Hydrochloric Acid → 1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester

온도

60 °C

1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml) and 1.4N HCl in H2O (75 ml) was added to the solution. The mixture was stirred at 60° C. for 1 h. The mixture was concentrated to remove the solvents, followed by co-evaporation with toluene (×2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHCO3 aqueous solution while monitoring CO2 evolution. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used without further purification in the next step. The crude material was dissolved in CH2Cl2 (360 ml) and morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0° C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 min at 0° C. Saturated aqueous NaHCO3 solution was added to quench the reaction. After stirring for another 20 min, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester as a yellow solid (12 g, 50% yield). LCMS found 924.63 [M+H]+.

1. concentrationThe mixture was concentrated
2. customto remove the solvents
3. customto remove residual acetic acid
4. dissolutionThe residue was then dissolved in EtOAc (500 ml)
5. washThe organic layer was washed with brine
6. dry with materialdried (Na2SO4)
7. concentrationconcentrated in vacuo
8. customThe residue was further dried under high vacuum for 1 h
9. customused without further purification in the next step
10. dissolutionThe crude material was dissolved in CH2Cl2 (360 ml)
11. waitThe reaction was complete in 10 min at 0° C
12. customto quench
13. customthe reaction
14. stirringAfter stirring for another 20 min
15. washthe organic layer was washed with brine
16. dry with materialdried (Na2SO4)
17. concentrationconcentrated in vacuo
18. customThe residue was purified by silica gel chromatography

ORD 기록

ord-864ff4104bb740a9a152e1dbc2694389

출처 데이터셋

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08809267B2