تفاعل #79533

معادلة التفاعل

sodium hydroxide

(+)-β-chlorodiisopinocamphenylborane

diethanolamine

4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester

→

piperidine

المردود 34.0%

(R)-α-(2,3-dimethoxyphenyl)-4-piperidinemethanol

المردود 34.0%

المذيبات

water

tetrahydrofuran

water

acetone

tetrahydrofuran

tetrahydrofuran

water

acetone

tetrahydrofuran

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةA suitable reactor maintained under argon
2. 2
   درجة الحرارةThis stirred mixture was cooled to and
3. 3
   درجة الحرارةmaintained below −10° C.
4. 4
   درجة الحرارةThe stirred mixture was maintained below −10° C. for 20 hours
5. 5
   workup.WAITbelow +5° C. for 30 hours
6. 6
   درجة الحرارةwhile maintaining the reaction temperature below 20° C
7. 7
   أخرىThe reaction mixture was transferred to a larger reactor
8. 8
   workup.DISTILLATION19 L of tetrahydrofuran was distilled off at atmospheric pressure
9. 9
   workup.ADDITIONThe mixture was diluted with 30 L of water
10. 10
    workup.DISTILLATIONthe remaining tetrahydrofuran was distilled off below 45° C. at 300 torr
11. 11
    workup.ADDITIONA solution of 5 kg of 33% hydrochloric acid in 40 L of water was added over 5 minutes
12. 12
    درجة الحرارةwhile maintaining a reaction temperature of 15° C
13. 13
    استخلاصThe reaction mixture was extracted with 75 L of heptane
14. 14
    أخرىThe organic phase was separated
15. 15
    استخلاصextracted successively with a solution of 2.2 kg of 33% hydrochloric acid in 20 L of water
16. 16
    أخرىcrystallized
17. 17
    درجة الحرارةThe stirred mixture was cooled
18. 18
    درجة الحرارةmaintained at 5° C. for 1 hour
19. 19
    ترشيحproduct was filtered off
20. 20
    غسيلwashed with 3 L of water
21. 21
    أخرىAfter drying at ambient temperature
22. 22
    أخرىthe quantity obtained
23. 23
    درجة الحرارةThe stirred mixture was heated
24. 24
    درجة الحرارةat reflux for 30 minutes
25. 25
    درجة الحرارةwas slowly cooled to room temperature over 20 hours
26. 26
    درجة الحرارةAfter cooling to 3° C.
27. 27
    ترشيحproduct was filtered off
28. 28
    غسيلwashed with 2×3 L of water
29. 29
    أخرىair dried at 40° C.
30. 30
    أخرىto give 4.6 kg (93% ee)
31. 31
    درجة الحرارةThe stirred mixture was heated
32. 32
    درجة الحرارةat reflux for 30 minutes
33. 33
    درجة الحرارةwas slowly cooled to room temperature over 20 hours
34. 34
    درجة الحرارةAfter cooling to 3° C.
35. 35
    ترشيحproduct was filtered off
36. 36
    غسيلwashed with 2×2 L of water
37. 37
    أخرىair dried at 40° C.

الإجراء التجريبي

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).

المصدر