Alkylation of picolinamides with substituted chloroacylals utilizing a crown ether catalyst

1. A method, comprising the steps of:

reacting a picolinamide of Formula (I):

with a substituted chloroacylal of Formula (II):

to produce a compound of Formula (III):

wherein:

the picolinamide of Formula (I) is (3S,6S,7R,8R)-8-benzyl-3-{[(3-hydroxy-4-methoxypyri-2-yl)carbonyl]amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate], the substituted chloroacylal of Formula (II) is chloromethyl isobutyrate, and the compound of Formula (III) is (3S,6S,7R,8R)-8-benzyl-3-{[(4-methoxy-3-{[(2-methylpropanoyl)oxy]methoxy}-pyridin-2-yl)carbonyl]amino}-6-methyl-4,9-diox-1,5-dioxonan-7-yl 2-methylpropanoate]; and

wherein the reacting step is conducted in the presence of a crown ether and an inorganic halide co-catalyst, wherein the crown ether is at least one ether selected from the group consisting of: 12-crown-4, 15-crown-5, 18-crown-6, and benzo- and dibenzo-crown ethers thereof.

2. The method of claim 1 , wherein the crown ether is at least one ether selected from the group consisting of: 12-crown-4, 15-crown-5, 18-crown-6, benzo-12-crown-4, benzo-15-crown-5, and dibenzo-18-cown-6.

3. The method of claim 1 , wherein the crown ether is at least one ether selected from the group consisting of: 15-crown-5, 18-crown-6, and benzo-15-crown-5.

4. The method of claim 1 , wherein the inorganic halide co-catalyst is an inorganic iodide.

5. The method of claim 4 , wherein the inorganic iodide is at least one iodide salt selected from the group consisting of sodium iodide and potassium iodide.

6. The method of claim 1 , wherein the reaction is carried out in an organic solvent.

7. The method of claim 6 , wherein the organic solvent is at least one organic solvent selected from the group consisting of ketonic, acetate ester, aromatic hydrocarbon, chlorinated organic, and organic nitrile.

8. The method of claim 7 , wherein the organic solvent is at least one solvent selected from the group consisting of acetone, ethyl acetate, and toluene.

9. The method of claim 1 , wherein the reaction is carried out in a basic environment.

10. The method of claim 9 , wherein the basic environment is provided by a metallic carbonate.

11. The method of claim 10 , wherein the metal carbonate is at least one carbonate selected from the group consisting of sodium carbonate and potassium carbonate.

12. A method comprising:

reacting (3S,6S,7R,8R)-8-benzyl-3-{[(3-hydroxy-4-methoxypyridin-2-yl)carbonyl]-amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate] with chloromethyl isobutyrate in the presence of a crown ether and an inorganic iodide to produce (3S,6S,7R,8R)-8-benzyl-3-{[(4-methoxy-3-{[(2-methylpropanoyl)oxy]methoxy}-pyridin-2-yl)carbonyl]amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate] and one or more by-products, wherein the crown ether is at least one ether selected from the group consisting of: 12-crown-4, 15-crown-5, 18-crown-6, and benzo- and dibenzo-crown ethers thereof.

13. The method of claim 12 , wherein the one or more by-products is a compound of Formula VII:

14. The method of claim 12 , wherein the yield of (3S,6S,7R,8R)-8-benzyl-3-{[(4-methoxy-3-{[(2-methylpropanoyl)oxy]methoxy}-pyridin-2-yl)carbonyl]amino}-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate] is about 80% (±2%) or greater.

15. The method of claim 12 , wherein the crown ether is at least one ether selected from the group consisting of: 12-crown-4, 15-crown-5, 18-crown-6, benzo-12-crown-4, benzo-15-crown-5, and dibenzo-18-cown-6.

16. The method of claim 12 , wherein the inorganic iodide is at least one iodide selected from the group consisting of sodium iodide and potassium iodide.

17. The method of claim 12 , wherein the reaction is carried out in at least one organic solvent selected from the group consisting of acetone, ethyl acetate, and toluene.

18. The method of claim 12 , wherein the crown ether is at least one ether selected from the group consisting of: 15-crown-5, 18-crown-6, and benzo-15-crown-5.