1,2-Dichloroethane → N1-(3-Fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(2-methoxyphenyl)malonamide

HRID 418667Notes

Reaction equation

HRID 418667 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=3)[S:18][C:11]=12)[NH2:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:40])[CH2:36][C:37](O)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH3:26])=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=3)[S:18][C:11]=12

Participants

7

Reactant 4

HCID 111,2-Dichloroethane2×HCID 757711-HydroxybenzotriazoleHCID 12664594N-(2-Methoxy-phenyl)-malonamic acid2×HCID 167179683-Fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)aniline

Product 1

HCID 66649180N1-(3-Fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(2-methoxyphenyl)malonamideYield 50,909.102%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)aniline (230) (50 mg, 0.110 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid 27 (34 mg, 0.165 mmol) (scheme 8), EDC (25 mg, 0.165 mmol) and HOBt (22 mg, 0.165 mmol) in DMF (1.1 mL) was stirred overnight at room temperature. More 27 (34 mg, 0.165 mmol) and EDC (25 mg, 0.165 mmol) were added and the mixture stirred for a further 6 h. The mixture was diluted with EtOAc, extracted with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was re-dissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) followed by flash chromatography (MeOH/CHCl3/NH4Cl 1:9:0.1) giving title compound 224 (19 mg, 0,056 mmol, 51% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1H), 9.64 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (dd, J=8.8 Hz, J=1.4 Hz, 1H), 7.86 (dd, J=2.3 Hz, J=13.1 Hz, 1H), 7.49-7.41 (m, 3H), 7.11-7.05 (m, 2H), 6.92 (m, 1H), 6.61 (dd, J=0.8 Hz, J=5.5 Hz, 1H), 6.43 (m, 1H), 3.86 (s, 3H), 3.64 (s, 2H), 3.33 (m, 2H), 2.52-2.50 (m, 2H), 2.49 (m, 2H), 2.36-2.33 (m, 5H). MS (m/z): 547.42 (100% yield).

Workup

  1. extractionextracted with water
  2. dry with materialdried over anhydrous Na2SO4
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe residue was re-dissolved in MeOH
  5. custompurified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min)

Sources & evidence

ORD record
ord-02e4950345e24fa280bb6fb0082617c2
Source dataset
uspto-grants-2012_01
Patent number
US08093264B2

Reaction notes

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