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4-Methylmorpholine → (R)-N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476384
Notes
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Reaction equation

HRID 476384 reaction equation
[CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.C[N:9]1CCOCC1.ClC(OCC(C)C)=O.Cl[C:24]1[CH:29]=[C:28]([O:30][C:31]2[C:36]([F:37])=[CH:35][C:34]([NH:38][C:39]([C:41]3([C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:45])[CH2:43][CH2:42]3)=[O:40])=[C:33]([F:54])[CH:32]=2)[CH:27]=[CH:26][N:25]=1>C(Cl)Cl>[F:54][C:33]1[CH:32]=[C:31]([O:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:9][C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH:29]=2)[C:36]([F:37])=[CH:35][C:34]=1[NH:38][C:39]([C:41]1([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)=[O:45])[CH2:43][CH2:42]1)=[O:40]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 2733584(2R)-2-methoxypropanoic acidHCID 86662871N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576732(R)-N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Yield 21%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-2-methoxy-propionic acid (300 mg, 2.88 mmol) and N-methylmorpholine (432 mg, 4.32 mmol) in anhydrous CH2Cl2 was added drop wise isobutyl chloroformate (588 mg, 4.32 mmol). The resultant mixture was stirred at RT for 1 h. N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at RT for 12 h. The reaction mixture was concentrated under vacuo and purified by HPLC separation to give (R)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (50 mg, 21%). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 9.07 (s, 1H), 8.51 (s, 1H), 8.32-8.27 (m, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 7.48-7.44 (m, 2H), 7.06-6.98 (m, 3H), 6.66-6.64 (m, 1H), 3.82 (q, J=6.8 Hz, 1H), 3.50 (s, 3H), 1.75-1.67 (m. 4H), 1.42 (d, J=6.8 Hz, 3H); MS (ESI): m/z 529.1[M+H]+.

Workup

  1. concentrationThe reaction mixture was concentrated under vacuo
  2. custompurified by HPLC separation

Sources & evidence

ORD record
ord-831e51de4da24aacb62bb9a185099e40
Source dataset
uspto-grants-2014_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08637672B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes