Ethyl Acetoacetate → Ethyl 4-amino-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridine-5-carboxylate

HRID 573576Notes

Reaction equation

HRID 573576 reaction equation
[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:17]([C:16]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:20])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[C:6]=12

Participants

5

Reactant 3

HCID 8868Ethyl AcetoacetateHCID 24287Tin tetrachlorideHCID 672369692-Amino-4-(3-methylphenyl)-3-thiophenecarbonitrile

Product 1

HCID 68323806Ethyl 4-amino-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridine-5-carboxylateYield 19.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a stirred solution of 2-amino-4-(3-methylphenyl)-3-thiophenecarbonitrile (Description 56) (2.98 g, 13.91 mmol) in toluene (75 mL) at RT was added ethyl acetoacetate (1.76 mL, 13.91 mmol) and SnCl4 (3.26 mL, 27.8 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for ca. 4 h and was then cooled to RT and concentrated in vacuo. The residue was re-partitioned between ethyl acetate and water (ca. 80 mL each) and the aqueous layer separated and re-extracted with ethyl acetate (ca. 50 mL×2). The combined organic layer was then passed though a phase separator and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (880 mg). LCMS (A) m/z: 327 [M+1]+, Rt 1.23 min (acidic).

Workup

  1. temperatureThe reaction mixture was refluxed under a nitrogen atmosphere for ca. 4 h
  2. concentrationconcentrated in vacuo
  3. customThe residue was re-partitioned between ethyl acetate and water (ca. 80 mL each)
  4. customthe aqueous layer separated
  5. extractionre-extracted with ethyl acetate (ca. 50 mL×2)
  6. customthe solvent removed in vacuo
  7. customThe residue was purified by chromatography on silica
  8. washeluting with a gradient of 0-50% ethyl acetate in cyclohexane

Sources & evidence

ORD record
ord-f0726800eda643d3a7f0b935ed57b39d
Source dataset
uspto-grants-2015_05
Patent number
US09029545B2

Reaction notes

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