1-Hydroxybenzotriazole → N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 1676408Notes

Reaction equation

HRID 1676408 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]([I:19])[S:18][C:11]=12)[NH2:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:32](=[O:33])[C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:31]2[C:32](=[O:33])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[O:35])[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]([I:19])[S:18][C:11]=12

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 584749503-Fluoro-4-((2-iodothieno[3,2-b]pyridin-7-yl)oxy)anilineHCID 667671712-(4-Fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

Product 1

HCID 67348506N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 85.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A, 1.00 g, 2.59 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.728 g, 3.11 mmol, example 104, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.596 g, 3.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.420 g, 3.11 mmol), N-ethyl-N-isopropylpropan-2-amine (0.669 g, 5.178 mmol) and DMF (50 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (200 mL) and H2O (200 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (1.34 g, 85.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 603 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 8.43 (m, 2H), 8.24 (d, 1H), 7.96 (dd, 1H), 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 7.21-7.28 (m, 3H), 6.48 (m, 1H).

Workup

  1. customhad been consumed (overnight)
  2. customThen the reaction was partitioned between EtOAc (200 mL) and H2O (200 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×200 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a crude product
  9. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1

Sources & evidence

ORD record
ord-2208230781ea4278a97f40c91c9ca804
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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