تفاعل #1869168

معادلة التفاعل

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

المردود 65.0%

المذيبات

tetrahydrofuran

Water

tetrahydrofuran

water

tetrahydrofuran

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةmaintaining the temperature below 30° C
2. 2
   workup.STIRRINGThe resulting solution was stirred for 60 minutes at 15° C
3. 3
   أخرىWhen 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
   درجة الحرارةmaintaining the temperature below 30° C
6. 6
   درجة الحرارةThe mixture was cooled to 15° C.
7. 7
   workup.ADDITIONNaOH (34% w/w, 79 Kg) was added over 60 minutes
8. 8
   درجة الحرارةmaintaining the temperature below 30° C
9. 9
   أخرىWhen all the chloroalcohol intermediate was consumed
10. 10
    أخرىthe 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
    أخرىto separate
14. 14
    غسيلThe organic phase was washed with water (2×30 L)
15. 15
    workup.DISTILLATIONThe equipment was set for distillation and DCM
16. 16
    أخرىto give a final volume of 160 litres
17. 17
    workup.WAITThe reaction mixture was left
18. 18
    درجة الحرارةat reflux overnight
19. 19
    درجة الحرارةAfter cooling to room temperature
20. 20
    غسيلthe mixture was washed with water (3×30 L)
21. 21
    workup.DISTILLATIONThe equipment was set for distillation
22. 22
    أخرىto give a final volume of 84 litres
23. 23
    درجة الحرارةthe mixture was cooled to 5° C. over 8 hours
24. 24
    workup.WAITgranulated at 5° C. for 6 hours
25. 25
    ترشيحThe product was collected by filtration
26. 26
    غسيلwashed with ααα-trifluorotoluene (2×30 L)
27. 27
    أخرىdried at 45° C. under vacuum overnight

الإجراء التجريبي

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+).

المصدر