Process for preparing triazole-containing ketolide antibiotics
View Patent ↗The invention described herein pertains to processes for the preparation of macrolide antibacterial agents. In particular, the invention pertains to processes for preparing macrolides and ketolides from erythromycin A.
1. A process comprising (a) the step of contacting a compound of formula (III)
or a salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, with an acylating agent to form a compound of formula (IV)
or a salt thereof, wherein R is an acyl group; or
(b) the step of contacting a compound of formula (IV), or a salt thereof, with a methylating agent, to form a compound of formula (V)
or a salt thereof; or
(c) the step of contacting a compound of formula (V), or a salt thereof, with a deoximating agent to form a compound of formula (II)
or a salt thereof; or
(d) any combination of (a), (b), and (c).
2. The process of claim 1 comprising (a) and (b).
3. The process of claim 1 comprising (a) and (c).
4. The process of claim 1 comprising (b) and (c).
5. The process of claim 1 comprising (a), (b), and (c).
6. A process for preparing a compound of formula (II)
or a salt thereof, wherein:
R is an acyl group;
the process comprising (c) the step of contacting a compound of formula (V)
or a salt thereof, with a deoximating agent to form the compound of formula (II).
7. The process of claim 6 further comprising (b) the step of contacting a compound of formula (IV)
or a salt thereof, wherein R is an acyl group, with a methylating agent, to form a compound of formula (V)
or a salt thereof.
8. The process of claim 7 further comprising (a) the step of contacting a compound of formula (III)
or a salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, with an acylating agent to form a compound of formula (IV)
or a salt thereof, wherein R is an acyl group.
9. The process of claim 6 comprising (a) the step of contacting a compound of formula (III)
or a salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, with an acylating agent to form a compound of formula (IV)
or a salt thereof, wherein R is an acyl group(b) and (c).
10. A compound of formula (IV) or (V)
or an acid addition salt thereof, wherein Q in combination with the oxime oxygen forms an acetal or ketal, and R is an acyl group.
11. The compound of claim 10 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl.
12. The compound of claim 10 wherein Q is 2-methoxy-2-propyl.
13. The compound of claim 10 wherein R is a sterically hindered acyl group.
14. The compound of claim 10 wherein R is benzoyl.
15. The process of claim 1 wherein the acylating agent is the anhydride.
16. The process of claim 1 wherein the methylating agent in step (b) is methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate or methyl methanesulfonate.
17. The process of claim 1 wherein the deoximating agent in step (c) comprises a reducing agent.
18. The process of claim 1 wherein the deoximating agent in step (c) comprises formic acid and sodium metabisulfite.
19. The process of claim 1 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl.
20. The process of claim 1 wherein Q is 2-methoxy-2-propyl.
21. The process of claim 1 wherein R is benzoyl.
22. The process of claim 6 wherein the acylating agent is the anhydride.
23. The process of claim 6 wherein the methylating agent in step (b) is methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate or methyl methanesulfonate.
24. The process of claim 6 wherein the deoximating agent in step (c) comprises formic acid and sodium metabisulfite.
25. The process of claim 6 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl.
26. The process of claim 6 wherein Q is 2-methoxy-2-propyl.
27. The process of claim 6 wherein R is benzoyl.
28. The compound of claim 10 of formula (IV), or a salt thereof.
29. The compound of claim 28 wherein Q is 2-methoxy-2-propyl.
30. The compound of claim 28 wherein R is benzoyl.
31. The compound of claim 28 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl; and R is benzoyl.
32. The compound of claim 10 of formula (V), or a salt thereof.
33. The compound of claim 32 wherein Q is 2-methoxy-2-propyl.
34. The compound of claim 32 wherein R is benzoyl.
35. The compound of claim 32 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or 1-isopropoxycyclohexyl; and R is benzoyl.