Hydrochloric Acid → 2-Amino-4,6-dimethoxybenzamide

Temperature

107.5 °C

2-amino-4,6-dimethoxybenzonitrile (50.0 g, 0.2805 mol, 1 eq.) was charged to a 3-L glass vessel under N2 atmosphere and agitation was started. Methanesulfonic acid (537 mL, 8.29 mol, 29.5 eq.) was charged to the vessel and the reaction was heated at 100-115° C. for 1-2 hours. Upon verification of reaction completion by HPLC, the batch was cooled to 20-30° C. Upon cooling, dichloromethane (334 mL) and cool water (807 mL) (5-10° C.) was added to keep the temperature in the range of 10-30° C. 50% caustic (423 mL) was charged to the vessel using an addition funnel while maintaining 0-30° C. Fine pH adjustment to 6.5 to 7.5 was completed using either 32% HCl or 50% caustic, or diluted solutions thereof. Upon equilibration, the first organic phase cut was performed. The aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively). Dichloromethane (271 mL) was added to the combined organic layers and the organic layer was washed with water (714 mL) to remove methanesulfonate salts. Dichloromethane (79 mL) was added to the combined organic layers and the organic layer was washed once more with water (714 mL) to remove methanesulfonate salts. The batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 6 volumes DCM (300 mL). Solvent exchange with isopropyl acetate (2 exchanges of 402 mL and 484 mL respectively) was completed when less than 1-2% DCM remained and the pot volume was between 400-450 mL. The contents of the vessel were stirred for 1 hour at 85-90° C. The vessel was cooled to 50° C. over at least 2 hours with slow agitation. The vessel was slowly charged with MtBE (250 mL) and the batch was agitated for 30 min at 50° C. The batch was slowly cooled to 30° C. over at least 1 hour. The batch was cooled to −5° C. and 5° C. over at least 2 hours. The batch was held between −5° C. and 5° C. over at least 1 hour. Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution. The batch was isolated by filtration and the wet cake washed with cold (0° C.) MtBE (100 mL). The 2-amino-4,6-dimethoxybenzamide wet cake was dried in a vacuum oven (40-45 C, 25 inches Hg) to give 2-amino-4,6-dimethoxybenzamide (42.79 g, 0.218 mol, 77.7% yield; 54.5% yield over 5 steps from 3,5-dimethoxyaniline). Variations of the volumes of solvent used during extraction and the precipitation portions in this example may give improved or reduced yield and/or purity. One skilled in the art may modify these conditions for the desired result.

1. customUpon verification of reaction completion by HPLC
2. temperaturethe batch was cooled to 20-30° C
3. temperatureUpon cooling
4. additionwas added
5. customin the range of 10-30° C
6. addition50% caustic (423 mL) was charged to the vessel
7. temperaturewhile maintaining 0-30° C
8. extractionThe aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively)
9. additionDichloromethane (271 mL) was added to the combined organic layers
10. washthe organic layer was washed with water (714 mL)
11. customto remove methanesulfonate salts
12. additionDichloromethane (79 mL) was added to the combined organic layers
13. washthe organic layer was washed once more with water (714 mL)
14. customto remove methanesulfonate salts
15. distillationThe batch was distilled
16. temperatureThe vessel was cooled to 50° C. over at least 2 hours with slow agitation
17. additionThe vessel was slowly charged with MtBE (250 mL)
18. stirringthe batch was agitated for 30 min at 50° C
19. temperatureThe batch was slowly cooled to 30° C. over at least 1 hour
20. temperatureThe batch was cooled to −5° C. and 5° C. over at least 2 hours
21. waitThe batch was held between −5° C. and 5° C. over at least 1 hour
22. customPrecipitation
23. customwas verified through collection of at least two samples from the liquor
24. customThe batch was isolated by filtration
25. washthe wet cake washed with cold (0° C.) MtBE (100 mL)
26. dry with materialThe 2-amino-4,6-dimethoxybenzamide wet cake was dried in a vacuum oven (40-45 C, 25 inches Hg)

ORD record

ord-83f236a0639d4847a8566dbb37884529

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346743B2