Process for preparing glycopeptide phosphonate derivatives
View Patent ↗Disclosed are processes for preparing glycopeptide phosphonate derivatives having an amino-containing side chain. Several of the process steps are conducted in a single reaction vessel without isolation of intermediate reaction products, thereby generating less waste and improving the overall efficiency and yield of the process.
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 4 is C 1-10 alkylene;
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 alklene, C 1-6 alkenylene and C 1-6 alkynylene;
Cy 1 is selected from the group consisting of C 2-8 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 a salt thereof;
the process comprising:
(a) reacting 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; and a reducing agent to form a compound of formula III:
wherein R 1 , R 2 and R 3 are as defined herein, or a salt thereof;
(b) reacting the compound of formula III with an amine to provide a compound of formula IV:
wherein R 1 and R 2 are as defined herein, or a salt thereof; wherein step (a) and step (b) are conducted in the same reaction mixture without isolation of the intermediate from step (a).
(c) reacting the compound of formula IV with formaldehyde and a compound of formula V:
in the presence of a base 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 R 4 is C 1-6 alkylene.
10. The process according to claim 9 , wherein R 4 is —CH 2 —.
11. The process according to claim 1 , wherein the reducing agent in step (a) is amine/borane complex.
12. The process according to claim 11 , wherein the reducing agent in step (a) is pyridine/borane or tert-butylamine/borane.
13. The process according to claim 1 , wherein step (a) comprises the steps of:
(i) combining vancomycin or a salt thereof with a compound of formula II in the presence of base to form a reaction mixture;
(ii) acidifying the reaction mixture from step (i) with an acid; and
(iii) contacting the reaction mixture from step (ii) with a reducing agent.
14. The process according to claim 13 , wherein the base in step (i) is a tertiary amine.
15. The process according to claim 14 , wherein the base in step (i) is diisopropylethylamine.
16. The process according to claim 13 , wherein the acid in step (ii) is trifluoroacetic acid or acetic acid.
17. The process according to claim 1 , wherein the amine in step (b) is ammonium hydroxide or a primary amine.
18. The process according to claim 17 , wherein the amine in step (b) is ammonium hydroxide, methylamine or tert-butylamine.
19. The process according to claim 18 , wherein the amine in step (b) is tert-butylamine.
20. The process according to claim 1 , wherein the base in step (c) is a tertiary amine.
21. The process according to claim 20 , wherein the base in step (c) is diisopropylethylamine.
22. The process according to claim 20 , wherein the molar ratio of tertiary amine to compound of formula V is about 3:1 to about 5:1.
23. The process according to claim 22 , wherein the molar ratio is about 4:1.
24. 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;
R 4 is —CH 2 —;
the reducing agent in step (a) is tert-butylamine/borane;
and the amine in step (b) is tert-butylamine.