| 87.6% |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; |
Example 42: Preparation of 5-[5-Fluoro-2-oxo-l,2-dihydro-indol-(3Z)- yIidenemethyl]-2,4-dimethyI-lH-pyrrole-3-carboxylic acid [(R)-2-(2-hydroxy- ethyI)-3-oxo-isoxazolidin-4-yl]-amidePreparation of 5-[5-Fluoro-2-oxo-l ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4- dimethyl- 1 H-pyrrole-3-carboxylic acid ((R)-3-oxo-isoxazolidin-4-yl)-amide (42b)42a 42bTo the solution of A4 (1.75g, 4.2mmol) and DIEA (2.5g, 17mmol) in 15OmL of DMF, was added compound 42a (800mg, S.lmmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (50OmL) under sonication. The solid was collected by filtration and washed with methanol, dried under vacuum to provide to provide 42b (1.41g, 87.6% yield): 1H NMR (300 MHz, DMSO-d6): delta=13.68(s, 1 H),10.88(S,1 H), 7.71-7.77(m, 3H), 7.41(s, IH), 6.82-6.96(m, 2H), 4.08- 4.13(m, IH), 3.06-3.13(m, IH), 2.41-2.45(ds, 6H), 2.25-2.31(m, 2H), 1.79-1.98(m, 3H). LC/MS: 395.3 [M-H]+. |
| 87.6% |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; |
Example 42 Preparation of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole3-carboxylic acid [(R)-2-(2-hydroxy-ethyl)-3-oxo-isoxazolidin-4-yl]-amide Preparation of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((R)-3-oxo-isoxazolidin-4-yl)-amide (42b) To the solution of A4 (1.75 g, 4.2 mmol) and DIEA (2.5 g, 17 mmol) in 150 mL of DMF, was added compound 42a (800 mg, 5.1 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (500 mL) under sonication. The solid was collected by filtration and washed with methanol, dried under vacuum to provide to provide 42b (1.41 g, 87.6% yield): 1H NMR (300 MHz, DMSO-d6): delta=13.68(s, 1H),10.88(s,1H), 7.71-7.77(m, 3H), 7.41(s, 1H), 6.82-6.96(m, 2H), 4.08-4.13(m, 1H), 3.06-3.13(m, 1H), 2.41-2.45(ds, 6H), 2.25-2.31(m, 2H), 1.79-1.98(m, 3H). LC/MS: 395.3 [M-H]+.To the solution of 42b (1.0 eq.) cooled on ice bath was added NaH (4.0 or 1.5 eq.). The resulting mixture was stirred for an hour and was then added 2-bromoethanol (3 eq.), the reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol under sonication. The solid was collected by filtration, washed with methanol twice, and further purified by Prep-LC to obtain the title compound (18 mg, 11%yield) as orange solids: 1H NMR (300 MHz, DMSO-d6): delta=13.70(s, 1H), 10.91(s, 1H), 8.08-8.10(d, 1H), 7.72-7.79(m, 2H), 6.82-6.97(m, 2H), 5.01-5.10(q, 1H), 4.79-4.81(t, 1H), 4.56-4.62(t, 1H), 4.02-4.08(q, 1H), 3.49-3.63(m, 4H), 2.41-2.43(ds, 6H). LC/MS: 428.9 [M+H]+. |
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