CN104530112A - Method for preparing everolimus intermediate and ethylated impurities thereof - Google Patents
Method for preparing everolimus intermediate and ethylated impurities thereof Download PDFInfo
- Publication number
- CN104530112A CN104530112A CN201410812150.2A CN201410812150A CN104530112A CN 104530112 A CN104530112 A CN 104530112A CN 201410812150 A CN201410812150 A CN 201410812150A CN 104530112 A CN104530112 A CN 104530112A
- Authority
- CN
- China
- Prior art keywords
- everolimus
- acid
- impurity
- ethylization
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a method for preparing everolimus intermediate and ethylated impurities thereof, and particularly relates to a method for synthetizin an immuno-suppressor everolimus intermediate and ethylated impurities thereof. The everolimus intermediate is synthesized by substituting everolimus so as to obtain a target compound. The intermediate is simple in preparation process and high in yield, does not need column chromatography, and is suitable for industrial application. An efficient industrial synthesis method of ethylated impurities is provided for the first time. The structural formula of the everolimus intermediate is as shown in the specification.
Description
Technical field
The present invention relates to field of medicine and chemical technology, be specifically related to the preparation method of a kind of everolimus intermediate and ethylization impurity thereof.
Background technology
Everolimus (Everolimus, structure is as follows) is developed by Novartis (Novartis) and is gone on the market.Current listing 5 trade(brand)names, are respectively Afinitor, Afinitor Disperz, Zortress, Certican and Votubia.The trade(brand)name of going on the market in different areas due to same indication may be different, therefore are described according to the approval of indication or the time sequence of listing below.
In April, 2004, Certican was in Germany's listing for preventing heart and kidney transplantation exclusion reaction, within 2005, went on the market successively in European other countries; Zortress got the Green Light in the U.S. and went on the market for preventing kidney transplantation exclusion reaction of being grown up in April, 2010; In March, 2007, Certican was used for heart transplant rejection in Japan's listing, and in December, 2011 gets the Green Light for preventing kidney transplantation exclusion reaction in Japan.
In March, 2009, Afinitor was used for second line treatment advanced renal cell carcinoma in U.S.'s listing, and August in the same year, Afinitor was used for second line treatment advanced renal cell carcinoma in European Community's listing, and in April, 2010, Afinitor was used for the treatment of renal cell carcinoma in Japan's listing.
In October, 2010, Afinitor to go on the market the SEGA be used for the treatment of with TSC in the U.S.; In September, 2011, Votubia to get the Green Light the SEGA be used for the treatment of with TSC in European Union; In August, 2012 is used for the treatment of the SEGA with TSC at U.S. approval Afinitor Disperz.
In May, 2011 Afinitor acquisition FDA approval is used for the treatment of PNET; Votubia got the Green Light in Europe and was used for the treatment of PNET in September, 2011; Afinitor got the Green Light in Japan and was used for the treatment of PNET in December, 2011.
Afinitor got the Green Light in the U.S. and used the ER+/HER2-mammary cancer of the menopausal women of letrozole or Anastrozole Endodontic failure for combining exemestane therapy early stage in July, 2012; July in the same year Afinitor the European Community get the Green Light be used for the treatment of use the treatment of nonsteroidal arimedex after palindromia or progress, again in conjunction with advanced hormone receptor positive, the HER2/neu negative advanced breast cancer of exemestane therapy without the menopausal women of viscera disease function symptom.
Everolimus is in building-up process, contact with ethanol and solvolysis may occur produce ethylization impurity (its possible production process is as follows), but due to the limitation of level of response and self structure stability, it is difficult to again by degraded, is separated and obtains in a large number.And in document, have no again the synthesis report of this compound.Still the synthetic method of this compound is studied, have found more convenient, an efficient synthetic route.This impurity of synthesis can be used for the quality approach of everolimus, contributes to improving drug quality, reduces drug risk.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of everolimus intermediate (I-a), comprising:
Rapamycin, methylamine, sodium bicarbonate and 2-(tert-butyl diphenyl is silica-based) oxygen ethyl triflate are reacted in methylene dichloride, reaction solution treated concentrated after, directly obtain described intermediate,
Preferably, the temperature of described reaction is 20-35 DEG C, preferred room temperature.
Another object of the present invention is also the preparation method providing everolimus shown in a kind of formula (II), comprises and intermediate compound I-a is reacted obtained in organic solvent with hydrogen fluoride pyridine solution,
Another object of the present invention is to the preparation method that the everolimus ethylization impurity shown in a kind of formula (I) is provided.
The method obtains target product after being substituted by everolimus shown in formula II.
Preferably, described preparation method specifically comprises the steps:
Add in reaction flask by formula II compound, acid, dehydrated alcohol, temperature control reacts, and monitoring reaction is complete, adds water, extraction, and washing is dry, prepares purifying and obtains formula I;
Preferably, described acid is selected from mineral acid and organic acid, and described mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid etc., and described organic acid is selected from trifluoroacetic acid or tosic acid etc., more preferably tosic acid.
Preferably, described preparation process temperature control is 20-30 DEG C.
Particularly preferred reaction process is as follows:
Formula I is the ethylization impurity of everolimus, at present without No. CAS, not yet finds that prior art discloses preparation and the separation method of this compound.The present invention first determine can efficiently, high-quality obtains production, the separating technology of required impurity, for pharmaceutical production from now on and quality control play an important role.
Intermediate Preparation technique of the present invention is simple, yield is high, through column chromatography, need not be applicable to industrial applications, the efficient industrial preparative method of ethylization impurity that the present invention provides first.
Accompanying drawing explanation
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
Should be appreciated that, those skilled in the art, based on content disclosed herein, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should all drop in the scope of patent protection of claim definition of the application.In addition, should be appreciated that, embodiment provided herein only for illustration of object of the present invention, and should not be construed as restriction of the present invention.
Embodiment 1:
In single neck flask of 100ml, add the rapamycin of 4.50g and 2-(tert-butyl diphenyl is silica-based) the oxygen ethyl triflate of 9.50g respectively, then add 150ml methylene dichloride, stirring at room temperature, solution is oyster white suspension liquid.Then add methylamine, sodium bicarbonate, stirring at room temperature, react 4 ~ 5 hours.Concentrating under reduced pressure obtains white foam solid, uses a small amount of petroleum ether, suction filtration, vacuum-drying, obtains white solid intermediate 4.89g, yield 81%.
Embodiment 2
Everolimus (0.2g) is dissolved in dehydrated alcohol (20ml), add the hydrochloric acid (10ml) of 0.1N, stir 24 hours at 20 DEG C-30 DEG C, add 200ml water, extraction into ethyl acetate (150ml × 3), merge organic phase, saturated sodium bicarbonate washes 1 time, saturated common salt water washing 2 times.Anhydrous Na
2sO
4drying, filters, and filtrate 25 DEG C of vacuum concentration are to dry.Crude product obtains target product ethylization impurity (102mg, white solid), yield 51% through preparation liquid phase purifying, and as shown in Figure 1, the HPLC collection of illustrative plates of product as shown in Figure 2 for products obtained therefrom high resolution mass spectrum.
Preparation condition:
Chromatographic column: Phenomenex Luna C18 (2) 10u 250mm × 50mm
Wavelength: 275nm
Flow velocity: 100ml/min
Moving phase: 0.002M potassium primary phosphate-acetonitrile (30:70)
Embodiment 2:
Everolimus (0.2g) is dissolved in dehydrated alcohol (20ml), add tosic acid (80mg), 20 DEG C-30 DEG C are stirred 7 hours, add 120ml water, extraction into ethyl acetate (150ml × 3), merge organic phase, saturated sodium bicarbonate washes 1 time, saturated common salt water washing 2 times.Anhydrous Na
2sO
4drying, filters, and filtrate 25 DEG C of vacuum concentration are to dry.Crude product obtains target product ethylization impurity (154mg, white solid), yield 77% through preparation liquid phase purifying.
Preparation condition:
Chromatographic column: Phenomenex Luna C18 (2) 10u 250mm × 50mm
Wavelength: 275nm
Flow velocity: 100ml/min
Moving phase: 0.002M potassium primary phosphate-acetonitrile (30:70)
Embodiment 3:
Everolimus (0.2g) is dissolved in dehydrated alcohol (20ml), drip trifluoroacetic acid (0.5ml), stir 9 hours at 20 DEG C-30 DEG C, add 200ml water, extraction into ethyl acetate (150ml × 3), merge organic phase, saturated sodium bicarbonate washes 1 time, saturated common salt water washing 2 times.Anhydrous Na
2sO
4drying, filters, and filtrate 25 DEG C of vacuum concentration are to dry.Crude product obtains target product ethylization impurity (97mg, white solid), yield 49% through preparation liquid phase purifying.
Preparation condition:
Chromatographic column: Phenomenex Luna C18 (2) 10u 250mm × 50mm
Wavelength: 275nm
Flow velocity: 100ml/min
Moving phase: 0.002M potassium primary phosphate-acetonitrile (30:70).
Claims (8)
1. the preparation method of everolimus intermediate shown in formula (I-a), comprising:
Rapamycin, methylamine, sodium bicarbonate and 2-(tert-butyl diphenyl is silica-based) oxygen ethyl triflate are reacted in methylene dichloride, reaction solution treated concentrated after, directly obtain the intermediate shown in formula (I-a),
2. the preparation method of everolimus intermediate according to claim 1, is characterized in that, the temperature of described reaction is 20-35 DEG C, preferred room temperature.
3. the preparation method of everolimus shown in formula (II), comprises and intermediate (I-a) and hydrogen fluoride pyridine solution is reacted obtained in organic solvent,
4. everolimus ethylization impurity shown in formula (I)
5. prepare the method for everolimus ethylization impurity according to claim 4, comprise, after being substituted by everolimus formula (II) Suo Shi, obtain target product
6. the method for preparation according to claim 5 everolimus ethylization according to claim 4 impurity, specifically comprises the steps:
Add in reaction flask by compound (II), acid, dehydrated alcohol, temperature control reacts, and monitoring reaction is complete, adds water, extraction, and washing is dry, prepares purifying and obtains formula I compound.
7. the method for preparation according to claim 6 everolimus ethylization according to claim 4 impurity, it is characterized in that, described acid is selected from mineral acid or organic acid, preferably, described mineral acid is selected from hydrochloric acid, Hydrogen bromide or sulfuric acid, described organic acid is selected from trifluoroacetic acid or tosic acid, most preferably tosic acid.
8. the method for preparation according to claim 6 everolimus ethylization according to claim 4 impurity, is characterized in that, described reaction temperature control is 20-30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410812150.2A CN104530112B (en) | 2014-12-23 | 2014-12-23 | The preparation method of everolimus intermediate and its ethylization impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410812150.2A CN104530112B (en) | 2014-12-23 | 2014-12-23 | The preparation method of everolimus intermediate and its ethylization impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104530112A true CN104530112A (en) | 2015-04-22 |
| CN104530112B CN104530112B (en) | 2018-01-09 |
Family
ID=52845778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410812150.2A Active CN104530112B (en) | 2014-12-23 | 2014-12-23 | The preparation method of everolimus intermediate and its ethylization impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104530112B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process 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 |
-
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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process of everolimus |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104530112B (en) | 2018-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2008516005A (en) | Improved preparation of letrozole | |
| CN105814020A (en) | Substituted nicotinamide derivatives as kinase inhibitors | |
| CN105418581A (en) | Preparation method of trelagliptin succinate | |
| RU2011141429A (en) | IMPROVED METHOD FOR PRODUCING MEROPENEM USING ZINC POWDER | |
| EP3495370A1 (en) | Method for producing intermediate of biotin and method for producing biotin | |
| CN104557975A (en) | Methods for preparing everolimus intermediates and everolimus degradation impurities | |
| US20210070724A1 (en) | Method for producing 2-acetyl-4h,9h-naphtho[2,3-b]furan-4,9-dione | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN105524042B (en) | A method of preparing bent Ge Lieting | |
| CN103254265B (en) | Abiraterone acetate trifluoroacetate and its preparation method and application | |
| CN105732754B (en) | Synthesis method of alkyl acid testosterone compound | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| US11053255B2 (en) | Synthesis of mahanine and related compounds | |
| WO2022202982A1 (en) | Method for preparing biotin, l-lysine salt of biotin, and method for preparing same | |
| CN108558890A (en) | A kind of silaenafil intermediate synthetic method | |
| CN104016954A (en) | Method for preparing and purifying nebivolol intermediate | |
| CN101883486B (en) | Process for preparing r-gossypol l-phenylalaninol dienamine | |
| CN113045583B (en) | Preparation method of pinoxaden metabolite | |
| CN102718711A (en) | Novel method for preparing (R)-a-amino caprolactam hydrochloride | |
| JP5501054B2 (en) | Method for producing 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate | |
| KR101525493B1 (en) | Process for preparation of high purity tamsulosin or salt thereof | |
| CN107089942B (en) | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB | |
| CN107868055B (en) | Preparation method of macitentan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
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. |
|
| TA01 | Transfer of patent application right | ||
| CB02 | Change of applicant information |
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. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |