Dimethyl malonate → Methyl 4-amino-2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate

HRID 573560Notes

Reaction equation

HRID 573560 reaction equation
[NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:18](OC)(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:6]2[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[C:4]([CH3:17])[S:3][C:2]=2[NH:1][C:18](=[O:24])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]

Participants

5

Reactant 3

HCID 7943Dimethyl malonateHCID 24287Tin tetrachlorideHCID 672368862-Amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophenecarbonitrile

Product 1

HCID 68323874Methyl 4-amino-2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylateYield 41%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophene carbonitrile (Description 3) (2.80 g, 11.46 mmol) in toluene (75 mL) was added dimethyl malonate (1.31 mL, 11.46 mmol) and SnCl4 (2.68 mL, 22.92 mmol). The reaction mixture was then refluxed under nitrogen for ca. 2 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (ca. 150 mL each) and the organic layer separated and washed with water (ca. 100 mL). The combined aqueous layer was re-extracted with ethyl acetate (ca. 100 mL). All organic layers were combined and passed through a phase separator and the mixture concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (1.62 g). LCMS (A) m/z: 343 [M−1]−, Rt 1.18 min (acidic).

Workup

  1. temperatureThe reaction mixture was then refluxed under nitrogen for ca. 2 h
  2. concentrationconcentrated in vacuo
  3. customThe residue was partitioned between water and ethyl acetate (ca. 150 mL each)
  4. customthe organic layer separated
  5. washwashed with water (ca. 100 mL)
  6. extractionThe combined aqueous layer was re-extracted with ethyl acetate (ca. 100 mL)
  7. concentrationthe mixture concentrated in vacuo
  8. customThe residue was purified by normal phase chromatography
  9. washeluting with a gradient of 0-60% ethyl acetate in DCM

Sources & evidence

ORD record
ord-f673c1b0b8af498ea9338dfc0a037172
Source dataset
uspto-grants-2015_05
Patent number
US09029545B2

Reaction notes

Loading…