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 hydrochloride salt of a compound of formula I:
the process comprising,
(a) combining vancomycin, or a salt thereof, with a compound of formula II:
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;
(d) contacting the reaction mixture from step (c) with an amine to provide a compound of formula IV:
or a salt thereof; 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, or a salt thereof, with formaldehyde and a compound of formula V:
in the presence of a base;
(f) acidifying the reaction mixture from step (e) to a pH in the range of from 2 to 3 with hydrochloric acid; and
(g) adding acetonitrile to the reaction mixture from step (F) to precipitate a hydrochloride salt of the compound of formula I.
2. The process according to claim 1 , wherein the process further comprises:
(h) isolating the hydrochloride salt of the compound of formula I from step (g) by filtration.
3. The process according to claim 2 , wherein the process further comprises:
(i) washing the hydrochloride salt of the compound of formula I from step (h) with acetonitrile.
4. The process according to claim 1 , wherein the base in step (a) is a tertiary amine.
5. The process according to claim 1 , wherein the base in step (a) is diisopropylethylamine.
6. The process according to claim 1 , wherein the acid in step (b) is trifluoroacetic acid.
7. The process according to claim 1 , wherein the acid in step (b) is acetic acid.
8. The process according to claim 1 , wherein the reducing agent in step (c) is an amine/borane complex.
9. The process according to claim 1 , wherein the reducing agent in step (c) is tert-butylamine/borane.
10. The process according to claim 1 , wherein the reducing agent in step (c) is pyridine/borane.
11. The process according to claim 1 , wherein the amine in step (d) is ammonium hydroxide or a primary amine.
12. The process according to claim 1 , wherein the amine in step (d) is ammonium hydroxide, methylamine or tert-butylamine.
13. The process according to claim 1 , wherein the amine in step (d) is tert-butylamine.
14. The process according to claim 1 , wherein the base in step (e) is a tertiary amine.
15. The process according to claim 1 , wherein the base in step (e) is diisopropylethylamine.
16. 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.
17. A process for preparing a hydrochloride salt of a compound of formula I:
the process comprising:
(a) combining vancomycin, or a salt thereof, with a compound of formula II:
in the presence of diisopropylethylamine to form a reaction mixture;
(b) acidifying the reaction mixture from step (a) with trifluoroacetic acid;
(c) contacting the reaction mixture from step (b) with tert-butylamine/borane;
(d) contacting the reaction mixture from step (c) with tert-butylamine to provide a compound of formula IV:
or a salt thereof 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, or a salt thereof, with formaldehyde and a compound of formula V:
in the presence of diisopropylethylamine;
(f) acidifying the reaction mixture from step (e) to a pH in the range of from 2 to 3 with hydrochloric acid;
(g) adding acetonitrile to the reaction mixture from step (f) to precipitate a hydrochloride salt of the compound of formula I;
(h) isolating the hydrochloride salt of the compound of formula I from step (g) by filtration; and
(i) washing the hydrochloride salt of the compound of formula I from step (h) with acetonitrile.