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Cesium fluoride → 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester

HRID 1627549
Notes
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Reaction equation

HRID 1627549 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[CH3:21][O:22][C:23](=[O:41])[C:24]([CH3:40])([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25].[F-].[Cs+]>COCCOC.O>[CH3:21][O:22][C:23](=[O:41])[C:24]([N:26]1[CH:30]=[C:29]([C:17]2[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[Cl:1])[CH3:11])[CH:18]=2)[CH:28]=[N:27]1)([CH3:40])[CH3:25]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 211113953-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-iodopyridin-2-amineHCID 59599416Methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazol-1-yl)propanoate

Product 1

HCID 595994112-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester

Reagents, catalysts & solvents 2

HCID 962
Water
Solvent
HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]propionic acid methyl ester (4.6 g, 15.64 mmol) in DME (27 mL) was added a solution of CsF (6.79 g, 44.7 mmol) in water (9.3 mL). The reaction mixture was degassed 3 times with N2. Pd(dppf)CH2Cl2 was added and the reaction mixture was degassed 3 times with N2. The reaction was heated to 120° C. in the microwave (subsequent Pd was added in intervals of 30 minutes until the reaction was complete). Water was added and the reaction was extracted with EtOAc, dried over Na2SO4, and concentrated to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester. The crude product was purified by a silica gel column chromatography with a gradient of 25%-50% EtOAc/hexanes to provide 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester (1.46 g, 21% yield) with a Rf 0.11 (50% EtOAc/hexanes).

Workup

  1. customThe reaction mixture was degassed 3 times with N2
  2. additionPd(dppf)CH2Cl2 was added
  3. customthe reaction mixture was degassed 3 times with N2
  4. additionwas added in intervals of 30 minutes until the reaction
  5. additionWater was added
  6. extractionthe reaction was extracted with EtOAc
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-4e673d3666c84cb5ac800b218e209a7c
Source dataset
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08785632B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes