CN104530112B - The preparation method of everolimus intermediate and its ethylization impurity - Google Patents
The preparation method of everolimus intermediate and its ethylization impurity Download PDFInfo
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- CN104530112B CN104530112B CN201410812150.2A CN201410812150A CN104530112B CN 104530112 B CN104530112 B CN 104530112B CN 201410812150 A CN201410812150 A CN 201410812150A CN 104530112 B CN104530112 B CN 104530112B
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Abstract
The invention discloses the preparation method of everolimus intermediate and its ethylization impurity.In particular it relates to the synthetic method of a kind of immunodepressant everolimus intermediate and its ethylization impurity, it is synthesized by being substituted everolimus to obtain target compound.The middle preparation process of the present invention is simple, high income, without column chromatography, is adapted to industrial applications, the present invention provides the efficient industrial preparative method of ethylization impurity first.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to a kind of preparation of everolimus intermediate and its ethylization impurity
Method.
Background technology
Everolimus (Everolimus, structure are as follows) is developed and listed by Novartis (Novartis).5 business of listing at present
The name of an article, respectively Afinitor, Afinitor Disperz, Zortress, Certican and Votubia.Due to same adaptation
Disease may be different in the trade name of different area listings, therefore are carried out below according to the time sequencing of approval or the listing of indication
Description.
In April, 2004, Certican was listed for preventing heart and kidney transplantation exclusion reaction in Germany, was existed successively within 2005
European other countries' listing；Zortress got the Green Light in the U.S. and listed for preventing adult's renal transplant rejection in April, 2010
Reaction；In March, 2007, Certican was listed for heart transplant rejection in Japan, and in December, 2011 gets the Green Light in Japan
For preventing kidney transplantation exclusion reaction.
In March, 2009, Afinitor was listed in the U.S. for second line treatment advanced renal cell carcinoma, and the same year, August Afinitor existed
The European Community is listed for second line treatment advanced renal cell carcinoma, and in April, 2010, Afinitor was listed for treating nephrocyte in Japan
Cancer.
In October, 2010, Afinitor was listed in the U.S. for treating the SEGA with TSC；The Votubia of in September, 2011 exists
European Union is approved for SEGA of the treatment with TSC；In August, 2012 is used to treat in U.S. approval Afinitor Disperz
SEGA with TSC.
In May, 2011 Afinitor acquisitions FDA ratifies to be used to treat PNET；The Votubia of in September, 2011 is criticized in Europe
It is mutatis mutandis in treatment PNET；In December, 2011, Afinitor was approved for treating PNET in Japan.
In July, 2012 Afinitor be approved in the U.S. joint exemestane therapy early stage using Letrozole or Ah
The ER+/HER2- breast cancer of the menopausal women of Nagqu azoles Endodontic failure；July in the same year, Afinitor was approved in the European Community
Treatment using after the treatment of nonsteroidal arimedex palindromia or progress, in conjunction with exemestane therapy without interior
Advanced hormone receptor positive, the HER2/neu feminine gender advanced breast cancers of the menopausal women of dirty function of diseases symptom.
In building-up process, solvolysis may be occurred by being contacted with ethanol produces ethylization impurity (its is possible everolimus
Generation process is as follows), but due to the extent of reaction and the limitation of self structure stability, it is difficult by degraded again, divided
From and largely obtain.And the synthesis report of the compound is had no in document again.Still the synthetic method of the compound is entered
Go research, have found a more convenient, efficient synthetic route.The impurity of synthesis can be used for the quality of everolimus to grind
Study carefully, be favorably improved drug quality, reduce drug risk.
The content of the invention
It is an object of the invention to provide a kind of preparation method of everolimus intermediate (I-a), including：
By rapamycin, methylamine, sodium acid carbonate and 2- (tert-butyl diphenyl silicon substrate) oxygen ethyl triflate two
Being reacted in chloromethanes, reaction solution directly obtains the intermediate after processing concentrates,
Preferably, the temperature of the reaction is 20-35 DEG C, preferably room temperature.
Another object of the present invention also resides in the preparation method for providing everolimus shown in a kind of formula (II), including by centre
Body I-a reacts obtained in organic solvent with hydrogen fluoride pyridine solution,
Another object of the present invention is to provide the preparation method of the everolimus ethylization impurity shown in a kind of formula (I).
This method obtains target product after everolimus is substituted as shown in Formula II.
Preferably, the preparation method specifically comprises the following steps：
Formula II compound, acid, absolute ethyl alcohol are added in reaction bulb, temperature control reaction, monitoring reaction finishes, and adds water, extracts,
Washing, dry, preparation purifies to obtain compound of formula I；
Preferably, the acid is selected from inorganic acid and organic acid, and the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid etc., described
Organic acid is selected from trifluoroacetic acid or p-methyl benzenesulfonic acid etc., more preferably p-methyl benzenesulfonic acid.
Preferably, the preparation process temperature control is 20-30 DEG C.
Particularly preferred course of reaction is as follows：
Compound of formula I is the ethylization impurity of everolimus, at present without No. CAS, not yet finds that prior art discloses the change
The preparation of compound and separation method.The present invention determines the production for being capable of impurity needed for efficient, high-quality acquisition, separation work first
Skill, played an important role for pharmaceutical production from now on and quality control.
The middle preparation process of the present invention is simple, high income, without column chromatography, is adapted to industrial applications, this hair
The bright efficient industrial preparative method of ethylization impurity provided first.
Brief description of the drawings
Fig. 1 is the high resolution mass spectrum figure of everolimus ethylization impurity of the present invention, Mass Spectrometry Conditions：Capillary exit potential-
175, collision energy -0, ionization mode-ESI.
Fig. 2 is the HPLC collection of illustrative plates of everolimus ethylization impurity of the present invention.
Embodiment
It should be understood that those skilled in the art based on content disclosed herein, the present invention can be carried out it is various without departing from
Various modifications and improvements in spirit and scope of the invention.They should all fall the patent defined in claims hereof and protect
In the range of shield.Moreover, it should be understood that embodiment provided herein is merely to illustrate the purpose of the present invention, and it should not be construed as this
The limitation of invention.
Embodiment 1：
In 100ml single neck flask, 4.50g rapamycin and 9.50g 2- (tert-butyl diphenyl silicon are separately added into
Base) oxygen ethyl triflate, 150ml dichloromethane is added, is stirred at room temperature, solution is milky suspension.Then plus
Enter methylamine, sodium acid carbonate, be stirred at room temperature, react 4~5 hours.Be concentrated under reduced pressure to obtain white foam solid, is washed with a small amount of petroleum ether
Wash, filter, vacuum drying, obtain white solid intermediate 4.89g, yield 81%.
Embodiment 2
Everolimus (0.2g) is dissolved in absolute ethyl alcohol (20ml), 0.1N hydrochloric acid (10ml) is added, is stirred at 20 DEG C -30 DEG C
Mix 24 hours, add 200ml water, ethyl acetate extraction (150ml × 3), merge organic phase, saturated sodium bicarbonate washes 1 time, saturation
Brine It 2 times.Anhydrous Na2SO4Dry, filtering, 25 DEG C of filtrate is concentrated in vacuo to dry.Crude product purifies to obtain mesh through preparing liquid phase
Product ethylization impurity (102mg, white solid) is marked, yield 51%, products obtained therefrom high resolution mass spectrum is as shown in figure 1, product
HPLC collection of illustrative plates is as shown in Figure 2.
Preparation condition：
Chromatographic column：Phenomenex Luna C18(2)10u 250mm×50mm
Wavelength：275nm
Flow velocity：100ml/min
Mobile phase：0.002M potassium dihydrogen phosphates-acetonitrile (30:70)
Embodiment 2：
Everolimus (0.2g) is dissolved in absolute ethyl alcohol (20ml), adds p-methyl benzenesulfonic acid (80mg), 20 DEG C of -30 DEG C of stirrings
7 hours, 120ml water is added, ethyl acetate extraction (150ml × 3), merges organic phase, saturated sodium bicarbonate is washed 1 time, saturation food
Salt water washing 2 times.Anhydrous Na2SO4Dry, filtering, 25 DEG C of filtrate is concentrated in vacuo to dry.Crude product purifies to obtain target through preparing liquid phase
Product ethylization impurity (154mg, white solid), yield 77%.
Preparation condition：
Chromatographic column：Phenomenex Luna C18(2)10u 250mm×50mm
Wavelength：275nm
Flow velocity：100ml/min
Mobile phase：0.002M potassium dihydrogen phosphates-acetonitrile (30:70)
Embodiment 3：
Everolimus (0.2g) is dissolved in absolute ethyl alcohol (20ml), trifluoroacetic acid (0.5ml) is added dropwise, is stirred at 20 DEG C -30 DEG C
Mix 9 hours, add 200ml water, ethyl acetate extraction (150ml × 3), merge organic phase, saturated sodium bicarbonate washes 1 time, saturation
Brine It 2 times.Anhydrous Na2SO4Dry, filtering, 25 DEG C of filtrate is concentrated in vacuo to dry.Crude product purifies to obtain mesh through preparing liquid phase
Mark product ethylization impurity (97mg, white solid), yield 49%.
Preparation condition：
Chromatographic column：Phenomenex Luna C18(2)10u 250mm×50mm
Wavelength：275nm
Flow velocity：100ml/min
Mobile phase：0.002M potassium dihydrogen phosphates-acetonitrile (30:70) .
Claims (6)
1. prepare the method for everolimus ethylization impurity, including by rapamycin, methylamine, sodium acid carbonate and the 2- (tert-butyl groups two
Phenyl silicon substrate) oxygen ethyl triflate reacts in dichloromethane, and reaction solution directly obtains formula (I- after processing concentrates
A) intermediate shown in, the temperature of the reaction is 20-35 DEG C；Intermediate (I-a) is with hydrogen fluoride pyridine solution in organic solvent
Formula (II) is made in middle reaction, and target product is obtained after further everolimus shown in formula (II) is substituted,
2. the method according to claim 1 for preparing everolimus ethylization impurity, specifically comprises the following steps：
Compound (II), acid, absolute ethyl alcohol are added in reaction bulb, temperature control reaction, monitoring reaction finishes, and adds water, extracts, washes
Wash, dry, preparation purifies to obtain formula (I) compound.
3. the method according to claim 2 for preparing everolimus ethylization impurity, it is characterised in that the acid is selected from nothing
Machine acid or organic acid.
4. the method according to claim 3 for preparing everolimus ethylization impurity, it is characterised in that the inorganic acid choosing
From hydrochloric acid, hydrobromic acid or sulfuric acid, the organic acid is selected from trifluoroacetic acid or p-methyl benzenesulfonic acid.
5. the method according to claim 4 for preparing everolimus ethylization impurity, it is characterised in that the organic acid is
P-methyl benzenesulfonic acid.
6. the method according to claim 2 for preparing everolimus ethylization impurity, it is characterised in that the reaction temperature control
For 20-30 DEG C.
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| CN201410812150.2A CN104530112B (en) | 2014-12-23 | 2014-12-23 | The preparation method of everolimus intermediate and its ethylization impurity |
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| CN201410812150.2A CN104530112B (en) | 2014-12-23 | 2014-12-23 | The preparation method of everolimus intermediate and its ethylization impurity |
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| CN104530112B true CN104530112B (en) | 2018-01-09 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557975B (en) * | 2014-12-23 | 2017-06-20 | 连云港恒运医药有限公司 | The preparation method of everolimus intermediate and its degradation impurity |
| CN109206441B (en) * | 2017-06-30 | 2022-05-20 | 正大天晴药业集团股份有限公司 | Purification method of everolimus |
| CN115028658A (en) * | 2022-07-06 | 2022-09-09 | 国药集团川抗制药有限公司 | Rapamycin silanol ester and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101378751A (en) * | 2006-02-02 | 2009-03-04 | 诺瓦提斯公司 | Tuberous sclerosis treatment |
| CN102127092A (en) * | 2010-01-18 | 2011-07-20 | 东南大学 | Preparation of Everolimus |
| CN103848849A (en) * | 2014-03-24 | 2014-06-11 | 上海医药工业研究院 | Preparation technology for everolimus |
| CN104557975A (en) * | 2014-12-23 | 2015-04-29 | 连云港恒运医药科技有限公司 | Methods for preparing everolimus intermediates and everolimus degradation impurities |
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2014
- 2014-12-23 CN CN201410812150.2A patent/CN104530112B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101378751A (en) * | 2006-02-02 | 2009-03-04 | 诺瓦提斯公司 | Tuberous sclerosis treatment |
| CN102127092A (en) * | 2010-01-18 | 2011-07-20 | 东南大学 | Preparation of Everolimus |
| CN103848849A (en) * | 2014-03-24 | 2014-06-11 | 上海医药工业研究院 | Preparation technology for everolimus |
| CN104557975A (en) * | 2014-12-23 | 2015-04-29 | 连云港恒运医药科技有限公司 | Methods for preparing everolimus intermediates and everolimus degradation impurities |
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Effective date of registration: 20170519 Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Jiangsu city of Lianyungang province Guanyun County Harbor Industrial Zone weft seven road No. 1 Applicant before: LIANYUNGANG HENGYUN MEDICAL TECHNOLOGY CO., LTD. |
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Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant before: Lianyungang Hengyun Pharmaceutical Co. Ltd. |
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