CN114230627B - Preparation method of betamethasone epoxy hydrolysate intermediate - Google Patents
Preparation method of betamethasone epoxy hydrolysate intermediate Download PDFInfo
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- CN114230627B CN114230627B CN202111676952.1A CN202111676952A CN114230627B CN 114230627 B CN114230627 B CN 114230627B CN 202111676952 A CN202111676952 A CN 202111676952A CN 114230627 B CN114230627 B CN 114230627B
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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
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Abstract
The application belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of a betamethasone epoxy hydrolysate intermediate, wherein a compound A is subjected to methyl and then alkynylation reaction to obtain a compound C, and the reaction route is as follows:
Description
Technical Field
The application belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of a betamethasone epoxy hydrolysate intermediate.
Background
The betamethasone epoxy hydrolysate is an important intermediate for synthesizing betamethasone, is a main raw material for synthesizing betamethasone, and has a molecular formula: c (C) 22 H 28 O 5 Commodity alias: DB11; the chemical name is 9 beta, 11 beta-epoxy-16 beta-methyl pregna-1, 4-diene-17 alpha, 21-diol-3, 20-dione; betamethasone epoxy. CAS No. 981-34-0, molecular structural formula:
in the synthesis of betamethasone epoxy hydrolysate, an important intermediate is provided, and the structural formula is as follows:
there is currently no better way to synthesize the above intermediates.
Disclosure of Invention
The technical problem to be solved by the application is to provide a preparation method of a betamethasone epoxy hydrolysate intermediate, which has simple process, and the 16-position alpha methyl is translocated into beta methyl while alkynylating, so that the product yield and purity are higher.
The application discloses a preparation method of a betamethasone epoxy hydrolysate intermediate, which comprises the steps of carrying out methyl on a compound A, and then carrying out alkynylation reaction to obtain a compound C (namely the betamethasone epoxy hydrolysate intermediate), wherein the reaction route is as follows:
the step of the alkynylation reaction is that the compound B is added into acetylene solution, reacted and treated to obtain compound C, wherein the acetylene solution is a mixture of tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide in which acetylene is dissolved (namely, the acetylene solution is composed of at least three raw materials, namely, tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide respectively).
Preferably, the weight ratio of tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide is 10:1-1.5:2-2.5.
Preferably, the reaction temperature of the alkynylation reaction is from 0 to 5 ℃.
Preferably, in the alkynylation reaction and in a treatment mode, the reactant is kept still, and the organic phase is concentrated, filtered and recrystallized to obtain the betamethasone epoxy hydrolysate intermediate.
Preferably, the preparation method of the compound B comprises the steps of mixing the compound A with a reaction solution at the temperature of minus 40 ℃ to minus 35 ℃, heating to 0 ℃ to 10 ℃ for reaction, cooling to the temperature of minus 45 ℃ to minus 40 ℃, adding bromomethane, controlling the temperature to be minus 20 ℃ to 10 ℃ for reaction, and treating to obtain the compound B;
the preparation method of the reaction solution is that format liquid, tetrahydrofuran and hexamethylphosphoramide are mixed, and the preparation method of the format liquid is that the mixed liquid of styrene and tetrahydrofuran is added into the mixed liquid of diisopropylamine and metallic lithium.
Preferably, the mixed solution of styrene and tetrahydrofuran is added into the mixed solution of diisopropylamine and metallic lithium, and the temperature is controlled to be 40-50 ℃.
Preferably, the weight ratio of the styrene, the tetrahydrofuran, the diisopropylamine and the metallic lithium is 1:2.5-3.5:1.5-2:0.1-0.2.
Preferably, the weight ratio of the tetrahydrofuran to the hexamethylphosphoramide is 1:0.1-0.2
The application has the beneficial effects that the application discloses a preparation method of a key intermediate of betamethasone epoxy hydrolysate. The preparation method takes the compound A as a raw material, and the betamethasone epoxy hydrolysate key intermediate is prepared by methylation reaction, alkynylation transposition reaction and refining in sequence.
In the female ring of steroid hormone, if beta methyl is firstly arranged at the 16 th position, LDA (lithium diisopropylamide) or butyl lithium and other reagents are needed to carry out the alkynylation reaction subsequently, and the cost is obviously increased; the application firstly carries out the alkynylation reaction on the alpha methyl at the 16-position, uses acetylene solution dissolved with acetylene to carry out the alkynylation reaction and transposition, and obviously reduces the cost.
The alkynylation reaction generally requires acetylene to be dissolved in an aprotic solvent such as acetone to increase the solubility of acetylene and increase the reaction efficiency. According to the application, solvents such as acetone and the like are not added in the alkynylation reaction, but ethanol is added, so that the 16-position alpha methyl is translocated into beta methyl during the alkynylation reaction, the translocation of the 16-position methyl can be completed simultaneously without additional operation, the efficiency is higher, and the cost is lower.
Detailed Description
Example 1
0.8kg of diisopropylamine is pumped into a reaction tank, after nitrogen is replaced for 2 times, 0.051kg of metallic lithium is added, the temperature of the system is raised to 40-45 ℃, the temperature is controlled to 40-45 ℃, and about thirty percent of a mixed solution of 0.48kg of styrene and 1.5kg of tetrahydrofuran is added into the reaction tank dropwise to initiate the reaction (fogging and the temperature rise is 2-5 ℃). After initiation, controlling the temperature to be 40-50 ℃, and dripping the rest mixed solution of styrene and tetrahydrofuran. After the dripping is completed, the temperature is kept between 40 and 50 ℃ for reaction for about 2 hours until no metal lithium remains. Cooling the prepared format liquid to 0-10deg.C for use.
4.5kg of tetrahydrofuran and 0.78kg of hexamethylphosphoramide are pumped into the low-temperature kettle, nitrogen is replaced for 2 times, and the temperature is reduced to 0-5 ℃. And slowly pumping the prepared format liquid into a main reaction kettle. After the addition, nitrogen is replaced for 2 times, and the temperature is kept between 5 and 10 ℃ for reaction for 1 hour. And cooling the system to-35 to-40 ℃ under the protection of nitrogen. 1.0kg of Compound A was added 4-5 times at intervals of 5-10min. After the completion of the addition, the reaction is carried out for 2 hours at the temperature of 0-10 ℃. And cooling the system to-40 to-45 ℃ under the protection of nitrogen, firstly introducing a small amount of bromomethane, severely releasing heat, and rapidly introducing the rest bromomethane (0.9 kg in total) after isothermal stability. After the introduction, the system is kept at-20 to 10 ℃ for reaction for at least 2 hours. After the raw materials are reacted completely, 0.25kg of water is added to stop the reaction, and the temperature is controlled between 10 and 20 ℃ and the stirring is carried out for at least 2 hours. Concentrating the system at 45-55deg.C under negative pressure (vacuum is less than or equal to-0.08 Mpa) until no fraction is present, adding 5kg of dichloromethane, stirring to dissolve, washing with 2kg of water and 1kg of water sequentially, adding 0.5kg of sodium sulfate into the system, drying, filtering, concentrating the filtrate at 45-55deg.C under negative pressure (vacuum is less than or equal to-0.08 Mpa) until no fraction is present, adding 3.5kg of tetrahydrofuran to dissolve to obtain tetrahydrofuran solution of compound B, and directly adding into the next step.
Under the protection of nitrogen, 10kg of tetrahydrofuran, 1.2kg of absolute ethyl alcohol and 2kg of powdery potassium hydroxide are added into a reaction kettle, the temperature is reduced to 0-10 ℃, acetylene gas is introduced, and the acetylene gas is introduced at a constant speed for 2 hours until the acetylene gas is not absorbed any more. Cooling the system to 0-5deg.C, stirring for 10min, maintaining the temperature at 0-5deg.C, slowly adding tetrahydrofuran solution dropwise, maintaining the temperature at 0-5deg.C for 3.5 hr until the raw materials react completely, quenching with 2kg water, and stirring for 30-60min. Standing for separating liquid, retaining tetrahydrofuran layer, extracting lower layer with 1kg tetrahydrofuran layer once, mixing tetrahydrofuran layers, concentrating under negative pressure at 50deg.C (vacuum is less than or equal to-0.08 Mpa) until no fraction is obtained, replacing with 4kg water, concentrating again until no fraction is obtained, cooling to 30deg.C, filtering to obtain crude product of target product, and recrystallizing the crude product with 10kg ethyl acetate repeatedly for 3-4 times to obtain refined product of target product. Purity 99%, total yield 80%.
Comparative example 1
Compared with example 1, 2kg of acetone was used instead of 1.2kg of absolute ethanol, and the other main products had the structural formula of the following main products, wherein the yield of the target product compound C was 60%, the purity was 98.5% and the same as in example 1
The yield thereof was found to be 55%.
Those of ordinary skill in the art will appreciate that: the discussion of any of the embodiments above is merely exemplary and is not intended to suggest that the scope of protection of the application is limited to these examples; the technical features of the above embodiments or in the different embodiments may also be combined within the idea of the application, the steps may be implemented in any order and there are many other variations of the different aspects of one or more embodiments of the application as described above, which are not provided in detail for the sake of brevity.
One or more embodiments of the present application are intended to embrace all such alternatives, modifications and variations as fall within the broad scope of the present application. Accordingly, any omissions, modifications, equivalents, improvements and others which are within the spirit and principles of the one or more embodiments of the application are intended to be included within the scope of the application.
Claims (6)
1. A preparation method of a betamethasone epoxy hydrolysate intermediate is characterized in that a compound A is subjected to methyl and then to an alkynylation reaction to obtain a compound C, wherein the reaction route is as follows:
，
the step of the alkynylation reaction is that a compound B is added into an acetylene solution, and the acetylene solution is reacted and treated to obtain a compound C, wherein the acetylene solution is a mixture of tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide in which acetylene is dissolved;
tetrahydrofuran or methyltetrahydrofuran, absolute ethyl alcohol or isopropanol and potassium hydroxide in a weight ratio of 10:1-1.5:2-2.5;
the preparation method of the compound B comprises the steps of mixing the compound A with a reaction solution at the temperature of minus 40 ℃ to minus 35 ℃, heating to 0 ℃ to 10 ℃ for reaction, cooling to the temperature of minus 45 ℃ to minus 40 ℃, adding bromomethane, controlling the temperature to minus 20 ℃ to 10 ℃ for reaction, and treating to obtain the compound B;
the preparation method of the reaction solution is that format liquid, tetrahydrofuran and hexamethylphosphoramide are mixed, and the preparation method of the format liquid is that the mixed liquid of styrene and tetrahydrofuran is added into the mixed liquid of diisopropylamine and metallic lithium.
2. The process of claim 1, wherein the reaction temperature of the alkynylation reaction is from 0 to 5 ℃.
3. The preparation method according to claim 1, wherein the betamethasone epoxy hydrolysate intermediate is obtained by the steps of standing the reactant in a treatment manner, concentrating the organic phase, filtering and recrystallizing.
4. The preparation method according to claim 1, wherein the mixture of styrene and tetrahydrofuran is added to the mixture of diisopropylamine and metallic lithium at a temperature of 40-50 ℃.
5. The method according to claim 1, wherein the weight ratio of styrene, tetrahydrofuran, diisopropylamine and metallic lithium is 1:2.5-3.5:1.5-2:0.1-0.2.
6. The preparation method according to claim 1, wherein the weight ratio of tetrahydrofuran to hexamethylphosphoramide is 1:0.1-0.2.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0148616A2 (en) * | 1984-01-05 | 1985-07-17 | The Upjohn Company | Stabilised monolithium acetylide and the ethynylation of steroids |
| US4707358A (en) * | 1984-01-30 | 1987-11-17 | The University Of Chicago | Vaccine against Epstein-Barr Virus |
| WO1993015103A2 (en) * | 1992-01-28 | 1993-08-05 | Schering Corporation | Novel steroid intermediates and processes for their preparation |
| CN1372565A (en) * | 1999-09-06 | 2002-10-02 | 阿克佐诺贝尔公司 | Non-aromatic estrogenic steroids with hydrocarbon substituent in position 11 |
| CN1662549A (en) * | 2002-06-19 | 2005-08-31 | 卡罗生物股份公司 | Glucocorticoid receptor ligands for the treatment of metabolic disorders |
| CN101486721A (en) * | 2009-02-17 | 2009-07-22 | 浙江联盛化学工业有限公司 | Use of lithium diisopropyl amido in 1-methyl cyclopropene preparation |
| CN102225959A (en) * | 2011-04-29 | 2011-10-26 | 中国科学院上海有机化学研究所 | 16beta-methyl-17alpha-hydroxypreg-3, 20- diketone compound and synthesis thereof |
| CN103641878A (en) * | 2013-11-22 | 2014-03-19 | 湖南新合新生物医药有限公司 | Preparation method for betamethasone intermediate or its analogue |
| CN103965277A (en) * | 2014-05-19 | 2014-08-06 | 中国科学院上海有机化学研究所 | Method for synthesizing difluprednate from sterol fermentation product |
| CN106986908A (en) * | 2017-03-23 | 2017-07-28 | 湖南玉新药业有限公司 | The preparation method of betamethasone |
| CN106986907A (en) * | 2017-04-01 | 2017-07-28 | 湖南玉新药业有限公司 | For the preparation method for the intermediate for preparing betamethasone |
| CN107033207A (en) * | 2017-05-04 | 2017-08-11 | 山东赛托生物科技股份有限公司 | A kind of preparation method of the steroid nucleus derivative containing alkynyl |
| CN110099915A (en) * | 2016-10-07 | 2019-08-06 | 欧瑞克制药公司 | Glucocorticoid receptor inhibitor |
-
2021
- 2021-12-31 CN CN202111676952.1A patent/CN114230627B/en active Active
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0148616A2 (en) * | 1984-01-05 | 1985-07-17 | The Upjohn Company | Stabilised monolithium acetylide and the ethynylation of steroids |
| US4707358A (en) * | 1984-01-30 | 1987-11-17 | The University Of Chicago | Vaccine against Epstein-Barr Virus |
| WO1993015103A2 (en) * | 1992-01-28 | 1993-08-05 | Schering Corporation | Novel steroid intermediates and processes for their preparation |
| US5502183A (en) * | 1992-01-28 | 1996-03-26 | Schering Corporation | Steroid intermediates and processes for their preparation |
| CN1372565A (en) * | 1999-09-06 | 2002-10-02 | 阿克佐诺贝尔公司 | Non-aromatic estrogenic steroids with hydrocarbon substituent in position 11 |
| CN1662549A (en) * | 2002-06-19 | 2005-08-31 | 卡罗生物股份公司 | Glucocorticoid receptor ligands for the treatment of metabolic disorders |
| CN101486721A (en) * | 2009-02-17 | 2009-07-22 | 浙江联盛化学工业有限公司 | Use of lithium diisopropyl amido in 1-methyl cyclopropene preparation |
| CN102225959A (en) * | 2011-04-29 | 2011-10-26 | 中国科学院上海有机化学研究所 | 16beta-methyl-17alpha-hydroxypreg-3, 20- diketone compound and synthesis thereof |
| CN103641878A (en) * | 2013-11-22 | 2014-03-19 | 湖南新合新生物医药有限公司 | Preparation method for betamethasone intermediate or its analogue |
| CN103965277A (en) * | 2014-05-19 | 2014-08-06 | 中国科学院上海有机化学研究所 | Method for synthesizing difluprednate from sterol fermentation product |
| CN110099915A (en) * | 2016-10-07 | 2019-08-06 | 欧瑞克制药公司 | Glucocorticoid receptor inhibitor |
| CN106986908A (en) * | 2017-03-23 | 2017-07-28 | 湖南玉新药业有限公司 | The preparation method of betamethasone |
| CN106986907A (en) * | 2017-04-01 | 2017-07-28 | 湖南玉新药业有限公司 | For the preparation method for the intermediate for preparing betamethasone |
| CN107033207A (en) * | 2017-05-04 | 2017-08-11 | 山东赛托生物科技股份有限公司 | A kind of preparation method of the steroid nucleus derivative containing alkynyl |
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