Cesium carbonate → 5-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester

HRID 2065569Notes

Reaction equation

HRID 2065569 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[N:7][C:6]=1[CH3:12])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH:11][C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:8]=[N:7][C:6]=1[CH3:12])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27610202-Chloro-5-(4-methoxyphenyl)pyrimidineHCID 22180329Ethyl 5-amino-2-methylnicotinate

Product 1

HCID 673656505-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A vial is charged with 5-amino-2-methyl-nicotinic acid ethyl ester 8 (1.25 mmol), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine 3 (1.25 mmol), Pd(OAc)2 (0.187 mmol), xanthphos (0.187 mmol), Cs2CO3 (1.25 mmol), and anhydrous 1,4-dioxane (8 mL). The vial is evacuated and refilled with N2 twice and the mixture is heated in an oil bath at 100° C. for 2 h. The vial is cooled down to rt and the reaction mixture is diluted with DCM, washed with 10% NH4Cl solution, brine and dried over Na2SO4. The solvent is removed under vacuum and the crude is purified by short silica gel chromatography using DCM:MeCN:MeOH=8:2.5:0.5 to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester 9 as pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ10.13 (s, 1H), 9.10 (d, J=4.0 Hz, 1H), 8.94 (s, 2H), 8.78 (d, J=4.0 Hz, 1H), 7.79-7.77 (m, 2H), 7.16-7.14 (m, 2H), 4.45 (q, J=8.0 Hz, 2H), 3.90 (s, 3H), 2.75 (s, 3H), 1.45 (t, J=8.0 Hz, 3H). MS (m/z) (M+1)+: 365.1.

Workup

  1. customThe vial is evacuated
  2. additionrefilled with N2 twice
  3. temperatureThe vial is cooled down to rt
  4. additionthe reaction mixture is diluted with DCM
  5. washwashed with 10% NH4Cl solution, brine
  6. dry with materialdried over Na2SO4
  7. customThe solvent is removed under vacuum
  8. customthe crude is purified by short silica gel chromatography

Sources & evidence

ORD record
ord-cf2f9ca2af8e4bd3826f1c405f728850
Source dataset
uspto-grants-2012_10
Patent number
US08288540B2

Reaction notes

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