CN102304163A - Fluorous synthesis method of betamethasone - Google Patents
Fluorous synthesis method of betamethasone Download PDFInfo
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- CN102304163A CN102304163A CN201110192377A CN201110192377A CN102304163A CN 102304163 A CN102304163 A CN 102304163A CN 201110192377 A CN201110192377 A CN 201110192377A CN 201110192377 A CN201110192377 A CN 201110192377A CN 102304163 A CN102304163 A CN 102304163A
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- 0 CC1*[C@]2[C@](*)(*[C@@](C)(C(CC3)[C@](C[C@](*)CO)C(*)(C*C(CO)=*)O)F)C3*(C)OCC2C1 Chemical compound CC1*[C@]2[C@](*)(*[C@@](C)(C(CC3)[C@](C[C@](*)CO)C(*)(C*C(CO)=*)O)F)C3*(C)OCC2C1 0.000 description 1
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Abstract
The invention relates to a fluorous synthesis method of betamethasone, belonging to the technical field of steride medicament synthesis methods in pharmaceutical chemistry. The method comprises the following process steps: fluorinating and refining betamethasone epoxide which is used as a raw material so as to obtain betamethasone. According to the invention, the fluorous synthesis method of betamethasone is reasonable in design, thus chemical reaction time is greatly reduced, production period is shortened, a whole technical level of a product is greatly improved, cost is reduced by 15% as compared with the conventional process, and the fluorous yield of betamethasone reaches 85-90%.
Description
Technical field
The invention belongs to the technical field of steroid drugs compound method in the pharmaceutical chemistry, be specifically related to fluorine compound method on a kind of Betamethasone Valerate.
Background technology
Betamethasone Valerate; Its structural formula (formula (1)); Belong to efficient Halogen corticosteroids medicine, act on carbohydrate metabolism, can alleviate body tissue the infringement pathological change that sexual stimulus produced; And curative effect is high, spinoff is little, can treat grave illness such as lupus erythematosus, rheumatic arthritis, asthma in the world clinical being widely used.Succeed in developing from 1970's in the world, its market outlet is in very great demand always, occupies the hormones first place.Domestic also only have tens companies in ordinary production, and fluorine composite part yield is merely 75% on it.
Formula (1).
The fluorine operational path is very complicated on the synthetic Betamethasone Valerate of production, technical difficulty is higher, quality product is strict.This is because the complex construction of corticosteroids medicine determines.The chemical structure of this type medicine is to be condensed together by five-ring of three six-rings, forms a special molecular structure of being made up of 21 carbon atoms, has the stereoeffect of particular molecule configuration and the steric hindrance of spatial obstacle.Sense group on the medicines structure interferes with each other, and institute is so that chemical reaction is very complicated.Show that synthesis route is complicated, chemical reaction step is many, raw material availability is low, the auxiliary material amount is bigger than normal, the production cycle is long, side reaction is many; Various problems such as the solvent that reaction process has use is many, waste water and gas is many, recovery difficulty; Each item economic and technical norms are low; Aspects such as cost height, compound method described as follows.And external production technique is similar basically with domestic technology, also has same problem.
Document Synthetic Communication36 (7), 865-874; 2006 operational path is following: cold THF is joined (dry ice acetone bath) in the hydrofluoric acid; The compd A (100mg 0.28mmol) that will be dissolved in the 4ml methylene dichloride joins in the solution-70～0 ℃; Stir 5h, pour into then in the ice-cold sodium hydrogen carbonate solution, the aqueous solution is with 4 * 50ml dichloromethane extraction; Merge organic phase (anhydrous sodium sulfate drying); And vacuum-drying, filtrating obtains compd B (84.5mg 80%) with the quick preparative hplc column purification of 30% ethyl acetate/dichloromethane.
(A?) (B)
Domestic patent open (public) number is that the operational path of CN101397320A is following:
Add 8.9g epoxy material C in the reaction flask, the 60ml THF stirs, and cools to-5 ℃; Add the 30ml47% aqueous hydrogen fluoride solution, remain on-5 ℃ of reaction 1h, TLC monitors to there not being raw material, is diluted in the frozen water; Transfer to pH=7 with ammoniacal liquor, filter, drying obtains 7.9g fluoride D.
（C） （D）
Summary of the invention
To the problem that prior art exists, the objective of the invention is to design the technical scheme of fluorine compound method on the Betamethasone Valerate that a kind of new, simple, pollution-free, less energy-consumption is provided.
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that comprising following process step: with the betamethasone epoxy thing is raw material, obtains Betamethasone Valerate through last fluorine with refining, and its concrete reaction formula is following:
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that comprising following process step:
1) hydrogen fluoride is fed in the water; After being cooled to-40～-30 ℃; Add the betamethasone epoxy thing, described betamethasone epoxy thing, hydrogen fluoride and water three's add-on proportion relation is 1:1.5～3:1～2, and controlling the fluoride reaction temperature simultaneously is-25～-10 ℃; Reaction is cooled to feed liquid-35～-30 ℃ after accomplishing;
2) get feed liquid that step 1) obtains under 20～50 ℃ of temperature, add concentration and be 15～25% aqueous sodium carbonate and carry out elutriation, filter then, the dried Betamethasone Valerate fluoride article that wet that obtain filters in flushing;
3) get step 2) obtain the wet article of Betamethasone Valerate after the wet thick essence of article of the Betamethasone Valerate fluoride that obtains, Betamethasone Valerate wets article under 55～60 ℃ of temperature, and drying 2～4 hours obtains Betamethasone Valerate.
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that in the described step 1) hydrogen fluoride being fed in the water, be cooled to-36～-34 ℃ after, add the betamethasone epoxy thing.
Fluorine compound method on described a kind of Betamethasone Valerate, the add-on proportion relation that it is characterized in that betamethasone epoxy thing in the described step 1), hydrogen fluoride and water three is 1:2～2.5:1.5～1.8.
Fluorine compound method on described a kind of Betamethasone Valerate, the add-on proportion relation that it is characterized in that betamethasone epoxy thing in the described step 1), hydrogen fluoride and water three is 1:1.8:1.2.
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that the fluoride reaction temperature is-24～-12 ℃ in the described step 1), is preferably-20～-15 ℃.
Fluorine compound method on described a kind of Betamethasone Valerate, it is characterized in that in the described step 1) that fluoride reaction is accomplished after, feed liquid is cooled to-34～-31 ℃, be preferably-33～-32 ℃.
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that described step 2) in feed liquid add aqueous sodium carbonates down 22～28 ℃ of temperature and carry out elutriation.
Fluorine compound method on described a kind of Betamethasone Valerate; It is characterized in that described step 2) in add-on and the weightmeasurement ratio of betamethasone epoxy thing of aqueous sodium carbonate be 15～25:1, promptly the ratio between the weight of the volume of aqueous sodium carbonate and betamethasone epoxy thing is 15～25:1.
Fluorine compound method on described a kind of Betamethasone Valerate is characterized in that Betamethasone Valerate wets article under 56～59 ℃ of temperature in the described step 3), dry 2.5～3.5 hours.
Fluorine compound method on above-mentioned a kind of Betamethasone Valerate, reasonable in design, significantly reduce chemical time; Shortened the production cycle; The overall technology level of product is increased substantially, and cost descends 15% than old technology, and the fluorine yield reaches 85～90% on its Betamethasone Valerate.
And the present invention need not to use DMF, and the occupational hazards of DMF is eliminated in the source, can alleviate effectively to the harm of human body and to the pollution of environment, realizes the greenization of production process.Its technical costs is low, low in the pollution of the environment, yield is high, has application promise in clinical practice in the alternative aspect of poisonous and harmful solvent.
Can reduce poisonous material DMF usage quantity every year of the present invention and reach 12 tons, add up to and practice thrift about 210,000 yuan of Financial cost, and can reduce 300 tons/year of discharge of wastewater, and alleviated environmental protection pressure greatly.
Embodiment
Further specify the present invention below in conjunction with specific embodiment.
Embodiment 1
50g hydrogen fluoride is fed in 24g water, be cooled to-30 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-20 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-30 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 20 ℃, add the 100g yellow soda ash 400ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.2g Betamethasone Valerate down in dry 2 hours at 55 ℃.
Embodiment 1 Betamethasone Valerate yield is 86%, content 98.3%.
Embodiment 2
36g hydrogen fluoride is fed in 30g water, be cooled to-32 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-20 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-32 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 25 ℃, add the 125g yellow soda ash 375ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.2g Betamethasone Valerate down in dry 3 hours at 60 ℃.
Embodiment 2 Betamethasone Valerate yields are 87%, content 98.2%.
Embodiment 3
36g hydrogen fluoride is fed in 24g water, be cooled to-34 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-10 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-35 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 30 ℃, add the 75g yellow soda ash 425ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.4g Betamethasone Valerate down in dry 4 hours at 58 ℃.
Embodiment 3 Betamethasone Valerate yields are 87%, content 98.8%.
Embodiment 4
20g hydrogen fluoride is fed in 26g water, be cooled to-35 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-15 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-30 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 40 ℃, add the 100g yellow soda ash 500ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral; The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.2g Betamethasone Valerate down in dry 2 hours at 60 ℃.
Embodiment 4 Betamethasone Valerate yields are 86%, content 97.5%.
Embodiment 5
50g hydrogen fluoride is fed in 25g water, be cooled to-30 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-20 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-30 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 30 ℃, add the 100g yellow soda ash 450ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.1g Betamethasone Valerate down in dry 2 hours at 60 ℃.
Embodiment 5 Betamethasone Valerate yields are 85.5%, content 97.9%.
Embodiment 6
40g hydrogen fluoride is fed in 20g water, be cooled to-30 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-25 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-33 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 35 ℃, add the 100g yellow soda ash 400ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got 17.12 Betamethasone Valerates down in dry 3 hours at 60 ℃.
Embodiment 6 Betamethasone Valerate yields are 85.6%, content 98.2%.
Embodiment 7
50g hydrogen fluoride is fed in 30g water, be cooled to-35 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-24 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-35 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 50 ℃, add the 100g yellow soda ash 400ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.26g Betamethasone Valerate down in dry 4 hours at 55 ℃.
Embodiment 7 Betamethasone Valerate yields are 86.3%, content 98.2%.
Embodiment 8
30g hydrogen fluoride is fed in 30g water, be cooled to-35 ℃ after, slowly add 20g betamethasone epoxy thing again, and Nei Wen-25 ℃ of fluoride reaction of control, after reaction finishes, feed liquid is cooled to-30 ℃, subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 50 ℃, add the 100g yellow soda ash 300ml aqueous solution then and carry out elutriation, the product of separating out filters successively, and bath is filtered the dried wet article of Betamethasone Valerate fluoride that obtain to neutral;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.3g Betamethasone Valerate down in dry 3 hours at 55 ℃.
Embodiment 8 Betamethasone Valerate yields are 86.5%, content 97.5%.
Embodiment 9
60g hydrogen fluoride is fed the aqueous solution in 20g, be cooled to-40～-30 ℃ after, slowly add doubly his epoxy material of 20g again, control fluoride reaction Nei Wen-25～-10 ℃ after reaction finishes, is cooled to feed liquid-35～-30 ℃, and is subsequent use;
Get the above-mentioned feed liquid that obtains and be warming up to 20～50 ℃, add 100g yellow soda ash 400ml aqueous solution elutriation, filter, bath, filter do the wet article of Betamethasone Valerate fluoride;
The wet article of Betamethasone Valerate fluoride are dropped in the 400ml methyl alcohol, add the 4g activated carbon and refluxed 30 minutes, filtration is concentrated into the 40ml mother liquor, is cooled to 10 ℃ of filtrations, the Betamethasone Valerate that the obtains article that wet.
Get the wet article of the above-mentioned Betamethasone Valerate that obtains and got the 17.1g Betamethasone Valerate in 2～4 hours 55～60 ℃ of dryings.
Embodiment 9 Betamethasone Valerate yields 85.5%, content 98.0%.
Claims (10)
1. fluorine compound method on the Betamethasone Valerate, it is characterized in that comprising following process step: with the betamethasone epoxy thing is raw material, obtains Betamethasone Valerate through last fluorine with refining, its concrete reaction formula is following:
2. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that comprising following process step:
1) hydrogen fluoride is fed in the water; After being cooled to-40～-30 ℃; Add the betamethasone epoxy thing, described betamethasone epoxy thing, hydrogen fluoride and water three's add-on proportion relation is 1:1.5～3:1～2, and controlling the fluoride reaction temperature simultaneously is-25～-10 ℃; Reaction is cooled to feed liquid-35～-30 ℃ after accomplishing;
2) get feed liquid that step 1) obtains under 20～50 ℃ of temperature, add concentration and be 15～25% aqueous sodium carbonate and carry out elutriation, filter then, the dried Betamethasone Valerate fluoride article that wet that obtain filters in flushing;
3) get step 2) obtain the wet article of Betamethasone Valerate after the wet thick essence of article of the Betamethasone Valerate fluoride that obtains, Betamethasone Valerate wets article under 55～60 ℃ of temperature, and drying 2～4 hours obtains Betamethasone Valerate.
3. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that in the described step 1) hydrogen fluoride being fed in the water, be cooled to-36～-34 ℃ after, add the betamethasone epoxy thing.
4. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1, the add-on proportion relation that it is characterized in that betamethasone epoxy thing in the described step 1), hydrogen fluoride and water three is 1:2～2.5:1.5～1.8.
5. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1, the add-on proportion relation that it is characterized in that betamethasone epoxy thing in the described step 1), hydrogen fluoride and water three is 1:1.8:1.2.
6. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that the fluoride reaction temperature is-24～-12 ℃ in the described step 1), is preferably-20～-15 ℃.
7. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1, it is characterized in that in the described step 1) that fluoride reaction is accomplished after, feed liquid is cooled to-34～-31 ℃, be preferably-33～-32 ℃.
8. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that described step 2) in feed liquid add aqueous sodium carbonates down 22～28 ℃ of temperature and carry out elutriation.
9. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that described step 2) in add-on and the weightmeasurement ratio of betamethasone epoxy thing of aqueous sodium carbonate be 15～25:1.
10. fluorine compound method on a kind of Betamethasone Valerate as claimed in claim 1 is characterized in that Betamethasone Valerate wets article under 56～59 ℃ of temperature in the described step 3), dry 2.5～3.5 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110192377A CN102304163A (en) | 2011-07-11 | 2011-07-11 | Fluorous synthesis method of betamethasone |
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| CN201110192377A CN102304163A (en) | 2011-07-11 | 2011-07-11 | Fluorous synthesis method of betamethasone |
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| CN102304163A true CN102304163A (en) | 2012-01-04 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749464A (en) * | 2016-12-29 | 2017-05-31 | 奥锐特药业有限公司 | Steroidal epoxide carries out open loop, the method for fluorination reaction and its device |
| CN109179763A (en) * | 2018-09-29 | 2019-01-11 | 河南利华制药有限公司 | The waste water treatment process being incorporated on betamethasone in fluorine |
| CN109368859A (en) * | 2018-11-15 | 2019-02-22 | 河南利华制药有限公司 | Upper fluorine waste water zero discharge treatment process in steroidal drug production |
| CN110845562A (en) * | 2019-11-25 | 2020-02-28 | 湖南新合新生物医药有限公司 | Method for recycling betamethasone or dexamethasone synthetic mother liquor material |
| CN112341510A (en) * | 2020-11-12 | 2021-02-09 | 湖南新合新生物医药有限公司 | Preparation method of betamethasone |
| CN113024623A (en) * | 2019-12-24 | 2021-06-25 | 天津天药药业股份有限公司 | Continuous production steroid fluorinating process |
| CN115010198A (en) * | 2022-07-11 | 2022-09-06 | 西安国康瑞金制药有限公司 | Wastewater treatment process integrated in fluorination of betamethasone |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749464A (en) * | 2016-12-29 | 2017-05-31 | 奥锐特药业有限公司 | Steroidal epoxide carries out open loop, the method for fluorination reaction and its device |
| CN106749464B (en) * | 2016-12-29 | 2019-01-18 | 奥锐特药业股份有限公司 | Steroidal epoxide carries out the method and device thereof of open loop, fluorination reaction |
| CN109179763A (en) * | 2018-09-29 | 2019-01-11 | 河南利华制药有限公司 | The waste water treatment process being incorporated on betamethasone in fluorine |
| CN109179763B (en) * | 2018-09-29 | 2021-08-17 | 河南利华制药有限公司 | Wastewater treatment process integrated in fluorination of betamethasone |
| CN109368859A (en) * | 2018-11-15 | 2019-02-22 | 河南利华制药有限公司 | Upper fluorine waste water zero discharge treatment process in steroidal drug production |
| CN110845562A (en) * | 2019-11-25 | 2020-02-28 | 湖南新合新生物医药有限公司 | Method for recycling betamethasone or dexamethasone synthetic mother liquor material |
| CN113024623A (en) * | 2019-12-24 | 2021-06-25 | 天津天药药业股份有限公司 | Continuous production steroid fluorinating process |
| CN112341510A (en) * | 2020-11-12 | 2021-02-09 | 湖南新合新生物医药有限公司 | Preparation method of betamethasone |
| CN115010198A (en) * | 2022-07-11 | 2022-09-06 | 西安国康瑞金制药有限公司 | Wastewater treatment process integrated in fluorination of betamethasone |
| CN115010198B (en) * | 2022-07-11 | 2023-05-09 | 西安国康瑞金制药有限公司 | Wastewater treatment process integrated in fluorine on betamethasone |
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Application publication date: 20120104 |