2-Fluoro-3-methoxyphenylboronic acid → 5-(2-Fluoro-3-methoxyphenyl)-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methyl-2,4(1H,3H)-pyrimidinedione

HRID 1049106Notes

Reaction equation

HRID 1049106 reaction equation
[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[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].[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[OH-].[K+].O>CC(C)=O>[F: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]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:10]=1[CH3:11]

Participants

5

Reactant 3

HCID 49857442-Fluoro-3-methoxyphenylboronic acidHCID 23719240Potassium hydroxide monohydrateHCID 426062771-[2-fluoro-6-(trifluoromethyl)benzyl]-5-iodo-6-methylpyrimidine-2,4(1H,3H)-dione

Product 1

HCID 671055715-(2-Fluoro-3-methoxyphenyl)-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methyl-2,4(1H,3H)-pyrimidinedioneYield 83.3%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
15 °C

Procedure

To a reactor was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (20.0 kg), 2-fluoro-3-methoxyphenylboronic acid (8.7 kg), and acetone (60 L). The mixture was agitated and cooled to 15° C. and a potassium hydroxide/water solution (10.8 kg/64 L) was charged. The reactor contents were degassed for 30 min, then tri-t-butylphosphonium tetrafluoroborate (142 g) was added to the reactor and the contents mixed at 45° C. for 20 min. Palladium (II) acetate (52 g) was charged to the reactor and the contents were mixed at 55° C. The reaction mixture was stirred until the reaction was complete. Acetic acid (5.6 kg) was charged to the reactor over 1 hr, then the mixture was stirred at 55° C. for 30 min. The reactor contents were cooled to 25° C. over 2 hr. The solid was collected by centrifugation and the cake washed with water (40 L) followed by methanol (80 L). The solid was dried in a vacuum oven at 50° C. until the loss-on-drying was less than 1% to provide 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.6 kg, 83% molar yield) as an off-white solid. LCMS (ESI) m/z 427.1 (MH+).

Workup

  1. customThe reactor contents were degassed for 30 min
  2. additiontri-t-butylphosphonium tetrafluoroborate (142 g) was added to the reactor
  3. additionthe contents mixed at 45° C. for 20 min
  4. additionPalladium (II) acetate (52 g) was charged to the reactor
  5. additionthe contents were mixed at 55° C
  6. stirringThe reaction mixture was stirred until the reaction
  7. additionAcetic acid (5.6 kg) was charged to the reactor over 1 hr
  8. stirringthe mixture was stirred at 55° C. for 30 min
  9. temperatureThe reactor contents were cooled to 25° C. over 2 hr
  10. customThe solid was collected by centrifugation
  11. washthe cake washed with water (40 L)
  12. customThe solid was dried in a vacuum oven at 50° C. until the loss-on-drying

Sources & evidence

ORD record
ord-af42faa5c05b40df9885bbd41dc5c9eb
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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