反应详情

A mixture of 4-hydroxy-4-thiophen-2-yl-piperidine (3.3 g, 18 mmol) and (R)-4-methyl-3-(pyrid-2-yl)-[1,2,3]-oxathiazolidine-2,2-dioxide (3.7 g, 17.5 mmol) was stirred in dimethylformamide (70 ml) at ambient temperature for 40 minutes, then evaporated to dryness in vacuo and the residue dissolved in tetrahydrofuran (30 m) and water (10 ml). Concentrated sulfuric acid (2.9 g) was dropwise added while maintaining room temperature. Thereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion and the resulting suspension stirred at ambient temperature overnight. Water (100 ml) and ethylacetate (100 ml) were added to the reaction mixture and the pH adjusted to 10 with the addition of 0.5N NaOH. The product was extracted with ethylacetate (3×100 ml) and the combined organic layer washed with brine (150 ml), dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained residue was dissolved in acetic acid (300 ml) and heated to 140° C. bath temperature for 3 hours. After cooling to room temperature the mixture was evaporated in vacuo and the residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated in vacuo. Column chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid gave 4.2 g of the title compound as the fumarate salt hemihydrate, m.p. 63°-8° C.

1. customevaporated to dryness in vacuo
2. dissolutionthe residue dissolved in tetrahydrofuran (30 m)
3. additionConcentrated sulfuric acid (2.9 g) was dropwise added
4. additionThereafter sodium hydrogencarbonate (6.7 g) were added in a portion wise fashion
5. additionWater (100 ml) and ethylacetate (100 ml) were added to the reaction mixture
6. additionthe pH adjusted to 10 with the addition of 0.5N NaOH
7. extractionThe product was extracted with ethylacetate (3×100 ml)
8. washthe combined organic layer washed with brine (150 ml)
9. dry with materialdried over magnesium sulfate
10. filtrationfiltered
11. customevaporated to dryness
12. dissolutionThe obtained residue was dissolved in acetic acid (300 ml)
13. temperatureheated to 140° C. bath temperature for 3 hours
14. temperatureAfter cooling to room temperature the mixture
15. customwas evaporated in vacuo
16. customthe residue partitioned between chloroform and 5% aqueous sodium hydrogencarbonate
17. customThe organic layer was separated
18. dry with materialdried over magnesium sulfate
19. filtrationfiltered
20. customevaporated in vacuo
21. additionColumn chromatography on 120 g of silica gel with 2% methanol/ethylacetate as eluant, followed by trituration in ether with the addition of two molequivalent of fumaric acid