Oxalyl chloride → Ethyl 2-Chloro-4-fluoro-5-methyl-3-nitrobenzoylacetate

온도

80 °C

Magnesium (115 mg), ethanol (1 ml) and carbon tetrachloride (0.1 ml) were stirred at room temperature to activate them. A solution of ethyl malonate (0.69 ml) in tetrahydrofuran (5 ml) was added dropwise to the activated mixture, followed by stirring at 80° C. for 3 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (650 mg) and N,N-dimethylformamide (1 drop) were added to a solution of 2-chloro-4-fluoro-5-methyl-3-nitrobenzoic acid (1.0 g) in methylene chloride (10 ml). The mixture was stirred overnight at room temperature, and the solvent and the like were distilled off. Toluene was added to the residue to conduct azeotropic distillation. The resultant residue was dissolved in tetrahydrofuran (5 ml), and the solution was added dropwise at -40° C. to the reaction mixture obtained previously. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The solvent was distilled off, and 12N hydrochloric acid (1 ml) was added to the resultant residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off. Water (10 ml) and p-toluenesulfonic acid monohydrate (50 mg) were added to the resultant residue, and the mixture was stirred for 1 hour while heating under reflux. After the reaction mixture was allowed to cool, it was extracted with chloroform. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography on silica gel to obtain the title compound (630 mg) as a pale yellow oil from a fraction eluted with a 1:10 mixture of ethyl acetate and hexane.

1. temperatureto cool
2. temperatureit was chilled to -40° C
3. stirringThe mixture was stirred overnight at room temperature
4. distillationthe solvent and the like were distilled off
5. additionToluene was added to the residue
6. distillationdistillation
7. dissolutionThe resultant residue was dissolved in tetrahydrofuran (5 ml)
8. additionthe solution was added dropwise at -40° C. to the reaction mixture
9. customobtained previously
10. additionAfter the addition
11. customwas given back to room temperature
12. stirringto conduct stirring overnight
13. distillationThe solvent was distilled off
14. addition12N hydrochloric acid (1 ml) was added to the resultant residue
15. extractionThe residue was then extracted with chloroform
16. distillationthe solvent was distilled off
17. additionWater (10 ml) and p-toluenesulfonic acid monohydrate (50 mg) were added to the resultant residue
18. stirringthe mixture was stirred for 1 hour
19. temperaturewhile heating
20. temperatureunder reflux
21. temperatureto cool
22. extractionit was extracted with chloroform
23. washAn organic layer was washed with water
24. dry with materialdried over anhydrous magnesium sulfate
25. concentrationconcentrated under reduced pressure

ORD 기록

ord-728ee888e7df4323807f1070d0c1d000

출처 데이터셋

uspto-grants-2000_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US06136823