Reaktion #1869165

Reaktionsgleichung

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

Ausbeute 78.8%

Lösungsmittel

TBME

TBME

water

TBME

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwas added drop-wise over 1 hour
2. 2
   Temperaturmaintaining the temperature between −74° C. and −69° C
3. 3
   Temperaturmaintaining 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
   Sonstigeto separate
8. 8
   WaschenThe 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
   Einengenbefore concentrating in vacuo
10. 10
    workup.ADDITIONIPA (1.50 L) was added to the residue
11. 11
    Temperaturthe mixture was heated to reflux
12. 12
    workup.STIRRINGstirred overnight
13. 13
    Temperaturbefore cooling to 8-12° C. for 1 hour
14. 14
    FiltrationThe product was collected by filtration
15. 15
    Waschenwashed with IPA (2×0.1 L)
16. 16
    Sonstigedried at 45° C. under vacuum overnight

Vorschrift

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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