Ethyl Propionate → 1-(Dimethylamino)-2-pyridin-4-ylpent-1-en-3-one

The above intermediate (4-pyridinyl)methyl ethyl ketone was obtained in a mixture with hexamethylphosphoramide as follows: To a mixture containing 200 cc. of tetrahydrofuran and 70 cc. of diisopropylamine under nitrogen at 0°-5° C. was added 210 cc. of 2.4 N n-butyllithium in n-hexane and the resulting mixture was stirred for 30 minutes. Next was added over a 10 minute period 90 cc. of hexamethylphosphoramide followed by stirring of the mixture for 15 minutes. Then was added over a 15 minute period a solution of 48 cc. of 4-picoline in 150 cc. of tetrahydrofuran followed by stirring for 30 minutes at about 0° C. The ice/acetone bath cooling the reaction mixture was replaced with a dry ice/acetone bath and to the reaction mixture was added over a 20 minute period a mixture of 75 cc. of ethyl propionate in an equal volume of tetrahydrofuran. The reaction mixture was then allowed to warm up to room temperature over a period of about 90 minutes and then was warmed at about 35° C. for 30 minutes. The mixture was next cooled in an ice/acetone bath and to it was added 60 cc. of glacial acetic acid over 30 minutes. The resulting pale yellow suspension was diluted with 200 cc. of water. The mixture was extracted with three 150 cc. portions of ethyl acetate and the ethyl acetate extract was back washed with saline solution. The extract was heated in vacuo to remove the ethyl acetate and the residue was taken up again with ethyl acetate. The solution was washed with water and then heated in vacuo to remove the ethyl acetate followed by heating the residue in vacuo at 50° C. for about 30 minutes to yield 100 g. of pale yellow oil. The pale yellow oil was combined with corresponding samples obtained from two additional runs and then distilled in vacuo to yield a 256 g. fraction, b.p. 85°-105° C. at 0.5-1.0 mm. The NMR of this fraction showed it to be a mixture of (4-pyridinyl)methyl ethyl ketone and hexamethylphosphoramide in a respective molar ratio of 1:1.55, that is, 35% or 0.35×256=90 g. of said ketone.

1. additionTo a mixture containing 200 cc
2. additionNext was added over a 10 minute period 90 cc
3. additionThen was added over a 15 minute period a solution of 48 cc
4. stirringby stirring for 30 minutes at about 0° C
5. customwas replaced with a dry ice/acetone bath and to the reaction mixture
6. additionwas added over a 20 minute period
7. additiona mixture of 75 cc
8. temperaturewas warmed at about 35° C. for 30 minutes
9. temperatureThe mixture was next cooled in an ice/acetone bath and to it
10. additionwas added 60 cc
11. additionThe resulting pale yellow suspension was diluted with 200 cc
12. extractionThe mixture was extracted with three 150 cc
13. extractionportions of ethyl acetate and the ethyl acetate extract
14. washwas back washed with saline solution
15. temperatureThe extract was heated in vacuo
16. customto remove the ethyl acetate
17. washThe solution was washed with water
18. temperatureheated in vacuo
19. customto remove the ethyl acetate
20. temperatureby heating the residue in vacuo at 50° C. for about 30 minutes
21. customto yield 100 g
22. customobtained from two additional runs
23. distillationdistilled in vacuo
24. customto yield a 256 g

ORD-Eintrag

ord-4f7b7f19228f4713b9c8975c539dffff

Quelldatensatz

uspto-grants-1982_12

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US04365065