反応 #1869165

反応方程式

HCl

2-chloro-N-methoxy-N-methylacetamide

5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine

n-Butyl lithium

→

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

収率 78.8%

溶媒

TBME

TBME

water

TBME

反応条件

後処理

1. 1
   workup.ADDITIONwas added drop-wise over 1 hour
2. 2
   温度maintaining the temperature between −74° C. and −69° C
3. 3
   温度maintaining the temperature between −73° C. and −67° C
4. 4
   workup.STIRRINGThe resulting mixture was then stirred at temperature between −73 and −67° C. for a further 100 minutes
5. 5
   workup.ADDITIONto rise from −70° C. to 17° C. during the addition
6. 6
   workup.STIRRINGthe mixture was stirred
7. 7
   その他to separate
8. 8
   洗浄The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L)
9. 9
   濃縮before concentrating in vacuo
10. 10
    workup.ADDITIONIPA (1.50 L) was added to the residue
11. 11
    温度the mixture was heated to reflux
12. 12
    workup.STIRRINGstirred overnight
13. 13
    温度before cooling to 8-12° C. for 1 hour
14. 14
    ろ過The product was collected by filtration
15. 15
    洗浄washed with IPA (2×0.1 L)
16. 16
    その他dried at 45° C. under vacuum overnight

実験手順

A solution of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.00 Kg 3.98 mol) in TBME (7.5 L) was cooled to −70° C. n-Butyl lithium (2.5N in hexane; 1.73 L, 4.32 mol) was added drop-wise over 1 hour maintaining the temperature between −74° C. and −69° C. The mixture was then stirred at a temperature between −74° C. and −69° C. for a further 15 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.65 Kg, 4.72 mol) in TBME (3.0 L) was then added drop-wise over 100 minutes maintaining the temperature between −73° C. and −67° C. The resulting mixture was then stirred at temperature between −73 and −67° C. for a further 100 minutes. 2N HCl (5.0 L) was then added drop-wise over 45 minutes, allowing the temperature to rise from −70° C. to 17° C. during the addition. TBME (4.0 L) and water (2.0 L) was added to the resulting suspension and the mixture was stirred before allowing the phases to separate. The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L) before concentrating in vacuo. IPA (1.50 L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, before cooling to 8-12° C. for 1 hour. The product was collected by filtration, washed with IPA (2×0.1 L) and dried at 45° C. under vacuum overnight. Yield 78.8% (0.78 Kg), δH (CDCl3, 300 MHz) 2.20 (6H, s), 4.70 (2H, s), 5.95 (2H, s), 7.35 (1H, d), 8.40 (1H, dd), 9.15 (1H, d) ppm. MS m/z 249 (MH+).

出典