Potassium Carbonate → 6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid

HRID 1517470Notes

Reaction equation

HRID 1517470 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[N:38]1.I[C:52]1[CH:53]=[C:54]([C:70]([OH:72])=[O:71])[C:55](=[O:69])[N:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[C:57]=1[CH3:58]>O.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:58][C:57]1[N:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:67])([F:68])[F:66])[CH:60]=2)[C:55](=[O:69])[C:54]([C:70]([OH:72])=[O:71])=[CH:53][C:52]=1[C:41]1[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 49129081-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 582180465-Iodo-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxylic acid

Product 1

HCID 594558756-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acidYield 77%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
50 °C

Procedure

Acetonitrile (30.3 L, 3 rel vol) was charged, followed by palladium(II) acetate (260 g, 0.05 mol eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (980 g, 0.1 mol eq). The mixture was stirred for 15 minutes. A solution of potassium carbonate (10.0 kg, 3.0 mol eq) in water (60.6 L, 6 rel vol) was added to the reaction. 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (31.8% w/w, 20.3 kg, 1.3 mol eq) as a solution in acetonitrile was added, followed by 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (10.1 kg, 1 mol eq, limiting reagent). The reaction mixture was heated to reflux and stirred until the reaction was complete as judged by HPLC analysis. The reaction mixture was cooled and filtered. The cake was washed with acetonitrile (10.1 L, 1 rel vol) and the cake discarded. The filtrate was heated to 50° C. 6 M Hydrochloric acid (60.6 L, 6 rel vol) was added carefully to the reaction. The reaction mixture was stirred at 50° C. for 60 minutes, cooled to 5° C. and stirred overnight. The solid was collected by filtration, washed twice with water (2×20.2 L, 2×2 rel vol) and with cold (around 5° C.) acetonitrile (10.1 L, 1 rel vol). The solid was dried to constant weight to yield the title compound (8.1 kg, 21.5 mol, 77%); 1H NMR (d6-DMSO): δ 1.87 (s, 3H); 3.73 (s, 3H); 6.35-6.37 (m, 1H); 7.54-7.55 (m, 1H); 7.83-7.91 (m, 2H); 7.95-7.97 (m, 1H); 8.07 (s, 1H); 8.25 (s, 1H); 13.80 (s, 1H); LCMS: m/z 378.3 (MH+).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux
  3. stirringstirred until the reaction
  4. temperatureThe reaction mixture was cooled
  5. filtrationfiltered
  6. washThe cake was washed with acetonitrile (10.1 L, 1 rel vol)
  7. addition6 M Hydrochloric acid (60.6 L, 6 rel vol) was added carefully to the reaction
  8. stirringThe reaction mixture was stirred at 50° C. for 60 minutes
  9. temperaturecooled to 5° C.
  10. stirringstirred overnight
  11. filtrationThe solid was collected by filtration
  12. washwashed twice with water (2×20.2 L, 2×2 rel vol) and with cold (around 5° C.) acetonitrile (10.1 L, 1 rel vol)
  13. customThe solid was dried to constant weight

Sources & evidence

ORD record
ord-7a111f5d4a0844e4ab67840359fc0512
Source dataset
uspto-grants-2012_07
Patent number
US08232296B2

Reaction notes

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