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

HRID 495031
Notes
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Reaction equation

HRID 495031 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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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 178418476
HCID 178418476, compound
Catalyst
HCID 962WaterSolvent
HCID 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):

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-2a908c9352944840aa079bc20e42e430
Source dataset
uspto-grants-2009_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07538214B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes