CN104876944B - A kind of preparation method of everolimus - Google Patents
A kind of preparation method of everolimus Download PDFInfo
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- CN104876944B CN104876944B CN201510253340.XA CN201510253340A CN104876944B CN 104876944 B CN104876944 B CN 104876944B CN 201510253340 A CN201510253340 A CN 201510253340A CN 104876944 B CN104876944 B CN 104876944B
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- 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
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Abstract
The present invention relates to a kind of preparation method of everolimus, comprise the following steps：Rapamycin carries out single step reaction with oxirane under strong acid catalyst, obtains everolimus.The preparation method process is simple, convenient post-treatment, and product yield is high, quality is good, is adapted to industrialization 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, also known as
40-O- (2- ethoxys)-rapamycin, belongs to macrolide immunosuppressants and antineoplastic of new generation.The medicine is by auspicious
Scholar Novartis Co., Ltd (Novartis Corp.) develops, and is listed first in Germany in March, 2004, in August, 2008 obtains European EMEA
Approval, obtain U.S. FDA approval in March, 2009, be primarily adapted for use in be in and gently arrive in global tens national clinical practices so far
The prevention of grow up kidney, liver and the cardiac transplant recipients' organ rejection of moderate immune risk.
The structural formula of everolimus and rapamycin is as follows：
It is related to the preparation method of everolimus it has been reported that for example：
American documentation literature US5665772 discloses a kind of preparation method of everolimus, its syntheti c route such as following formula institute
Show.Rapamycin is initiation material, is reacted with O- (t-Butyldimethylsilyl) ethylene glycol triflate, obtains 40-O-
(2- t-Butyldimethylsilyls) oxygen ethyl rapamycin, then obtain everolimus in methanol hydrochloride solution reclaimed water solution.The preparation
The poor reproducibility of method, molar yield is extremely low, there was only 5%, is unsuitable for industrialization production.
Chinese patent literature CN102127092A discloses a kind of preparation method of everolimus, its syntheti c route such as following formula
It is shown.It is acid binding agent by initiation material, diisopropylethylamine of rapamycin, with 2- (tert-butyl diphenyl silicon substrate) oxygen ethyl three
Fluorine methanesulfonates in toluene 50-60 DEG C reaction, obtain an intermediate through column chromatography for separation, the intermediate again with hydrogen fluoride pyridine
Solution is reacted in tetrahydrofuran, and everolimus is obtained through column chromatography for separation.Raw material 2- (the tert-butyl diphenyls of the preparation method
Silicon substrate) oxygen ethyl triflate is not easy to buy, need to voluntarily synthesize；Reaction mole total recovery it is still very low, be 21%, into
This height, equally it is unsuitable for industrialization production.
As can be seen here, there is many defects in the preparation method of everolimus disclosed in prior art, it is necessary to which research and development can be full
Preparation method needed for sufficient actual production.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the present invention to provide a kind of new preparation method of everolimus, its work is made
Skill is more reasonable, safer environmental protection, obtains low cost, the product of high quality, is adapted to industrialized production.
The preparation method of everolimus provided by the invention, comprises the following steps：
Rapamycin carries out single step reaction with oxirane under strong acid catalyst, obtains everolimus.
The strong acid is organic acid or inorganic acid；Preferably, the strong acid is selected from trifluoromethanesulfonic acid, methanesulfonic acid, right
Toluenesulfonic acid, sulfuric acid, boron trifluoride etherate or its mixture；Most preferably, the strong acid be selected from trifluoromethanesulfonic acid or
Sulfuric acid.
Preferably, the mole dosage of strong acid is the 5%~20% of rapamycin mole dosage.
Preferably, the mole dosage of rapamycin and oxirane ratio is 1: 10~1: 50, more preferably 1: 20~1: 30.
The reaction can be carried out in organic solvent, and organic solvent is selected from halogenated alkane, fragrant alkane or ether；Preferably, institute
State organic solvent and be selected from dichloromethane, toluene, dimethylbenzene or glycol dimethyl ether.
The reaction also can be in solvent-free lower progress.In the case of solvent-free, mole of the optimization ethylene oxide than rapamycin
Dosage is excessive, and more preferably the mole dosage ratio of rapamycin and oxirane is 1: 10~1: 50, further preferred rapamycin
Mole dosage ratio with oxirane is 1: 20~1: 30.
The reaction is carried out under elevated pressure, and reaction pressure is selected from 0.2~2MPa, preferably 0.8~1.3MPa.
The temperature of the reaction is 30~100 DEG C, preferably 60~80 DEG C.
The time of the reaction is 2~20 hours, preferably 5~10 hours.
Room temperature, concentration and recovery solvent are cooled to after the completion of reaction, residue is directly separated with silica gel column chromatography, obtained according to dimension
Crude product is not taken charge of, crude product is separated with HP-20 resins again, obtains the everolimus finished product that HPLC purity is more than 99.0%, and isomers contains
Amount is less than 0.5%, and molar yield reaches more than 50%.
The structural formula of isomers is as follows：
Compared with prior art, the raw material expoxy propane that preparation method of the invention uses is cheap and easy to get, and reaction only needs
One step, post processing is simple, and product yield is high, quality is good, is adapted to industrialization production.
Embodiment
It will be helpful to further understand the present invention by the following examples, but be not used in limitation present disclosure.
Test analytical instrument and condition in embodiment：
Icp mses (ICP-MS) model：The ICP-MS of XSERIES 2 (U.S.'s thermoelectricity).
LC-20AT types high performance liquid chromatograph (Japanese Shimadzu Corporation)；
HPLC test conditions：SHIMADZU LC-2010 liquid chromatographs；Chromatographic column：250 × 4.6, C18,5 μm, Erie
It is special；Mobile phase A：1.0ml formic acid adds water 1000ml to add diethylamine 1.0ml；Mobile phase B：90% acetonitrile solution；Ultraviolet inspection
Survey device wavelength 278nm；Flow 1.5ml/min；35 DEG C of column temperature；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% |
Unless otherwise instructed, various reagents used in embodiment are commercially available.
Unless otherwise instructed, the temperature in embodiment is room temperature (10~25 DEG C).
Embodiment 1
9.14 grams of rapamycins (0.01mol), 13.2g oxirane (0.3mol), 0.15g trifluoromethanesulfonic acids, after mixing
Autoclave is added, is warming up to 60 DEG C, keeps 0.5MPa pressure, reaction stops reaction after 5 hours, is cooled to room temperature, depressurizes back
Oxirane is received, (200-300 mesh silica gel, eluant, eluent is ethyl acetate to residue: petroleum ether=20: 1), is obtained with silica gel column chromatography
To the everolimus of 7.5 gram of 95% content, the crude product again with HP-20 resins column chromatography (eluant, eluent is acetonitrile: water=65: 35),
Obtain 5.9g everolimus white solids, 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 oxirane (0.4mol), 0.2g methanesulfonic acids, added after mixing high
Kettle is pressed, is warming up to 70 DEG C, keeps 1.0MPa pressure, reaction stops reaction after 3 hours, is cooled to room temperature, epoxy is recovered under reduced pressure
Ethane, with silica gel column chromatography, (200-300 mesh silica gel, eluant, eluent is ethyl acetate to residue: petroleum ether=20: 1), obtains 7.0
The everolimus of gram 96% content, with HP-20 resins column chromatography, (eluant, eluent is acetonitrile to the crude product: water=65: 35), is obtained again
6.2g everolimus white solids, 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 oxirane (0.2mol), 0.1g trifluoromethanesulfonic acids, add after mixing
Enter autoclave, be warming up to 60 DEG C, keep 0.5MPa pressure, reaction stops reaction after 10 hours, is cooled to room temperature, is recovered under reduced pressure
Oxirane, with HP-20 resins column chromatography, (eluant, eluent is acetonitrile to residue: water=65: 35) twice, obtains 5.6g everolimuses
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 oxirane (0.1mol), 50mL dichloromethane, 0.2g sulfuric acid, mix
Autoclave is added after conjunction, is warming up to 100 DEG C, keeps 1.3MPa pressure, reaction stops reaction after 20 hours, is cooled to room temperature,
Solvent is fallen in concentration, and with silica gel column chromatography, (200-300 mesh silica gel, eluant, eluent is ethyl acetate to residue: petroleum ether=20: 1), is obtained
To the everolimus of 7.0 gram of 97% content, the crude product again with HP-20 resins column chromatography (eluant, eluent is acetonitrile: water=65: 35),
Obtain 5.0g everolimus white solids, 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 oxirane (0.5mol), 100mL toluene, 0.25g is to toluene sulphur
Acid, autoclave is added after mixing, be warming up to 30 DEG C, keep 0.2MPa pressure, reaction stops reaction after 2 hours, is cooled to room
Temperature, concentrates dry solvent, residue with silica gel column chromatography (200-300 mesh silica gel, eluant, eluent is ethyl acetate: petroleum ether=20:
1), obtain the everolimus of 7.1 gram of 96% content, the crude product again with HP-20 resins column chromatography (eluant, eluent is acetonitrile: water=65:
35) 5.1g everolimus white solids, HPLC purity, are obtained：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 oxirane (0.3mol), 30mL toluene, 0.2g methanesulfonic acids, mix
Autoclave is added after conjunction, is warming up to 60 DEG C, keeps 0.8MPa pressure, reaction stops reaction after 10 hours, is cooled to room temperature, subtracts
Recycling design is pressed, (200-300 mesh silica gel, eluant, eluent is ethyl acetate to residue: petroleum ether=20: 1), is obtained with silica gel column chromatography
To the everolimus of 7.7 gram of 97% content, the crude product again with HP-20 resins column chromatography (eluant, eluent is acetonitrile: water=65: 35),
Obtain 6.7g everolimus white solids, 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 oxirane (0.2mol), 30mL toluene, 0.3g trifluoromethanesulfonic acids,
Autoclave is added after mixing, is warming up to 80 DEG C, keeps 1.3MPa pressure, reaction stops reaction after 5 hours, is cooled to room temperature,
Oxirane is recovered under reduced pressure, (200-300 mesh silica gel, eluant, eluent is ethyl acetate to residue: petroleum ether=20 with silica gel column chromatography
: 1), the everolimus of 7.5 gram of 98% content is obtained, (eluant, eluent is acetonitrile to the crude product: water=65 with HP-20 resins column chromatography again
: 35), obtain 6.7g everolimus white solids, 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 oxirane (0.25mol), 0.1g trifluoromethanesulfonic acids, 30mL toluene,
Autoclave is added after mixing, is warming up to 70 DEG C, keeps 1.0MPa pressure, reaction stops reaction after 8 hours, is cooled to room temperature,
Be recovered under reduced pressure solvent, residue with silica gel column chromatography (200-300 mesh silica gel, eluant, eluent is ethyl acetate: petroleum ether=20: 1),
Obtain the everolimus of 7.7 gram of 97.5% content, the crude product again with HP-20 resins column chromatography (eluant, eluent is acetonitrile: water=65:
35) 6.9g everolimus white solids, HPLC purity, are obtained：99.6%, content of isomer：0.12%.Molar yield：
72.0%.MS(m/z)：980.31[M+Na]+。
Claims (14)
1. a kind of preparation method of everolimus, comprises the following steps：
Rapamycin carries out single step reaction with oxirane under strong acid catalyst, obtains everolimus；It is characterized in that, described strong
Acid is selected from trifluoromethanesulfonic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, sulfuric acid or its mixture.
2. preparation method according to claim 1, the strong acid is selected from trifluoromethanesulfonic acid or sulfuric acid.
3. preparation method according to claim 1 or 2, it is characterised in that the mole dosage of strong acid is rapamycin mole
The 5%~20% of dosage.
4. preparation method according to claim 1 or 2, it is characterised in that the mole dosage of rapamycin and oxirane
Than for 1:10~1:50.
5. preparation method according to claim 4, it is characterised in that the mole dosage of rapamycin and oxirane ratio is
1:20~1:30.
6. according to the preparation method any one of claim 1~2 or 5, it is characterised in that reaction is entered in organic solvent
OK, organic solvent is selected from halogenated alkane, fragrant alkane or ether.
7. preparation method according to claim 6, it is characterised in that the organic solvent is selected from dichloromethane, toluene, two
Toluene or glycol dimethyl ether.
8. according to the preparation method any one of claim 1~2 or 5, it is characterised in that reaction is entered under solvent-free
OK.
9. according to the preparation method any one of claim 1~2,5 or 7, it is characterised in that the pressure of reaction is selected from
0.2~2MPa.
10. preparation method according to claim 9, it is characterised in that the pressure of reaction is 0.8~1.3MPa.
11. according to the preparation method any one of claim 1~2,5,7 or 10, it is characterised in that the temperature of reaction is
30~100 DEG C.
12. preparation method according to claim 11, it is characterised in that the temperature of reaction is 60~80 DEG C.
13. according to the preparation method any one of claim 1~2,5,7,10 or 12, it is characterised in that reaction when
Between be 2~20 hours.
14. preparation method according to claim 13, it is characterised in that the time of reaction is 5~10 hours.
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| 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 |
| 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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| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
| WO2012103960A1 (en) * | 2011-02-04 | 2012-08-09 | Synthon Bv | Process for making trisubstituted silyloxyethyl triflates |
| CN102786534A (en) * | 2012-05-25 | 2012-11-21 | 上海现代制药股份有限公司 | Preparation method of everolimus |
| 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 |
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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 |
| CN102786534A (en) * | 2012-05-25 | 2012-11-21 | 上海现代制药股份有限公司 | Preparation method of everolimus |
| 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 |
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