反应详情

Methanesulfonyl chloride (10.62 mmol) was added to a mixture of 2-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A4) (4.09 mmol), pyridine (14.01 mmol) and DMAP (1.226 mmol) in CH2Cl2 (70 mL). After stirring for 20 h, the reaction mixture was diluted with CH2Cl2 and washed with a saturated aqueous solution of NH4Cl (2×). The combined aqueous phases were back-extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. A mixture of the crude intermediate and 3-chloro-2-fluoro-phenylamine [2106-04-9] (11.64 mmol) in dioxane (90 mL) was stirred at 90° C. for 11 h. After cooling to rt, the reaction mixture was diluted with EtOAc and successively washed with 10% w/w aqueous citric acid and brine. The combined aqueous phases were back-extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 9.08 min (HPLC 2); ESI-MS: tR=1.54 min, [M]+318/320 (i.e. fragmented pyrrolium ion) (LC-MS 1); TLC: Rf=0.45 (1:4 EtOAc/hexanes).

1. washwashed with a saturated aqueous solution of NH4Cl (2×)
2. extractionThe combined aqueous phases were back-extracted with CH2Cl2
3. dry with materialThe combined organic phases were dried (Na2SO4)
4. filtrationfiltered
5. concentrationconcentrated
6. stirringwas stirred at 90° C. for 11 h
7. washsuccessively washed with 10% w/w aqueous citric acid and brine
8. extractionThe combined aqueous phases were back-extracted with EtOAc
9. dry with materialThe combined organic phases were dried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated
12. customThe residue was purified