Processes for the preparation of 6-11 bicyclic erythromycin derivatives
View Patent ↗The present invention relates to processes and intermediates for the preparation of 6–11 bicyclic erythromycin derivatives. In particular, the present invention relates to processes and intermediates for the preparation of a compound of formula (IX-c):
1. A process comprising the step of reacting a compound of formula (I):
or a pharmaceutically acceptable salt thereof, with a compound of formula II:
to produce a compound of formula III:
wherein,
Each R 1 is independently hydrogen, acyl, silane, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group;
Each of R 3 and R 4 is independently hydrogen, acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group; or can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring;
Q is independently R 1 , OR 1 , or OC(O)R 1 ;
Z is R 1 , OR 1 , OC(O)R 1 , OC(O)NR 3 R 4 , OS(O) n R 1 , or
one of J or G is hydrogen and the other is R 1 , OR 1 , or NR 3 R 4 ;
or, J and G, taken together with the carbon atom to which they are attached, are C═O, C═NR 1 , C═NOR 1 , C═NO(CH 2 ) m R 1 , C═NNHR 1 , C═NNHCOR 1 , C═NNHCONR 3 R 4 , C═NNHS(O) n R 1 , or C═N—N═CHR 1 ;
R 11 is independently R 1 ;
R p is independently R 1 ;
m is an integer between 1 and about 24; and
n is 0, 1, or 2.
2. The process of claim 1 , wherein the step of reacting occurs in the presence of a palladium catalyst.
3. The process of claim 2 , wherein the palladium catalyst is a palladium (0) catalyst.
4. The process of claim 2 , wherein the palladium catalyst is (dibenzylideneacetone)dipalladium [Pd 2 (dba) 3 ].
5. The process of claim 1 , wherein the step of reacting is in the presence of a monodentate phosphorous-containing ligand.
6. The process of claim 1 , wherein the step of reacting is in the presence of a bidentate phosphorous-containing ligand.
7. The process of claim 1 , wherein the step of reacting is in the presence of 1,4-bis(diphenylphosphino)butane.
8. The process of claim 1 , wherein the step of reacting occurs in an aprotic solvent.
9. The process of claim 8 , wherein the aprotic solvent is tetrahydrofuran.
10. The process of claim 1 , wherein for formula I, Q is OAc, R p is Ac, and Z is
11. The process of claim 1 , wherein for formula II, R 11 is hydrogen and R 1 is tert-butyl.
12. The process of claim 1 , wherein for formula III, R 11 is hydrogen, Q is OAc, R p is Ac, and Z is
13. The process of claim 1 , further comprising the steps of:
(a) hydrolyzing a compound of formula (III) with a mild acid to provide a compound of formula (IV-a):
(b) reducing a compound of formula (IV-a) with a reducing agent to provide a compound of formula (V):
(c) acylating a compound of formula (V) with an acylating agent to provide a compound of formula (VI-a):
(d) oxidatively cleaving a compound of formula (VI-a) with a cleaving reagent or reagents to provide a compound of formula (VII-a):
(e) oxidizing a compound of formula (VII-a) with an oxidizing agent or agents to provide a compound of formula (VIII-a):
and
(f) reacting a compound of formula (VIII-a) with a compound of formula (X):
R 1 —O—NH 2 in the presence of an acid or base to provide a compound of formula (IX-a):
14. The process of claim 13 , wherein the steps of reacting and hydrolyzing are carried out in a one pot process.
15. The process of claim 13 , wherein the steps of reducing and acylating are carried out in a one pot process.
16. The process of claim 13 , wherein the steps of oxidatively cleaving and oxidizing are carried out in a one pot process.
17. The process of claim 13 , wherein for the step of hydrolyzing, the mild acid is hydrochloric acid, sulfuric acid, chloroacetic acid, dichloroacetic acid, or trifluoroacetic acid.
18. The process of claim 13 , wherein for the step of hydrolyzing, the mild acid is aqueous hydrochloric acid.
19. The process of claim 13 , wherein the step of hydrolyzing occurs in a protogenic solvent.
20. The process of claim 19 , wherein the protogenic solvent is water, methanol, ethanol, isopropanol, or butanol.
21. The process of claim 19 , wherein the protogenic solvent is water.
22. The process of claim 13 , wherein for formula IV, Q is hydroxy, R 11 is hydrogen, and R p is Ac.
23. The process of claim 13 , wherein for the step of reducing, the reducing agent is lithium aluminum hydride, titanium(III)chloride, borane, hydrogen sulfide, or sodium nitrite.
24. The process of claim 13 , wherein for the step of reducing, the reducing agent is a titanium (III) reducing agent.
25. The process of claim 24 , wherein for the step of reducing, the titanium (III) reducing agent is titanium(III)chloride.
26. The process of claim 13 , wherein the step of reducing occurs in a protogenic solvent.
27. The process of claim 26 , wherein the protogenic solvent is water, methanol, ethanol, isopropanol, butanol, or mixtures thereof.
28. The process of claim 26 , wherein the protogenic solvent is ethanol.
29. The process of claim 13 , wherein the step of reducing occurs in the presence of an acid.
30. The process of claim 29 , wherein the acid is acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoric acid, or dilute sulfuric acid.
31. The process of claim 29 , wherein the acid is aqueous hydrochloric acid.
32. The process of claim 13 , wherein for formula V, R 11 is hydrogen and R p is Ac.
33. The process of claim 13 , wherein for the step of acylating, the acylating agent is acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, or benzyl chloroformate.
34. The process of claim 13 , wherein the acylating agent is acetic anhydride.
35. The process of claim 13 , wherein the step of acylating occurs in an aprotic solvent.
36. The process of claim 35 , wherein the aprotic solvent is dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone, or mixtures thereof.
37. The process of claim 35 , wherein the aprotic solvent is dichloromethane.
38. The process of claim 13 , wherein for formula VI-a, Q is Ac, R 11 is hydrogen, and R p is Ac.
39. The process of claim 13 , wherein for the step of oxidatively cleaving, the oxidative cleavage reagents are an oxidant and a cleaving reagent.
40. The process of claim 39 , wherein the oxidant is permanganate or ion osmium tetroxide.
41. The process of claim 39 , wherein the oxidant is osmium tetroxide.
42. The process of claim 39 , wherein the cleaving reagent is periodic acid, lead tetraacetate, manganese dioxide, potassium permanganate, sodium periodate, sodium metaperiodate, or N-iodosuccinamide.
43. The process of claim 39 , wherein the cleaving reagent is sodium periodate.
44. The process of claim 39 , wherein the step of oxidatively cleaving occurs in a solvent mixture is a mixture of water and one of the following solvents: 1,4-dioxane, tetrahydrofuran, tert-butanol, acetone, or diethyl ether.
45. The process of claim 44 , wherein the solvent mixture is water in acetone.
46. The process of claim 13 , wherein for formula VII-a, R 1 is methyl and R p is Ac.
47. The process of claim 13 , wherein for the step of oxidizing, the oxidizing agents is a chromium(VI) reagent, Swern reagent, or Corey-Kim reagent.
48. The process of claim 13 , wherein the step of oxidizing occurs in an aprotic solvent.
49. The process of claim 48 , wherein the aprotic solvent is methylene chloride.
50. The process of claim 13 , wherein for formula VIII-a, R 1 is methyl and R p is Ac.
51. The process of claim 13 , wherein for the step of reacting, the acid is hydrochloric acid, phosphoric acid, caomphorsulfonic acid, sulfuric acid, para-toluenesulfonic acid, or pyridinium para-toluene sulfonate.
52. The process of claim 13 , wherein for the step of reacting, the acid is aqueous hydrochloric acid.
53. The process of claim 13 , wherein the step of reacting occurs in a protogenic solvent.
54. The process of claim 53 , wherein the protogenic solvent is ethanol.
55. The process of claim 13 , wherein for the formula (X), R 1 is pyridyl-pyrazolyl.
56. The process of claim 13 , wherein for the formula (IX-a), R 1 is pyridyl-pyrazolyl.