Ethyl Acetate → Methyl methyl-4-((5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethynyl)-3-methylbenzoate

HRID 1259200Notes

Reaction equation

HRID 1259200 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:10]#[C:11][C:12]2[CH:21]=[CH:20][C:15](C(OC)=O)=[CH:14][C:13]=2[CH3:22])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].C[C:24]1[CH:29]=[CH:28][C:27]([NH:30]C(=O)OC(C)(C)C)=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.[CH:47]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:84]([O:87][CH2:88]C)(=[O:86])[CH3:85]>C(O)CCC.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C:14]1[C:13]([CH3:22])=[C:12]([C:11]#[C:10][C:4]2[CH:5]=[N:6][C:7]3[C:8]([NH2:9])=[N:30][C:27]4[CH:26]=[C:25]([CH3:47])[CH:24]=[CH:29][C:28]=4[C:2]=3[CH:3]=2)[CH:21]=[CH:20][C:85]=1[C:84]([O:87][CH3:88])=[O:86]

Participants

9

Reactant 5

HCID 8857Ethyl AcetateHCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 66874787Methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoateHCID 66893267Tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate

Product 1

HCID 66892812Methyl methyl-4-((5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethynyl)-3-methylbenzoate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 22253497Water butanolSolvent

Procedure

A solution of methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate (from the previous step) (1.0 eq.), tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (From Example 5/Step 2) (1.5 eq.), tris(dibenzylideneacetone)dipalladium(0) (10 mol %), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (20 mol %), and potassium phosphate (2.0 eq.) in n-butanol/H2O (2.5:1, 0.04 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give methyl methyl-4-((5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethynyl)-3-methylbenzoate as a white solid.

Workup

  1. customwas stirred at 100° C. overnight
  2. customThe two phases were separated
  3. extractionthe aqueous layer was extracted twice with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over anhydrous MgSO4
  6. concentrationconcentrated en vaccuo
  7. customThe crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO)

Sources & evidence

ORD record
ord-592ef100427c48de956b1425cc94ee83
Source dataset
uspto-grants-2013_06
Patent number
US08466167B2

Reaction notes

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