(R)-N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide → (R)-N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476386Notes

Reaction equation

HRID 476386 reaction equation
C([O:8][C@H:9]([CH3:44])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([NH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[O:34])[CH2:32][CH2:31]3)=[O:29])=[C:22]([F:43])[CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:43][C:22]1[CH:21]=[C:20]([O:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10](=[O:11])[C@H:9]([OH:8])[CH3:44])[CH:18]=2)[C:25]([F:26])=[CH:24][C:23]=1[NH:27][C:28]([C:30]1([C:33]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[O:34])[CH2:32][CH2:31]1)=[O:29]

Participants

4

Reactant 1

HCID 66604800(R)-N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576733(R)-N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 11.7%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolvent

Procedure

To a solution of (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.331 mmol) in methanol (20 mL) was added Pd(OH)2 (50 mg). The mixture was then hydrogenated (1 atm) for 12 h. The reaction mixture was filtered, concentrated and purified by HPLC chromatography to give (R)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (20 mg, 11.7% yield). 1H NMR (400 MHz, CD3OD): δ 8.23-8.18 (m, 2H), 7.69 (s, 1H), 7.54-7.50 (m, 2H), 7.31-7.28 (m, 1H), 7.09-7.05 (m, 2H), 6.86-6.84 (m, 1H), 4.28-4.23 (q, J=6.8 Hz, 1H), 1.76-1.67 (m, 4H), 1.39 (d, J=6.8 Hz, 3H); MS (ESI); m/z 515.1 [M+H]+

Workup

  1. filtrationThe reaction mixture was filtered
  2. concentrationconcentrated
  3. custompurified by HPLC chromatography

Sources & evidence

ORD record
ord-d64c47b049b24b68a252295e8df41732
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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