Carbon tetrabromide → Tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate

200 ml of a solution of 19.7 g of triphenylphosphine and 12.4 g of carbon tetrabromide in dichloromethane was stirred under ice-cooling and 20 ml of a solution of 4.0 g of 1-(tert-butoxycarbonyl)piperidine-4-carbaldehyde in dichloromethane was dropped thereinto. After stirring for 1 hour, the reaction mixture was diluted with diethyl ether and filtered through celite to thereby remove the insoluble residue. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 5.7 g of 4-(2,2-dibromovinyl)-1-(tert-butoxycarbonyl)piperidine as a colorless oily component. Next, 2.72 g of this product was dissolved in 50 ml of dry tetrahydrofuran in a nitrogen atmosphere and cooled to −78° C. A 1.0 M solution of n-buthyllithium (15 ml; 15 mmol) in hexane was dropped thereinto and the resulting mixture was stirred for 1 hour and then at room temperature for additional 1 hour. After cooling to −78° C. again, ethyl chloroformate was dropped into the reaction mixture. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 2.2 g of ethyl(1-(tert-butoxycarbonyl)piperidin-4-yl)propionate as a colorless oily component. A 1.1 g portion of this product was dissolved in a mixture of anisole (5 ml) with dichloromethane (5 ml). To this solution was added trifluoroacetic acid until the material disappeared. The reaction mixture was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted and dried over potassium carbonate. After distilling off the solvent under reduced pressure, the residue was dissolved in 20 ml of N,N-dimethylformamide. After adding 350 mg of potassium carbonate and 630 mg of 8-chloromethyl-10H-pyrazino[2.3-b][1,4]benzothiazine, the resulting mixture was heated to 80° C. for 1 hour. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 550 mg of yellow crystals of ethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propiolate.

1. temperaturecooling
2. filtrationfiltered through celite
3. customto thereby remove the insoluble residue
4. distillationAfter distilling off the solvent under reduced pressure
5. customthe residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane)

ORD record

ord-c6ec6d26cdd3457697721f480db57efc

Source dataset

uspto-grants-2003_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06518423B1