WO2009007988A1 - Process for the preparation of 6-o-methylerythromycin a 9-oxime - Google Patents
Process for the preparation of 6-o-methylerythromycin a 9-oxime Download PDFInfo
- Publication number
- WO2009007988A1 WO2009007988A1 PCT/IN2007/000380 IN2007000380W WO2009007988A1 WO 2009007988 A1 WO2009007988 A1 WO 2009007988A1 IN 2007000380 W IN2007000380 W IN 2007000380W WO 2009007988 A1 WO2009007988 A1 WO 2009007988A1
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- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- methylerythromycin
- oxime
- polar
- mixture
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- the present invention relates to an improved process for the preparation of 6-O- methylerythromycin A 9-oxime of formula (I).
- 6-0-methylerythromycin A 9-oxime is an important intermediate of Clarithromycin i.e. 6-0- methylerythromycin A. 6-O-methylerythromycin A 9-oxime acts as an antibiotic with great antibacterial activity. 6-0-methylerythromycin A 9-oxime is having molecular formula C 38 H 7O N 2 O 13 and molecular weight 762.9.
- US patent no. 4670549 describes a process for the preparation of 6-O-methylerythromycin A 9-oxime by treating erythromycin A 9- oxime with benzyl or allyl halide.
- the major drawback of this process is low yield of final product.
- Another object of the present invention is to provide a process for the preparation of 6-O- methylerythromycin A 9-oxime which is operationally simple, easy to handle and applicable at an industrial scale.
- Another object of the present invention is to provide a process for the preparation of 6-O- methylerythromycin A 9-oxime 'E' isomer substantially free of 'Z' isomer.
- Another object of invention is to provide a process for the preparation of 6-0- methylerythromycin A 9-oxime by treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride, which results in high yield and purity of the product.
- a further object of the present invention is to provide process for the preparation of 6-O- methylerythromycin A 9-oxime which comprises treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride.
- Yet another object of present invention is to provide process for the preparation of 6-O- methylerythromycin A 9-oxime comprising steps of: (i) treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride in the presence of a base and a solvent (ii) purifying crude 6-O-methylerythromycin A-9-oxime obtained in (i) with a suitable solvent
- treating refers to suspending, dissolving, mixing and adding starting materials at refluxing temperature.
- '6-O-methylerythromycin A' as used hereinabove includes 6-O-methylerythromycin A in any polymorphic form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
- the meaning of term 'substantially free' as used hereinabove refers to 'E' isomer of 6-O-methylerythromycin A 9-oxime containing not more than 10 % 'Z' isomer of 6-O-methylerythromycin A 9-oxime by HPLC.
- Crude 6-O-methylerythromycin A-9-oxime obtained in step (i) may be isolated or not isolated, if isolated from reaction mass, by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
- 6-O-methylerythromycin A 9-oxime obtained in step (ii) may be isolated from reaction mass, by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
- purifying refers to any method known to a person skilled in the art such as purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature, filtering and precipitating the compound by cooling the solution or removing solvent from the solution or both. Jt further includes methods such as solvent/antisolvent or precipitation.
- base includes but not limited to organic bases and inorganic bases.
- the organic bases includes imidazole, triethyl amine, diethyl amine, methylamine, t- butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, luridines, collidines, dicyclo hexyl amine and the like or mixture thereof.
- the inorganic bases includes alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides and the like or mixture thereof.
- suitable solvent is sodium carbonate.
- solvent includes but not limited to substituted or unsubstituted; i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof.
- solvent is methanol.
- suitable solvent includes but not limited to substituted or unsubstituted; i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof.
- suitable solvent is dichloromethane.
- Example 1 Preparation of crude 6-O-methyI erythromycin A-9-oxime Mixture of sodium carbonate (20 gm) and hydroxylamine hydrochloride (50 gm) was charged in methanol (200ml) at ambient temperature. This mixture was heated to 30-40 0 C, stirred and again cooled to 20-30 0 C. To this mixture, 6-O-methyl erythromycin (100 gm) was added. The reaction mixture was heated to 50-65 0 C for 12 to 24 hours till reaction completion. After completion, reaction was quenched by addition of water and dichloromethane. The pH of this solution was adjusted to 9-12 by aqueous sodium hydroxide solution followed by separation of layers. The organic layer was evaporated completely at atmospheric pressure to obtain reaction mass.
Abstract
The present invention relates to process for the preparation of 6-O-methylerythromycin A 9-oxime by treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride in the presence of a base and a solvent.
Description
PROCESS FOR THE PREPARATION OF 6-O-METHYLERYTHROMYCIN A 9-OXIME
Field of invention
The present invention relates to an improved process for the preparation of 6-O- methylerythromycin A 9-oxime of formula (I).
Background of the invention
6-0-methylerythromycin A 9-oxime is an important intermediate of Clarithromycin i.e. 6-0- methylerythromycin A. 6-O-methylerythromycin A 9-oxime acts as an antibiotic with great antibacterial activity. 6-0-methylerythromycin A 9-oxime is having molecular formula C38H7ON2O13 and molecular weight 762.9.
There are two known forms of 6-0-methylerythromycin A 9-oxime namely, i) 6-0- methylerythromycin A (E) 9-oxime having structural formula (I) and ii) 6-0- methylerythromycin A (E) 9-oxime having structural formula (II).
Considering the structural similarity between 6-0-methylerythromycin A (E) 9-oxime (I) and
6-O-methylerythromycin A (Z) 9-oxime (II), it is very difficult to obtain 6-0- methylerythromycin A (E) 9-oxime substantially free of 6-O-methylerythromycin A (Z) 9- oxime.
US patent no. 4670549 describes a process for the preparation of 6-O-methylerythromycin A 9-oxime by treating erythromycin A 9- oxime with benzyl or allyl halide. The major drawback of this process is low yield of final product.
Another US patent having no. 4680386 describe a process for the preparation of 6-O- methylerythromycin A 9-oxime. This process is also does not describe in terms of the content of undesired isomer of 6-O-methylerythromycin A 9-oxime.
Another US patent having no. 5837829 describe a process of preparation of 6-O- methylerythromycin A 9-oxime from 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9 (O-t-butyldiphenylsilyl) oxime. The major drawback of this process is the use of silylating agent as they are very expensive and sensitive towards acids and bases.
Yet another US patent having no. 6528628 describe a process of preparation of 6-O- methylerythromycin A 9-oxime form α, α'-bis (6-O-methylerythromycin A 9-oxime)-9-O-p-
xylene. This process is also does not describe in terms of the content of undesired isomer of 6-O-methylerythromycin A 9-oxime.
Therefore, there exists the need to develop a process which gives 6-O-methylerythromycin A 9-oxime of desired purity which is practically simple, easy to handle and cost effective on commercial scale.
Object of the invention
It is therefore an object of the invention to provide a process for the preparation of 6-O- methylerythromycin A 9-oxime.
Another object of the present invention is to provide a process for the preparation of 6-O- methylerythromycin A 9-oxime which is operationally simple, easy to handle and applicable at an industrial scale.
Another object of the present invention is to provide a process for the preparation of 6-O- methylerythromycin A 9-oxime 'E' isomer substantially free of 'Z' isomer.
Another object of invention is to provide a process for the preparation of 6-0- methylerythromycin A 9-oxime by treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride, which results in high yield and purity of the product.
A further object of the present invention is to provide process for the preparation of 6-O- methylerythromycin A 9-oxime which comprises treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride.
Yet another object of present invention is to provide process for the preparation of 6-O- methylerythromycin A 9-oxime comprising steps of:
(i) treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride in the presence of a base and a solvent (ii) purifying crude 6-O-methylerythromycin A-9-oxime obtained in (i) with a suitable solvent
Detailed description of the invention
In an embodiment of the present invention, it provides process for the preparation of 6-O- methylerythromycin A (E) 9-oxime which comprises a step of treating 6-O- methylerythromycin A with hydroxyl amine hydrochloride in the presence of a base and a solvent.
In another embodiment of the present invention, it provides a process for the purification of crude 6-O-methylerythromycin A-9-oxime using suitable solvent.
For the purpose of this specification, the meaning of term "treating" as used hereinabove refers to suspending, dissolving, mixing and adding starting materials at refluxing temperature.
For the purpose of this specification, the meaning of term '6-O-methylerythromycin A' as used hereinabove includes 6-O-methylerythromycin A in any polymorphic form, or hydrate, clathrate, solvate or their mixtures and in any state of purity, unless specifically mentioned.
For the purpose of this specification, the meaning of term 'substantially free' as used hereinabove refers to 'E' isomer of 6-O-methylerythromycin A 9-oxime containing not more than 10 % 'Z' isomer of 6-O-methylerythromycin A 9-oxime by HPLC.
Crude 6-O-methylerythromycin A-9-oxime obtained in step (i) may be isolated or not isolated, if isolated from reaction mass, by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
6-O-methylerythromycin A 9-oxime obtained in step (ii) may be isolated from reaction mass, by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
The term "purifying" refers to any method known to a person skilled in the art such as purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature, filtering and precipitating the compound by cooling the solution or removing solvent from the solution or both. Jt further includes methods such as solvent/antisolvent or precipitation.
The term "base" as used hereinabove includes but not limited to organic bases and inorganic bases. The organic bases includes imidazole, triethyl amine, diethyl amine, methylamine, t- butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, luridines, collidines, dicyclo hexyl amine and the like or mixture thereof. The inorganic bases includes alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides and the like or mixture thereof. The preferred example of suitable solvent is sodium carbonate.
The term "solvent" as used hereinabove includes but not limited to substituted or unsubstituted; i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof. The preferred example of solvent is methanol.
The term "suitable solvent" as used hereinabove includes but not limited to substituted or unsubstituted; i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii)
nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent and the like or mixture thereof. The preferred example of suitable solvent is dichloromethane.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1 Preparation of crude 6-O-methyI erythromycin A-9-oxime Mixture of sodium carbonate (20 gm) and hydroxylamine hydrochloride (50 gm) was charged in methanol (200ml) at ambient temperature. This mixture was heated to 30-40 0C, stirred and again cooled to 20-30 0C. To this mixture, 6-O-methyl erythromycin (100 gm) was added. The reaction mixture was heated to 50-65 0C for 12 to 24 hours till reaction completion. After completion, reaction was quenched by addition of water and dichloromethane. The pH of this solution was adjusted to 9-12 by aqueous sodium hydroxide solution followed by separation of layers. The organic layer was evaporated completely at atmospheric pressure to obtain reaction mass. To this mass, small quantity of dichloromethane was added and stirred to obtain solid. The solid was filtered, washed and dried to get crude 6-O-methyl erythromycin A-9-oxime (1 lOgm). Purity ~ 62.5% (by HPLC)
Example 2 Purification of crude 6-O-methyl erythromycin A-9-oxime
The mixture of 6-O-methyl erythromycin A-9-oxime obtain in example 1 (100 gm) and dichloromethane (600ml) was stirred at 20-35 0C for 1 to 2 hr., filtered and washed with dichloromethane. The filtrate was completely removed to get wet solid which was dried to get 6-O-methyl erythromycin A (E)-9-oxime (60-70 gm). Purity ~ 95% (by HPLC)
Claims
1. A process for the preparation of 6-O-methylerythromycin A 9-oxime comprising steps of: (i) treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride in the presence of a base and a solvent
(ii) purifying crude 6-O-methylerythromycin A-9-oxime obtained in (i) with a suitable solvent
2. The process according to claim 1, wherein solvent used herein is substituted or unsubstituted i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent or mixture thereof
3. The process according to claim 1, wherein base used herein is imidazole, triethyl amine, diethyl amine, rnethylamine, t-butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, luridines, collidines, dicyclo hexyl amine, alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides or mixture thereof.
4. The process according to claim 1, wherein suitable solvent used herein is substituted or unsubstituted i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent or mixture thereof
5. A process for the preparation of 6-O-methylerythromycin A 9-oxime 'E' isomer substantially free of 'Z' isomer comprising steps of:
(i) treating 6-O-methylerythromycin A with hydroxyl amine hydrochloride in presence of a base and a solvent (ii) purifying crude 6-O-methylerythromycin A-9-oxime obtained in (i) with suitable solvent
6. The process according to claim 5, wherein solvent used herein is substituted or unsubstituted i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent or mixture thereof
7. The process according to claim 5, wherein base used herein is imidazole, triethyl amine, diethyl amine, methylamine, t-butylamine, pyrrolidine, pyridine, morpholine, di-N-propylamine, n-butylamine, isopropylamine, piperidine, picoline, luridines, collidines, dicyclo hexyl amine, alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides or mixture thereof.
8. The process according to claim 5, wherein suitable solvent used herein is substituted or unsubstituted i) alcoholic solvent, ii) halogenated hydrocarbon solvent, iii) aliphatic or aromatic hydrocarbon solvent, iv) ester solvent, v) ether solvent, vi) cyclic ether solvent, vii) nitrile solvent, viii) aqueous solvent, ix) ketonic solvent x) polar or nonpolar protic solvent, xi) polar or nonpolar aprotic solvent or mixture thereof.
9. 6-O-methylerythromycm Ά y-oxime ~c isomer suDsxanuauy iree of 'Z' isomer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1329/MUM/2007 | 2007-07-11 | ||
| IN1329MU2007 IN2007MU01329A (en) | 2005-03-04 | 2007-08-30 |
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| WO2009007988A1 true WO2009007988A1 (en) | 2009-01-15 |
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| PCT/IN2007/000380 WO2009007988A1 (en) | 2007-07-11 | 2007-08-30 | Process for the preparation of 6-o-methylerythromycin a 9-oxime |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
| WO2013079521A1 (en) | 2011-11-30 | 2013-06-06 | Sicpa Holding Sa | Marked coating composition and method for its authentication |
| WO2014086556A1 (en) | 2012-12-07 | 2014-06-12 | Sicpa Holding Sa | Oxidatively drying ink compositions |
| CN104447918A (en) * | 2014-11-27 | 2015-03-25 | 广东东阳光药业有限公司 | Method for preparing impurity C of clarithromycin |
| WO2017001666A1 (en) | 2015-07-01 | 2017-01-05 | Sicpa Holding Sa | Environmentally friendly ink and fountain solution for wet offset printing process and wet offset printing process |
| CN108948114A (en) * | 2018-09-06 | 2018-12-07 | 黄石世星药业有限责任公司 | One kind being applied to the impurity-removing method of 9- (E)-erythromycin oxime |
| WO2021084411A1 (en) * | 2019-10-29 | 2021-05-06 | Hikal Limited | Substantially pure clarithromycin 9-oxime and its preparation thereof |
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| US6110965A (en) * | 1998-04-06 | 2000-08-29 | Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo | Ketolides from the class of 15-membered lactams |
| WO2004101585A1 (en) * | 2003-05-13 | 2004-11-25 | Glaxo Group Limited | Macrolides substituded at the 4'-position |
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| US6110965A (en) * | 1998-04-06 | 2000-08-29 | Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo | Ketolides from the class of 15-membered lactams |
| WO2004101585A1 (en) * | 2003-05-13 | 2004-11-25 | Glaxo Group Limited | Macrolides substituded at the 4'-position |
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| Title |
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| CHEN SHENGXI ET AL: "3-Keto-9-O-substituted Oxime Derivatives of 6-O-Methyl Erythromycin A - Synthesis and In Vitro Activity", JOURNAL OF ANTIBIOTICS, vol. 54, 2001, pages 506 - 509, XP001109508 * |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013079521A1 (en) | 2011-11-30 | 2013-06-06 | Sicpa Holding Sa | Marked coating composition and method for its authentication |
| CN102718821A (en) * | 2012-06-27 | 2012-10-10 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
| CN102718821B (en) * | 2012-06-27 | 2014-12-03 | 浙江国邦药业有限公司 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
| WO2014086556A1 (en) | 2012-12-07 | 2014-06-12 | Sicpa Holding Sa | Oxidatively drying ink compositions |
| US9840632B2 (en) | 2012-12-07 | 2017-12-12 | Sicpa Holding Sa | Oxidatively drying ink compositions |
| CN104447918A (en) * | 2014-11-27 | 2015-03-25 | 广东东阳光药业有限公司 | Method for preparing impurity C of clarithromycin |
| WO2017001666A1 (en) | 2015-07-01 | 2017-01-05 | Sicpa Holding Sa | Environmentally friendly ink and fountain solution for wet offset printing process and wet offset printing process |
| US10590292B2 (en) | 2015-07-01 | 2020-03-17 | Sicpa Holding Sa | Environmentally friendly ink and fountain solution for wet offset printing process and wet offset printing process |
| CN108948114A (en) * | 2018-09-06 | 2018-12-07 | 黄石世星药业有限责任公司 | One kind being applied to the impurity-removing method of 9- (E)-erythromycin oxime |
| CN108948114B (en) * | 2018-09-06 | 2021-08-17 | 黄石世星药业有限责任公司 | Impurity removal method applied to 9- (E) -erythromycin oxime |
| WO2021084411A1 (en) * | 2019-10-29 | 2021-05-06 | Hikal Limited | Substantially pure clarithromycin 9-oxime and its preparation thereof |
| EP4051289A4 (en) * | 2019-10-29 | 2024-03-27 | Hikal Ltd | Substantially pure clarithromycin 9-oxime and its preparation thereof |
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