Preparation of 2S,3S-
View Patent ↗The present invention provides a new process for the preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride, wherein this compound is prepared directly from the chloromethylalcohol. Importantly, the process of the present invention results in higher yields of 2S,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 2S,3S-derivative, but also the 2R,3S-, 2S,2R- and the 2R,3R-derivatives.
1. A process for preparing a compound having the following general formula:
said process comprising:
(a) combining nosyl chloride with an alkyl acetate to form a first reaction mixture;
(b) combining a tertiary amine with a compound of Formula I in an aromatic solvent to form a second reaction mixture, said compound of Formula I having the following general formula:
(c) adding said first reaction mixture while hot with said second reaction mixture to form a third reaction mixture and heating said third reaction mixture until the reaction is complete, thereby forming said compound of Formula II;
wherein:
R 1 is an amino acid side chain or a functionalized amino acid side chain;
R 2 is a protecting group; and
R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and -NHP, wherein P is selected from the group consisting of H, alkyl, cycloalkyl, aryl and a protecting group, or R 3 and R 4 together form a cyclic structure selected from the group consisting of quinoline and isoquinoline.
2. The process in accordance with claim 1 , wherein said alkyl acetate is a member selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate and isobutyl acetate.
3. The process in accordance with claim 2 , wherein said alkyl acetate is ethyl acetate.
4. The process in accordance with claim 1 , wherein said tertiary amine is a member selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine.
5. The process in accordance with claim 4 , wherein said tertiary amine is triethylamine.
6. The process in accordance with 1 , wherein said aromatic solvent is a member selected from the group consisting of toluene, benzene and xylene.
7. The process in accordance with 6 , wherein said aromatic solvent is toluene.
8. The process in accordance with 1 , wherein said reaction mixture is heated to a temperature of about 50° C. to about 100° C.
9. The process in accordance with 1 , wherein said reaction mixture is heated to a temperature of about 60° C. to about 75° C.
10. The process in accordance with 1 , wherein said compound of Formula I has the following general formula:
11. The process in accordance with 10 , wherein said compound of Formula II has the following general formula:
12. A process for preparing a compound having the following general formula:
said process comprising:
(a) combining nosyl chloride with a halogenated solvent to form a first reaction mixture;
(b) combining a tertiary amine with a compound of Formula I in said halogenated solvent to form a second reaction mixture, said compound of Formula I having the following general formula:
(c) adding said first reaction mixture to the said second reaction mixture to form a third reaction mixture and heating said third reaction mixture to a temperature ranging from about 10° C. to about 50° C. until the reaction is complete, thereby forming said compound of Formula II;
wherein:
R 1 is an amino acid side chain or a functionalized amino acid side chain;
R 2 is a protecting group; and
R 3 is a member selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and -NHP, wherein P is selected from the group consisting of H, alkyl, cycloalkyl, aryl and a protecting group.
13. The process in accordance with claim 12 , wherein said halogenated solvent is a member selected from the group consisting of methylene chloride, chloroform, trifluorotoluene (oxsol), parachlorotrifluorotoluene and trichloroethylene.
14. The process in accordance with claim 12 , wherein said tertiary amine is a member selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine.
15. The process in accordance with claim 12 , wherein said reaction mixture is heated to a temperature ranging from about 30° C. to about 35° C.
16. The process in accordance with claim 12 , wherein said compound of Formula I has the following general formula:
17. The process in accordance with claim 16 , wherein said compound of Formula II has the following general formula:
18. The process in accordance with claim 12 , wherein said halogenated solvent is methylene chloride.