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 , and —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 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, and 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 and 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 at a temperature in the range from about −20° C. to about 20° C. 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, and 1,1-dioxobenzo[b]thiophene-2-ylmethyl, wherein the 9-fluorenylmethyl group is optionally substituted with 1 to 3 substituents 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 substituents 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.