Reaktion #2286289

Reaktionsgleichung

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

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

sodium acetate

→

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

Ausbeute 32.0%

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

Ausbeute 32.0%

Lösungsmittel

acetic acid

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturAt this time, the reaction mixture was cooled to room temperature
2. 2
   Einengenconcentrated under vacuum
3. 3
   workup.ADDITIONThe resulting residue was diluted with water
4. 4
   workup.ADDITIONbrought to pH=10 by the addition of a 1N aqueous sodium hydroxide solution
5. 5
   Extraktionwas extracted with ethyl acetate
6. 6
   workup.ADDITIONThe water layer was acidified by the addition of a 3N aqueous hydrochloric acid solution
7. 7
   Extraktionwas extracted with ethyl acetate
8. 8
   Waschenwashed with water
9. 9
   Trocknena saturated aqueous sodium chloride solution, dried with magnesium sulfate
10. 10
    Filtrationfiltered
11. 11
    Einengenconcentrated under vacuum
12. 12
    workup.DISSOLUTIONThe resulting solid was dissolved in methylene chloride
13. 13
    Sonstigemethanol and then was absorbed onto silica
14. 14
    SonstigeThe preabsorbed solid was purified by column chromatography
15. 15
    Wascheneluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid
16. 16
    EinengenThe desired fractions were concentrated
17. 17
    Sonstigeas several separate batches
18. 18
    workup.ADDITIONThe solid was diluted with a 1:1 methylene chloride
19. 19
    SonstigeThe solid was dried under high vacuum overnight
20. 20
    Filtrationfiltered
21. 21
    Sonstigedried in the vacuum oven at 80° C. overnight

Vorschrift

A solution of [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (9b) (1.0 g, 2.81 mmol) in glacial acetic acid (30 mL) was treated with sodium acetate (808 mg, 9.83 mmol) at room temperature. The reaction mixture was heated to 105° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was diluted with water, brought to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The ethyl acetate layer was discarded. The water layer was acidified by the addition of a 3N aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dissolved in methylene chloride and methanol and then was absorbed onto silica. 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 15 min. The solid was diluted with a 1:1 methylene chloride:hexanes solution. This process was performed three times. The solid was dried under high vacuum overnight. The solid was then slurried in acetonitrile, filtered, and dried in the vacuum oven at 80° C. overnight to afford [3-chloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid (10b) (300 mg, 32%) as a white solid; EI(+)-HRMS m/z calcd for C16H17ClN2O4 (M+H)+ 337.0950, found 337.0949. Molecular Weight=336.7779; Exact Mass=336.0877

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