Process for preparing glycopeptide derivatives
View Patent ↗Disclosed are processes for preparing glycopeptide antibiotic derivatives having an amino-containing side chain. The multi-step process is conducted in a single reaction vessel without isolation of intermediate reaction products.
1. A process for preparing a compound of formula I:
wherein
R 1 is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene and C 2-10 alkynylene;
R 2 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 6-10 aryl, C 2-9 heteroaryl, C 2-9 heterocyclic, —R a -Cy 1 , —R a -Ar 1 -Ar 2 , —R a -Ar 1 -R b -Ar 2 , —R a -Ar 1 -O—R b -Ar 2 ;
R a is selected from the group consisting of C 1-10 alkylene, C 1-10 alkenylene and C 1-10 alkynylene;
R b is selected from the group consisting of C 1-6 alkylene, C 1-6 alkenylene and C 1-6 alkynylene;
Cy 1 is selected from the group consisting of C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 6-10 aryl, C 2-9 heteroaryl, C 2-9 heterocyclic;
Ar 1 and Ar 2 are independently selected from C 6-10 aryl and C 2-9 heteroaryl;
wherein each aryl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, nitro and trifluoromethyl, and each heteroaryl and heterocyclic group contains from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur;
or salts thereof;
the process comprising:
(a) combining vancomycin or a salt thereof, with a compound of formula II:
wherein R 1 and R 2 are as defined herein; and R 3 is a amine-labile protecting group; in the presence of a base to form a reaction mixture;
(b) acidifying the reaction mixture from step (a) with an acid;
(c) contacting the reaction mixture from step (b) with a reducing agent;
(d) contacting the reaction mixture from step (c) with an amine, to provide a compound of formula I or a salt thereof.
2. The process according to claim 1 , wherein R 1 is C 1-6 alkylene.
3. The process according to claim 2 , wherein R 1 is —CH 2 —.
4. The process according to claim 1 , wherein R 2 is C 6-14 alkyl.
5. The process according to claim 4 , wherein R 2 is n-decyl.
6. The process according to claim 1 , wherein R 3 is a group of formula (A):
W—OC(O)— (A)
wherein W is selected from the group consisting of 9-fluorenylmethyl, 3-indenylmethyl, benz[f]inden-3-ylmethyl, 17-tetrabenzo[a,c,g,i]fluorenylmethyl, 2,7-di-tert-butyl[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 1,1-dioxobenzo[b]thiophene-2-ylmethyl, wherein the 9-fluorenylmethyl group is optionally substituted with 1 to 3 substitutents selected from the group consisting of C 1-6 alkyl, halo, nitro and sulfo.
7. The process according to claim 6 , wherein W is 9-fluorenylmethyl, wherein the 9-fluorenylmethyl group is optionally substituted with 1 to 3 substitutents selected from the group consisting of C 1-6 alkyl, halo, nitro and sulfo.
8. The process according to claim 7 , wherein W is 9-fluorenylmethyl.
9. The process according to claim 1 , wherein the base in step (a) is a tertiary amine.
10. The process according to claim 9 , wherein the base in step (a) is diisopropylethylamine.
11. The process according to claim 1 , wherein the acid in step (b) is trifluoroacetic acid or acetic acid.
12. The process according to claim 1 , wherein the reducing agent in step (c) is amine/borane complex.
13. The process according to claim 12 , wherein the reducing agent in step (c) is pyridine/borane or tert-butylamine/borane.
14. The process according to claim 1 , wherein the amine in step (d) is ammonium hydroxide or a primary amine.
15. The process according to claim 14 , wherein the amine in step (d) is ammonium hydroxide, methylamine or tert-butylamine.
16. The process according to claim 15 , wherein the amine in step (d) is tert-butylamine.
17. The process according to claim 1 , wherein:
R 1 is —CH 2 —;
R 2 is n-decyl;
R 3 is W—OC(O)—, where W is 9-fluorenylmethyl;
the base in step (a) is diisopropylethylamine;
the acid in step (b) is trifluoroacetic acid or acetic acid;
the reducing agent in step (c) is pyridine/borane or tert-butylamine/borane;
and the amine in step (d) is ammonium hydroxide, methylamine or tert-butylamine.
18. The process according to claim 17 , wherein the reducing agent in step (c) is tert-butylamine/borane; and the amine in step (d) is tert-butylamine.