Synthesis and resolution of nicotine
The present disclosure generally relates to methods of preparing nicotine and resolving R,S nicotine to enrich the (S)(−) enantiomer. The method may comprise combining N-methyl-2-pyrrolidone or a salt thereof with a nicotinate compound in the presence of a solvent and a strong base to form 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof; and reducing the 1-methyl-3-nicotinoyl-2-pyrrolidone or salt thereof in solution with Na 2 S 2 O 4 to produce racemic nicotine or salt thereof. Resolving the racemic nicotine (or other enantiomeric mixture) may comprise combining the nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA).
1. A method of preparing a nicotine composition, the method comprising:
combining nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA) in a molar ratio of L-PTTA to nicotine ranging from about 0.3 to about 1.3, wherein the nicotine comprises a mixture of (S)-(−)-nicotine and (R)-(−)-nicotine, and wherein the (S)-(−)-nicotine and the L-PTTA form a salt; and
separating at least a portion of the (S)-(−)-nicotine from the salt.
2. The method of claim 1 , wherein the nicotine composition has an enantiomeric excess of (S)-(−)-nicotine greater than 60%.
3. The method of claim 1 , wherein the nicotine composition has an enantiomeric excess of (S)-(−)-nicotine greater than 95%.
4. The method of claim 1 , wherein the molar ratio of L-PTTA to nicotine ranges from about 0.5 to about 1.1.
5. The method of claim 1 , wherein the molar ratio of L-PTTA to nicotine ranges from about 0.7 to about 0.8.
6. The method of claim 1 , further comprising recrystallizing the salt before separating the (S)-(−)-nicotine from the salt.
7. The method of claim 1 , wherein the nicotine and the L-PTTA are combined in a solution comprising an alcohol, water, acetone, acetonitrile, or a combination thereof.
8. The method of claim 7 , further comprising separating the salt from the solution before separating the (S)-(−)-nicotine from the salt.
9. The method of claim 8 , further comprising recovering unresolved nicotine from the solution after separating the salt from the solution.
10. The method of claim 9 , further comprising enriching an amount of (S)-(−)-nicotine in the unresolved nicotine.
11. The method of claim 8 , further comprising recovering L-PTTA from the solution after separating the salt from the solution.
12. The method of claim 8 , further comprising adding a pure (S)-(−)-nicotine L-PTTA salt to the solution before separating the (S)-(−)-nicotine from the solution.
13. A method of preparing a nicotine composition, the method comprising:
combining nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA) in a molar ratio of L-PTTA to nicotine ranging from about 0.6 to about 1 in solution, wherein the nicotine comprises a mixture of (S)-(−)-nicotine and (R)-(−)-nicotine, and wherein the (S)-(−)-nicotine and the L-PTTA form a salt; and
separating at least a portion of the (S)-(−)-nicotine from the salt.
14. The method of claim 13 , further comprising recovering unresolved nicotine from the solution after separating the (S)-(−)-nicotine from the salt.
15. The method of claim 14 , wherein the nicotine composition has an enantiomeric excess of (S)-(−)-nicotine greater than 60%.
16. The method of claim 13 , wherein the mixture of (S)-(−)-nicotine and (R)-(−)-nicotine is a racemic mixture.
17. The method of claim 13 , further comprising recrystallizing the salt before separating the (S)-(−)-nicotine from the salt.
18. A method of preparing a nicotine composition, the method comprising:
combining nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA) in a molar ratio of L-PTTA to nicotine ranging from about 0.6 to about 1, wherein the nicotine comprises a mixture of (S)-(−)-nicotine and (R)-(−)-nicotine, and wherein the (S)-(−)-nicotine and the L-PTTA form a salt; and
separating at least a portion of the (S)-(−)-nicotine from the salt;
wherein the nicotine composition has an enantiomeric excess of (S)-(−)-nicotine greater than 90%.
19. The method of claim 18 , wherein the nicotine and the L-PTTA are combined in solution, the method further comprising adding a pure (S)-(−)-nicotine L-PTTA salt to the solution.
20. The method of claim 18 , further comprising recrystallizing the salt before separating the (S)-(−)-nicotine from the salt.