1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide

HRID 2241329Notes

Reaction equation

HRID 2241329 reaction equation
[NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH:48]3[C:46]([C:50](O)=[O:51])([CH2:47]3)[C:45]2=[O:53])=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[CH:19]1[CH2:20][CH2:21][N:16]([C:15]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:34]=[CH:35][C:2]([NH:1][C:50]([C:46]45[CH2:47][CH:48]4[CH2:49][N:44]([C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)[C:45]5=[O:53])=[O:51])=[CH:3][C:4]=3[F:36])[N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:14]=2)[CH2:17][CH2:18]1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 673496483-(4-Fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-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 68512071N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamideYield 53.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (39 mg, 0.079 mmol, obtained from Example 93, Step A), 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (37 mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol) and HOBT (64 mg, 0.48 mmol) was stirred in DMF (10 mL) for 12 hours. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer washed with NaHCO3, 10% aqueous LiCl, dry with Na2SO4, filtered and concentrated. The residue was purified with flash silica gel chromatography (5% MeOH in CH2Cl2) to afford the product (30 mg, 53%) as a white solid. LRMS (APCI pos) m/e 708.3 (M+1).

Workup

  1. extractionextracted with EtOAc
  2. washThe organic layer washed with NaHCO3, 10% aqueous LiCl
  3. dry with materialdry with Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified with flash silica gel chromatography (5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-4acd67b8f3ae43f287c2575502e57aed
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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