Dichloromethane → t-Butyl 4-[(3S)-4-Benzyl-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate

In a 5 L flask, (2S)-1-benzyl-2-methylpiperazine (260.0 g, 1.366 mol), dichloromethane (1000 mL), t-butyl 4-oxo-1-piperidinecarboxylate (272 g, 1.37 mol) and titanium tetraisopropoxide (480.0 mL, 1.626 mol) were mixed and the mixture was stirred at room temperature for 20 h. The mixture was cooled down to 0° C. and diethylaluminum cyanide in toluene (1.0 M, 1600 mL) was added dropwise. The resulting mixture was stirred at room temperature for 20 h. The reaction content was then split into two 5 L flasks, To each flask, 1 L of ethyl acetate, 500 g of sodium bicarbonate, 150 g of celite were added before they were cooled down to −40° C. using dry ice/acetonitrile. To each flask, 200 mL of saturated aqueous sodium sulfate was then slowly added with vigorous stirring. After the reaction mixture was slowly warmed up to room temperature and stirred for 4 hours, 1 L of methanol was added to each flask. After being stirred overnight, the reaction mixture was filtered through a thin layer of sand. The cake was taken back into a 5 L flask and stirred with 3 L of methanol for 5 hours, and insoluble solid was filtered off. The combined filtrates were concentrated to dryness, and 3 L of methylene chloride was added. Insoluble solid was filtered off. The filtrate was dried with magnesium sulfate, the solvent was removed to give 484 g (88.9%) of product as a slight yellow solid. The crude product was essentially pure and used directly for next step. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.32 (m, 5H), 4.04 (d, 1H), 3.95 (brs, 2H), 3.15 (d, 1H), 3.15 (brs, 2H), 2.82 (m, 1H), 2.73 (m, 2H), 2.44 (m, 2H), 2.25 (t, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.66 (m, 1H), 1.46 (s, 9H), 1.17 (d, 3H); MS (EI) 399.2 (M+1).

1. temperatureThe mixture was cooled down to 0° C.
2. stirringThe resulting mixture was stirred at room temperature for 20 h
3. customThe reaction content was then split into two 5 L flasks, To each flask
4. addition1 L of ethyl acetate, 500 g of sodium bicarbonate, 150 g of celite were added before they
5. temperaturewere cooled down to −40° C.
6. additionTo each flask, 200 mL of saturated aqueous sodium sulfate was then slowly added with vigorous stirring
7. temperatureAfter the reaction mixture was slowly warmed up to room temperature
8. stirringstirred for 4 hours
9. addition1 L of methanol was added to each flask
10. stirringAfter being stirred overnight
11. filtrationthe reaction mixture was filtered through a thin layer of sand
12. customThe cake was taken back into a 5 L flask
13. stirringstirred with 3 L of methanol for 5 hours
14. filtrationinsoluble solid was filtered off
15. concentrationThe combined filtrates were concentrated to dryness, and 3 L of methylene chloride
16. additionwas added
17. filtrationInsoluble solid was filtered off
18. dry with materialThe filtrate was dried with magnesium sulfate
19. customthe solvent was removed

ORD record

ord-1d94d23025ab48bd999644d164aeb047

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09067921B2