Ethyl Bromide → HCID 69669890, compound

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence