Toluene → 5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine

HRID 1632036Notes

Reaction equation

HRID 1632036 reaction equation
Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[N:21][CH:22]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1

Participants

7

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 2783397(6-Fluoropyridin-3-yl)boronic acidHCID 577037013-Bromomethyl-3'-chloro-2-fluoro-6-methoxy-biphenyl

Product 1

HCID 577037115-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridineYield 93.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

A flask was charged with 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-32, 3.3 g, 10 mmol), 2-fluoro-pyridine-5-boronic acid (1.4 g, 10 mmol), toluene (40 mL), 2M aq. Na2CO3 (10 mL, 20 mmol), ethanol (10 mL) and Pd(PPh3)4 (577 mg, 0.5 mmol). The reaction mixture was bubbled with nitrogen gas for 5 minutes. Then the yellow reaction mixture was stirred at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted in EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with hexane/EtOAc (9:1) to produce 3.23 g (93% yield) of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd, J=8.4, 2.8 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H) ppm.

Workup

  1. customThe reaction mixture was bubbled with nitrogen gas for 5 minutes
  2. stirringAfter overnight stirring the reaction mixture
  3. temperaturewas cooled to room temperature
  4. concentrationconcentrated in-vacuo
  5. additionThe residue was diluted in EtOAc (20 mL)
  6. washwashed with water (30 mL)
  7. extractionThe aqueous layer was extracted with EtOAc (2×20 mL)
  8. washThe combined organic layers were washed with brine (50 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated in-vacuo
  11. customThe crude was purified by silica gel column chromatography
  12. washeluted with hexane/EtOAc (9:1)

Sources & evidence

ORD record
ord-33783ea393ec40ffb4e021e01ba7b750
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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