Hydrochloric Acid → Lazabemide hydrochloride

A 10 liter four-necked sulphonation flask, equipped with a mechanical stirrer, thermometer and gas inlet arrangement, is charged under argon with 692 g (3.2 mol) of 2-butyl 5-chloropyridine-2-carboxylate and 7 l of ethylene diamine and the clear solution obtained is stirred, whereby the internal temperature rises slowly from 22° to a maximum of 30° during the stirring. The course of the reaction is followed by gas chromatography. After a reaction period of 3 hours (the internal temperature still amounts to 27°) the reaction solution is evaporated at 30°-40° under reduced pressure. The evaporation residue--a clear, yellow oil--weighs 753 g. A 20 liter stirring vessel as well as two 5 liter separating funnels are charged with, respectively, 2.250 l of ice-cold 3N hydrochloric acid, 750 ml of 1.5N hydrochloric acid and 750 ml of deionized water. The evaporation residue (753 g of a clear, yellow oil) is subsequently treated with 1.500 l of methylene chloride and the solution obtained is added to the stirring vessel. After intermixing of the two phases the pH value of the aqueous phase amounts to about 1. Subsequently, the organic phase from the stirring vessel as well as two 1.5 l portions of methylene chloride are passed in sequence and with good intermixing through the stirring vessel and the two separating funnels. The aqueous phases are combined in the stirring vessel and adjusted to about pH 11 by the addition of 3 l of ice-cold 3N sodium hydroxide solution. The two separating funnels are charged with two 750 ml portions of semi-saturated sodium chloride solution. Then, in each case with good intermixing, six 1.5 l portions of methylene chloride are passed through the stirring vessel and the two separating funnels. The organic phases are combined and dried over 500 g of sodium sulphate. The drying agent is filtered off and the filtrate is evaporated at 30°-40° under reduced pressure. The yellow, oily residue is dried at 40°/0.1 Pa for a further 15 hours and thereafter weighs 616 g (3.08 mol). It crystallizes upon standing at 20°. The crystallizate is dissolved in 3.2 l of methanol at 20°. 688 ml of 4.48N methanolic hydrochloric acid (3.08 mol) are added in one portion to the solution while cooling in an ice bath. The reaction mixture is stirred for 15 minutes and the resulting suspension is subsequently heated to 50°, whereby a clear solution again results. Thereto there are added within 30 minutes 5.8 l of t-butyl methyl ether (pre-heated to 50°). The suspension obtained is left to cool to 20° (duration about 1.5 hours) and it is subsequently cooled to 0°-5° with an ice bath. The solid is subsequently filtered off and rinsed with 1.100 l of petroleum ether (low-boiling). The crystallizate is subsequently dried to constant weight at 40° in a vacuum drying oven and thereafter weighs 693 g (95% crystallization yield). For further purification, the crystallizate is heated to 55° in 3.6 l of methanol and dissolved. While stirring vigorously there are allowed to drop in within 1.5 hours 5.500 l of t-butyl methyl ether (pre-heated to 50°), whereby the mixture is seeded with pure crystals of the end product after the addition of 1.5 l of solvent. The suspension obtained is left to cool to about 20° (duration about 1.5 hours), whereupon it is cooled to 0°-5° with an ice bath. The crystallizate is filtered off and washed with 1.11 of pentane. The N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride obtained is dried in a high vacuum at 50°/1 Pa for two days and thereafter weighs 665 g (87%), m.p. 197°-199°.

1. customA 10 liter four-necked sulphonation flask, equipped with a mechanical stirrer
2. customthe clear solution obtained
3. customslowly from 22°
4. customto a maximum of 30°
5. customAfter a reaction period of 3 hours (the internal temperature
6. customstill amounts to 27°
7. customis evaporated at 30°-40° under reduced pressure
8. stirringA 20 liter stirring vessel as well as two 5 liter
9. customseparating funnels
10. additionare charged with, respectively, 2.250 l of ice-cold 3N hydrochloric acid, 750 ml of 1.5N hydrochloric acid and 750 ml of deionized water
11. additionThe evaporation residue (753 g of a clear, yellow oil) is subsequently treated with 1.500 l of methylene chloride
12. customthe solution obtained
13. additionis added to the stirring vessel
14. dry with materialdried over 500 g of sodium sulphate
15. filtrationThe drying agent is filtered off
16. customthe filtrate is evaporated at 30°-40° under reduced pressure
17. customThe yellow, oily residue is dried at 40°/0.1 Pa for a further 15 hours
18. customIt crystallizes
19. customupon standing at 20°
20. dissolutionThe crystallizate is dissolved in 3.2 l of methanol at 20°
21. temperaturewhile cooling in an ice bath
22. stirringThe reaction mixture is stirred for 15 minutes
23. temperaturethe resulting suspension is subsequently heated to 50°
24. customwhereby a clear solution again results
25. customThe suspension obtained
26. waitis left
27. temperatureto cool to 20° (duration about 1.5 hours) and it
28. temperatureis subsequently cooled to 0°-5° with an ice bath
29. filtrationThe solid is subsequently filtered off
30. washrinsed with 1.100 l of petroleum ether (low-boiling)
31. customThe crystallizate is subsequently dried to constant weight at 40° in a vacuum
32. customdrying oven
33. custom693 g (95% crystallization yield)
34. customFor further purification
35. temperaturethe crystallizate is heated to 55° in 3.6 l of methanol
36. dissolutiondissolved
37. stirringWhile stirring vigorously there
38. customto drop in within 1.5 hours 5.500 l of t-butyl methyl ether (pre-heated to 50°), whereby
39. additionafter the addition of 1.5 l of solvent
40. customThe suspension obtained
41. waitis left
42. temperatureto cool to about 20° (duration about 1.5 hours)
43. temperaturewhereupon it is cooled to 0°-5° with an ice bath
44. filtrationThe crystallizate is filtered off
45. washwashed with 1.11 of pentane

ORD record

ord-75c67e402bbb4c68be06f8fa8f1d0b70

Source dataset

uspto-grants-1996_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05534635