Ethyl Bromide → HCID 69669890, compound

Temperature

40 °C

14.23 g Freshly distilled 4-(isopropylamino)piperidine (100 mmole, fw=142.25), 28.43 g diisopropylethylamine (DIPEA, 220 mmole, fw=129.25) and 75 mL acetonitrile are placed in a 200 mL heavy-walled, glass pressure vessel that is equipped with a magnetic stirring-bar, thermocouple and pressure head with relief valve. 35.96 g ethyl bromide (330 mmole, fw=108.97) is added to the stirring mixture and pressure vessel is sealed. Initially there is a mild exotherm. The reaction mixture is heated and stirred at 40° C. for 24 hours, and then it is cooled to room temperature. During cooling, white crystals of DIPEA hydrobromide begin to form. The reaction vessel is vented in a hood, and then the reaction mixture is filtered through sintered-glass to remove the unwanted solid. The solvent is removed on a rotary evaporator, and then just enough 50% aqueous NaOH is added (˜28 g) until the mixture is strongly basic. The liquid (acetonitrile, water, DIEPA) is removed using a rotary evaporator and then a vacuum pump (0.5 torr). The residue is twice extracted with 100 mL hot acetonitrile, and the liquids are combined. Anhydrous magnesium sulfate (˜15 g) is added, the liquid is filtered and then placed on a rotary evaporator to remove most of the solvent. Small amounts of acetonitrile are added back to ensure a homogeneous solution, and then peroxide-free diethylether is added to induce crystallization. The mixture is allowed to stand at room temperature for about 4 hours and then at 4° C. overnight. The cold acetonitrile/ether mixture is filtered through sintered glass, washed with ether and then dried by passing dry N2 through the filter. The off-white solid is dried in a vacuum oven overnight yielding 22.1 g (72%) of a sticky, white crystalline solid with purity (HPLC) of about 97%. Recrystallization from acetonitrile/isopropanol/ether mixtures yields a purified product (˜99%). This reaction illustrates a method to carry out multiple alkylations of primary and secondary amines in the presence of a strong, soluble, nonreactive base. Despite the excess alkylating agent, there was no evidence (HPLC) of the tetraalkylated impurity in the reaction mixture or in the final trialkylated product.

1. customglass pressure vessel that is equipped with a magnetic stirring-bar
2. customis sealed
3. temperatureThe reaction mixture is heated
4. temperatureit is cooled to room temperature
5. temperatureDuring cooling
6. customto form
7. filtrationthe reaction mixture is filtered through sintered-glass
8. customto remove the unwanted solid
9. customThe solvent is removed on a rotary evaporator
10. additionjust enough 50% aqueous NaOH is added (˜28 g) until the mixture
11. customThe liquid (acetonitrile, water, DIEPA) is removed
12. customa rotary evaporator
13. extractionThe residue is twice extracted with 100 mL hot acetonitrile
14. additionAnhydrous magnesium sulfate (˜15 g) is added
15. filtrationthe liquid is filtered
16. customplaced on a rotary evaporator
17. customto remove most of the solvent
18. additionSmall amounts of acetonitrile are added back
19. additionperoxide-free diethylether is added
20. customcrystallization
21. waitto stand at room temperature for about 4 hours
22. customat 4° C.
23. customovernight
24. filtrationThe cold acetonitrile/ether mixture is filtered through sintered glass
25. washwashed with ether
26. customdried
27. customThe off-white solid is dried in a vacuum oven overnight
28. customyielding 22.1 g (72%) of a sticky, white crystalline solid with purity (HPLC) of about 97%
29. customRecrystallization from acetonitrile/isopropanol/ether

ORD record

ord-ae6f3522a955484490af724b4a719e63

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08361779B2