Hydrochloric Acid → Methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate

HRID 244059Notes

Reaction equation

HRID 244059 reaction equation
Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=2[Cl:27])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.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].CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=3[OH:12])[CH:24]=[CH:25][C:26]=2[Cl:27])=[CH:31][CH:32]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 15281236Methyl 6-bromo-5-hydroxy-2-pyridinecarboxylateHCID 66841212(4-Chloro-3-((4-methoxybenzyl)oxy)phenyl)boronic acid

Product 1

HCID 66841290Methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-hydroxypyridine-2-carboxylateYield 76.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A solution of 80 g (345 mmol) of methyl 6-bromo-5-hydroxy-2-pyridinecarboxylate and 146 g (499 mmol) of [3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid in 1600 mL of anhydrous dioxane is stirred for 15 minutes while sparging with argon, followed by addition of 143 g (1034 mmol) of anhydrous K2CO3 and 14 g (17.2 mmol) of PdCl2(dppf). The reaction medium is stirred for 10 hours at 95° C. under argon, cooled to room temperature and then poured at room temperature into 2 L of EtOAc and 350 mL of aqueous 1N HCl solution. The organic phase is washed with 300 mL of aqueous 1N HCl solution and 600 mL of water. After drying over Na2SO4 and concentrating under reduced pressure, the precipitate is taken up in 500 mL of a 7/3 pentane/DCM mixture, filtered and washed with 200 mL of pentane. 105 g of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate are thus obtained in the form of a brown powder, which is used without further purification in the following step.

Workup

  1. customwhile sparging with argon
  2. temperaturecooled to room temperature
  3. washThe organic phase is washed with 300 mL of aqueous 1N HCl solution and 600 mL of water
  4. dry with materialAfter drying over Na2SO4
  5. concentrationconcentrating under reduced pressure
  6. filtrationfiltered
  7. washwashed with 200 mL of pentane

Sources & evidence

ORD record
ord-e41b9879a4be408a8bffbf938b0a30ca
Source dataset
uspto-grants-2014_02
Patent number
US08653276B2

Reaction notes

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