1-Cbz-(S)-3-methylpiperazine

74879-18-8

501-53-1

612493-87-5

Example 4: To a 1 L four-necked round-bottomed flask equipped with a thermometer, condenser tube and stirring device were added 100.2 g (1.00 mol) of racemic 2-methylpiperazine, 90.0 g (0.600 mol) of D-tartaric acid, 170 g of water and 36.0 g (0.600 mol) of acetic acid. The mixture was heated to 72 °C and aged at this temperature for 2 hours. The amount of solvent was 1.69 times the weight of racemic 2-methylpiperazine. Subsequently, the mixture was cooled to 15 °C over 12 hours and the precipitated crystals were collected by filtration. The resulting crystals were dried under vacuum to give 114.0 g (0.456 mol) of diastereoisomeric salt with an optical purity of 93.25% ee. Based on the amount of S-isomer in racemic 2-methylpiperazine, the yield of S-isomer was 88.0%. Next, 190 g of water and 114.0 g of the above crystals (44.0 g of pure (S)-2-methylpiperazine) were added to a 500 mL flask. After complete dissolution at 80 to 85 °C, the solution was cooled to 15 °C over 5 hours. The precipitated crystals were collected by filtration and dried under vacuum to give 100.5 g of salt with an optical purity of 99.5% ee. Based on the amount of (S)-2-methylpiperazine in the supplied crystals, the yield of the S-isomer was 91.1%. To a 200 mL four-necked round-bottomed flask equipped with a thermometer, condenser tube, and stirring device were added 75 g of water, 25.1 g of (S)-2-methylpiperazine D-tartrate (0.100 mol, 99.5% ee optical purity), and 7.8 g (0.100 mol) of 95% pure calcium hydroxide. The slurry was heated to 70 to 80 °C, stirred for 3 hours and then cooled to room temperature. The undissolved solids were removed by filtration to obtain the mother liquor.GC analysis showed that the mother liquor contained 9.2 g (0.0918 mol) of 2-methylpiperazine in 91.8% yield.HPLC analysis showed that (S)-2-methylpiperazine was optically pure at 99.5% ee.Subsequently, the mother liquor was concentrated to about 50 wt% water content, and azeotropically dehydrated by the addition of 1 -butanol until the system's water content was below 1 wt%. (S)-2-methylpiperazine was isolated by reduced pressure distillation. Using optically pure (S)-2-methylpiperazine (optical purity 99.5% ee) obtained by the above method, the reaction was carried out under the same conditions as in Example 1. The reaction was stirred at 0 to 5°C for 2 hours and then at room temperature for 12 hours. Analysis of the reaction solution showed a yield of 84.6% (based on the amount of 2-methylpiperazine) of 1-benzyloxycarbonyl-3-methylpiperazine and an optical purity of 99.5% ee, with no decrease in optical purity observed.