Potassium Carbonate → 1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-piperazine

HRID 1632112Notes

Reaction equation

HRID 1632112 reaction equation
COC(=O)O[CH2:5][C:6]1[C:7]([F:21])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(CC)CC)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CN(C)C=O>[Cl:20][C:16]1[CH:15]=[C:14]([C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[N:35][CH:36]=3)[C:7]=2[F:21])[CH:19]=[CH:18][CH:17]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 162179462-(Piperazin-1-yl)pyridine-5-boronic acid, pinacol esterHCID 57703696Carbonic acid 3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl esterHCID 87189959Bis-diphenylphosphinopentane

Product 1

HCID 580200671-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-piperazineYield 18%

Reagents, catalysts & solvents 2

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

To carbonic acid 3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl ester methyl ester (0.2 g, 0.62 mmol), 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.2 g, 0.68 mmol), bis-diphenylphosphinopentane (0.08 g, 0.18 mmol), potassium carbonate (0.26 g, 1.85 mmol) and allyl palladium (II) chloride dimer (0.034 g, 0.09 mmol) was added dimethyl formamide (6 mL). The reaction was degassed with an argon stream for 10 min. The reaction was stirred at 85° C. for 18 h. The reaction was cooled to room temperature, poured onto crushed ice-water (150 mL), filtered, washed with water, dried over sodium sulfate, filtered, and the solvent removed under vacuum. The residue was purified by silica gel column chromatography using 10% methanol in dichloromethane to afford P-423 (0.05 g, 18% yield) as light brown gummy solid. 1H NMR (400 MHz, DMSO-d6): 3.20 (br s, 3H) 3.55-3.99 (m, 10H), 6.95 (d, J=8.59 Hz, 1H), 7.11 (br s, 1H), 7.23-7.39 (m, 3H), 7.39-7.55 (m, 2H), 7.69 (br s, 1H), 8.02 (s, 1H), 9.33 (br s, 2H) ppm. Calc. 411.9; APCI+ (M+1): 412.1, 97%.

Workup

  1. customThe reaction was degassed with an argon stream for 10 min
  2. temperatureThe reaction was cooled to room temperature
  3. additionpoured
  4. customonto crushed ice-water (150 mL)
  5. filtrationfiltered
  6. washwashed with water
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. customthe solvent removed under vacuum
  10. customThe residue was purified by silica gel column chromatography
  11. customto afford P-423 (0.05 g, 18% yield) as light brown gummy solid

Sources & evidence

ORD record
ord-deae22c6d6ef4afaaa28440fa4d10602
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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