84477-72-5

22476-74-0

84477-72-5

Example 4 Synthesis of 2,2-dimethylpiperazine: 3,3-dimethylpiperazin-2-one (8.28 kg, 64.6 mol) was mixed with tetrahydrofuran (THF, 60 kg) and heated to 50-60 °C to form a slightly turbid solution. LiAlH4 (250 g, encapsulated in a soluble plastic bag) was slowly added to the stirring THF (50 kg) under nitrogen protection and a slow gas release was observed. After the gas release ceased, the addition of LiAlH4 (total 3.0 kg, 79.1 mol) was continued and the reaction was exothermic causing the temperature to rise from 22°C to 50°C. Subsequently, a solution of 3,3-dimethylpiperazin-2-one was added slowly and dropwise over a period of 2 h at 41-59 °C. The solution was then added to the suspension over a period of 2 h. The solution was then added to the suspension over a period of 1 h at 41-59 °C. After addition, the suspension was continued to be stirred at 59 °C (jacket temperature 60 °C) for 1 hour. After the reaction mixture was cooled, water (3 L) was added slowly over a period of 2 h. The temperature was controlled to be lower than 25 °C (cooling by EPO, jacket temperature 0 °C). Next, 15% aqueous sodium hydroxide solution (3.50 kg) was added over 20 min at 23 °C and cooled if necessary. Subsequently, water (9 L) was added within half an hour, cooling was required to maintain the temperature, and the mixture was stirred overnight under nitrogen protection. Celite filter (4 kg) was added, the mixture was filtered and the filter cake was washed with THF (40 kg). The filtrates were combined and concentrated in a reactor until the temperature in the reactor reached 70 °C (distillation temperature 66 °C, pressure 800 mbar). The residue (12.8 kg) was further concentrated by rotary evaporator to about 10 L. Finally, the mixture was fractionated at atmospheric pressure and the 163-164 °C fraction was collected to give 5.3 kg of product (72% yield). The structure of the product was confirmed by NMR.