Synthesis and resolution of nicotine
View Patent ↗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 (S)-(−)-nicotine or a salt thereof, the method comprising:
combining N-methyl-2-pyrrolidone or a salt thereof with a nicotinate compound in the presence of a solvent and a base to form 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof;
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 a salt thereof;
enriching (S)-(−)-nicotine by combining the racemic nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA) to produce a nicotine-L-PTTA salt; and
isolating the (S)-(−)-nicotine from the nicotine-L-PTTA salt.
2. The method of claim 1 , wherein reducing the 1-methyl-3-nicotinoyl-2-pyrrolidone or salt thereof is performed at a pH ranging from about pH 8 to about pH 11.
3. The method of claim 2 , wherein reducing the 1-methyl-3-nicotinoyl-2-pyrrolidone or salt thereof comprises adjusting the pH while adding the Na 2 S 2 O 4 in two or more portions.
4. The method of claim 1 , wherein the nicotinate compound comprises methyl nicotinate.
5. The method of claim 1 , wherein the racemic nicotine comprises crude nicotine product without purification.
6. The method of claim 1 , wherein the L-PTTA has a molar ratio with respect to nicotine (L-PTTA:nicotine) ranging from about 0.7 to about 0.8.
7. The method of claim 1 , wherein enriching the (S)-(−)-nicotine comprises recrystallizing the nicotine-L-PTTA salt.
8. The method of claim 1 , wherein the method produces (S)(−)-nicotine with an enantiomeric excess of at least 75%.
9. The method of claim 1 , wherein the method produces (S)(−)-nicotine with an enantiomeric excess of at least 90%.
10. A method of preparing (S)(−)-nicotine or a salt thereof, the method comprising:
reducing 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 by combining the racemic nicotine with (−)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA) to produce a nicotine-L-PTTA salt; and
separating (S)(−)-nicotine from the nicotine-L-PTTA salt.
11. The method of claim 10 , wherein the L-PTTA has a molar ratio with respect to nicotine (L-PTTA:nicotine) ranging from about 0.7 to about 0.8.
12. The method of claim 10 , further comprising recovering unresolved nicotine.
13. The method of claim 12 , further comprising racemizing the unresolved nicotine.
14. The method of claim 13 , further comprising enriching an amount of (S)(−)-nicotine enantiomer in the racemized nicotine.
15. The method of claim 14 , wherein the enriched nicotine has an enantiomeric excess of at least 90%.
16. The method of claim 10 , wherein the separated (S)(−)-nicotine is in free base form.
17. The method of claim 10 , wherein the 1-methyl-3-nicotinoyl-2-pyrrolidone or salt thereof is produced by combining N-methyl-2-pyrrolidone or a salt thereof with a nicotinate compound in the presence of a solvent and a base.