CN111606901A - Synthetic method of micafungin side chain intermediate - Google Patents
Synthetic method of micafungin side chain intermediate Download PDFInfo
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- CN111606901A CN111606901A CN202010548226.0A CN202010548226A CN111606901A CN 111606901 A CN111606901 A CN 111606901A CN 202010548226 A CN202010548226 A CN 202010548226A CN 111606901 A CN111606901 A CN 111606901A
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Abstract
The invention discloses a synthetic method of a micafungin side chain intermediate, which only needs three steps to obtain an important side chain intermediate for synthesizing micafungin, and the steps are simple, firstly, 4-pentyloxyacetophenone and methyl p-formylbenzoate are taken as initial raw materials, under the action of an alkali catalyst cesium carbonate, aldol condensation reaction is carried out to obtain an intermediate M1, then, under the action of an alkali catalyst cesium carbonate, the intermediate M1 and N-hydroxy-p-toluenesulfonamide are cyclized to obtain an intermediate M2, and finally, the intermediate M2 and 1-hydroxybenzotriazole are subjected to ester exchange reaction to obtain the high-purity micafungin side chain intermediate shown in a formula M; provides a brand new synthetic route and lays a foundation for preparing the final product micafungin.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of a micafungin side chain intermediate.
Background
Micafungin (Micafungin) is a novel echinocandin antifungal drug obtained by modifying a natural product of Coleophoma empetri and chemically synthesizing; it has good inhibitory activity against Candida, such as Candida albicans, Candida glabrata, Candida thermonatns, Candida krusei and Candida parapsilosis, and also has good in vitro inhibitory activity against Aspergillus, but has no inhibitory activity against Cryptococcus neoformans, Fusarium, Zygomycetes and Trichosporon baijiensis. Micafungin (Micafungin) was developed by japan tenzel corporation and marketed in japan in 12 months 2002 under the trade name Fungusrd, approved by the U.S. FDA in 3 months 2005, and is currently approved only for prophylactic treatment of esophageal candida infection, bone marrow transplantation, and neutropenia in ADS patients.
The micafungin side chain is a key intermediate for preparing micafungin, and the provision of a simple and efficient synthetic method of the micafungin side chain is of great importance.
Disclosure of Invention
The invention aims to provide a synthetic method of a micafungin side chain intermediate.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of a micafungin side chain intermediate specifically comprises the following steps:
firstly, weighing 50mmol of 4-pentyloxyacetophenone, 51-53mmol of methyl p-formylbenzoate, an alkali catalyst and 200ml of ethanol aqueous solution, adding the materials into a reaction bottle, heating to 45-50 ℃ while stirring, keeping the temperature and stirring for 5-6h, after the reaction is finished, naturally cooling to room temperature, placing the reaction bottle into a cold salt bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10-15% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M1;
secondly, weighing 20mmol of the intermediate M1 prepared in the first step, 50-60mmol of N-hydroxy-p-toluenesulfonamide, an alkali catalyst and 250-300ml of ethanol aqueous solution, heating to 60-65 ℃ while stirring, keeping the temperature for reaction overnight, naturally cooling to room temperature after the reaction is finished, placing a reaction bottle in a salt-freezing bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10-15% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M2;
and thirdly, adding 10mmol of intermediate M2 and 100ml of solvent NMP into a three-neck flask, stirring and dissolving completely, slowly adding 10.5-11mmol of 1-hydroxybenzotriazole, gradually heating to perform heat preservation reaction, naturally cooling to room temperature, removing the solvent by rotary evaporation, and separating the crude product by column chromatography to obtain the micafungin side chain intermediate shown in the formula M.
Further, in the first step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 10-12 g.
Further, in the first step, the mass fraction of the ethanol water solution is 50-60%.
Further, in the second step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 15-20 g.
Further, in the second step, the mass fraction of the ethanol water solution is 75-80%.
Further, in the third step, the temperature of the heat preservation is 70-75 ℃.
Further, in the third step, the time of the heat preservation reaction is 2.5-3.5 h.
Further, in the third step, the chromatographic solution used for column chromatography is petroleum ether: dichloromethane: ethyl acetate 7:1: 2.
The invention has the beneficial effects that:
the invention provides a synthetic method of a micafungin side chain intermediate, which only needs three steps to obtain an important side chain intermediate for synthesizing micafungin, and the steps are simple, firstly, 4-pentyloxyacetophenone and methyl p-formylbenzoate are taken as initial raw materials, under the action of an alkali catalyst cesium carbonate, aldol condensation reaction is carried out to obtain an intermediate M1, then, under the action of an alkali catalyst cesium carbonate, the intermediate M1 and N-hydroxy-p-toluenesulfonamide are cyclized to obtain an intermediate M2, and finally, the intermediate M2 and 1-hydroxybenzotriazole are subjected to ester exchange reaction to obtain the high-purity micafungin side chain intermediate shown in a formula M; provides a brand new synthetic route and lays a foundation for preparing the final product micafungin.
Of course, it is not necessary for any product in which the invention is practiced to achieve all of the above-described advantages at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a flow chart of the synthesis of the micafungin side chain intermediate of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1, the present invention is a method for synthesizing a micafungin side chain intermediate, comprising the following steps:
firstly, weighing 50mmol of 4-pentyloxyacetophenone, 51mmol of methyl p-formylbenzoate, 11g of cesium carbonate and 200ml of 55% ethanol aqueous solution by mass, adding the weighed materials into a reaction bottle, heating to 50 ℃ while stirring, keeping the temperature and stirring for 5 hours, after the reaction is finished, naturally cooling to room temperature, placing the reaction bottle into a cold salt bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M1; the yield is 84.6%;
the mass spectrum result of intermediate M1 was: HRMS M/z (M + H)+)：353.172；
Secondly, weighing 20mmol of intermediate M1, 55mmol of N-hydroxy-p-toluenesulfonamide prepared in the first step, 15g of cesium carbonate and 300ml of 75% ethanol water solution by mass fraction, heating to 60 ℃ while stirring, keeping the temperature for reaction overnight (12-14h), after the reaction is finished, naturally cooling to room temperature, placing a reaction bottle in a salt-freezing bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M2; the yield is 80.4%;
the mass spectrum result of intermediate M2 was: HRMS M/z (M + H)+)：366.041；
And step three, adding 10mmol of intermediate M2 and 100ml of solvent NMP into a three-neck flask, stirring and dissolving completely, slowly adding 10.5mmol of 1-hydroxybenzotriazole, gradually heating to 70-75 ℃ for heat preservation reaction for 3 hours, naturally cooling to room temperature, removing the solvent by rotary evaporation, separating a crude product by column chromatography, wherein a chromatographic solution used in the column chromatography is petroleum ether: dichloromethane: ethyl acetate 7:1:2 to obtain the micafungin side chain intermediate shown in the formula M; the purity of the product is 99.64 percent by HPLC detection,
the mass spectrum result of the micafungin side chain intermediate M is as follows: HRMS M/z (M + H)+)：469.159。
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (8)
1. A synthetic method of a micafungin side chain intermediate is characterized by comprising the following steps: the method specifically comprises the following steps:
firstly, weighing 50mmol of 4-pentyloxyacetophenone, 51-53mmol of methyl p-formylbenzoate, an alkali catalyst and 200ml of ethanol aqueous solution, adding the materials into a reaction bottle, heating to 45-50 ℃ while stirring, keeping the temperature and stirring for 5-6h, after the reaction is finished, naturally cooling to room temperature, placing the reaction bottle into a cold salt bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10-15% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M1;
secondly, weighing 20mmol of the intermediate M1 prepared in the first step, 50-60mmol of N-hydroxy-p-toluenesulfonamide, an alkali catalyst and 250-300ml of ethanol aqueous solution, heating to 60-65 ℃ while stirring, keeping the temperature for reaction overnight, naturally cooling to room temperature after the reaction is finished, placing a reaction bottle in a salt-freezing bath, adjusting the pH of the reaction solution to 2.0-2.5 by using 10-15% dilute hydrochloric acid, performing suction filtration, washing a filter cake by using absolute ethanol, and drying to obtain an intermediate M2;
and thirdly, adding 10mmol of intermediate M2 and 100ml of solvent NMP into a three-neck flask, stirring and dissolving completely, slowly adding 10.5-11mmol of 1-hydroxybenzotriazole, gradually heating to perform heat preservation reaction, naturally cooling to room temperature, removing the solvent by rotary evaporation, and separating the crude product by column chromatography to obtain the micafungin side chain intermediate shown in the formula M.
2. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the first step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 10-12 g.
3. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the first step, the mass fraction of the ethanol water solution is 50-60%.
4. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the second step, the alkali catalyst is cesium carbonate, and the addition amount of the cesium carbonate is 15-20 g.
5. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the second step, the mass fraction of the ethanol water solution is 75-80%.
6. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the third step, the temperature of the heat preservation is 70-75 ℃.
7. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the third step, the time of the heat preservation reaction is 2.5-3.5 h.
8. The method of claim 1, wherein the synthesis of the micafungin side chain intermediate is as follows: in the third step, the chromatographic solution used for column chromatography is petroleum ether: dichloromethane: ethyl acetate 7:1: 2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116178296A (en) * | 2023-03-02 | 2023-05-30 | 广东新达瑞生物科技有限公司 | Preparation method of micafungin side chain and preparation method of micafungin |
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| CN102786488A (en) * | 2012-08-06 | 2012-11-21 | 天津信汇制药股份有限公司 | Preparation method of intermediate for synthesis of micafungin and derivative thereof |
| CN103492409A (en) * | 2011-04-04 | 2014-01-01 | 赛利亚医药公司 | Methods for manufacturing an antifungal agent |
| CN103917531A (en) * | 2011-09-09 | 2014-07-09 | 桑多斯股份公司 | Preparation of micafungin intermediates |
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| CN110734408A (en) * | 2019-10-22 | 2020-01-31 | 重庆康乐制药有限公司 | preparation method of micafungin derivative side chain intermediate |
| CN111116503A (en) * | 2019-12-25 | 2020-05-08 | 南京奇可药业有限公司 | Preparation method of high-purity micafungin intermediate |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103492409A (en) * | 2011-04-04 | 2014-01-01 | 赛利亚医药公司 | Methods for manufacturing an antifungal agent |
| CN103917531A (en) * | 2011-09-09 | 2014-07-09 | 桑多斯股份公司 | Preparation of micafungin intermediates |
| CN102786488A (en) * | 2012-08-06 | 2012-11-21 | 天津信汇制药股份有限公司 | Preparation method of intermediate for synthesis of micafungin and derivative thereof |
| CN106866650A (en) * | 2017-01-09 | 2017-06-20 | 博瑞生物医药泰兴市有限公司 | A kind of synthesis of MFG and method of purification |
| CN110734408A (en) * | 2019-10-22 | 2020-01-31 | 重庆康乐制药有限公司 | preparation method of micafungin derivative side chain intermediate |
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| Title |
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| M. TOMISHIMA ET AL.: "Novel echinocandin antifungals. Part 2: Optimization of the side chain of the natural product FR901379.Discovery of micafungin", 《BIOORG. MED. CHEM. LETT.》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116178296A (en) * | 2023-03-02 | 2023-05-30 | 广东新达瑞生物科技有限公司 | Preparation method of micafungin side chain and preparation method of micafungin |
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