Cesium fluoride → 6-Amino-5-chloro-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid methyl ester

HRID 1907109Notes

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](B(O)O)=[C:17]([F:24])[CH:16]=1.[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[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])=[CH:16][C:17]=2[F:24])[N:6]=1)=[O:4]

Participants

Conditions

Temperature: 100 °C

Procedure

6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (1.11 g, 5 mmol, see WO 2007/082076 A1 for preparation), 4-chloro-2-fluorophenylboronic acid (1.13 g, 6.5 mmol), bis(triphenylphosphine)-palladium(II) dichloride (350 mg, 0.5 mmol), and cesium fluoride (1.52 g, 10 mmol) were combined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The product was purified by column chromatography (methylene chloride/ethyl acetate gradient) then purified again by column chromatography (ethyl acetate/hexane gradient) to yield the title compound (574 mg, 40.8% yield): mp 194-196° C.; 1H NMR (CDCl3): δ 7.96 (m, 1H), 7.2 (m, 2H), 5.64 (br s, 2H), 4.01 (s, 3H).

Workup

customThe cooled reaction mixture
washwashed with water
customdried
concentrationconcentrated
customThe product was purified by column chromatography (methylene chloride/ethyl acetate gradient)
customthen purified again by column chromatography (ethyl acetate/hexane gradient)

Sources & evidence

ORD record: ord-57e05fd18ab3467c803cd5060c5309ba
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08598085B2

Reaction notes

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