Diethanolamine → (R)-(2,3-Dimethoxyphenyl)-4-piperidinemethanol

Temperature

15 °C

A suitable reactor maintained under argon was charged with (+)-β-chlorodiisopinocamphenylborane (18.2 kg, 56.7 mol) and 4 L of tetrahydrofuran. This stirred mixture was cooled to and maintained below −10° C. while adding a solution of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) (15.05 kg, 39.8 mol, 13.03 kg theory) in 4 L of tetrahydrofuran over a period of 2 hours. The stirred mixture was maintained below −10° C. for 20 hours, then below −5° C. for 20 hours, then below +5° C. for 30 hours, and finally it was maintained at 15° C. for 4 days. The reaction mixture was diluted with 11 L of tetrahydrofuran, followed by the addition of a solution of diethanolamine (6 kg, 57.1 mol) in 18 L of tetrahydrofuran while maintaining the reaction temperature below 20° C. The reaction mixture was transferred to a larger reactor and 19 L of tetrahydrofuran was distilled off at atmospheric pressure. The mixture was diluted with 30 L of water and the remaining tetrahydrofuran was distilled off below 45° C. at 300 torr. A solution of 5 kg of 33% hydrochloric acid in 40 L of water was added over 5 minutes while maintaining a reaction temperature of 15° C. The reaction mixture was extracted with 75 L of heptane. The organic phase was separated and extracted successively with a solution of 2.2 kg of 33% hydrochloric acid in 20 L of water, followed by a solution of 0.55 kg of 33% hydrochloric acid in 5 L of water. The acid extracts were combined and diluted with a mixture of 20% sodium hydroxide (23.9 kg, 119.5 mol) and 5 L of water. The aqueous basic solution was stirred for 17 hours at room temperature while the product crystallized. The stirred mixture was cooled and maintained at 5° C. for 1 hour, then product was filtered off and washed with 3 L of water. After drying at ambient temperature, the quantity obtained was 6.45 kg (72.9% ee). The 6.45 kg was added to a solution of 43 L of acetone and 86 L of water. The stirred mixture was heated at reflux for 30 minutes, then was slowly cooled to room temperature over 20 hours. After cooling to 3° C., product was filtered off, washed with 2×3 L of water, then air dried at 40° C. to give 4.6 kg (93% ee). The 4.6 kg was added to a solution of 11 L of acetone and 22 L of water. The stirred mixture was heated at reflux for 30 minutes, then was slowly cooled to room temperature over 20 hours. After cooling to 3° C., product was filtered off, washed with 2×2 L of water, then air dried at 40° C. to give (R)-α-(2,3-dimethoxyphenyl)methyl]piperidine (1) (34% yield, 95.5% ee).

1. temperatureA suitable reactor maintained under argon
2. temperatureThis stirred mixture was cooled to and
3. temperaturemaintained below −10° C.
4. temperatureThe stirred mixture was maintained below −10° C. for 20 hours
5. waitbelow +5° C. for 30 hours
6. temperaturewhile maintaining the reaction temperature below 20° C
7. customThe reaction mixture was transferred to a larger reactor
8. distillation19 L of tetrahydrofuran was distilled off at atmospheric pressure
9. additionThe mixture was diluted with 30 L of water
10. distillationthe remaining tetrahydrofuran was distilled off below 45° C. at 300 torr
11. additionA solution of 5 kg of 33% hydrochloric acid in 40 L of water was added over 5 minutes
12. temperaturewhile maintaining a reaction temperature of 15° C
13. extractionThe reaction mixture was extracted with 75 L of heptane
14. customThe organic phase was separated
15. extractionextracted successively with a solution of 2.2 kg of 33% hydrochloric acid in 20 L of water
16. customcrystallized
17. temperatureThe stirred mixture was cooled
18. temperaturemaintained at 5° C. for 1 hour
19. filtrationproduct was filtered off
20. washwashed with 3 L of water
21. customAfter drying at ambient temperature
22. customthe quantity obtained
23. temperatureThe stirred mixture was heated
24. temperatureat reflux for 30 minutes
25. temperaturewas slowly cooled to room temperature over 20 hours
26. temperatureAfter cooling to 3° C.
27. filtrationproduct was filtered off
28. washwashed with 2×3 L of water
29. customair dried at 40° C.
30. customto give 4.6 kg (93% ee)
31. temperatureThe stirred mixture was heated
32. temperatureat reflux for 30 minutes
33. temperaturewas slowly cooled to room temperature over 20 hours
34. temperatureAfter cooling to 3° C.
35. filtrationproduct was filtered off
36. washwashed with 2×2 L of water
37. customair dried at 40° C.

ORD record

ord-1173c8a6d7b2434f8b80bc93ca0dadc1

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06713627B2