CN106243179A - A kind of exemestane industrialized preparing process - Google Patents
A kind of exemestane industrialized preparing process Download PDFInfo
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- CN106243179A CN106243179A CN201610624506.9A CN201610624506A CN106243179A CN 106243179 A CN106243179 A CN 106243179A CN 201610624506 A CN201610624506 A CN 201610624506A CN 106243179 A CN106243179 A CN 106243179A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
A kind of exemestane industrialized preparing process.Isosorbide-5-Nitrae androsadiendione, dehydrated alcohol, triethyl orthoformate, p-methyl benzenesulfonic acid are added in reactor, stirring, it is spin-dried for, crystallizes to obtain intermediate YXMT01；By intermediate YXMT01, dehydrated alcohol, oxolane, 37% formaldehyde, N monomethylaniline., p-methyl benzenesulfonic acid is sequentially added in reactor, obtains intermediate YXMT02 after being spin-dried for；Intermediate YXMT02, ethyl acetate, hydrochloric acid are sequentially added in reactor, separate out, sucking filtration, obtain white solid, then through re crystallization from toluene, obtain intermediate YXMT03；Intermediate YXMT03, toluene, IBX being sequentially added in reactor, stirring, cooling, filtrate concentrates, and recrystallization obtains white solid YXMT.The inventive method avoids one kettle way in the industrial production uncontrollable, and raw material sources are cheap, and technological operation is easy to control, and yield is high, stay in grade, is suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of organic synthesis, be specifically related to a kind of exemestane industrialized preparing process.
Background technology
Exemestane, is called for short YXMT, and Chinese name: Isosorbide-5-Nitrae-diene-3,17-diketone-6-methylenandrosta, exemestane is one
Planting irreversibility steroidal aromatase inactivator, in structure, the natural substrates androstenedione to this enzyme is similar, for the pseudo-end of aromatase
Thing, can make it inactivate (this effect is also referred to as " destructive suppression ") by being irreversibly combined with the avtive spot of this enzyme, thus
Substantially reduce the estrogen level in menopausal women blood circulation, but to corticosteroid in adrenal gland and the biological conjunction of aldosterome
One-tenth has no significant effect, and when being higher than 600 times of suppression aromatase activity, does not produces other enzymes in Steroidgenesis approach
Life significantly affects, and it can have by suppressing aromatase to stop estrogen production to be that a kind of effective as selective treatment post menopausal swashs
Element independent mammary tumor.But current production method technological operation difficulty controls, and yield is low, quality is unstable, is not suitable for industry
Metaplasia is produced.
Summary of the invention
The technical problem to be solved in the present invention is the defect overcoming prior art, it is provided that a kind of exemestane industrialized production
Method.
In order to solve above-mentioned technical problem, the invention provides following technical scheme: a kind of exemestane industry metaplasia
Product method, its scheme is as follows:
1, Isosorbide-5-Nitrae-androsadiendione, dehydrated alcohol, triethyl orthoformate, p-methyl benzenesulfonic acid are added in reactor, 20～
Stir 1～24h at 75 DEG C, after being spin-dried for, then obtain exemestane intermediate YXMT01 through alcohol crystal；
2, by intermediate YXMT01, dehydrated alcohol, oxolane, 37% formaldehyde, methylphenylamine, p-methyl benzenesulfonic acid is successively
Add in reactor, at keeping 20～75 DEG C, after being spin-dried for, obtain exemestane intermediate YXMT02；
3, intermediate YXMT02, ethyl acetate, hydrochloric acid are sequentially added in reactor, at keeping 0～25 DEG C, stir 12h,
Have white solid to separate out, sucking filtration, obtain white solid, then through re crystallization from toluene, obtain exemestane intermediate YXMT03；
4, intermediate YXMT03, toluene, IBX are sequentially added in reactor, at keeping 50～90 DEG C, stir 48h, cold
But, having white solid and separate out, sucking filtration, obtaining white solid is IBX, and filtrate concentrates, and obtains faint yellow solid, more heavily ties through ethanol
Crystalline substance, obtains white solid exemestane YXMT.
The inventive method all separates for often walking product, purifies, it is to avoid one kettle way in the industrial production uncontrollable,
Raw material sources are cheap, and technological operation is easy to control, and yield is high, stay in grade, are suitable for industrialized production.
Detailed description of the invention
Embodiment 1
1. prepared by intermediate YXMT01:
Add Isosorbide-5-Nitrae-androsadiendione 4Kg, triethyl orthoformate 4L, p-methyl benzenesulfonic acid 104g and oxolane 26L, anhydrous
Ethanol 4L, is warming up to 40--45 DEG C of stirring reaction 12 hours, and detection raw material residual, less than 5.0% stopping, then filtering, adds
15L ethyl alcohol recrystallization, obtains 3.45Kg white solid intermediate YXMT01, purity 98.5%, yield spectra 78.3%, intermediate
YXMT01 structural formula is as follows:
2. prepared by intermediate YXMT02:
Add 3.45KgYXMT01,10L oxolane, 10L ethanol, 1.76KgN-monomethylaniline. and 0.87Kg37% formaldehyde
Stirring 10 hours under conditions of at least 40--45 DEG C, detection raw material residual, less than 3.0% stopping, steaming solvent, directly throws
The next step, it is not necessary to refined, obtains 3.25Kg intermediate YXMT02, purity 98.9%, yield spectra 73.5%, intermediate
YXMT02 structural formula is as follows:
3. prepared by intermediate YXMT03:
3.25KgYXMT02,8L oxolane and 8L ethanol are put in single port flask, adds under cryogenic
21.2L concentrated hydrochloric acid continues stirring reaction 1 hour, and at being cooled to 0--5 DEG C, add water 70Lml, continues stirring 1 hour, filters washing,
Obtaining 1.92Kg crude product, add 19L toluene, temperature rising reflux is the most molten, slow cooling, centrifugal, puts in vacuum drying oven and obtains
1.78Kg intermediate YXMT03, yield 74.4%, purity 99.1%, intermediate YXMT03 structural formula is as follows:
4. prepared by exemestane YXMT:
1.78KgYXMT03 is dissolved in DMSO17L and 34L toluene, adds 5.34KgIBX, under nitrogen protection, heating
To 85 DEG C, stirring 48h, reactant cools down, and adds 6L normal heptane, centrifugal, and filtering residue normal heptane washs, and obtains white solid
4.45Kg (this solid is IBX reduzate), filtrate is washed 2 times with 10%NaOH, then is washed 1 time with saturated sodium-chloride, by nothing
Aqueous sodium persulfate is dried, and filtrate is spin-dried for obtaining faint yellow solid, adds 20L ethanol, 170g activated carbon, and temperature rising reflux is the most molten, while hot
Filter pressing is in another clean still, and the stage lowers the temperature, and centrifugal, wet product is put in drying under reduced pressure case, obtains 1.0Kg white solid Yi Ximei
Smooth YXMT, yield 56.7%, purity 99.5%, the structural formula of exemestane YXMT is as follows:
Claims (1)
1. an exemestane industrialized preparing process, it is characterised in that its scheme is as follows:
1, Isosorbide-5-Nitrae-androsadiendione, dehydrated alcohol, triethyl orthoformate, p-methyl benzenesulfonic acid are added in reactor, 20～75 DEG C
Lower stirring 1～24h, after being spin-dried for, then obtains exemestane intermediate YXMT01 through alcohol crystal；
2, by intermediate YXMT01, dehydrated alcohol, oxolane, 37% formaldehyde, methylphenylamine, p-methyl benzenesulfonic acid is sequentially added into
In reactor, at keeping 20～75 DEG C, after being spin-dried for, obtain exemestane intermediate YXMT02；
3, intermediate YXMT02, ethyl acetate, hydrochloric acid are sequentially added in reactor, at keeping 0～25 DEG C, stir 12h, have
White solid separates out, and sucking filtration obtains white solid, then through re crystallization from toluene, obtains exemestane intermediate YXMT03；
4, intermediate YXMT03, toluene, IBX are sequentially added in reactor, at keeping 50～90 DEG C, stir 48h, cooling, meeting
Having white solid to separate out, sucking filtration, obtaining white solid is IBX, and filtrate concentrates, and obtains faint yellow solid, then through ethyl alcohol recrystallization, obtains
White solid exemestane YXMT.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610624506.9A CN106243179B (en) | 2016-07-31 | 2016-07-31 | A kind of Exemestane industrialized preparing process |
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| CN201610624506.9A CN106243179B (en) | 2016-07-31 | 2016-07-31 | A kind of Exemestane industrialized preparing process |
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| CN106243179A true CN106243179A (en) | 2016-12-21 |
| CN106243179B CN106243179B (en) | 2018-09-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409432A (en) * | 2020-11-16 | 2021-02-26 | 陕西理工大学 | Synthesis method of exemestane |
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| EP1709062B9 (en) * | 2004-01-16 | 2013-02-13 | Cedarburg Pharmaceuticals, Inc. | Exemestane and its intermediates and methods of making the same |
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| CN105294807A (en) * | 2014-06-26 | 2016-02-03 | 浙江医药股份有限公司新昌制药厂 | Exemestane intermediate oxime compound, and preparation method and application thereof |
| CN105622694A (en) * | 2014-10-29 | 2016-06-01 | 赵建英 | Exemestane synthesis technology |
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| CN1453288A (en) * | 2002-04-25 | 2003-11-05 | 北京万全阳光医药科技有限公司 | Catalytic dehydrogenation process of preparing Exemestane |
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| RU2425052C1 (en) * | 2010-03-04 | 2011-07-27 | Татьяна Степановна Савинова | Method of producing 6-methyleneandrost-4-ene-3,17-dione from androst-4-ene-3,17-dione, method of producing 6-methyleneandrost-1,4-diene-3,17-dione (exemestane) using obtained 6-methyleneandrost-4-ene-3,17-dione |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409432A (en) * | 2020-11-16 | 2021-02-26 | 陕西理工大学 | Synthesis method of exemestane |
| CN112409432B (en) * | 2020-11-16 | 2023-07-07 | 陕西理工大学 | Synthesis method of exemestane |
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| Publication number | Publication date |
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| CN106243179B (en) | 2018-09-11 |
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Effective date of registration: 20170801 Address after: 210038 Nanjing economic and Technological Development Zone, Jiangsu, No. 20 Xingang Avenue Applicant after: Nanjing Cuccess Pharmaceutical Co., Ltd. Address before: High tech Zone camphor road in Hefei city Anhui province 230001 No. 168 Technology Industrial Park building D17/22 Applicant before: HEFEI YUANZHI PHARMACEUTICAL R & D CO., LTD. |
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