Cesium carbonate → 2-(3-{3-[4-(3,5-Dimethylisoxazol-4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-propylphenoxy)benzoic acid sodium salt

温度

95 °C

A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (305 mg, 0.448 mmol), 3,5-dimethyl-4-iodoisoxazole (110 mg, 0.493 mmol), cesium carbonate (293 mg, 0.899 mmol), and PdCl2(dppf) (15 mg, 0.018 mmol) in de-oxygenated toluene (10 mL) was heated at 95° C. for 10 h. Additional portions of 3,5-dimethyl-4-iodoisoxazole (110 mg), cesium carbonate (260 mg), and PdCl2(dppf) (˜15 mg) were added and heating continued at 110° C. for 20 h. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel with 20% ethyl acetate/80% hexane. The filtrate was concentrated in vacuo. The resulting colorless oil was dissolved in methylene chloride (4 mL), cooled to 0° C., and treated with iodotrimethylsilane (0.40 mL, 2.7 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 18 h. An additional portion of iodotrimethylsilane (0.70 mL) was added and stirring continued for 72 h. The mixture was poured into dilute sodium thiosulfate solution. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. The resulting foam was dissolved in a 1:1 mixture of tetrahydrofuran/l N hydrochloric acid (5 mL) and stirred at room temperature for 18 h. The mixture was concentrated in vacuo and treated with 1 equivalent 1 N sodium hydroxide solution in ether. The resulting mixture was concentrated in vacuo to provide 59 mg (23%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 7.40 (dd, J=9, 2 Hz, 1H), 7.13 (dt, J=8, 2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H), 6.68 (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.21 (d, J=8 Hz, 1H), 4.19 (t, J=6 Hz, 2H), 4.01 (t, J=6 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 2.48 (q, J=8 Hz, 2H), 2.24 (s, 3H), 2.17 (quintet, J=6 Hz, 2H), 2.07 (s, 3 H), 1.49 (hextet, J=8 Hz, 2H), 1.07 (t, J=7 Hz, 3H), 0.85 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C32H36NO7 (p+1): m/z=546.2492. Found: 546.2514; IR (KBr, cm−1) 3400, 1605, 1460.

1. temperatureheating
2. temperatureThe mixture was cooled to room temperature
3. concentrationconcentrated in vacuo
4. additiondiluted with methylene chloride
5. filtrationfiltered down a short plug of silica gel with 20% ethyl acetate/80% hexane
6. concentrationThe filtrate was concentrated in vacuo
7. dissolutionThe resulting colorless oil was dissolved in methylene chloride (4 mL)
8. temperaturecooled to 0° C.
9. temperatureto warm to room temperature
10. stirringstirring
11. waitcontinued for 72 h
12. customThe organic layer was separated
13. washwashed with water
14. dry with materialdried (sodium sulfate)
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. dissolutionThe resulting foam was dissolved in a 1:1 mixture of tetrahydrofuran/l N hydrochloric acid (5 mL)
18. stirringstirred at room temperature for 18 h
19. concentrationThe mixture was concentrated in vacuo
20. concentrationThe resulting mixture was concentrated in vacuo

ORDレコード

ord-d48f6934650f40d5bbf73bd7d715fa83

出典データセット

uspto-grants-2004_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US06797723B1