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

HRID 2241316Notes

Reaction equation

HRID 2241316 reaction equation
[CH3:1][O:2][C:3]1[CH:36]=[CH:35][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]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=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>[CH3:34][N:32]([CH3:33])[CH:29]1[CH2:30][CH2:31][N:26]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:51]([C:48]4[C:49](=[O:50])[N:44]([C:41]5[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=5)[N:45]=[CH:46][CH:47]=4)=[O:52])=[CH:20][C:19]=3[F:25])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[N:9]=2)[CH2:27][CH2:28]1

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 685138871-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine

Product 1

HCID 68513227N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 64.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 100 mL round-bottomed flask was charged with 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (25.63 mg, 0.1095 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.95 mg, 0.3649 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol), N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. 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 (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707 (M+1).

Workup

  1. customThen the reaction was partitioned between EtOAc and H2O
  2. customThe phases were separated
  3. extractionthe aqueous phase was re-extracted with EtOAc
  4. dry with materialThe combined organic layers were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto yield a crude product
  8. 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-636d45a8308245c492ac7e818273dea5
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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