CN104876944A - Preparation method of everolimus - Google Patents
Preparation method of everolimus Download PDFInfo
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- CN104876944A CN104876944A CN201510253340.XA CN201510253340A CN104876944A CN 104876944 A CN104876944 A CN 104876944A CN 201510253340 A CN201510253340 A CN 201510253340A CN 104876944 A CN104876944 A CN 104876944A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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Abstract
The invention relates to a preparation method of everolimus. The preparation method of everolimus comprises the following step: carrying out one-step reaction on rapamycin and ethylene oxide in presence of strong acid, so that everolimus is obtained. The preparation method of everolimus has the advantages that the process is simple, the after-treatment is convenient, the product yield is high, and the quality is good, so that the preparation method of everolimus is applicable to industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field.In particular to a kind of preparation method of everolimus.
Background technology
Everolimus (Everolimus) is a kind of orally active rapamycin (Rapamycin) derivative, be also called 40-O-(2-hydroxyethyl)-rapamycin, belong to macrolide immunosuppressants of new generation and antitumor drug.This medicine is developed by Novartis Co., Ltd of Switzerland (Novartis Corp.), first go on the market in Germany in March, 2004, in August, 2008 is obtained European EMEA and ratifies, obtain U.S. FDA approval in March, 2009, so far in tens the national clinical applications in the whole world, be mainly applicable to the prevention being in the light adult kidney to moderate immune risk, liver and cardiac transplant recipients's organ rejection.
The structural formula of everolimus and rapamycin is as follows:
The preparation method relating to everolimus has been reported, such as:
American documentation literature US5665772 discloses a kind of preparation method of everolimus, and its syntheti c route is shown below.Rapamycin is starting raw material, react with O-(t-Butyldimethylsilyl) ethylene glycol triflate, obtain 40-O-(2-t-Butyldimethylsilyl) oxygen ethyl rapamycin, then hydrolysis obtains everolimus in methanol hydrochloride solution.The poor reproducibility of this preparation method, molar yield is extremely low, only have 5%, is unsuitable for industrialization and produces.
Chinese patent literature CN102127092A discloses a kind of preparation method of everolimus, and its syntheti c route is shown below.Take rapamycin as starting raw material, diisopropylethylamine is acid binding agent, with 2-(tert-butyl diphenyl is silica-based) oxygen ethyl triflate in toluene 50-60 DEG C react, an intermediate is obtained through column chromatography for separation, this intermediate reacts in tetrahydrofuran (THF) with hydrogen fluoride pyridine solution again, obtains everolimus through column chromatography for separation.Raw material 2-(tert-butyl diphenyl is silica-based) the oxygen ethyl triflate of this preparation method is not easily bought, and need synthesize voluntarily; Reaction mole total recovery still very low, be 21%, cost is high, be unsuitable for equally industrialization produce.
As can be seen here, disclosed in prior art there is many defects in the preparation method of everolimus, is necessary to research and develop the preparation method that can meet needed for actual production.
Summary of the invention
For the deficiencies in the prior art, the object of the invention is to provide a kind of new preparation method of everolimus, makes more reasonable, the safer environmental protection of its technique, obtains low cost, high-quality product, is applicable to suitability for industrialized production.
The preparation method of everolimus provided by the invention, comprises the following steps:
Rapamycin and oxyethane carry out single step reaction under strong acid catalyst, obtain everolimus.
Described strong acid is organic acid or inorganic acid; Preferably, described strong acid is selected from trifluoromethanesulfonic acid, methylsulfonic acid, tosic acid, sulfuric acid, boron trifluoride ethyl ether complex or its mixture; Most preferably, described strong acid is selected from trifluoromethanesulfonic acid or sulfuric acid.
Preferably, the mole dosage of strong acid is 5% ~ 20% of rapamycin mole dosage.
Preferably, rapamycin is 1: 10 ~ 1: 50 with the mole dosage ratio of oxyethane, is more preferably 1: 20 ~ 1: 30.
This reaction can be carried out in organic solvent, and organic solvent is selected from halogenated alkane, fragrant alkane or ether; Preferably, described organic solvent is selected from methylene dichloride, toluene, dimethylbenzene or glycol dimethyl ether.
This reaction also can be carried out under solvent-free.In solvent-free situation, optimization ethylene oxide is more excessive than the mole dosage of rapamycin, and more preferably rapamycin is 1: 10 ~ 1: 50 with the mole dosage ratio of oxyethane, and preferably rapamycin is 1: 20 ~ 1: 30 with the mole dosage ratio of oxyethane further.
This reaction is carried out under elevated pressure, and reaction pressure is selected from 0.2 ~ 2MPa, is preferably 0.8 ~ 1.3MPa.
The temperature of this reaction is 30 ~ 100 DEG C, is preferably 60 ~ 80 DEG C.
The time of this reaction is 2 ~ 20 hours, is preferably 5 ~ 10 hours.
Cool to room temperature after having reacted, concentration and recovery solvent, resistates is directly separated with silica gel column chromatography, obtain everolimus crude product, crude product uses HP-20 resin isolation again, obtains the everolimus finished product that HPLC purity is greater than 99.0%, content of isomer is less than 0.5%, and molar yield reaches more than 50%.
The structural formula of isomer is as follows:
Compared with prior art, the starting material propylene oxide that preparation method of the present invention uses is cheap and easy to get, and reaction only needs a step, and aftertreatment is simple, and product yield is high, quality good, is applicable to industrialization and produces.
Embodiment
To contribute to by the following examples understanding the present invention further, but be not used in restriction content of the present invention.
Test analytical instrument in embodiment and condition:
Icp ms (ICP-MS) model: XSERIES 2 ICP-MS (U.S.'s thermoelectricity).
LC-20AT type high performance liquid chromatograph (Japanese Shimadzu Corporation);
HPLC test condition: SHIMADZU LC-2010 liquid chromatograph; Chromatographic column: 250 × 4.6, C18,5 μm, Erie is special; Mobile phase A: the 1.0ml formic acid 1000ml that adds water adds diethylamine 1.0ml again; Mobile phase B: 90% acetonitrile solution; UV-detector wavelength 278nm; Flow 1.5ml/min; Column temperature 35 DEG C; Gradient methods:
| T(min) | Mobile phase A | Mobile phase B | T(min) | Mobile phase A | Mobile phase B |
| 0 | 35％ | 65％ | 40 | 10％ | 90％ |
| 20 | 35％ | 65％ | 41 | 35％ | 65％ |
| 25 | 10％ | 90％ | 50 | 35％ | 65％ |
If no special instructions, all ingredients used in embodiment is commercially available.
If no special instructions, the temperature in embodiment is room temperature (10 ~ 25 DEG C).
embodiment 1
9.14 grams of rapamycins (0.01mol), 13.2g oxyethane (0.3mol), 0.15g trifluoromethanesulfonic acid, autoclave is added after mixing, be warmed up to 60 DEG C, keep the pressure of 0.5MPa, react stopped reaction after 5 hours, cool to room temperature, reclaim under reduced pressure oxyethane, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.5 gram of 95% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 5.9g everolimus white solid, HPLC purity: 99.3%, content of isomer: 0.23%.Molar yield: 61.5%.MS(m/z)：980.31[M+Na]
+。
embodiment 2
9.14 grams of rapamycins (0.01mol), 17.6g oxyethane (0.4mol), 0.2g methylsulfonic acid, autoclave is added after mixing, be warmed up to 70 DEG C, keep the pressure of 1.0MPa, react stopped reaction after 3 hours, cool to room temperature, reclaim under reduced pressure oxyethane, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.0 gram of 96% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 6.2g everolimus white solid, HPLC purity: 99.1%, content of isomer: 0.33%.Molar yield: 64.7%.MS(m/z)：980.31[M+Na]
+。
embodiment 3
9.14 grams of rapamycins (0.01mol), 8.8g oxyethane (0.2mol), 0.1g trifluoromethanesulfonic acid, autoclave is added after mixing, be warmed up to 60 DEG C, keep the pressure of 0.5MPa, react stopped reaction after 10 hours, cool to room temperature, reclaim under reduced pressure oxyethane, (eluent is acetonitrile to resistates HP-20 resin column chromatography: water=65: 35) twice, obtains 5.6g everolimus white solid, HPLC purity: 99.7%, content of isomer: 0.05%.Molar yield: 58.5%.MS(m/z)：980.31[M+Na]
+。
embodiment 4
9.14 grams of rapamycins (0.01mol), 4.4g oxyethane (0.1mol), 50mL methylene dichloride, 0.2g sulfuric acid, autoclave is added after mixing, be warmed up to 100 DEG C, keep the pressure of 1.3MPa, react stopped reaction after 20 hours, cool to room temperature, concentrate solvent, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.0 gram of 97% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 5.0g everolimus white solid, HPLC purity: 99.0%, content of isomer: 0.40%.Molar yield: 52.2%.MS(m/z)：980.31[M+Na]
+。
embodiment 5
9.14 grams of rapamycins (0.01mol), 22g oxyethane (0.5mol), 100mL toluene, 0.25g tosic acid, autoclave is added after mixing, be warmed up to 30 DEG C, keep the pressure of 0.2MPa, react stopped reaction after 2 hours, cool to room temperature, concentrated dry solvent, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.1 gram of 96% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 5.1g everolimus white solid, HPLC purity: 99.1%, content of isomer: 0.33%.Molar yield: 53.2%.MS(m/z)：980.31[M+Na]
+。
embodiment 6
9.14 grams of rapamycins (0.01mol), 13.2g oxyethane (0.3mol), 30mL toluene, 0.2g methylsulfonic acid, autoclave is added after mixing, be warmed up to 60 DEG C, keep the pressure of 0.8MPa, react stopped reaction after 10 hours, cool to room temperature, decompression and solvent recovery, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.7 gram of 97% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 6.7g everolimus white solid, HPLC purity: 99.5%, content of isomer: 0.13%.Molar yield: 70.0%.MS(m/z)：980.31[M+Na]
+。
embodiment 7
9.14 grams of rapamycins (0.01mol), 8.8g oxyethane (0.2mol), 30mL toluene, 0.3g trifluoromethanesulfonic acid, autoclave is added after mixing, be warmed up to 80 DEG C, keep the pressure of 1.3MPa, react stopped reaction after 5 hours, cool to room temperature, reclaim under reduced pressure oxyethane, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.5 gram of 98% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 6.7g everolimus white solid, HPLC purity: 99.4%, content of isomer: 0.20%.Molar yield: 70.0%.MS(m/z)：980.31[M+Na]
+。
embodiment 8
9.14 grams of rapamycins (0.01mol), 11g oxyethane (0.25mol), 0.1g trifluoromethanesulfonic acid, 30mL toluene, autoclave is added after mixing, be warmed up to 70 DEG C, keep the pressure of 1.0MPa, react stopped reaction after 8 hours, cool to room temperature, decompression and solvent recovery, residue over silica gel column chromatography (200-300 order silica gel, eluent is ethyl acetate: sherwood oil=20: 1), obtain the everolimus of 7.7 gram of 97.5% content, this crude product uses HP-20 resin column chromatography again, and (eluent is acetonitrile: water=65: 35), obtain 6.9g everolimus white solid, HPLC purity: 99.6%, content of isomer: 0.12%.Molar yield: 72.0%.MS(m/z)：980.31[M+Na]
+。
Claims (9)
1. a preparation method for everolimus, comprises the following steps:
Rapamycin and oxyethane carry out single step reaction under strong acid catalyst, obtain everolimus.
2. preparation method according to claim 1, is characterized in that, described strong acid is selected from trifluoromethanesulfonic acid, methylsulfonic acid, tosic acid, sulfuric acid, boron trifluoride ethyl ether complex or its mixture; Preferably, described strong acid is selected from trifluoromethanesulfonic acid or sulfuric acid.
3. preparation method according to claim 2, is characterized in that, the mole dosage of strong acid is 5% ~ 20% of rapamycin mole dosage.
4. preparation method according to claim 1, is characterized in that, rapamycin is 1: 10 ~ 1: 50 with the mole dosage ratio of oxyethane; Preferably, rapamycin is 1: 20 ~ 1: 30 with the mole dosage ratio of oxyethane.
5. the preparation method according to any one of claim 2 ~ 4, is characterized in that, reaction is carried out in organic solvent, and organic solvent is selected from halogenated alkane, fragrant alkane or ether; Preferably, described organic solvent is selected from methylene dichloride, toluene, dimethylbenzene or glycol dimethyl ether.
6. the preparation method according to any one of claim 2 ~ 4, is characterized in that, reacts and carries out under solvent-free.
7. the preparation method according to any one of claim 2 ~ 4, is characterized in that, the pressure of reaction is selected from 0.2 ~ 2MPa; Preferably, the pressure of described reaction is 0.8 ~ 1.3MPa.
8. the preparation method according to any one of claim 2 ~ 4, is characterized in that, the temperature of reaction is 30 ~ 100 DEG C; Preferably, the temperature of described reaction is 60 ~ 80 DEG C.
9. the preparation method according to any one of claim 2 ~ 4, is characterized in that, the time of reaction is 2 ~ 20 hours; Preferably, the time of described reaction is 5 ~ 10 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671890A (en) * | 2020-12-24 | 2022-06-28 | 鲁南制药集团股份有限公司 | Efficient and stable everolimus preparation method |
| KR20230027521A (en) | 2021-08-19 | 2023-02-28 | 주식회사 산하첨단소재 | Method for producing high-purity everolimus using a metal catalyst, an acid catalyst, and a phase transfer catalyst |
| CN116813642A (en) * | 2023-06-29 | 2023-09-29 | 杭州华东医药集团康润制药有限公司 | Everolimus purification method |
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| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
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| CN102786534A (en) * | 2012-05-25 | 2012-11-21 | 上海现代制药股份有限公司 | Preparation method of everolimus |
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| WO2014203185A1 (en) * | 2013-06-20 | 2014-12-24 | Novartis Ag | Alkylation with an alkyl fluoroalkyl sulfonate |
| CN104478898A (en) * | 2014-11-18 | 2015-04-01 | 连云港恒运医药科技有限公司 | Preparation method of everolimus and intermediate of everolimus |
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2015
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1764622A (en) * | 2003-04-16 | 2006-04-26 | 高砂香料工业株式会社 | Process for producing 2-(l-menthoxy)ethanol compound |
| WO2012103960A1 (en) * | 2011-02-04 | 2012-08-09 | Synthon Bv | Process for making trisubstituted silyloxyethyl triflates |
| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
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| WO2014082286A1 (en) * | 2012-11-30 | 2014-06-05 | Hangzhou Zylox Pharma Co., Ltd. | Rafamycin analogs and methods for making same |
| WO2014203185A1 (en) * | 2013-06-20 | 2014-12-24 | Novartis Ag | Alkylation with an alkyl fluoroalkyl sulfonate |
| CN104478898A (en) * | 2014-11-18 | 2015-04-01 | 连云港恒运医药科技有限公司 | Preparation method of everolimus and intermediate of everolimus |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671890A (en) * | 2020-12-24 | 2022-06-28 | 鲁南制药集团股份有限公司 | Efficient and stable everolimus preparation method |
| CN114671890B (en) * | 2020-12-24 | 2024-03-15 | 鲁南制药集团股份有限公司 | Efficient and stable everolimus preparation method |
| KR20230027521A (en) | 2021-08-19 | 2023-02-28 | 주식회사 산하첨단소재 | Method for producing high-purity everolimus using a metal catalyst, an acid catalyst, and a phase transfer catalyst |
| CN116813642A (en) * | 2023-06-29 | 2023-09-29 | 杭州华东医药集团康润制药有限公司 | Everolimus purification method |
| CN116813642B (en) * | 2023-06-29 | 2024-04-19 | 浙江康润制药有限公司 | Everolimus purification method |
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