반응 #1869165

반응 방정식

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

수율 78.8%

용매

TBME

TBME

water

TBME

반응 조건

후처리

1. 1
   workup.ADDITIONwas added drop-wise over 1 hour
2. 2
   온도maintaining the temperature between −74° C. and −69° C
3. 3
   온도maintaining 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
   기타to separate
8. 8
   세척The 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
   농축before concentrating in vacuo
10. 10
    workup.ADDITIONIPA (1.50 L) was added to the residue
11. 11
    온도the mixture was heated to reflux
12. 12
    workup.STIRRINGstirred overnight
13. 13
    온도before cooling to 8-12° C. for 1 hour
14. 14
    여과The product was collected by filtration
15. 15
    세척washed with IPA (2×0.1 L)
16. 16
    기타dried at 45° C. under vacuum overnight

실험 절차

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+).

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