Preparation of 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-P-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines
View Patent ↗The present invention provides a new process for the preparation of 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbuty1)-p-nitrobenzenesulfonylamide hydrochloride, wherein this compound is prepared directly from the chloromethylalcohol. Importantly, the process of the present invention results in higher yields of 2R,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride without sacrificing its purity. The processes of the present invention can be used to prepare not only the 2R,3S-derivative, but also the 2S,3S-, 2S,2R- and the 2R,3R-derivatives.
1. A process for the preparation of a compound having the following general formula:
said process comprising: combining a halomethyl alcohol (HMA) with a sulfonamide to form a reaction mixture, and heating said reaction mixture until the reaction is complete, thereby forming the compound of Formula II; wherein said HMA has the following general formula:
and wherein:
R 1 is an amino acid side chain or a functionalized amino acid side chain;
R 2 is a protecting group;
R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of alkyl, cycloalkyl and aryl; and
X is a leaving group.
2. The process in accordance with claim 1 , wherein said HMA is a 2S,3S-HMA.
3. The process in accordance with claim 1 , wherein X is a halogen.
4. The process in accordance with claim 3 , wherein X is chloro or bromo.
5. The process in accordance with claim 1 , wherein R is a member selected from the group consisting of an alkyl group, a benzyl group, a phenyl thiomethyl group, a protected hydroxymethyl group, an S-alkyl group and a nitrobenzyl group.
6. The process in accordance with claim 1 , wherein R 2 is a protecting group selected from the group consisting of t-Boc, i-Boc, Moc, Cbz and Fmoc.
7. The process in accordance with claim 2 , wherein said 2S,3S- HMA has the following general formula:
8. The process in accordance with claim 2 , wherein said sulfonamide has the general formula:
wherein:
R 5 and R 6 independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl.
9. The process in accordance with claim 8 , wherein R 5 is alkyl and R 6 is aryl.
10. The process in accordance with claim 9 , wherein said aryl has the general formula:
wherein:
Z is a member selected from the group consisting of H, alkyl, halogen, hydroxy, alkoxy, and —NO 2 .
11. The process in accordance with claim 8 , wherein said sulfonamide is a member selected from the group consisting of isobutylparanitrobenzenesulfonamide, isobutylmetanitrobenzenesulfonamide and isobutylorthonitrobenzenesulfonamide.
12. The process in accordance with claim 1 , wherein said reaction mixture further comprises an acid scavenger.
13. The process in accordance with claim 12 , wherein said acid scavenger has the general formula M + B 31 , wherein M + is selected from the group consisting of K + , Na + , Li 30 , Ca +2 , Mg +2 and Al +2 ; and B 31 is selected from the group consisting of − 0 H, HCO 3 31 and CO 3 31 2 .
14. The process in accordance with claim 7 , wherein said compound of Formula II has the following general formula:
15. The process in accordance with claim 1 , wherein said reaction mixture is heated to a temperature ranging from about 50° C. to about 125° C.
16. The process in accordance with claim 1 , wherein said reaction mixture is heated to a temperature ranging from about 60° C. to about 80° C.