反应详情

温度

98 °C

400 L of purified water, USP and 45.4 kg NaOH pellets were charged to a 200 gallon glass-lined reactor and the agitator was set to 100-125 RPM. 123.5 kg of the ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate wet cake was charged to the reactor. The charging port was closed. Cooling water applied to the condenser and the valve reactor overheads were set for atmospheric distillation. The reactor contents were heated to 98° C. and conversion monitored by HPLC. Initially (approximately 40 minutes) the reactor refluxed at 68° C., however, as the ethanol was removed (over 3 hours) by distillation the reactor temperature rose to 98° C. The starting material disappeared, as determined by HPLC, at approximately 4 hours. The reactor contents were cooled to 27° C. 150 L of purified water and USP were charged to an adjacent 200 gallon glass-lined reactor and the agitator was set to 100-125 RPM. 104 L of concentrated (12M) hydrochloric acid was charged to the reactor and cooled to 24° C. The saponified reaction mixture was slowly (over 5 hours) charged to the 200-gallon glass-lined reactor. The material (45 L and 45 L) was split into 2 reactors (200 gallons each) because of carbon dioxide evolution. The product precipitated out of solution. The reaction mixture was adjusted to a pH of 2.0-4.0 with 50% NaOH solution (2 L water, 2 kg NaOH). The reactor contents were cooled to 9-15° C. The intermediate crystallized out of solution over approximately 9 hours. The reactor slurry was centrifuged to isolate the intermediate. 50 L of purified water and USP were charged to a 200-gallon glass-lined reactor and this rinse was used to wash the centrifuge wet cake. The wet cake was unloaded into double polyethylene bags placed inside a plastic drum. The N-(5-chlorosalicyloyl)-8-aminocaprylic acid was dried under vacuum (27″ Hg) at 68° C. for 38 hours. The dry cake was unloaded into double polyethylene bags placed inside a 55-gallon, steel unlined, open-head drums with a desiccant bag placed on top. The dried isolated yield was 81 kg of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

1. customThe charging port was closed
2. distillationthe valve reactor overheads were set for atmospheric distillation
3. temperatureInitially (approximately 40 minutes) the reactor refluxed at 68° C.
4. customhowever, as the ethanol was removed (over 3 hours)
5. distillationby distillation the reactor temperature
6. customrose to 98° C
7. temperatureThe reactor contents were cooled to 27° C
8. addition150 L of purified water and USP were charged to an adjacent 200 gallon glass-lined reactor
9. concentration104 L of concentrated (12M) hydrochloric acid
10. additionwas charged to the reactor
11. temperaturecooled to 24° C
12. custom(over 5 hours)
13. additioncharged to the 200-gallon glass-lined reactor
14. customThe material (45 L and 45 L) was split into 2 reactors (200 gallons each) because of carbon dioxide evolution
15. customThe product precipitated out of solution
16. temperatureThe reactor contents were cooled to 9-15° C
17. customThe intermediate crystallized out of solution over approximately 9 hours
18. customto isolate the intermediate
19. washto wash the centrifuge wet cake
20. dry with materialThe N-(5-chlorosalicyloyl)-8-aminocaprylic acid was dried under vacuum (27″ Hg) at 68° C. for 38 hours