1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → N1-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 1401334Notes

Reaction equation

HRID 1401334 reaction equation
O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12

Participants

7

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 43418433-(4-Fluorophenylamino)-3-oxopropanoic acidHCID 579195224-((2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)-3-fluoroaniline

Product 1

HCID 57967264N1-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To intermediate 38 (0.40 g, 0.98 mmol) in dry DMF (20 mL) was added 3-(4-fluorophenylamino)-3-oxopropanoic acid (47) (0.39 g, 2.0 mmol) [US 2007/0004675 A1], and EDC.HCl (0.38 g, 2.0 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water resulting in precipitate. The precipitate was isolated by suction filtration and combined with the organic phase from the filtrate, concentrated, and dried in vacuum. The residue was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 3 h, then cooled and concentrated. The precipitated product was isolated by suction filtration, and dried in vacuum to afford intermediate 48 (0.35 g, 66%, presumably as the trifluoroacetate salt). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 10.29 (s, 1H), 10.14 (s, 1H), 9.15 (s, 1H), 8.59 (s, 1H), 8.58 (m, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.39 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.17 (t, J=8.8 Hz, 2H), 6.75 (d, J=5.5 Hz, 1H), ˜3.50 (s, 2H, obscured by water peak). MS (m/z): 545.2 (M+H).

Workup

  1. customThe mixture was then partitioned between ethyl acetate and water resulting in precipitate
  2. customThe precipitate was isolated by suction filtration
  3. concentrationconcentrated
  4. customdried in vacuum
  5. dissolutionThe residue was dissolved in acetone (50 mL)
  6. customto give a colorless solution
  7. temperatureheated
  8. temperatureto reflux for 3 h
  9. temperaturecooled
  10. concentrationconcentrated
  11. customThe precipitated product was isolated by suction filtration
  12. customdried in vacuum

Sources & evidence

ORD record
ord-58f7f5f9bf604a1d85a02533bc1b052c
Source dataset
uspto-grants-2014_12
Patent number
US08907091B2

Reaction notes

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