1-Hydroxybenzotriazole → tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate

HRID 2241352Notes

Reaction equation

HRID 2241352 reaction equation
[CH3:1][O:2][C:3]1[CH:41]=[CH:40][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[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=[N:50]2)=[CH:45][CH:44]=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>CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:56]([C:53]2[C:54](=[O:55])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[N:50]=[CH:51][CH:52]=2)=[O:57])[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:41][CH:40]=3)[N:9]=[C:10]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:28][CH2:27]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 68515034tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate

Product 1

HCID 68511540tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylateYield 77.4%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

A 100 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate (110.4 mg, 0.1962 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (137.9 mg, 0.5887 mmol, prepared according to Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (188.1 mg, 0.9811 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (132.6 mg, 0.9811 mmol), N-ethyl-N-isopropylpropan-2-amine (253.6 mg, 1.962 mmol) and DMSO (25 mL). The reaction mixture was stirred at room temperature overnight. 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. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (118.3 mg, 77.4%). LRMS (APCI pos): m/e 679 (M−99).

Workup

  1. customThe 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. customThe crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1

Sources & evidence

ORD record
ord-5679e9efb4cc40828726f444aaa51167
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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