Potassium Carbonate → 5-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic acid methyl ester

HRID 1632083Notes

Reaction equation

HRID 1632083 reaction equation
COC(=O)O[CH2:5][C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:9]([O:12][CH:13]([F:15])[F:14])=[CH:10][CH:11]=1.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C(OCC)(=O)C.O.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[C:9]([O:12][CH:13]([F:14])[F:15])=[CH:10][CH:11]=2)=[CH:30][N:29]=1)=[O:27]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 27334141,5-Bis(diphenylphosphino)pentaneHCID 467386632-Methoxycarbonyl-5-pyridineboronic acid, pinacol esterHCID 57703732Carbonic acid 3'-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester

Product 1

HCID 577037065-(3'-Chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carboxylic acid methyl esterYield 56%

Reagents, catalysts & solvents 4

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

In a 40 mL vial equipped with a stir bar was placed carbonic acid 3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl ester methyl ester (I-151, 700 mg, 2.04 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylicacid methyl ester (590 mg, 2.24 mmol), potassium carbonate (846 mg, 6.12 mmol), 1,5-bis(diphenylphosphino)pentane (270 mg, 0.612 mmol) and DMF (10 mL). The reaction mixture was degassed for 15 minutes by bubbling nitrogen and then allylpalladium(II) chloride dimer (112 mg, 0.306 mmol) was added. The reaction mixture was heated to 85° C. for 4 hours. To the reaction mixture was added water (40 mL) and ethyl acetate (40 mL) and the mixture was filtered through Celite. The layers of the filtrate were separated and the aqueous portion was extracted with ethyl acetate (40 mL). The organic portions were combined, washed with brine (40 mL), dried (MgSO4) and concentrated. The crude material was purified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 12-100% ethyl acetate/hexanes to produce 458 mg of I-152 as a viscous yellow solid in 56% yield.

Workup

  1. customIn a 40 mL vial equipped with a stir bar
  2. customThe reaction mixture was degassed for 15 minutes
  3. customby bubbling nitrogen
  4. filtrationthe mixture was filtered through Celite
  5. customThe layers of the filtrate were separated
  6. extractionthe aqueous portion was extracted with ethyl acetate (40 mL)
  7. washwashed with brine (40 mL)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated
  10. customThe crude material was purified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument)
  11. washelution of 12-100% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-719017c13fd840ae8b13c8d9b5f96fc1
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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