Preparation of 2S,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 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 a compound of Formula II with an aromatic solvent/alkyl acetate to form a reaction mixture and heating said reaction mixture, said compound of Formula II having the following general formula:
(b) treating said reaction mixture with an acid having a pK a of less than about 4 until the reaction is complete, thereby forming said compound of Formula III;
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 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; and
X − is the conjugate base of said acid.
2. The process in accordance with claim 1 , wherein said compound of Formula II has the following general formula:
3. The process in accordance with claim 2 , wherein said compound of Formula III has the following general formula:
4. The process in accordance with claim 1 , further comprising recovering said compound of Formula III from said reaction mixture.
5. The process in accordance with claim 1 , wherein said acid is a member selected from the group consisting of HCl, HBr, CF 3 CO 2 H, CF 3 SO 3 H, CH 3 SO 3 H, H 2 SO 4 , citric acid, tartaric acid, oxalic acid and p-toluene sulfonic acid.
6. The process in accordance with claim 5 , wherein said acid is HCl.
7. The process in accordance with claim 5 , wherein said acid is CH 3 SO 3 H.
8. The process in accordance with claim 6 , wherein said hydrochloric acid is about 37% aqueous hydrochloric acid.
9. The process in accordance with claim 5 , wherein said hydrochloric acid is gaseous hydrochloric acid.
10. 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.
11. The process in accordance with claim 1 , wherein said aromatic solvent is a member selected from the group consisting of toluene, benzene and xylene.
12. The process in accordance with claim 1 , wherein said aromatic solvent/alkyl acetate is toluene/ethyl acetate.
13. The process in accordance with claim 1 , wherein said reaction mixture is heated to a temperature ranging from about 50° C. to about 100° C.
14. The process in accordance with claim 1 , wherein said reaction mixture is heated to a temperature ranging from about 50° C. to about 80° C.
15. The process in accordance with claim 1 , wherein said reaction mixture is treated with said acid for a time period of at least about 0.5 hours.
16. A process for preparing a compound having the following general formula:
said process comprising:
(a) combining a compound of Formula II with a halogenated solvent to form a reaction mixture and heating said reaction mixture to a temperature ranging from about 10° C. to about 50° C., said compound of Formula II having the following general formula:
(b) treating said reaction mixture with an acid having a pK a of less than about 4 until the reaction is complete, thereby forming said compound of Formula III;
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 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; and
X − is the conjugate base of said acid.
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 17 , wherein said compound of Formula III has the following general formula:
19. The process in accordance with claim 16 , further comprising recovering said compound of Formula III from said reaction mixture.
20. The process in accordance with claim 16 , wherein said halogenated solvent is a member selected from the group consisting of methylene chloride, chloroform, trifluorotoluene (oxsol), parachlorotrifluorotoluene and trichloroethylene.
21. The process in accordance with claim 16 , wherein said halogenated solvent is methylene chloride.
22. The process in accordance with claim 16 , wherein said acid is a member selected from the group consisting of HCl, HBr, CF 3 CO 2 H, CF 3 SO 3 H, CH 3 SO 3 H, H 2 SO 4 , citric acid, tartaric acid, oxalic acid and p-toluene sulfonic acid.
23. The process in accordance with claim 22 , wherein said acid is HCl.
24. The process in accordance with claim 22 , wherein said acid is CH 3 SO 3 H.
25. The process in accordance with claim 23 , wherein said hydrochloric acid is gaseous hydrochloric acid.
26. The process in accordance with claim 16 , wherein said reaction mixture is treated with said acid for a time period of at least about 0.5 hours.
27. The process in accordance with claim 16 , wherein said reaction mixture is heated to a temperature ranging from about 30° C. to about 35° C.