WO2006100691A2 - A process for the preparation of 6-o-methyl erythromycin a derivative - Google Patents
A process for the preparation of 6-o-methyl erythromycin a derivative Download PDFInfo
- Publication number
- WO2006100691A2 WO2006100691A2 PCT/IN2006/000095 IN2006000095W WO2006100691A2 WO 2006100691 A2 WO2006100691 A2 WO 2006100691A2 IN 2006000095 W IN2006000095 W IN 2006000095W WO 2006100691 A2 WO2006100691 A2 WO 2006100691A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- group
- derivative
- erythromycin
- methyl
- Prior art date
Links
- 0 CC[C@]([C@](C)([C@@]([C@@](*)C([C@](C)C[C@@](C)(*)[C@@]([C@@]([C@@]([C@]1C)OC(CC2(C)*)OC(C)C2O)C=C)O[C@@](C2O)OC(C)CC2N(C)C)=O)O)O)OC1=O Chemical compound CC[C@]([C@](C)([C@@]([C@@](*)C([C@](C)C[C@@](C)(*)[C@@]([C@@]([C@@]([C@]1C)OC(CC2(C)*)OC(C)C2O)C=C)O[C@@](C2O)OC(C)CC2N(C)C)=O)O)O)OC1=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Definitions
- the present invention relates to an improved process for the preparation of 6-0- methyl erythromycin A derivatives, intermediates of clarithromycin, by selective methylation of erythromycin A derivative in a mixture of acyclic or cyclic alkanes having C 6 - Ci 0 carbon atoms, such as hexanes, heptanes, cyclohexane and a polar aprotic solvent using a methylating agent in the presence of a base under mild conditions.
- Clarithromycin is a semi-synthetic macrolide antibiotic related to erythromycin A. It exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria etc. Clarithromycin is efficacious when administered orally.
- Clarithromycin has been first disclosed in US Patent 4,331,803. Thereafter several other approaches for preparing 6-(9-methyl erythromycin A have been published in literature. One of the most effective approaches involves the following steps: (a) protecting the 9-oxo group with a substituted oxime group; (b) protecting the hydroxyl group at positions 2' and 4" (c) methylating the hydroxyl group at position 6 to give a protected clarithromycin oxime derivative and (d) removing the protecting group at 2', 4" and 9 positions.
- the critical step in the synthesis of clarithromycin is the third step (c), which involves the selective methylation of 6-hydroxy position of erythromycin A of formula II,
- R is hydrogen atom or a substituent group such as a lower alkyl group, which is substituted or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group, or a thioalkyl group;
- Ri is 2 ' ,4" -bistrimethyls ⁇ lyl, 2 - carbobenzyloxy, 3 '-dicarbobenzyloxy or other hydroxyl protecting group.
- US Patent 4,331,803 discloses a process for methylation of hydroxyl group at 6- position of erythromycin with a methylating agent in the presence of a base and a polar solvent.
- US Patent 4,679,109 discloses selective methylation at 6-position using a polar aprotic solvent such as dimethyl sulphoxide, A ⁇ N-dimethylformamide, hexamethylphosphoric triamide or a mixture thereof and a mixture consisting of these solvents and tetrahydrofuran.
- a polar aprotic solvent such as dimethyl sulphoxide, A ⁇ N-dimethylformamide, hexamethylphosphoric triamide or a mixture thereof and a mixture consisting of these solvents and tetrahydrofuran.
- methylation quenching is effected using dimethylamine solution and extractions with hexane.
- the major drawback of this process is from commercial point of view because recovery of tetrahydrofuran is very difficult as it distributes almost equally among both aqueous dimethyl sulphoxide and hexane layers.
- US Patent 5,719,272 discloses a process for methylation wherein presence of methyl-t- butyl ether is recommended alongwith polar aprotic solvents
- the present invention relates to a process for the preparation of 6-(9-methyl erythromycin A derivative which comprises the selective methylation of erythromycin A derivative with a methylating agent in a mixture of acyclic or cyclic alkanes having C 6 - CiQ carbon atoms, such as hexanes, heptanes, cyclohexane and the like and a polar aprotic solvent in the presence of a base, under mild conditions.
- 6-O-methylated erythromycin A oxime derivative is used in the preparation of clarithromycin of high purity and yield.
- the present invention relates to preparation of 6-Omethyl erythromycin A derivative by selective methylation of 6-position of erythromycin A derivative.
- Erythromycin A derivative means erythromycin A having no substituent group or having conventional substituent groups in place of hydrogen atoms at position 2' and 4" hydroxyl groups, including 2', 4" bistrimethylsilyl, 2'-carbobenzyloxy or 3'-dicarbobenzyloxy.
- Erythromycin A derivatives are prepared by the methods known in prior art. Specifically methylation of erythromycin A derivative is carried out in a mixture of acyclic or cyclic alkanes having C 6 -Ci O carbon atoms, such as hexane, heptane, cyclohexane and the like and a polar aprotic solvent.
- the polar aprotic solvent can be selected from ⁇ iV-dimethylformamide, dimethyl sulfoxide, ⁇ iV-dimethylacetamide, 1,2-dimethoxyethane, hexamethylphosphoric triamide and the like.
- the methylating agent used is a common methylating agents known in art such as methyliodide, methyl bromide, methyl chloride dimethylsulfate, methyl /?-toluene sulphonate, methyl methane sulphonate and the like.
- the base usually used is metal hydroxides and metal hydrides such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like.
- acyclic or cyclic alkane preferably cyclohexane with a polar aprotic solvent because using alkanes the reaction mixture is biphasic and most of the impurities remain in dimethyl sulphoxide layer leading to pure product.
- the ratio of alkane and a polar aprotic solvent can be selected from 1 :0.5 to 1 :5 and preferably 1 :1 is used.
- the reaction is preferably carried out between 15° to 6O 0 C and most preferably between 18-3O 0 C. It is advantageous to carry out the reaction at around ambient temperature as at higher temperature formation of undesired side-products are more and at low temperature, rate of reaction is slow and sometimes, reaction is incomplete and further putting burden of cooling on equipment.
- the reaction is generally carried out between '/2-2 hr under mild conditions and preferably completed within 1 hour.
- the completion of reaction is monitored by high performance liquid chromatography.
- the reaction mixture is diluted with dimethylamine solution and water. Thereafter organic layer is separated and the desired methylated compound is isolated by distillation of solvent. Solvent is recovered quantitatively and recycled. Further the 6-Omethylated derivative is deprotected and clarithromycin is prepared in high yield and high purity.
- the methylated compound obtained in the above step was dissolved in 600 ml of ethanol/ water (1:1). To this solution 260 g of sodium hydrogen sulphite and 23 g of 98% formic acid were added and the reaction mixture was refluxed for three hours. Thereafter the reaction mixture was diluted with 200 ml of water and the pH was adjusted to 10.2 using aqueous sodium hydroxide. The reaction mixture was stirred at 25-35° C for one hour. The product which precipitated out was filtered, washed with water and recrystallized from ethanol to obtain 56g of title compound having purity 98.5%by HPLC.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2007011562A MX2007011562A (en) | 2005-03-23 | 2006-03-20 | A process for the preparation of 6-o-methyl erythromycin a derivative. |
IL186174A IL186174A0 (en) | 2005-03-23 | 2007-09-23 | A process for the preparation of 6-0-methyl erythromycin a derivative |
IL186185A IL186185A0 (en) | 2005-03-23 | 2007-09-23 | A process for the preparation of 6-0-methyl erythromycin a derivative |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN634/DEL/2005 | 2005-03-23 | ||
IN634DE2005 | 2005-03-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006100691A2 true WO2006100691A2 (en) | 2006-09-28 |
WO2006100691A3 WO2006100691A3 (en) | 2007-03-15 |
Family
ID=37024236
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2006/000095 WO2006100691A2 (en) | 2005-03-23 | 2006-03-20 | A process for the preparation of 6-o-methyl erythromycin a derivative |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN101146815A (en) |
IL (2) | IL186185A0 (en) |
MX (1) | MX2007011562A (en) |
WO (1) | WO2006100691A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010122571A2 (en) * | 2009-04-23 | 2010-10-28 | Elder Pharmaceuticals Ltd. | A process for the selective methylation of erythromycin a derivatives. |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106905204B (en) * | 2017-02-24 | 2018-07-20 | 杭州新桂实业有限公司 | A kind of recovery method of methylation reaction solvent in clarithromycin building-up process |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6437106B1 (en) * | 1999-06-24 | 2002-08-20 | Abbott Laboratories | Process for preparing 6-o-substituted erythromycin derivatives |
-
2006
- 2006-03-20 MX MX2007011562A patent/MX2007011562A/en not_active Application Discontinuation
- 2006-03-20 WO PCT/IN2006/000095 patent/WO2006100691A2/en not_active Application Discontinuation
- 2006-03-20 CN CNA2006800095128A patent/CN101146815A/en active Pending
-
2007
- 2007-09-23 IL IL186185A patent/IL186185A0/en unknown
- 2007-09-23 IL IL186174A patent/IL186174A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6437106B1 (en) * | 1999-06-24 | 2002-08-20 | Abbott Laboratories | Process for preparing 6-o-substituted erythromycin derivatives |
Non-Patent Citations (1)
Title |
---|
WATANABE Y. ET AL.: 'Chemical Modification of Erythromycin. VIII. A New Effective Route To Clarithromycin (6-O-Methylerythromycin A)' HETEROCYCLES vol. 31, no. 12, 1990, pages 2121 - 2124, XP008078531 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010122571A2 (en) * | 2009-04-23 | 2010-10-28 | Elder Pharmaceuticals Ltd. | A process for the selective methylation of erythromycin a derivatives. |
WO2010122571A3 (en) * | 2009-04-23 | 2011-01-06 | Elder Pharmaceuticals Ltd. | A process for the selective methylation of erythromycin a derivatives. |
Also Published As
Publication number | Publication date |
---|---|
MX2007011562A (en) | 2008-03-11 |
IL186174A0 (en) | 2008-01-20 |
WO2006100691A3 (en) | 2007-03-15 |
IL186185A0 (en) | 2008-01-20 |
CN101146815A (en) | 2008-03-19 |
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