Synthesis and novel salt forms of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine

1. A method for manufacture of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine comprising:

(a) treating compound 1

 with methanesulfonyl chloride to give compound 2

(b) treating compound 2 with diethylmalonate and a base selected from the group consisting of potassium tert-butoxide and sodium ethoxide to give compound 3

(c) hydrolyzing compound 3 to give compound 4

(d) decarboxylating compound 4 to give compound 5

(e) reducing compound 5 to give compound 6

(f) treating compound 6 with methanesulfonyl chloride to give compound 7

(g) reacting compound 7 with sodium iodide to give compound 8

 and

(h) treating compound 8 with potassium tert-butoxide to give compound 9, tert-butyl (R)-3-vinylpyrrolidine-1-carboxylate,

2. The method of claim 1 , wherein step (b) does not comprise column chromatography.

3. The method of claim 1 , wherein step (e) does not comprise column chromatography.

4. The method of claim 1 , wherein step (h) does not comprise column chromatography.

5. The method of claim 1 , wherein the hydrolysis of compound 3 is performed by reaction with potassium hydroxide.

6. The method of claim 1 , wherein the decarboxylation of compound 4 is performed in a solvent with heating, and wherein the solvent is selected from the group consisting of water, ethanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dioxane, 1-methyl-2-pyrrolidinone, dimethylsulfoxide, toluene, and mixtures thereof.

7. The method of claim 6 , wherein the solvent for the decarboxylation is selected from 1-methyl-2-pyrrolidinone, dimethylsulfoxide, toluene, and mixtures thereof.

8. The method of claim 1 , wherein the reduction of compound 5 is performed by reaction with a reagent selected from borane, diborane, borane-tetrahydrofuran complex, borane-dimethyl ether complex, and borane-dimethylsulfide complex.

9. The method of claim 8 , wherein the reduction of compound 5 is performed by reaction with borane-tetrahydrofuran complex.

10. The method of claim 1 , further comprising (i) reacting compound 9 with 5-bromo-pyrimidine to give compound 10

11. The method of claim 10 , wherein the reaction of step (i) is a palladium-catalyzed reaction.

12. The method of claim 10 , further comprising (j) deprotecting compound 10 to give compound 11

13. The method of claim 12 , wherein the deprotection reaction of step (j) is performed with a reagent selected from trifluoroacetic acid, hydrochloric acid, and sulfuric acid.

14. A method for manufacture of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-citrate comprising:

(i) mixing the free base, or a solution of the free base, of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine 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;

(ii) (a) cooling the resulting citrate salt solution to cause precipitation; or

(ii) (b) 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

(ii) (c) 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 (ii) (a) or (ii) (b); and

(iii) filtering to collect the (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-citrate.