Acetic Acid → HCID 58398762, compound

Participants

Reaction Conditions

Reaction Steps

(R)-Boc-2-methylpiperazine (350 g, 1.71 moles, 98% w/w), which is commercially available from Lanzhou Boc Chemical Co., was dissolved in EtOH (2.75 L) at tjacket=20° C. Acetic acid (1.37 L) was added in one portion followed by the addition of cyclobutanone (184 g, 2.57 moles). The charging vessel was rinsed with EtOH (250 mL) and the light yellow solution was left stirring at tjacket=20° C. for 1 h. NaBH(OAc)3 (497 g, 2.48 moles, 95% w/w) was added in 20 portions over 90 min. EtOH (340 mL) was used for rinsing. The reaction mixture was left stirring for 2 h. A sample was analyzed on GC using HP-5MS column (length 25 m, ID 0.32 mm, Film 0.52 μm) with a gradient method (2 min at 60° C., followed by 25° C./min during 8 min then 2 min at 260° C.). Frontinlet temperature=200° C. using He as gas and a detector temperature=300° C. More NaBH(OAc)3 (30 g, 0.14 moles) was added to complete the reaction within 1 h. The reaction mixture was cooled to tjacket=0° C. before quenching with 5M NaOH (5.5 L). EtOH was distilled off under vacuum at tjacket=50° C. The H2O phase was extracted with toluene (5.5 L) at tjacket=20° C. The organic phase was combined with a second batch, started with (R)-Boc-2-methylpiperazine (300 g, 1.47 moles, 98% w/w). The combined organic phases were concentrated under vacuum at tjacket=50° C. to approximately 2 L. The obtained toluene solution with the intermediate can be stored at 5° C. for several days. The toluene solution was diluted with 2-propanol (2 L) at tjacket=10° C., and HCl in 2-propanol (1.06 L, 6.36 moles, 6M) diluted in 2-propanol (2 L) was added over 30 min. The reaction solution was heated to tjacket=48° C. HCl in 2-propanol (2.12 L, 12.72 moles, 6M) diluted in 2-propanol (2 L) was added over 2 h at tinner=46° C. The reaction solution was kept at tjacket=48° C. for an additional 3 h before being cooled to tjacket=0° C. over 1 h. A seed mixture (0.4 L reaction solution with Example 6 (0.2 g, 0.89 mmoles)) was added. The reaction mixture was left stirring at tjacket=0° C. overnight and the product was filtered off. Drying under vacuum at 40° C. gave Example 6 (620 g, 2.63 moles, 96.3% w/w), 83% yield. 1H-NMR (DMSO-d6): δ 12.46 (s, 1H), 10.13 (s, 2H), 3.35-3.74 (m, 6H), 3.09 (m, 1H), 2.92 (m, 1H), 2.39 (m, 2H), 2.16 (m, 2H), 1.72 (m, 2H), 1.32 (d, 3H, J=6.4 Hz); 13C-NMR (DMSO-d6): δ 58.50, 49.62, 48.13, 44.30, 24.48, 24.38, 15.25, 13.26

Provenance & Evidence