Acetonitrile → Methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)picolinate

HRID 516554Notes

Reaction equation

HRID 516554 reaction equation
[F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[NH2:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:23]1[CH:28]=[C:27]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[Cl:34]

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 22677331Methyl 4-amino-3,6-dichloropyridine-2-carboxylateHCID 71150540(2,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane

Product 1

HCID 90409450Methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)picolinateYield 39.4%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
120 °C

Procedure

In a microwave vessel, a suspension of (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (see, e.g., WO 2013003740 A1) (0.6 g, 1.922 mmol), methyl 4-amino-3,6-dichloropicolinate (Head A) (0.354 g, 1.601 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.112 g, 0.160 mmol) and sodium carbonate (0.204 g, 1.922 mmol) in a 3:1 mixture of acetonitrile (4.00 mL) and water (1.334 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (0.234 g, 0.631 mmol, 39.4%): 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=8.7, 5.8 Hz, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.09 (dd, J=10.8, 4.1 Hz, 1H), 4.84 (s, 2H), 4.00 (s, 3H), 0.32 (d, J=0.7 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −106.56, −106.61, −124.00-124.06; ESIMS m/z 371 ([M+H]+).

Workup

  1. extractionwas extracted with EtOAc (3×)
  2. dry with materialThe combined organic layers were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient)

Sources & evidence

ORD record
ord-c6f25a0a78344b7e8f5fc420094f4f56
Source dataset
uspto-grants-2015_08
Patent number
US09113629B2

Reaction notes

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