Claims
- 1. A method for preparing a protected silylated clarithromycin oxime comprising
reacting a silylated erythromycin A oxime derivative with methylating agent while stirring in the presence of a base and a solvent comprising methyl tertbutyl ether.
- 2. The method of claim 1, wherein the methylating agent is selected from the group consisting of methyl iodide, methyl bromide, dimethylsulfate, methyl p-toluenesulfonate, and methanesulfonate.
- 3. The method of claim 1, wherein the base is selected from the group consisting of sodium hydride, potassium hydroxide, and sodium hydroxide.
- 4. The method of claim 1, wherein the solvent further comprises dimethyl sulfoxide.
- 5. The method of claim 1, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime and the silyl oxime derivative is 2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime.
- 6. A method of converting a protected silylated clarithromycin oxime to clarithromycin comprising
a) reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to obtain a solution, b) refluxing the solution obtained by step a), c) cooling the solution obtained after step b) to about 15° C. to about 25° C., and d) adding NaOH.
- 7. The method of claim 6, wherein the cooling is to about 20° C.
- 8. The method of claim 6, wherein the acid is formic acid.
- 9. The method of claim 6, wherein the deoximating agent is sodium metabisulfite.
- 10. The method of claim 6, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime.
- 11. A method of converting protected silylated clarithromycin oxime to clarithromycin including
reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture; cooling the reaction mixture to about 15° C. to about 25° C.; and adding sodium hydroxide solution to the reaction mixture; wherein essentially no additional water to process clarithromycin.
- 12. The method of claim 10 wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.
- 13. The method of claim 11, wherein the cooling is to about 20° C.
- 14. The method of claim 11, wherein the acid is formic acid.
- 15. The method of claim 11, wherein the deoximating agent is sodium metabisulfite.
- 16. Clarithromycin formed by a process comprising
converting erythromycin A to 2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime; reacting 2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with methylating agent while stirring in the presence of at least one solvent and a base, wherein the at least one solvent comprises methyl tertbutyl ether, to form 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime; and reacting the 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with an acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.
- 17. The clarithromycin of claim 16, wherein the methylating agent is selected from the group consisting of methyl iodide, methyl bromide, dimethylsulfate, methyl p-toluenesulfonate, and methanesulfonate.
- 18. The clarithromycin of claim 16, wherein the base is selected from the group consisting of sodium hydride, potassium hydroxide, and sodium hydroxide.
- 19. Clarithromycin formed by a process comprising
converting erythromycin A to protected silylated clarithromycin oxime; reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture; cooling the reaction mixture to about 15° C. to about 25° C.; and adding sodium hydroxide solution to the reaction mixture.
- 20. The method of claim 19, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.
- 21. The clarithromycin of claim 19, wherein the cooling is to about 20° C.
- 22. The clarithromycin of claim 19, wherein the acid is formic acid.
- 23. The clarithromycin of claim 19, wherein the deoximating agent is sodium metabisulfite.
- 24. A method of converting erythromycin A to clarithromycin comprising
converting erythromycin A to protected silylated clarithromycin oxime; reacting protected silylated clarithromycin oxime with methylating agent while stirring in the presence of at least one solvent, wherein the at least one solvent comprises methyl tertbutyl ether, and a base to form 6-O-methyl protected silylated clarithromycin oxime; and reacting the 6-O-methyl- protected silylated clarithromycin oxime with acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.
- 25. A method of converting erythromycin A to clarithromycin comprising
converting erythromycin A to protected silylated clarithromycin oxime; and reacting the protected silylated clarithromycin oxime with an acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1, cooling to about 20° C., and adding sodium hydroxide solution, wherein essentially no additional water is added to process clarithromycin.
- 26. The method of claim 25, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.
- 27. A process for preparing essentially oxime-free clarithromycin, which comprises heating a mixture of protected silylated clarithromycin oxime, formic acid and a deoximating agent in a ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent.
- 28. The method of claim 27, wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.
- 29. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of protected silylated clarithromycin oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent.
- 30. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by a method that includes converting a clarithromycin oxime intermediate to clarithromycin.
- 31. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by a method that includes converting 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime intermediate to clarithromycin.
- 32. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of protected silylated clarithromycin oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent.
- 33. Clarithromycin comprising less than 40 ppm of clarithromycin-S-MOP-Oxime intermediate formed by a method that includes converting a clarithromycin oxime intermediate to clarithromycin.
- 34. Clarithromycin comprising less than 40 ppm of its corresponding oxime intermediate formed by heating a mixture of 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime, formic acid and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of said deoximating agent.
- 35. A pharmaceutical composition comprising the product of claim 29, 30, 31, 32, 33 or 34.
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims the benefit of U.S. Provisional Application No. 60/185,888 filed on Feb. 29, 2000, No. 60/189,120 filed on Mar. 14, 2000, and No. 60/213,239 filed on Jun. 22, 2000.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60185888 |
Feb 2000 |
US |
|
60189120 |
Mar 2000 |
US |
|
60213239 |
Jun 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09736447 |
Dec 2000 |
US |
Child |
10435141 |
May 2003 |
US |