反応 #2286283

反応方程式

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

収率 65.0%

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

収率 65.0%

溶媒

methylene chloride

—

hexanes

ethyl acetate

acetic acid

反応条件

後処理

1. 1
   温度At this time, the reaction mixture was cooled to room temperature
2. 2
   濃縮was 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
   抽出was 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
   抽出was extracted with ethyl acetate (2×200 mL)
8. 8
   洗浄washed with a saturated aqueous sodium chloride solution
9. 9
   乾燥dried with magnesium sulfate
10. 10
    ろ過filtered
11. 11
    濃縮concentrated under vacuum
12. 12
    その他to afford a solid
13. 13
    その他to form a solution and it
14. 14
    その他was absorbed onto silica
15. 15
    濃縮concentrated under vacuum
16. 16
    その他The preabsorbed solid was purified by column chromatography
17. 17
    洗浄eluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid
18. 18
    濃縮The desired fractions were concentrated
19. 19
    その他as several separate batches
20. 20
    その他1H NMRs were obtained
21. 21
    その他The solid was dried under high vacuum overnight
22. 22
    ろ過filtered
23. 23
    その他The resulting solid was dried in the vacuum oven at 60° C. for 24 h

実験手順

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

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