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 1049107Notes

Reaction equation

HRID 1049107 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 87%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
25 °C

Procedure

To a reactor was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (5.0 kg), 2-fluoro-3-methoxyphenylboronic acid (2.58 kg), and acetone (5.5 L). The mixture was agitated and a potassium hydroxide/water solution (2.658 kg/19.0 L) was charged. The reactor contents were degassed for 30-60 min, then the internal temperature was adjusted to 40° C. 1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4 g) was added to the reactor and the contents mixed with jacket temperature set to 45° C. until the reaction was complete (2.5 hr). The reaction mixture was cooled to 20-30° C. Celite (1.25 kg) was charged to the reactor and stirred for more than one hour and the mixture was filtered through a Celite pad (0.51 kg). The reactor and Celite cake were washed with acetone/water/KOH (2.6 L/7.5 L/0.38 kg). The filtered solutions were passed through a line filter and added over a period of 1-1.5 hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L) maintained at 62° C. The reactor contents were cooled to 20° C. over 2-3 hr. The mixture was filtered and the cake washed with 60:40 water/MeOH (2×12.6 L) followed by methanol (2×16 L). The solid was dried in a vacuum oven at 65° C. for 18 hr to provide 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (4.312 kg, 87% molar yield) as an off-white solid. LCMS (ESI) m/z 427.1 (MH+). If necessary, the material may be solubilized, re-treated with Celite, and crystallized as above to increase purity.

Workup

  1. customThe reactor contents were degassed for 30-60 min
  2. customwas adjusted to 40° C
  3. addition1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4 g) was added to the reactor
  4. additionthe contents mixed with jacket temperature
  5. customset to 45° C. until the reaction
  6. custom(2.5 hr)
  7. additionCelite (1.25 kg) was charged to the reactor
  8. stirringstirred for more than one hour
  9. filtrationthe mixture was filtered through a Celite pad (0.51 kg)
  10. washThe reactor and Celite cake were washed with acetone/water/KOH (2.6 L/7.5 L/0.38 kg)
  11. filtrationfilter
  12. additionadded over a period of 1-1.5 hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L)
  13. temperaturemaintained at 62° C
  14. temperatureThe reactor contents were cooled to 20° C. over 2-3 hr
  15. filtrationThe mixture was filtered
  16. washthe cake washed with 60:40 water/MeOH (2×12.6 L)
  17. customThe solid was dried in a vacuum oven at 65° C. for 18 hr

Sources & evidence

ORD record
ord-f61054b885cf47739ba3e383a7a58916
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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