Cesium fluoride → 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl ester

HRID 1496891Notes

Reaction equation

[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]

Participants

Conditions

Temperature: 80 °C

Procedure

6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II)dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield):

Workup

customthe cooled reaction mixture
customwas partitioned between ethyl acetate and water
washThe organic phase was washed with water
customdried
concentrationconcentrated
customThe product was purified by column chromatography (ethyl acetate/hexane gradient)
customthen purified again by column chromatography (methylene chloride/ethyl acetate gradient)

Sources & evidence

ORD record: ord-b878dd26b75a403795f0d643c6558cec
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09199943B2

Reaction notes

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