Oxalyl chloride → Ethyl 2-Chloro-4-fluoro-5-methylbenzoylacetate

Temperature

80 °C

Magnesium (110 mg), ethanol (2 ml) and carbon tetrachloride (0.2 ml) were stirred at room temperature to activate them. A solution of ethyl malonate (0.7 ml) in tetrahydrofuran (6 ml) was added dropwise to the activated mixture, followed by stirring at 80° C. for 4 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (0.4 ml) and N,N-dimethylformamide (1 drop) were added to a solution of 2-chloro-4-fluoro-5-methylbenzoic acid (800 mg) in methylene chloride (2 ml). The mixture was stirred at room temperature for 3.5 hours, 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 4 hours 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 to obtain the title compound (1.0 g) as a pale yellow oil.

1. temperatureto cool
2. temperatureit was chilled to -40° C
3. stirringThe mixture was stirred at room temperature for 3.5 hours
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 4 hours
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 record

ord-f02fd6b4c152493994c1af578cbdae31

Source dataset

uspto-grants-2000_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06136823