CN107501375A - A kind of preparation method of megestrol acetate - Google Patents
A kind of preparation method of megestrol acetate Download PDFInfo
- Publication number
- CN107501375A CN107501375A CN201710787117.2A CN201710787117A CN107501375A CN 107501375 A CN107501375 A CN 107501375A CN 201710787117 A CN201710787117 A CN 201710787117A CN 107501375 A CN107501375 A CN 107501375A
- Authority
- CN
- China
- Prior art keywords
- megestrol acetate
- preparation
- palladium carbon
- acetate
- megestrol
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
Abstract
The present invention provides a kind of preparation method of megestrol acetate, including step：With the pregnant α acetates of 43,20 diketone of alkene of steroid 17 of 6 methylene for raw material, using palladium carbon as catalyst, with sodium acetate control palladium carbon activity, double bond translocation reaction is carried out in alcohols solvent with cyclohexene；After the reaction completely of question response liquid, aqueous chloride solution being added to reduce the activity of catalyst palladium carbon, then palladium carbon is recovered by filtration, the reaction solution after filtering obtains megestrol acetate crude product after carrying out normal pressure concentration, then filtered washing；Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work.A kind of preparation method of megestrol acetate provided by the invention, high income, the quality of target product are good, and production cost is low, have the feature of environmental protection, are adapted to industrial production.
Description
Technical field
The invention belongs to the synthesis of medicine and preparing technical field, and in particular to a kind of preparation side of megestrol acetate
Method.
Background technology
Megestrol acetate is a kind of progestogens medicine, is used primarily for treating the gynecological diseases such as menoxenia.Eight
After the ten's, medical field finds that heavy dose of megestrol acetate has the work of the malignant tumours such as treatment breast cancer, carcinoma of endometrium
With, and the appetite of patient can be improved, put on weight, improve the life quality of cancer patient.
At this stage, domestic and international company is all using classical synthetic route：With the pregnant Gona-4-ene-3 of 6- methylene, 20- bis-
The α of ketone-17-acetate is raw material, and double bond translocation reaction is carried out under the catalytic action of palladium carbon with cyclohexene, will be anti-after reaction completely
Answer liquid to carry out filtering and concentrating, obtain megestrol acetate crude product.But the technique has following lack in commercial process
Point：Longer the time required to being filtered in industrialized production, reaction solution is still being reacted in filter process so that reaction solution mistake
The content of accessory substance medroxyproges-terone acetate is higher in filtrate after filter, reduces the content and yield of megestrol acetate.
A kind of preparation method of megestrol acetate (Application No. 201710099711.2) of application for a patent for invention is first
Medroxyprogesterone acetate is dissolved in alcohols solvent, tetrachloroquinone is added and appropriate acid carries out back flow reaction, reaction finishes, and evaporates
Fall solvent, add absolute methanol and distilled water carries out ice bath crystallization, be filtrated to get megestrol acetate crude product, then use dichloromethane
The mixed solvent of alkane and absolute methanol is by dissolving crude product and adds activated carbon progress decoloring reaction, filters while hot, filtrate is evaporated
Fall solvent, residue adds absolute methanol and is stirred crystallization, filters, drying, obtains megestrol acetate finished product, reaction it is total
Yield reach 43.1% and more than, purity reaches more than 99%.Application for a patent for invention preparation technology is simple, but total recovery compared with
It is low, therefore production cost is high, is not suitable for industrial production.
Therefore it is badly in need of that a kind of high income of target product, quality are good, and production cost is low, there is the feature of environmental protection, is adapted to industry to give birth to
The preparation method of the megestrol acetate of production.
The content of the invention
The purpose of the present invention is in view of the shortcomings of the prior art, there is provided a kind of high income of target product, quality are good, production
Cost is low, has the feature of environmental protection, is adapted to the preparation method of industrial megestrol acetate.
The invention provides following technical scheme：
A kind of preparation method of megestrol acetate, comprises the following steps：
S1：Using -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate as raw material, using palladium carbon as catalyst, with vinegar
Sour sodium control palladium carbon activity, double bond translocation reaction is carried out with cyclohexene in alcohols solvent；
S2：After the reaction solution reaction completely in S1, aqueous chloride solution is added to reduce the activity of catalyst palladium carbon, so
Palladium carbon is recovered by filtration afterwards, it is with obtaining tumer pregnant after reaction solution progress the normal pressure concentration, then filtered washing after filtering
Ketone crude product；
S3：Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work.
Preferably, the chloride in the S2 includes sodium chloride, calcium chloride and magnesium chloride.
Preferably, the palladium carbon in the S1 is 5% palladium carbon.
Preferably, alcohols solvent is ethanol or methanol in the S1.
Preferably, -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate and the mass ratio of palladium carbon are in the S1
1：0.03-0.1.
Preferably, the mass ratio of -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate and cyclohexene in the S1
For 1：0.02-0.1.
Preferably, the mass body of -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate and sodium acetate in the S1
Product is than being 1：0.2-0.8.
Preferably, the time of key translocation reaction is 1.8-2.3 hours in the S1.
Preferably, the mass ratio of -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate and chloride in the S2
For 1:0.03-0.1.
The beneficial effects of the invention are as follows：
(1) present invention adds aqueous chloride solution, makes the palladium carbon in reaction solution fast after the completion of palladium carbon is catalyzed double bond indexing
Prompt drop low activity, so as to prevent the generation of accessory substance medroxyproges-terone acetate, improve the quality and yield of megestrol acetate.
(2) the raw materials used cost of the present invention is low, recycling using alcohols as solvent, reduces the processing of chemical pollutant
Cost.
(3) preparation method of megestrol acetate provided by the invention, technique is simple, workable, is adapted to industry raw
Production.
Embodiment
Embodiment 1
A kind of preparation method of megestrol acetate, comprises the following steps：
S1：Take -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate 50kg, alcohols solvent 1000L, palladium carbon
1.5kg, cyclohexene 4kg, sodium acetate 15kg mixing, temperature rising reflux react 2 hours, sample examination；
S2：It is qualified to chemically examine, i.e., after reaction solution reaction completely, adds sodium-chloride water solution (2kg sodium chloride+10kg running water
It is obtained by mixing), then filter, the reaction solution after filtering carries out normal pressure and is concentrated into pasty state, is cooled to less than 25 DEG C, and blowing centrifuges,
Washing, drying obtain megestrol acetate crude product 48kg, and megestrol acetate content in crude product is 97.28%；
S3：Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work 44kg, yield
88%, megestrol acetate fine work content is 99.75%.
Embodiment 2
S1：Take -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate 50kg, alcohols solvent 1000L, palladium carbon
3kg, cyclohexene 2.5kg, sodium acetate 30kg, temperature rising reflux react 2 hours, sample examination；
S2：It is qualified to chemically examine, i.e., after reaction solution reaction completely, adds sodium-chloride water solution (4kg sodium chloride+15kg running water
It is obtained by mixing), then filter, the reaction solution after filtering carries out normal pressure and is concentrated into pasty state, is cooled to less than 25 DEG C, and blowing centrifuges,
Washing, drying obtain megestrol acetate crude product 47.5kg, and megestrol acetate content in crude product is 96.84%；
S3：Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work 43.5kg, received
Rate 87%, megestrol acetate fine work content are 99.52%.
Embodiment 3
S1：Take -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate 50kg, alcohols solvent 1000L, palladium carbon
4kg, cyclohexene 1.5kg, sodium acetate 40kg, temperature rising reflux react 2 hours, sample examination；
S2：It is qualified to chemically examine, i.e., after reaction solution reaction completely, adds sodium-chloride water solution (5kg sodium chloride+20kg running water
It is obtained by mixing), then filter, the reaction solution after filtering carries out normal pressure and is concentrated into pasty state, is cooled to less than 25 DEG C, and blowing centrifuges,
Washing, drying obtain megestrol acetate crude product 48kg, and megestrol acetate content in crude product is 96.58%；
S3：Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work 43.5kg, received
Rate is 87%, and megestrol acetate fine work content is 99.61%.
From embodiment 1-3, a kind of preparation method of megestrol acetate provided by the invention, technique is simple, target
High income, the quality of product are good, and production cost is low, have the feature of environmental protection, are adapted to industrial production.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, although with reference to foregoing reality
Apply example the present invention is described in detail, for those skilled in the art, it still can be to foregoing each implementation
Technical scheme described in example is modified, or carries out equivalent substitution to which part technical characteristic.All essences in the present invention
God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.
Claims (9)
1. a kind of preparation method of megestrol acetate, it is characterised in that comprise the following steps：
S1：Using -17 α of 6- methylene DELTA4-pregn-3,20-diones-acetate as raw material, using palladium carbon as catalyst, with sodium acetate
Palladium carbon activity is controlled, double bond translocation reaction is carried out in alcohols solvent with cyclohexene；
S2：After the reaction solution reaction completely in S1, aqueous chloride solution is added to reduce the activity of catalyst palladium carbon, then will
Palladium carbon is recovered by filtration, and it is thick to obtain megestrol acetate after reaction solution progress the normal pressure concentration, then filtered washing after filtering
Product；
S3：Recrystallized with the mixed solvent of methanol and dichloromethane, obtain megestrol acetate fine work.
A kind of 2. preparation method of megestrol acetate according to claim 1, it is characterised in that the chlorination in the S2
Thing includes sodium chloride, calcium chloride and magnesium chloride.
A kind of 3. preparation method of megestrol acetate according to claim 1, it is characterised in that the palladium carbon in the S1
For 5% palladium carbon.
4. the preparation method of a kind of megestrol acetate according to claim 1, it is characterised in that alcohols is molten in the S1
Agent is ethanol or methanol.
A kind of 5. preparation method of megestrol acetate according to claim 1, it is characterised in that 6- methylenes in the S1
The mass ratio of the pregnant Gona-4-ene-3 of base, -17 α of 20- diketone-acetate and palladium carbon is 1：0.03-0.1.
A kind of 6. preparation method of megestrol acetate according to claim 1, it is characterised in that 6- methylenes in the S1
The mass ratio of the pregnant Gona-4-ene-3 of base, -17 α of 20- diketone-acetate and cyclohexene is 1：0.02-0.1.
A kind of 7. preparation method of megestrol acetate according to claim 1, it is characterised in that 6- methylenes in the S1
The mass volume ratio of the pregnant Gona-4-ene-3 of base, -17 α of 20- diketone-acetate and sodium acetate is 1：0.2-0.8.
8. the preparation method of a kind of megestrol acetate according to claim 1, it is characterised in that indexing is anti-in the S1
The time answered is 1.8-2.3 hours.
A kind of 9. preparation method of megestrol acetate according to claim 1, it is characterised in that 6- methylenes in the S2
The mass ratio of the pregnant Gona-4-ene-3 of base, -17 α of 20- diketone-acetate and chloride is 1:0.03-0.1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710787117.2A CN107501375A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation method of megestrol acetate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710787117.2A CN107501375A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation method of megestrol acetate |
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| CN107501375A true CN107501375A (en) | 2017-12-22 |
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| CN201710787117.2A Pending CN107501375A (en) | 2017-09-04 | 2017-09-04 | A kind of preparation method of megestrol acetate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111187326A (en) * | 2020-01-14 | 2020-05-22 | 上海灏翔生物科技有限公司 | Preparation method of nomegestrol acetate |
| CN113976113A (en) * | 2021-11-30 | 2022-01-28 | 西安凯立新材料股份有限公司 | Catalyst for synthesizing megestrol acetate, preparation method and application thereof |
| CN113976113B (en) * | 2021-11-30 | 2024-04-26 | 西安凯立新材料股份有限公司 | Catalyst for synthesis of megestrol acetate, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4154748A (en) * | 1978-01-20 | 1979-05-15 | The Upjohn Company | Phosphate catalyzed acylation of steroidal tertiary alcohols |
| WO2008145318A2 (en) * | 2007-05-31 | 2008-12-04 | Bayer Schering Pharma Ag | USE OF α, β-UNSATURATED CARBONYL COMPOUNDS AS QUENCHING REAGENTS FOR BIRCH REDUCTION |
| US20090012321A1 (en) * | 2007-06-06 | 2009-01-08 | Klaus Annen | Process for preparing 17alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate and megestrol acetate |
-
2017
- 2017-09-04 CN CN201710787117.2A patent/CN107501375A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4154748A (en) * | 1978-01-20 | 1979-05-15 | The Upjohn Company | Phosphate catalyzed acylation of steroidal tertiary alcohols |
| WO2008145318A2 (en) * | 2007-05-31 | 2008-12-04 | Bayer Schering Pharma Ag | USE OF α, β-UNSATURATED CARBONYL COMPOUNDS AS QUENCHING REAGENTS FOR BIRCH REDUCTION |
| US20090012321A1 (en) * | 2007-06-06 | 2009-01-08 | Klaus Annen | Process for preparing 17alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate and megestrol acetate |
Non-Patent Citations (1)
| Title |
|---|
| 倪元等: "简法合成甲地孕酮", 《有机化学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111187326A (en) * | 2020-01-14 | 2020-05-22 | 上海灏翔生物科技有限公司 | Preparation method of nomegestrol acetate |
| CN111187326B (en) * | 2020-01-14 | 2022-04-19 | 上海灏翔生物科技有限公司 | Preparation method of nomegestrol acetate |
| CN113976113A (en) * | 2021-11-30 | 2022-01-28 | 西安凯立新材料股份有限公司 | Catalyst for synthesizing megestrol acetate, preparation method and application thereof |
| CN113976113B (en) * | 2021-11-30 | 2024-04-26 | 西安凯立新材料股份有限公司 | Catalyst for synthesis of megestrol acetate, preparation method and application thereof |
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Application publication date: 20171222 |