1-Hydroxybenzotriazole → N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 2241426Notes

Reaction equation

HRID 2241426 reaction equation
[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:46](=[O:47])[C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=[N:42]2)=[CH:37][CH:36]=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>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:48]([C:45]2[C:46](=[O:47])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=[CH:43][CH:44]=2)=[O:49])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=3)[N:9]=[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[C:11]=12

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 667671712-(4-Fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acidHCID 685150213-Fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline

Product 1

HCID 68515088N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 59.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (143.2 mg, 0.322 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (377.3 mg, 1.61 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (308.8 mg, 1.61 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (217.7 mg, 1.61 mmol), N-ethyl-N-isopropylpropan-2-amine (208.2 mg, 1.61 mmol) and CH2Cl2 (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×50 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 (127 mg, 59.67%). LRMS (APCI pos): >99% purity, 254 nm, m/e 661 (M+1).

Workup

  1. customhad been consumed (overnight)
  2. customThen the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (3×50 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-b36625e524224b8bb47bef1800c95eeb
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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