Cesium carbonate → (6R)-9-fluoro-13,16-dioxa-2,11,17,21,22,25-hexazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one
Reaction equation
Cl[CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1Participants
Conditions
- Temperature
- 90 °C
Procedure
A mixture of (R)-N-(2-chloroethoxy)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) and Cs2CO3 (232 mg, 0.71 mmol) in DMF (1.4 mL) was heated at 90° C. for 20 minutes to reach completion. The reaction mixture was filtered (GF/F paper) and diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine and dried (Na2SO4). The crude material was purified on reverse phase column chromatography (Biotage SP4 system C18 12+M, acetonitrile/water 5 to 55%) to yield a mixture of the desired final product and impurities. This mixture was again purified by preparative TLC (10% MeOH/DCM) to yield the pure title product as white solid (1 mg, 1% yield). MS (apci) m/z=385.1 (M+H).
Workup
- filtrationThe reaction mixture was filtered (GF/F paper)
- additiondiluted with water (10 mL)
- extractionextracted with EtOAc (3×10 mL)
- washwashed with brine
- dry with materialdried (Na2SO4)
- customThe crude material was purified on reverse phase column chromatography (Biotage SP4 system C18 12+M, acetonitrile/water 5 to 55%)
- customto yield
Sources & evidence
- ORD record
- ord-13b176517035463d92cac0596e925694
- Source dataset
- uspto-grants-2015_01
- Patent number
- US08933084B2
Reaction notes
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