Phosphoric Acid → Methyl 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinate

HRID 1398470Notes

Reaction equation

HRID 1398470 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([F:29])[C:15]=1[O:30][CH3:31].P(=O)(O)(O)O.[K]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:29])[C:15]=1[O:30][CH3:31]

Participants

8

Reactant 4

HCID 1004Phosphoric AcidHCID 5462222PotassiumHCID 670174932-(4-Chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 84070460Methyl 4-chloro-2-methylpyridine-3-carboxylate

Product 1

HCID 86710441Methyl 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinateYield 31.2%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 4-chloro-2-methylnicotinate (1.5 g, 8.08 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.316 g, 8.08 mmol), phosphoric acid, potassium salt (3.43 g, 16.16 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.660 g, 0.808 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was purged with nitrogen for 5 min. The reaction was then heated to 100° C. for 18 h. After cooling, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 50% ethyl acetate in hexanes to yield methyl 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinate (1.2 g, 2.52 mmol, 31% yield) as pale brown oil. LC/MS (ESI) m/e 309.9 [(M+H)+, calcd for C15H14ClFNO3 310.1]; LC/MS retention time (method D): tR=0.84 min.

Workup

  1. customwas purged with nitrogen for 5 min
  2. temperatureAfter cooling
  3. additionthe reaction was diluted with water (50 mL)
  4. extractionextracted with ethyl acetate (2×75 mL)
  5. washThe combined organic layers were washed with brine solution
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-ecca1684e53e4cb092a918d5c103bd5f
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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