Malonic Acid → N1-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 1676242Notes

Reaction equation

HRID 1676242 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1.C(O)(=O)CC(O)=O.FC1C=CC(N)=CC=1.CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12

Participants

8

Reactant 5

HCID 867Malonic AcidHCID 97314-FluoroanilineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 43418433-(4-Fluorophenylamino)-3-oxopropanoic acidHCID 594244303-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline

Product 1

HCID 24983260N1-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)malonamideYield 11%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred mixture of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 1-B; 26 mg, 0.10 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (22 mg, 0.11 mmol; prepared from malonic acid and 4-fluoroaniline according to the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836), and CH2Cl2 (1 mL) was added EDCI (38 mg, 0.20 mmol). The reaction was stirred at room temperature for 2 days. The mixture was diluted with EtOAc (10 mL) and washed with water (3×5 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a pre-packed Isoelute silica gel column (10 g silica), eluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, and then neat EtOAc. The product was obtained as a waxy solid (5 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 9.10 (s, 1H), 8.52 (m, 1H), 7.80 (m, 2H), 7.57 (m, 3H), 7.27 (m, 2H), 7.04 (m, 2H), 6.53 (d, J=4 Hz, 1H), 3.52 (s, 2H). LRMS (ESI pos) m/e 440 (M+1). HPLC: 97% purity (220 nm).

Workup

  1. washwashed with water (3×5 mL), brine (5 mL)
  2. dry with materialdried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude was purified on a pre-packed Isoelute silica gel column (10 g silica)
  6. washeluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes

Sources & evidence

ORD record
ord-5470c80627494c03b5f59e2c25c101b0
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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