CN104478898A - Preparation method of everolimus and intermediate of everolimus - Google Patents
Preparation method of everolimus and intermediate of everolimus Download PDFInfo
- Publication number
- CN104478898A CN104478898A CN201410660846.8A CN201410660846A CN104478898A CN 104478898 A CN104478898 A CN 104478898A CN 201410660846 A CN201410660846 A CN 201410660846A CN 104478898 A CN104478898 A CN 104478898A
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- compound
- everolimus
- preparation
- acetonitrile
- organic solvent
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
The invention discloses preparation method of everolimus and an intermediate of everolimus and particularly relates to a preparation method of the medicine everolimus and the intermediate of the everolimus. The preparation method comprises the following step of carrying out reaction on a compound (II) in an organic solvent to prepare a target product in the presence of a deprotection system. The preparation method disclosed by the invention is safe, low in cost, high in yield and easy to purify and industrialize. The formula is shown in the description.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of low cost, the everolimus of environmental protection and the synthetic method of intermediate thereof.
Background technology
Everolimus is mainly used to the rejection after preventing renal transplantation and heart transplant operation clinically.Its mechanism of action mainly comprises immunosuppressive action, antitumor action, antivirus action, vascular protection effect.Other immunosuppressor conbined usage such as normal and ciclosporin are to reduce toxicity.
Compared with sirolimus, the pharmacokinetics of everolimus is more superior.
Everolimus is developed at first by Novartis Co., Ltd of Switzerland (Novartis), has the formulation such as tablet and dispersible tablet.Trade(brand)name Certican.Within 2003, first in Sweden's listing, captured European market in 2006 comprehensively.
In addition, except renal cell carcinoma, everolimus is also carrying out the research to neuroendocrine tumor, lymphoma, other cancers and tuberous sclerosis, can be used as unitary agent or share with existing cancer treatment method.As drugs, the security of everolimus and validity are not also set up at tumor area completely, are in now strict control and monitor the clinical experimental stage carried out.Designs of these tests are potential benefit in order to understand this compound better and corresponding risk.Due to the uncertainty of clinical trial, can't guarantee now that everolimus can as the business sale in the world of the medicine of tumour indication.
Current (2010) the approved trade(brand)name Certican. of everolimus is for preventing the organ rejection of heart and renal transplant recipients.Certican got the Green Light in Europe first in 2003, and (2010) are on sale more than 60 countries at present.
The structural formula of everolimus is:
Have been reported everolimus to prepare document more.Patent WO9409010, WO2012103959A1 and CN102127092A report that the preparation method of everolimus uses hydrochloric acid as deprotecting regent; see following reaction formula; the method needs to add hydrochloric acid under 0 DEG C of condition, there is the shortcomings such as deprotection by product is many, crude product column chromatography difficulty, yield are low.Patent CN103848849A report is with the hydrochloric acid of lower concentration or sulfuric acid for deprotection agent, and can obtain the everolimus of higher yields and purity, but midbody compound (II) needs through purifying, complicated operation, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, and provides a kind of safe, economical and efficiently prepare the method for everolimus.
Technical scheme of the present invention is realized by following manner:
The method of preparation formula (I) compound,
The method makes compound (II) react in organic solvent under being included in the existence of deprotection system, obtained target compound.
Preferably, described deprotecting regent is selected from trifluoroacetic acid, tetrabutyl ammonium fluoride, hydrogen fluoride pyridine solution, hydrochloric acid, triethylamine trihydrofluoride, preferred triethylamine trihydrofluoride.
Preferably, described organic solvent be selected from methyl alcohol, tetrahydrofuran (THF), ethanol, acetonitrile, Virahol and acetone one or more, particular methanol, ethanol and/or acetonitrile, more preferably acetonitrile.
Preferably, described temperature of reaction need control at-30 ~ 25 DEG C, preferably-15 ~ 25 DEG C, more preferably-15 ~-5 DEG C.
Another object of the present invention is also the preparation method providing a kind of everolimus midbody compound (II), and described intermediate is obtained with alkali reaction in organic solvent rapamycin and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester.
Preferably, described organic solvent is selected from DMF, acetonitrile or methyl-sulphoxide.
Preferably, described alkali is selected from organic bases or mineral alkali, more preferably mineral alkali, most preferably sodium hydroxide, sodium carbonate or sodium bicarbonate.
Everolimus preparation method temperature of reaction provided by the present invention is close to room temperature, easy to operate, reaction temperature and, fewer than hydrochloric acid deprotection product by product, purifying is simple, productive rate is high, easy suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is everolimus
1h nuclear magnetic resonance spectrum.
Fig. 2 is everolimus
13c nuclear magnetic resonance spectrum.
Embodiment
In order to understand content of the present invention better, be described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited to specific embodiment.
Embodiment 1:
Rapamycin 17.5g, sodium hydroxide 0.8g are dissolved in acetonitrile (150ml), be heated to 80 DEG C, stirring adds trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester 28.27g, react 3 hours, concentrating under reduced pressure, crude by column chromatography purifying obtains midbody compound II, yield 89.3%.
Embodiment 2:
Rapamycin 18.3g, sodium hydroxide 0.8g are dissolved in N, in dinethylformamide (150ml), be heated to 80 DEG C, stirring adds trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester 29.56g, react 3 hours, concentrating under reduced pressure, crude by column chromatography purifying obtains midbody compound II, yield 81.2%.
Embodiment 3:
By Compound II per (5.36g, 5mmol) join in acetonitrile (100ml), keep temperature-10 ~ 5 DEG C, add triethylamine trihydrofluoride (11ml) and react 7 ~ 8h, thin-layer chromatography detects basic reflection completely, add sodium hydrogen carbonate solution and regulate pH to 7 ~ 8, with methylene dichloride (100ml × 3) extraction, merge organic layer, wash with sodium chloride solution (300ml × 2), anhydrous sodium sulfate drying organic layer, filtering and concentrating, thickened solid, through preparative liquid chromatography purifying, obtains Compound I (white solid, 4.43g), molar yield 92.5%.HPLC：99.56％。LC/MS (m/c) 980.68 (M+Na
+), after NMR structure elucidation, determine that product is Compound I, its collection of illustrative plates is as shown in Figure 1 and Figure 2.
Embodiment 4:
By Compound II per (2.68g, 2.5mmol) join in methyl alcohol (50ml), keep temperature 5 ~ 15 DEG C, add triethylamine trihydrofluoride (6ml) and react 5 ~ 6h, thin-layer chromatography detects basic reflection completely, add sodium hydrogen carbonate solution and regulate PH to 7 ~ 8, extract with methylene dichloride (50ml × 3), merge organic layer, wash with sodium chloride solution (150ml × 2), anhydrous sodium sulfate drying organic layer, filtering and concentrating, thickened solid is through preparative liquid chromatography purifying, obtain Compound I (white solid, 4.32g), molar yield 90.1%, HPLC:97.40%.After NMR structure elucidation, determine that product is Compound I.
Embodiment 5:
By Compound II per (2.68g, 2.5mmol) join in acetonitrile (50ml), keep temperature 15 ~ 25 DEG C, add tetrabutyl ammonium fluoride (6ml) and react 10 ~ 12h, thin-layer chromatography detects basic reflection completely, add sodium hydrogen carbonate solution and regulate PH to 7 ~ 8, with methylene dichloride (50ml × 3) extraction, merge organic layer, wash with sodium chloride solution (150ml × 2), anhydrous sodium sulfate drying organic layer, filtering and concentrating, thickened solid, through preparative liquid chromatography purifying, obtains Compound I (white solid, 3.85g), molar yield 80.3%.After NMR structure elucidation, determine that product is Compound I.
Structure elucidation:
The hydrogen nuclear magnetic resonance data of table 1. everolimus and ownership
Table 2. everolimus
13c nuclear magnetic resonance data and ownership
Claims (7)
1. a method for preparation formula (I) compound,
The method makes compound (II) react in organic solvent under being included in the existence of deprotection system,
Obtained target compound.
2. the method for preparation formula according to claim 1 (I) compound; it is characterized in that; described deprotecting regent is selected from trifluoroacetic acid, tetrabutyl ammonium fluoride, hydrogen fluoride pyridine solution, hydrochloric acid, triethylamine trihydrofluoride, preferred triethylamine trihydrofluoride.
3. the method for formula according to claim 1 (I) compound, it is characterized in that, described organic solvent be selected from methyl alcohol, tetrahydrofuran (THF), ethanol, acetonitrile, Virahol and acetone one or more, particular methanol, ethanol and/or acetonitrile, more preferably acetonitrile.
4. the method for preparation formula according to claim 1 (I) compound, is characterized in that, described temperature of reaction need control at-30 ~ 25 DEG C, preferably-15 ~ 25 DEG C, more preferably-15 ~-5 DEG C.
5. the preparation method of everolimus midbody compound (II), is characterized in that, described intermediate is obtained with alkali reaction in organic solvent rapamycin and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester.
6. the preparation method of everolimus midbody compound (II) according to claim 5, it is characterized in that, described organic solvent is selected from DMF, acetonitrile or methyl-sulphoxide.
7. the preparation method of everolimus midbody compound (II) according to claim 5, it is characterized in that, described alkali is selected from organic bases or mineral alkali, preferred mineral alkali, more preferably sodium hydroxide, sodium carbonate or sodium bicarbonate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410660846.8A CN104478898A (en) | 2014-11-18 | 2014-11-18 | Preparation method of everolimus and intermediate of everolimus |
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| CN201410660846.8A CN104478898A (en) | 2014-11-18 | 2014-11-18 | Preparation method of everolimus and intermediate of everolimus |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876944A (en) * | 2015-05-13 | 2015-09-02 | 上海适济生物科技有限公司 | Preparation method of everolimus |
| CN108676014A (en) * | 2018-06-15 | 2018-10-19 | 国药集团川抗制药有限公司 | The method for purifying the method for everolimus intermediate and preparing everolimus |
| TWI646100B (en) * | 2015-06-23 | 2019-01-01 | 新拜爾斯製藥公司 | Method for synthesizing rapamycin derivatives |
| RU2716714C1 (en) * | 2019-08-26 | 2020-03-16 | Закрытое Акционерное Общество "Биокад" | New method for producing 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 (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994009010A1 (en) * | 1992-10-09 | 1994-04-28 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| CN1735402A (en) * | 2002-04-24 | 2006-02-15 | 太阳生物医学有限公司 | Polymer composition including large ring alkatriene compound |
| CN102268015A (en) * | 2011-08-30 | 2011-12-07 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
| WO2012066502A1 (en) * | 2010-11-19 | 2012-05-24 | Biocon Limited | Processes for preparation of everolimus and intermediates thereof |
| WO2012103959A1 (en) * | 2011-02-04 | 2012-08-09 | Synthon Bv | Process for making 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 |
| CN103848849A (en) * | 2014-03-24 | 2014-06-11 | 上海医药工业研究院 | Preparation technology for everolimus |
-
2014
- 2014-11-18 CN CN201410660846.8A patent/CN104478898A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994009010A1 (en) * | 1992-10-09 | 1994-04-28 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| CN1735402A (en) * | 2002-04-24 | 2006-02-15 | 太阳生物医学有限公司 | Polymer composition including large ring alkatriene compound |
| WO2012066502A1 (en) * | 2010-11-19 | 2012-05-24 | Biocon Limited | Processes for preparation of everolimus and intermediates thereof |
| WO2012103959A1 (en) * | 2011-02-04 | 2012-08-09 | Synthon Bv | Process for making everolimus |
| 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 |
| CN103848849A (en) * | 2014-03-24 | 2014-06-11 | 上海医药工业研究院 | Preparation technology for everolimus |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876944A (en) * | 2015-05-13 | 2015-09-02 | 上海适济生物科技有限公司 | Preparation method of everolimus |
| CN104876944B (en) * | 2015-05-13 | 2017-11-10 | 普济生物科技（台州）有限公司 | A kind of preparation method of everolimus |
| TWI646100B (en) * | 2015-06-23 | 2019-01-01 | 新拜爾斯製藥公司 | Method for synthesizing rapamycin derivatives |
| US10308665B2 (en) | 2015-06-23 | 2019-06-04 | Synbias Pharma Ag | Method for the synthesis of rapamycin derivatives |
| CN108676014A (en) * | 2018-06-15 | 2018-10-19 | 国药集团川抗制药有限公司 | The method for purifying the method for everolimus intermediate and preparing everolimus |
| RU2716714C1 (en) * | 2019-08-26 | 2020-03-16 | Закрытое Акционерное Общество "Биокад" | New method for producing 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 |
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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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Application publication date: 20150401 |
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