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

HRID 476385Notes

Reaction equation

[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 25 °C

Procedure

To a solution of (R)-2-benzyloxy-propionic acid (500 mg, 2.78 mmol) and N-methylmorpholine (416 mg, 4.16 mmol) in anhydrous CH2Cl2 was added isobutyl chloroformate (566 mg, 4.32 mmol) dropwise. The mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo to give (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 71.5%). It was used without further purification.

Workup

stirringthe resulting mixture was stirred at 25° C. for 12 h
concentrationThe reaction mixture was concentrated in vacuo

Sources & evidence

ORD record: ord-313260b451764a3cb17116b231f5b62d
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08637672B2

Reaction notes

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