Preparations containing amino acids and orotic acid
View Patent ↗The present invention describes compounds produced from an orotic acid molecule and an amino acid molecule. The compounds being in the form of amino acid orotate compounds bound by an amide linkage and produced by one of two disclosed methods; 1) reacting orotic acid or derivatives thereof with a thionyl halide, and then combining the acyl halide with an amino acid in the presence of dichloromethane and a DMAP catalyst; or 2) protecting the carboxylic acid of an amino acid and then combining the amino acid with a DCC activated orotic acid, followed by removal of the carboxylic acid protecting group. The resulting amino acid orotate amide has an enhanced stability in solution as compared to a related ester. In addition, specific benefits are conferred by the particular amino acid used to form the compounds in addition to, and separate from, the orotate substituent.
1. A compound having the general structure:
wherein R is selected from the group consisting of (CH 3 ) 2 CHCH 2 —; (CH 3 ) 2 CH—; and CH 3 CH 2 CH(CH 3 )—.
2. The compound of claim 1 , wherein said compound is produced by a method comprising at least the steps of: mixing at least equivalent molar amounts of a thionyl halide with orotic acid to form an acyl halide; said acyl halide then being added to a dichloromethane suspension of an amino acid selected from the group consisting of being one of leucine, valine and isoleucine, in the presence of a 4-dimethyl-aminopyridine; and isolating and purifying the resulting compound of claim 1 .
3. The compound of claim 2 , wherein the halide of the thionyl halide is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
4. The compound of claim 2 , wherein the amino acid Leucine.
5. The compound of claim 2 , wherein the 4-dimethyl-aminopyridine is present in catalytic amounts.
6. The compound of claim 2 , wherein the acyl halide is produced at temperatures from between about 30° C. to about 55° C.
7. The compound of claim 2 , wherein the acyl halide and the amino acid suspended in dichloromethane are reacted at temperatures from between about −15° C. to room temperature.
8. The compound of claim 2 , wherein the amino acid orotate amide is isolated by filtration and then concentrated in vacuo.
9. The compound of claim 2 , wherein the amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
10. The compound of claim 2 , wherein the amino acid orotate amide has the general structure of:
wherein R is (CH 3 ) 2 CHCH 2 —.
11. The compound of claim 1 , wherein said compound is produced by a method comprising at least the steps of: reacting an amino acid with N,N′-diisopropyl-O-benzylisourea to form a benzyl protected amino acid selected from the group consisting of leucine, valine and isoleucine; isolating said benzyl protected amino acid; reacting an activated orotic acid with the benzyl protected amino acid to form a benzyl protected amino acid orotate amide; isolating and purifying said benzyl protected amino acid orotate amide; removing the benzyl protecting group from said benzyl protected amino acid orotate amide; and isolating and purifying the deprotected compound of claim 1 .
12. The compound of claim 11 , wherein the amino acid Leucine.
13. The compound of claim 11 , wherein the benzyl protected amino acid is isolated by filtration.
14. The compound of claim 11 , wherein the orotic acid is activated in situ by dicyclohexylcarbodiimine.
15. The compound of claim 11 , wherein the benzyl protected amino acid orotate amide is produced at temperatures from between about 0° C. to about room temperature.
16. The compound of claim 11 , wherein the benzyl protected amino acid orotate amide is isolated by filtration through and then concentrated under reduced pressure.
17. The compound of claim 11 , wherein the benzyl protected amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
18. The compound of claim 11 , wherein the benzyl protected amino acid orotate amide is deprotected by the removal of the benzyl group from the carboxylic acid.
19. The compound of claim 18 , wherein the benzyl group from the carboxylic acid is removed via hydrogenation using a palladium on carbon catalyst.
20. The compound of claim 11 , wherein the deprotected amino acid orotate amide is isolated by filtration and then concentrated under reduced pressure.
21. The compound of claim 11 , wherein the deprotected amino acid orotate amide is purified by flash chromatography using a silica gel packed column.
22. The compound of claim 11 , wherein the deprotected amino acid orotate amide has the general structure of:
wherein R is (CH 3 ) 2 CHCH 2 —.