 mL) was added and stirred for 15 minutes. After settling, the layers were separated and the organic layer was filtered through celite, rinsing with hot THF (2×160 mL). The filtrate was concentrated in vacuo to a slurry, to which was added N-acetyl cysteine (15.84 g) as a solution in water (160 mL) and ethanol (640 mL) and stirred for 2 hours at 75° C. under an inert atmosphere. The slurry was cooled to RT, and the solids filtered off, washed with ethanol:water (8:2, 2×160 mL) to give 5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 7b as a white solid (58.6 g, 0.13 mol, 70%).

Workup

  1. custompurged with an inert atmosphere
  2. additionDegassed THF (560 mL) was added
  3. customthe layers were separated
  4. filtrationthe organic layer was filtered through celite
  5. washrinsing with hot THF (2×160 mL)
  6. concentrationThe filtrate was concentrated in vacuo to a slurry, to which
  7. additionwas added N-acetyl cysteine (15.84 g) as a solution in water (160 mL)
  8. stirringethanol (640 mL) and stirred for 2 hours at 75° C. under an inert atmosphere
  9. temperatureThe slurry was cooled to RT
  10. filtrationthe solids filtered off
  11. washwashed with ethanol:water (8:2, 2×160 mL)

Sources & evidence

ORD record
ord-38fd1da5b8d64dacb745b2229c790798
Source dataset
uspto-grants-2014_07
Patent number
US08765948B2

Reaction notes

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