Synthesis and novel salt forms of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine
The present invention relates to the stereospecific synthesis of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, its salt forms, and novel polymorphic forms of these salts.
1. A method for manufacture of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono citrate comprising:
(a) reacting compound 9, tert-butyl (R)-3-vinylpyrrolidine-1-carboxylate, with 5-bromo-pyrimidine to give compound 10
(b) deprotecting compound 10 to give compound 11
(c) mixing the free base, or a solution of the free base, of compound 11 in a first solvent with citric acid in pure form or as a solution of the citric acid in a first solvent to form a citrate salt solution, wherein the first solvent is selected from the group consisting of ethanol, methanol, isopropyl alcohol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, n-heptane, and acetonitrile;
(d) (i) cooling the resulting citrate salt solution to cause precipitation; or
(d) (ii) adding a second solvent selected from the group consisting of ethanol, methanol, isopropyl alcohol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, n-heptane, and acetonitrile to cause precipitation; or
(d) (iii) evaporating the first solvent and adding a second solvent selected from the group consisting of ethanol, methanol, isopropyl alcohol, isopropyl acetate, acetone, ethyl acetate, toluene, water, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, n-heptane, and acetonitrile, and repeating either step (d) (i) or (d) (ii); and
(e) filtering to collect the (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-citrate.
2. The method of claim 1 , wherein the reaction of step (a) is a palladium-catalyzed reaction.
3. The method of claim 2 , wherein the palladium-catalyzed reaction is performed with palladium acetate.
4. The method of claim 1 , wherein the reaction of step (a) is performed in N,N-dimethylacetamide.
5. The method of claim 1 , wherein the deprotection reaction of step (b) is performed with a reagent selected from the group consisting of trifluoroacetic acid, hydrochloric acid, and sulfuric acid.
6. The method of claim 5 , wherein the reagent is hydrochloric acid.
7. The method of claim 1 , wherein the first solvent for step (c) is methanol.
8. The method of claim 1 , wherein the second solvent for step (d)(ii) is methanol.
9. The method of claim 1 , wherein the first solvent for step (d)(iii) is methanol.
10. The method of claim 1 , wherein the second solvent for step (d)(iii) is methanol.