Carbon Dioxide → Halauxifen-methyl

Temperatur

50 °C

Methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 4) (9.0352 g) was loaded into a 100 mL three-necked flask equipped with a magnetic stirrer, heating mantle, thermometer, and condenser under a nitrogen atmosphere. Methanol (8.1 mL) was added, followed by 4-methyl-2-pentanone (MIBK, 26 mL). The resulting slurry was mixed, and anhydrous hydrogen chloride was introduced by adding 1.2 mL of acetyl chloride via syringe over 6 min. The acetyl chloride reacts with the methanol to form one equivalent of anhydrous hydrogen chloride and one equivalent of methyl acetate. Upon completion of the acetyl chloride addition, the mixture was heated to 50° C. and stirred at that temperature for seven hours. The remaining solid compound 4 initially dissolved to give a clear solution, which again formed a slurry over time. The resulting mixture was then cooled to ambient temperature and treated with saturated aqueous sodium hydrogen carbonate solution (20 mL). The solids dissolved and gas evolution (CO2) was evident. The mixture was transferred to a separatory funnel and separated. The organic phase was washed with saturated aqueous sodium chloride (20.5 mL). The resulting organic phase was then transferred to a 100 mL three-necked flask equipped with a magnetic stir bar, thermometer, heating mantle, and distillation head. The system was placed under vacuum (115 mmHg) and was heated to distill out a portion of the solvent. Approximately 15.5 mL of solvent was taken overhead, and additional MIBK (4.8 mL) was added to the distillation bottoms and the mixture was warmed to 55° C. Heptane (50 mL) was added dropwise to the clear solution over 20 min, resulting in the precipitation of the product. The product was recovered by filtration through Whatman #50 paper using a Buchner funnel. The filter cake was washed with heptane (20 mL), then dried overnight under vacuum. A total of 4.3506 g of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate was obtained (91.9% pure by HPLC assay, 92.6% yield based on loaded compound 4).

1. customto give a clear solution, which
2. customagain formed a slurry over time
3. temperatureThe resulting mixture was then cooled to ambient temperature
4. dissolutionThe solids dissolved
5. customThe mixture was transferred to a separatory funnel
6. customseparated
7. washThe organic phase was washed with saturated aqueous sodium chloride (20.5 mL)
8. customThe resulting organic phase was then transferred to a 100 mL three-necked flask
9. customequipped with a magnetic stir bar
10. temperaturethermometer, heating mantle
11. distillationdistillation head
12. temperaturewas heated
13. distillationto distill out a portion of the solvent
14. additionadditional MIBK (4.8 mL) was added to the distillation bottoms and the mixture
15. temperaturewas warmed to 55° C
16. additionHeptane (50 mL) was added dropwise to the clear solution over 20 min
17. customresulting in the precipitation of the product
18. filtrationThe product was recovered by filtration through Whatman #50 paper
19. washThe filter cake was washed with heptane (20 mL)
20. customdried overnight under vacuum

ORD-Eintrag

ord-53a5b4ef680f4d04bc6792956d8a8a99

Quelldatensatz

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08754110B2