反应 #1869168

反应方程式

DCM

sodium borohydride

2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone

(S)-(+)-2-amino-1-propanol

→

(2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-2-hydroxyethyl}amino]propan-1-ol

收率 65.0%

溶剂

tetrahydrofuran

Water

tetrahydrofuran

water

tetrahydrofuran

反应条件

后处理

1. 1
   温度maintaining the temperature below 30° C
2. 2
   workup.STIRRINGThe resulting solution was stirred for 60 minutes at 15° C
3. 3
   其他When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture
4. 4
   workup.ADDITIONwas treated with concentrated HCl (27% w/w, 47 Kg) over 80 minutes
5. 5
   温度maintaining the temperature below 30° C
6. 6
   温度The mixture was cooled to 15° C.
7. 7
   workup.ADDITIONNaOH (34% w/w, 79 Kg) was added over 60 minutes
8. 8
   温度maintaining the temperature below 30° C
9. 9
   其他When all the chloroalcohol intermediate was consumed
10. 10
    其他the aqueous phase was separated
11. 11
    workup.ADDITIONDCM (150 L) and water (140 L) were added
12. 12
    workup.STIRRINGthe mixture was stirred
13. 13
    其他to separate
14. 14
    洗涤The organic phase was washed with water (2×30 L)
15. 15
    workup.DISTILLATIONThe equipment was set for distillation and DCM
16. 16
    其他to give a final volume of 160 litres
17. 17
    workup.WAITThe reaction mixture was left
18. 18
    温度at reflux overnight
19. 19
    温度After cooling to room temperature
20. 20
    洗涤the mixture was washed with water (3×30 L)
21. 21
    workup.DISTILLATIONThe equipment was set for distillation
22. 22
    其他to give a final volume of 84 litres
23. 23
    温度the mixture was cooled to 5° C. over 8 hours
24. 24
    workup.WAITgranulated at 5° C. for 6 hours
25. 25
    过滤The product was collected by filtration
26. 26
    洗涤washed with ααα-trifluorotoluene (2×30 L)
27. 27
    其他dried at 45° C. under vacuum overnight

实验过程

Water (15.0 L) was added to a suspension of sodium borohydride (4.11 Kg, 109 mol) in tetrahydrofuran (140 L) at 15° C. and the resulting solution stirred at 15° C. A solution of 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone (30.0 Kg, 120.6 mol) in tetrahydrofuran (100 L) and water (15 L) was added over 40 minutes maintaining the temperature below 30° C. The resulting solution was stirred for 60 minutes at 15° C. When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture was treated with concentrated HCl (27% w/w, 47 Kg) over 80 minutes maintaining the temperature below 30° C. The mixture was cooled to 15° C. and NaOH (34% w/w, 79 Kg) was added over 60 minutes maintaining the temperature below 30° C. The mixture was then granulated at 20° C. overnight. When all the chloroalcohol intermediate was consumed, the aqueous phase was separated. DCM (150 L) and water (140 L) were added and the mixture was stirred before allowing the phases to separate. The organic phase was washed with water (2×30 L). (S)-(+)-2-amino-1-propanol (17.2 Kg, 229 mol) and tetrahydrofuran (15 L) were added over 20 minutes. The equipment was set for distillation and DCM was replaced by tetrahydrofuran to give a final volume of 160 litres. The reaction mixture was left at reflux overnight. After cooling to room temperature, DCM (150 L) was added and the mixture was washed with water (3×30 L). The equipment was set for distillation and the tetrahydrofuran and DCM were replaced by acetonitrile to give a final volume of 84 litres. ααα-trifluorotoluene (300 L) was added over 60 minutes, the mixture was cooled to 5° C. over 8 hours and granulated at 5° C. for 6 hours. The product was collected by filtration, washed with ααα-trifluorotoluene (2×30 L) and dried at 45° C. under vacuum overnight. Yield=65% (22.7 Kg) δH (CDCl3, 300 MHz) 1.10 (3H, t), 2.10 (6H, s), 2.7-3.2 (3H, m), 3.45 (1H, m), 3.70 (H, dd), 4.85 (1H, m), 5.90 (2H, s), 7.20 (1H, d), 7.90 (1H, dd), 8.60 (1H, d) ppm. MS m/z 290 (MH+). The intermediate epoxide was characterised as δH (CDCl3, 300 MHz) 2.10 (6H, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) ppm. MS m/z 215 (MH+).

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