Hexane → 5-Ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester

Temperature

-15 °C

An oven dried round-bottom flask is charged with toluene (35 mL) and cooled to −15° C. in a dry ice/acetone bath. A solution of butyl lithium in hexane (1.6M, 11.22 mL, 18.0 mmol) is added in one portion. To this mixture is added a solution of butylmagnesium bromide in tetrahydrofuran (2 M, 4.5 mL, 9.0 mmol) drop-wise over 1.25 hr to give a suspension. The reaction is stirred at −10° C. for 1 hr after which a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (5 g, 21.7 mmol) in anhydrous toluene (10 mL) is added drop-wise over 1.25 hr. The resulting suspension is stirred at −10° C. for 30 min. The bath is cooled to −30° C. and allowed to warm slowly to 0° C. over 12 hr. The reaction is allowed to stir at −10° C. for 5 hr before diluting with anhydrous tetrahydrofuran (15 mL) to give a cloudy cream solution. This solution is added drop-wise over 1.5 hr to a cold solution of dimethyl carbonate (9.14 mL, 108 mmol) in anhydrous toluene (10 mL) stirring under a nitrogen atmosphere at −20° C. The resulting mixture is allowed to warm slowly to 0° C. After 5.5 hr, the reaction is quenched with saturated aqueous ammonium chloride (20 mL) and then partitioned between water and ethyl acetate. The ethyl acetate layer is washed with a further portion of water, and the combined aqueous washes are extracted with seven portions of ethyl acetate and two portions of dichloromethane. The combined organic extract is dried over magnesium sulfate, filtered and evaporated to give crude 5-ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester (5.58 g) as an orange oil. This material is used without further purification. MS: m/e=210 (M+H); 1H NMR (CDCl3, δ, ppm): 7.94 (1H, s), 4.02 (3H, s), 3.90 (3H, s), 2.77 (3H, s), 2.59 (2H, q), 1.23 (3H, t).

1. customto give a suspension
2. additionis added drop-wise over 1.25 hr
3. temperatureThe bath is cooled to −30° C.
4. temperatureto warm slowly to 0° C. over 12 hr
5. stirringto stir at −10° C. for 5 hr
6. customto give a cloudy cream solution
7. stirringstirring under a nitrogen atmosphere at −20° C
8. temperatureto warm slowly to 0° C
9. waitAfter 5.5 hr
10. customthe reaction is quenched with saturated aqueous ammonium chloride (20 mL)
11. custompartitioned between water and ethyl acetate
12. washThe ethyl acetate layer is washed with a further portion of water
13. extractionthe combined aqueous washes are extracted with seven portions of ethyl acetate and two portions of dichloromethane
14. extractionThe combined organic extract
15. dry with materialis dried over magnesium sulfate
16. filtrationfiltered
17. customevaporated

ORD record

ord-81bfd98a098d43d8b9f6082c67bcde9a

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08173682B2