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 —CH 2 —;
R 2 is n-decyl;
R 4 is —CH 2 —;
or a salt thereof;
the process comprising:
(a) combining vancomycin or a salt thereof, with a compound of formula II:
wherein R 3 is W—OC(O)—, where W is 9-fluorenylmethyl, in the presence of 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 to form a compound of formula III:
or a salt thereof;
(d) reacting the compound of formula III with an amine to provide a compound of formula IV:
or a salt thereof; and wherein steps (a), (b), (c) and (d) are conducted in the same reaction mixture without isolation of the intermediate from step (a), (b) or (c);
(e) 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 the base in step (a) is a tertiary amine.
3. The process according to claim 1 , wherein the base in step (a) is diisopropylethylamine.
4. The process according to claim 1 , wherein the acid in step (b) is trifluoroacetic acid.
5. The process according to claim 1 , wherein the acid in step (b) is acetic acid.
6. The process according to claim 1 , wherein the reducing agent in step (c) is an amine/borane complex.
7. The process according to claim 1 , wherein the reducing agent in step (c) is tert-butylamine/borane.
8. The process according to claim 1 , wherein the reducing agent in step (c) is pyridine/borane.
9. The process according to claim 1 , wherein the amine in step (d) is ammonium hydroxide or a primary amine.
10. The process according to claim 1 , wherein the amine in step (d) is ammonium hydroxide, methylamine or tert-butylamine.
11. The process according to claim 1 , wherein the amine in step (d) is tert-butylamine.
12. The process according to claim 1 , wherein the base in step (e) is a tertiary amine.
13. The process according to claim 1 , wherein the base in step (e) is diisopropylethylamine.
14. The process according to claim 1 , wherein
the base in step (a) is diisopropylethylamine;
the acid in step (b) is trifluoroacetic acid;
the reducing agent in step (c) is tert-butylamine/borane;
the amine in step (d) is tert-butylamine; and
the base in step (e) is diisopropylethylamine.