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1,2-Dimethoxyethane → 3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid ethyl ester

HRID 216222
Notes
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Reaction equation

HRID 216222 reaction equation
[C:1]([O-:4])([O-])=[O:2].[Cs+].[Cs+].Cl[C:8]1[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:9]=1.C(C(OB([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)O)=O)C.CO[CH2:42][CH2:43]OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([O:4][C:1](=[O:2])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:35]=1)[CH3:43]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10796Cesium carbonateHCID 576360046-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-2-methoxy-4-pyrimidinamineHCID 69072163Ethylcarbonylphenyl boronic acid

Product 1

HCID 576361413-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

Cs2CO3 solution (407 mg, 1.25 mmol in 2 mL water) is added to a stirred solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (166 mg, 0.5 mmol) and ethylcarbonylphenyl boronic acid (135.8 mg, 0.7 mmol) in 1,2-dimethoxyethane (5 mL). The mixture is degassed over nitrogen for 10 minutes, tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) is added and the reaction mixture is refluxed at 90° C. for 6 hours. The reaction is cooled to room temperature, diluted with water (10 mL), filtered over a pad of Celite and the volatiles are removed under reduced pressure. The aqueous pH is adjusted to neutral (0.1 N HCl) and extracted twice with ethyl acetate. The combined extracts are washed with brine and water, dried over magnesium sulfate, filtered and concentrated in reduced pressure. The crude residue is purified by chromatography (SiO2 packed column), eluting with 5-15% Ethyl acetate/DCM to afford 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid ethyl ester (48 mg, Example 77). LCMS: RT=2.95 minutes, MS: 447 (M+H); 1H NMR, (300 MHz, CDCl3): □8.65 (1H, s), 8.3 (1H, d, J=3.5 Hz), 8.15 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.45 (1H, s), 7.25 (2H, s), 6.5 (1H, s), 4.95 (1H, b), 4.45 (2H, q, J=3.5 Hz), 4.05 (3H, s), 3.75 (2H, b), 3.1 (2H, t, J=3.5 Hz), 1.45 (3H, t, 3.5 Hz). IC50=149 nM

Workup

  1. customThe mixture is degassed over nitrogen for 10 minutes
  2. temperatureThe reaction is cooled to room temperature
  3. filtrationfiltered over a pad of Celite
  4. customthe volatiles are removed under reduced pressure
  5. extractionextracted twice with ethyl acetate
  6. washThe combined extracts are washed with brine and water
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in reduced pressure
  10. customThe crude residue is purified by chromatography (SiO2 packed column)
  11. washeluting with 5-15% Ethyl acetate/DCM

Sources & evidence

ORD record
ord-11288bd2bbac491fbd4dfd961c0e4d91
Source dataset
uspto-grants-2012_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08193183B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes