Trifluoroacetic acid → Ethyl 4-cyanomethyl-2-piperidinecarboxylate

To a solution of 19.9 g (67.2 mmol) of ethyl 4-cyanomethyl-N-t-butoxycarbonyl-2-piperidinecarboxylate (prepared in Example 3F) in 100 ml of dichloromethane was added 50 ml of trifluoroacetic acid (CO2 evolution). The mixture was stirred for 3 hr at room temperature and then was concentrated under vacuum. To the residue was added 100 ml of dichloromethane, and the solution was again concentrated under vacuum. The residue was dissolved in 200 ml of dichloromethane, 200 ml of saturated aqueous sodium bicarbonate was added, and the mixture was stirred for 15 minutes at room temperature. The organic layer was separated and washed with 100 ml of saturated aqueous sodium bicarbonate, and the combined aqueous washes were extracted twice with 100 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 12.7 g (96%) of ethyl 4-cyanomethyl-2-piperidinecarboxylate. GC analysis showed an 85:15 mixture of cis:trans isomers. To a solution of 11.6 g (59.1 mmol) of the product in 60 ml of dimethylsulfoxide was added 9.9 g (118.2 mmol) of sodium bicarbonate and 5.7 ml (7.9 g, 65.0 mmol) of allyl bromide. After 1 hr at room temperature, another 1.1 ml portion of allyl bromide was added, and after another 2 hours at room temperature, the mixture was poured into 100 ml of water and 100 ml of brine and was extracted 5 times with 50 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organics were washed with 100 ml of water, then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to afford 8.6 g (62%) of ethyl cis-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate and 1.2 g (9%) of ethyl trans-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate, both of which were >99.9% one isomer by GC.

1. concentrationwas concentrated under vacuum
2. additionTo the residue was added 100 ml of dichloromethane
3. concentrationthe solution was again concentrated under vacuum
4. dissolutionThe residue was dissolved in 200 ml of dichloromethane
5. addition200 ml of saturated aqueous sodium bicarbonate was added
6. stirringthe mixture was stirred for 15 minutes at room temperature
7. customThe organic layer was separated
8. washwashed with 100 ml of saturated aqueous sodium bicarbonate
9. extractionthe combined aqueous washes were extracted twice with 100 ml each of dichloromethane and once with 50 ml of diethyl ether
10. dry with materialThe combined organic extracts were dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated

ORD record

ord-5370d43177d046ada8f9037de8454b36

Source dataset

uspto-grants-1990_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04968678