Реакция #2286283

Уравнение реакции

methanol

[4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid

[4-(6-Chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid

sodium acetate

→

[4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid

Выход 65.0%

[4-(5-Isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid

Выход 65.0%

Растворители

methylene chloride

—

hexanes

ethyl acetate

acetic acid

Условия реакции

Обработка

1. 1
   ТемператураAt this time, the reaction mixture was cooled to room temperature
2. 2
   Концентрированиеwas concentrated under vacuum
3. 3
   workup.ADDITIONThe resulting residue was diluted with water (100 mL)
4. 4
   workup.ADDITIONmade basic by the addition of a 1N aqueous sodium hydroxide solution
5. 5
   Экстракцияwas extracted with ethyl acetate (200 mL)
6. 6
   workup.ADDITIONThe water layer was acidified to pH=4 by the addition of a 1N aqueous hydrochloric acid solution
7. 7
   Экстракцияwas extracted with ethyl acetate (2×200 mL)
8. 8
   Промывкаwashed with a saturated aqueous sodium chloride solution
9. 9
   Сушкаdried with magnesium sulfate
10. 10
    Фильтрацияfiltered
11. 11
    Концентрированиеconcentrated under vacuum
12. 12
    Другоеto afford a solid
13. 13
    Другоеto form a solution and it
14. 14
    Другоеwas absorbed onto silica
15. 15
    Концентрированиеconcentrated under vacuum
16. 16
    ДругоеThe preabsorbed solid was purified by column chromatography
17. 17
    Промывкаeluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid
18. 18
    КонцентрированиеThe desired fractions were concentrated
19. 19
    Другоеas several separate batches
20. 20
    Другое1H NMRs were obtained
21. 21
    ДругоеThe solid was dried under high vacuum overnight
22. 22
    Фильтрацияfiltered
23. 23
    ДругоеThe resulting solid was dried in the vacuum oven at 60° C. for 24 h

Методика

A solution of [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid (9a) (0.10 g, 0.29 mol) in glacial acetic acid (3 mL) was treated with sodium acetate (54 mg, 0.65 mol) at room temperature. The reaction mixture was heated to 100° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting residue was diluted with water (100 mL), made basic by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate (200 mL). The ethyl acetate layer was discarded. The water layer was acidified to pH=4 by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford a solid. The solid was dissolved in ethyl acetate by adding methanol to form a solution and it was absorbed onto silica and concentrated under vacuum. The preabsorbed solid was purified by column chromatography using silica gel eluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid. The desired fractions were concentrated as several separate batches and placed under high vacuum for 1 h. 1H NMRs were obtained to determine if batches contained only the desired isomer. The best batches were combined, diluted with a 1:1 methylene chloride:hexanes solution. This process was performed three times. The solid was dried under high vacuum overnight and then slurried in acetonitrile and filtered. The resulting solid was dried in the vacuum oven at 60° C. for 24 h to afford [4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid (10a) (61 mg, 65%) as a white solid; EI(+)-HRMS m/z calcd for C17H20N2O4 (M+) 316.1423, found 316.1427. Molecular Weight=316.3599; Exact Mass=316.1423

Источник