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

HRID 2063221Notes

Reaction equation

HRID 2063221 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.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])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]

Participants

7

Reactant 3

HCID 25953Cesium fluorideHCID 312630Methyl 6-amino-2,5-dichloropyrimidine-4-carboxylateHCID 577824192-(4-Chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane

Product 1

HCID 166568016-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl esterYield 53.5%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

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): 1H NMR (CDCl3): δ 7.64 (dd, 1H), 7.22 (dd, 1H), 5.64 (br s, 2H), 4.01 (s, 3H), 3.99 (d, 3H).

Workup

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

Sources & evidence

ORD record
ord-0fc21a9a906b4da9a1ae82ceb7594dd2
Source dataset
uspto-grants-2012_10
Patent number
US08288318B2

Reaction notes

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