Claims
- 1. A method of preparing clarithromycin of formula (I) consisting essentially of the steps of:(a) preparing erythromycin A N-oxide of formula (II) from erythromycin A; (b) reacting erythromycin A N-oxide of formula (II) with a methylating agent to obtain 6-O-methylerythromycin A N-oxide of formula (III); and (c) treating 6-O-methylerythromycin A N-oxide obtained in step (b) with a reducing agent to obtain clarithromycin:
- 2. The process of claim 1, wherein step (b) is carried out in an base at a temperature ranging from −15 to 40° C.
- 3. The process of claim 1, wherein the methylating agent is selected from the group consisting of methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, methyl methanesulfonate and a mixture thereof.
- 4. The process of claim 1, wherein the amount of methylating agent is in the range of 1 to 3 molar equivalents based on the amount of erythromycin A N-oxide.
- 5. The process of claim 2, wherein the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, N,N,N′, N′, N″,N″-hexamethylphosphoramide, tetrahydrofurane, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, 2-methoxy, 2-methoxyethylether, 2-ethoxyethylether, 1,2-bis(2-methoxyethoxy)ethane, tetraethylene glycol dimethylether, acetone, acetonitrile or a mixture thereof.
- 6. The process of claim 2, wherein the base is selected from the group consisting of alkali metal hydrides, hydroxides, alkoxides and a mixture thereof.
- 7. The process of claim 1, wherein the amount of the base is in the range of 0.9 to 2 molar equivalents based on the amount of erythromycin A N-oxide.
- 8. The process of claim 1, wherein the reducing agent is selected from the group consisting of hydrogen in the presence of a hydrogenation catalyst; a nickel-aluminum alloy(Ni—Al alloy) combined with potassium hydroxide; metallic zinc in the presence of formic acid or acetic acid; sodium hydrogen telluride(NaTeH); samarium iodide(SmI2); stannous chloride(SnCl2); hexabutylditin(Bu3SnSnBu3); a mixture of cyclohexene and osmium tetroxide(OsO4); ferrous sulfate; NaHSO3; Na2SO3; Na2S2O3; Na2S2O4; Na2S2O5; Na2S2O6; KHSO3; K2S2O3; K2S2O5; and a mixture thereof.
- 9. The process of claim 1, wherein the reducing agent is selected from the group consisting of stannous chloride(SnCl2); hexabutylditin(Bu3SnSnBu3); a nickel-aluminum alloy combined with potassium hydroxide; and hydrogen in the presence of a Raney-nickel or platinum oxide(PtO2) catalyst.
Priority Claims (1)
Number |
Date |
Country |
Kind |
1999/52371 |
Nov 1999 |
KR |
|
CROSS REFERENCE TO RELATED APPLICATION
This application is a National Stage Application of International Application Number PCT/KR00/01349, filed Nov. 23, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/KR00/01349 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO01/38340 |
5/31/2001 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5864023 |
Ku et al. |
Jan 1999 |
A |
Non-Patent Literature Citations (2)
Entry |
Ku et al., “An Efficient Synthesis of Des-N-Methyl-N-Acetyl Erythromycin Derivatives via the N-Oxide”, Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 9, pp. 1203-1206, May 1197.* |
Hill et al., “Novel Macrolides via Meso-Tetraarylmetalloporphyrin Assisted Oxidations”, Tetrahedron Letters, vol. 37, No. 6, pp. 787-790, Feb. 1996. |