Ethyl chloroformate → 4-(1-Benzothiophen-3-yl)piperidine

11 g of 1-methyl-4-(benzo[b]thien-3-yl)-piperidine is dissolved in 120 ml of toluene. At a reaction temperature of 50°, 20 g of chloroformic acid ethyl ester is slowly added dropwise under a strong flow of nitrogen. The solution is thereupon stirred for 20 hours at 50°; a further 10 g of chloroformic acid ethyl ester is added dropwise and stirring is continued for 2 hours at 50°. The excess chloroformic acid ethyl ester is subsequently distilled off under normal pressure, the solution is cooled to 70°, filtered under suction and the filter residue is afterwards washed with 500 ml of toluene. The combined filtrates are successively washed with 500 ml of water, 800 ml of a 10% solution of methanesulphonic acid in water, 500 ml of water, 500 ml of 2N sodium hydroxide solution and 500 ml of water; they are dried with sodium sulphate, filtered and concentrated by evaporation. The resulting 4-benzo[b]thien-3-yl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 110 ml of ethylene gylcol. After the addition of 13 g of solid sodium hydroxide, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°. The reaction solution is thereupon cooled to 20°, and extracted three times with 500 ml of ethyl acetate each time. The organic phases are washed 5 times with 1 litre of water each time, dried with sodium sulphate, filtered, combined, and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid and the acid solution is extracted with toluene. The aqueous solution is thereupon adjusted to have a pH-value of 12 by addition of 10% sodium hydroxide solution, and is then extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered and concentrated by evaporation; there is obtained crude 4-(benzo[b]thien-3-yl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallised from acetone, whereupon it melts above 270°.

1. stirringstirring
2. waitis continued for 2 hours at 50°
3. distillationThe excess chloroformic acid ethyl ester is subsequently distilled off under normal pressure
4. temperaturethe solution is cooled to 70°
5. filtrationfiltered under suction
6. washthe filter residue is afterwards washed with 500 ml of toluene
7. washThe combined filtrates are successively washed with 500 ml of water, 800 ml of a 10% solution of methanesulphonic acid in water, 500 ml of water, 500 ml of 2N sodium hydroxide solution and 500 ml of water
8. dry with materialthey are dried with sodium sulphate
9. filtrationfiltered
10. concentrationconcentrated by evaporation
11. dissolutionThe resulting 4-benzo[b]thien-3-yl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 110 ml of ethylene gylcol
12. additionAfter the addition of 13 g of solid sodium hydroxide
13. temperaturethe formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°
14. temperatureThe reaction solution is thereupon cooled to 20°
15. extractionextracted three times with 500 ml of ethyl acetate each time
16. washThe organic phases are washed 5 times with 1 litre of water each time
17. dry with materialdried with sodium sulphate
18. filtrationfiltered
19. concentrationconcentrated by evaporation
20. dissolutionThe residue is dissolved in 500 ml of 2N hydrochloric acid
21. extractionthe acid solution is extracted with toluene
22. additionby addition of 10% sodium hydroxide solution
23. extractionis then extracted with one litre of chloroform
24. dry with materialThe chloroform solution is dried with sodium sulphate
25. filtrationfiltered
26. concentrationconcentrated by evaporation

ORD record

ord-2a5a358e19cc44abb918f580b1993d22

Source dataset

uspto-grants-1976_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US03974280