Triethylamine → 1-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidine

Temperature

-10 °C

A stirred solution of 250 g (1.24 mole) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in 2.3 L of dichloromethane was cooled to −10° C. 188 g (1.86 mole) of triethylamine was added in a narrow stream over a 20 minute period. There was no significant temperature change. The resulting solution was stirred at −10° C. for 30 minutes and then 172 g (1.50 mole) of methanesulfonyl chloride was added dropwise over a 30 minute period. The temperature rose to 0° C. during the addition. The resulting suspension was stirred at temperatures reaching 21° C. over the next 18 hours. The mixture was filtered and the solid was washed with 800 mL of ethyl acetate. The washing was added to the filtrate which was concentrated by approximately 2 L. The residual suspension was diluted with 1 L of ethyl acetate and filtered. The solid was washed with 500 mL of ethyl acetate. The washing was added to the filtrate which was passed through a silica gel (230-400 mesh) pad containing 350 g of adsorbent. The pad was washed with 600 mL of ethyl acetate. The washing was added to the filtrate which was concentrated to approximately 800 mL and diluted with 400 mL of hexane. The suspension was stirred at −10° C. for 2 hours and filtered. The solid was rinsed with ethyl acetate:hexane (2: 1, 300 mL) and pressed dry under suction. Further drying in vacuo at 32° C. for 19 hours provided 307 g (89%) of product.

1. additionThe temperature rose to 0° C. during the addition
2. stirringThe resulting suspension was stirred at temperatures
3. customreaching 21° C. over the next 18 hours
4. filtrationThe mixture was filtered
5. washthe solid was washed with 800 mL of ethyl acetate
6. additionThe washing was added to the filtrate which
7. concentrationwas concentrated by approximately 2 L
8. additionThe residual suspension was diluted with 1 L of ethyl acetate
9. filtrationfiltered
10. washThe solid was washed with 500 mL of ethyl acetate
11. additionThe washing was added to the filtrate which
12. additioncontaining 350 g of adsorbent
13. washThe pad was washed with 600 mL of ethyl acetate
14. additionThe washing was added to the filtrate which
15. concentrationwas concentrated to approximately 800 mL
16. additiondiluted with 400 mL of hexane
17. stirringThe suspension was stirred at −10° C. for 2 hours
18. filtrationfiltered
19. washThe solid was rinsed with ethyl acetate:hexane (2: 1, 300 mL)
20. custompressed dry under suction
21. customFurther drying in vacuo at 32° C. for 19 hours

ORD record

ord-afef45d0fbad49a0a42f176842cd1731

Source dataset

uspto-grants-2009_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07485636B2