tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate → N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide

HRID 2241332Notes

Reaction equation

HRID 2241332 reaction equation
COC1C=CC(C[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]([NH:24][C:25]([C:27]56[CH2:32][CH:31]5[CH2:30][N:29]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:28]6=[O:40])=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]23[CH2:32][CH:31]2[CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:28]3=[O:40])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]3)[C:11]=12

Participants

3

Reactant 1

HCID 68514115tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate

Product 1

HCID 59304241N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamideYield 44.9%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

A solution of tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.131 mmol) was heated in TFA (4 mL) for 12 hours. Excess TFA was removed and the residue was purified by flash column chromatography (20% MeOH in CH2Cl2) to afford the product N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide (32 mg, 44.9% yield) as a yellow solid. LRMS (APCI pos) m/e 546.3 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.90 (s, 1H), 10.48 (s, 1H), 8.88 (s, br, 1H), 8.25 (d, 1H), 7.92 (d, 1H), 7.60-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.22-7.30 (m, 2H), 6.16-6.22 (d, 1H), 4.09-4.17 (m, 1H), 3.77-3.80 (m, 1H), 3.50-3.60 (m, 1H), 3.35-3.40 (m, 1H), 3.22-3.33 (m, 4H), 3.16-3.21 (m, 1H), 2.66-2.74 (m, 1H), 1.80-1.84 (m, 1H), 1.46-1.52 (m, 1H), 1.06-1.12 (m, 1H).

Workup

  1. customExcess TFA was removed
  2. customthe residue was purified by flash column chromatography (20% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-b77afc5c14c64393b793991d1732127c
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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