CN107417755A - A kind of synthetic method of Fluocinonide intermediate - Google Patents
A kind of synthetic method of Fluocinonide intermediate Download PDFInfo
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- CN107417755A CN107417755A CN201710320686.6A CN201710320686A CN107417755A CN 107417755 A CN107417755 A CN 107417755A CN 201710320686 A CN201710320686 A CN 201710320686A CN 107417755 A CN107417755 A CN 107417755A
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- synthetic method
- fluocinonide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic method of Fluocinonide intermediate, the use of the steroidal compounds with structure I is starting material, the precursor V of synthetic glucocorticoid similar drug Fluocinonide, α fluorine is introduced in the C6 positions of chemical compounds I, fluorine is introduced by oxidation, C9 positions, finally gives intermediate V, initiation material of the invention is cheap and easily-available, route process stabilizing, economical rationality.Synthetic route is as follows：
Description
Technical field：
The invention belongs to pharmaceutical synthesis field, is related to Fluocinonide intermediate, among especially a kind of Fluocinonide
The synthetic method of body.The invention further relates to the new intermediate occurred in said synthesis route.
Technical background：
The technique of existing synthesis Fluocinonide mainly has two kinds of routes：
One kind is to use 11 α, and 17 alpha-dihydroxy progesterone pass through for raw material takes off 11 α hydroxyls, dibasic acid esters, epoxy, on C6 positions
Fluorine, C1,2 dehydrogenations, fluorine on C9 positions, C16,17 dehydration rear oxidations, contracting acetone, it is light that decolorizing and refining obtains bulk drug acetic acid fluorine
Pine.This process route, production cycle length, labor intensity is big, and C1, and 2 dehydrogenations use severe poisonous chemicals, process dangerous
Height, environmental pollution are serious.
It using prednisolone is raw material that another kind, which is, and through esterification, epoxy, fluorine on C6 positions, fluorine on C9 positions, C16,17 de-
Water rear oxidation, contracting acetone, decolorizing and refining obtain bulk drug Fluocinonide.This process route, although avoiding hypertoxic chemistry
The use of product, but equally have the longer production cycle, and higher synthesis cost.
Some Patents of the country also all relate to the synthetic method of some intermediates in above two method at present, not
Have and selected in initiation material with being improved on process route.
The content of the invention：
Present invention aims to overcome that drawbacks described above, and provide in the Fluocinonide of a kind of economical rationality and process stabilizing
The new method of mesosome.The present invention contains the new synthetic route determined based on new initiation material and some involved tools
There is the synthetic method of the intermediate of new structure.The initiation material of the present invention is cheap and easily-available, and the product finally obtained is one kind
Known Fluocinonide intermediate, the technique that Fluocinonide is synthesized by the intermediate are mature and stable already.
Technical scheme is as follows：
The present invention is a kind of new synthesis route of the Fluocinonide intermediate (compound V) of known structure, is directed to
Three kinds of intermediates (structure II in synthetic route, structure III, structure IV) with new structure.It is by change cheap and easy to get
Compound I passes through enol ester, and 6 α F are aoxidized, and 9F four-step reactions obtain compound V.Synthetic route is as follows：
The preparation of compound ii：Chemical compounds I is dissolved in appropriate solvent, is warming up to 30~60 DEG C, add esterifying reagent with
Organic acid catalyst, react 1~5 hour, add organic base and be quenched, solvent is evaporated to obtain compound ii.Wherein, suitably
Solvent can be ethyl acetate, dioxane, tetrahydrofuran or toluene；Esterifying reagent can be isopropenyl acetate or benzene first
Acyl chlorides；Organic acid catalyst can be p-methyl benzenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid；Organic base can be triethylamine, two
Ethamine or pyridine.
The preparation of compound III：Compound ii is dissolved in appropriate solvent orange 2 A, at temperature -20~20 DEG C, adds fluorine examination
Agent, react 3~7 hours；Reaction solution is poured in water, extracted using solvent B；Solvent B is evaporated, obtains compound III.Its
In, appropriate solvent orange 2 A can be acetonitrile, dimethylformamide, methanol, acetone, one kind in dimethyl sulfoxide (DMSO) or theirs is mixed
Close liquid；Solvent B can be ethyl acetate, dichloromethane or chloroform；Fluorine reagent is the compound for having following structure：
Wherein R=OH, CH3, CH2Cl；X=CF3SO3, BF4。
The preparation of compounds Ⅳ：Compound III is dissolved in appropriate acetone, under the conditions of temperature is -20~10 DEG C, added
Enter the acid potassium permanganate aqueous solution, react 1~3 hour, be quenched using sodium sulfite；Filtering, the organic solvent in filtrate is steamed
It is dry, filtered after washing, obtain compounds Ⅳ.The acid wherein configured used in the acid potassium permanganate aqueous solution can be formic acid, dilute salt
Acid or dilute sulfuric acid.
The preparation of compound V：Compounds Ⅳ is put into the aqueous solution or DMF solution of hydrogen fluoride,
Reacted 4~7 hours at 0~30 DEG C；Reaction solution is poured in the ammoniacal liquor of 10 times of dilutions.Filtering, washing, obtains compound V.
The advantages and positive effects of the present invention are：
1st, production process and cycle time of the invention compared with existing production technology, production equipment are reduced, and production station subtracts
Few, energy consumption is reduced, and blowdown cost is reduced, and totle drilling cost will be caused to be significantly lower than current cost.
2nd, poisonous and harmful product control：Because this technique eliminates 1,2 dehydration processes, therefore heavy metallic salt acetic acid is not further related to
Mercury and toxic articles selenium dioxide, eliminate 11 sulfonation of high pollution, de- ester process so that storage and producers' safety wind
Danger, environmentally friendly risk reduce.
Embodiment:
Below by specific embodiment, the invention will be further described, and following examples are descriptive, is not limit
Qualitatively, it is impossible to which protection scope of the present invention is limited with this.
Embodiment 1
30g chemical compounds Is are dissolved in 100mL ethyl acetate, chlorobenzoyl chloride and 1mL trifluoromethanesulfonic acids are added at 30 DEG C, instead
Answer 1~5 hour, add 5mL pyridines and be quenched, solvent is evaporated to obtain compound ii.
Compound ii is dissolved in 200mL dimethylformamides, at 10 DEG C of temperature, adds fluorine reagent, reaction 3~7 is small
When；Reaction solution is poured in 1000mL water, extracted using 100mL ethyl acetate；Ethyl acetate is evaporated, obtains compound III.
Compound III is dissolved in 1000mL acetone, temperature be 0 DEG C under the conditions of, add by 20g potassium permanganate,
The solution that 20mL4M hydrochloric acid, 400mL water are made into, react 1~3 hour, be quenched using 20g sodium sulfites；Filtering, by filtrate
Acetone is evaporated, and is filtered after washing, obtains compounds Ⅳ.
By in 20 DEG C of 150mL of compounds Ⅳ input aqueous hydrogen fluoride solution, react 4~7 hours；Reaction solution is poured
In the ammoniacal liquor of 10 times of dilutions of 4500mL.Filtering, washing, obtains compound V.
The content of compound V is 75%, and the yield relative to chemical compounds I is 93%.
Embodiment 2
20g chemical compounds Is are dissolved in 60mL tetrahydrofurans, isopropenyl acetate and 1g p-methyl benzenesulfonic acid are added at 30 DEG C,
Reaction 1~5 hour, adds 5mL triethylamines and is quenched, solvent is evaporated to obtain compound ii.
Compound ii is dissolved in 140mL acetone, at 10 DEG C of temperature, fluorine reagent is added, reacts 3~7 hours；Will be anti-
Answer liquid to pour in 1000mL water, extracted using 50mL chloroforms；Chloroform is evaporated, obtains compound III.
Compound III is dissolved in 600mL acetone, temperature be 0 DEG C under the conditions of, add by 14g potassium permanganate,
The solution that 14mL4M hydrochloric acid, 300mL water are made into, react 1~3 hour, be quenched using 14g sodium sulfites；Filtering, by filtrate
Acetone is evaporated, and is filtered after washing, obtains compounds Ⅳ.
By in the dimethyl formamide solution of 20 DEG C of 100mL of compounds Ⅳ input hydrogen fluoride, react 4~7 hours；Will
Reaction solution is poured in the ammoniacal liquor of 10 times of dilutions of 3000mL.Filtering, washing, obtains compound V.
The content of compound V is 77%, and the yield relative to chemical compounds I is 90%.
Above-described is only the preferred embodiment of the present invention, it is noted that for one of ordinary skill in the art
For, on the premise of inventive concept is not departed from, various modifications and improvements can be made, these belong to the protection of the present invention
Scope.
Claims (10)
- A kind of 1. synthetic method of Fluocinonide intermediate, it is characterised in that：Using the steroidal compounds with structure I as Starting material, realized by following synthetic route：
- 2. the synthetic method of Fluocinonide intermediate according to claim 1, it is characterised in that：From compound I to change Compound II synthetic method is：Chemical compounds I is dissolved in appropriate solvent, is warming up to 30~60 DEG C, add esterifying reagent with it is organic Acid catalyst, react 1~5 hour, add organic base and be quenched, solvent is evaporated to obtain compound ii.
- 3. the synthetic method of Fluocinonide intermediate according to claim 1 or 2, it is characterised in that：Described esterification Reagent is isopropenyl acetate or chlorobenzoyl chloride.
- 4. the synthetic method of Fluocinonide intermediate according to claim 2, it is characterised in that：Described organic acid Catalyst is p-methyl benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid.
- 5. the synthetic method of Fluocinonide intermediate according to claim 2, it is characterised in that：Described solvent is second Acetoacetic ester, dioxane, tetrahydrofuran, toluene；Described organic base is triethylamine, diethylamine, pyridine.
- 6. the synthetic method of Fluocinonide intermediate according to claim 1, it is characterised in that：From change and thing II to change Compound III synthetic method is：Compound ii is dissolved in appropriate solvent orange 2 A, at temperature -20~20 DEG C, adds fluorine reagent, Reaction 3~7 hours；Reaction solution is poured in water, extracted using solvent B；Solvent B is evaporated, obtains compound III.
- 7. the synthetic method of the Fluocinonide intermediate according to claim 1 or 6, it is characterised in that：Described fluorine examination Agent is the compound for having following structure：Wherein R=OH, CH3, CH2Cl；X=CF3SO3, BF4。
- 8. the synthetic method of Fluocinonide intermediate according to claim 6, it is characterised in that：Described solvent orange 2 A is One or more of mixed liquors in acetonitrile, dimethylformamide, methanol, acetone, dimethyl sulfoxide (DMSO)；Solvent B be ethyl acetate, Dichloromethane, chloroform.
- 9. the synthetic method of Fluocinonide intermediate according to claim 1, it is characterised in that：From change and thing III to The synthetic method of compounds Ⅳ is：Compound III is dissolved in appropriate acetone, under the conditions of temperature is -20~10 DEG C, added The acid potassium permanganate aqueous solution, react 1~3 hour, be quenched using sodium sulfite；Filtering, the organic solvent in filtrate is evaporated, Filtered after washing, obtain compounds Ⅳ.
- 10. the synthetic method of Fluocinonide intermediate according to claim 1, it is characterised in that：From change and thing IV to Compound V synthetic method is：Compounds Ⅳ is put into the aqueous solution or DMF solution of hydrogen fluoride, 0 Reacted 4~7 hours at~30 DEG C；Reaction solution is poured in the ammoniacal liquor of 10 times of dilutions, filtered, washing, obtain compound V.
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| CN201710320686.6A CN107417755A (en) | 2017-05-09 | 2017-05-09 | A kind of synthetic method of Fluocinonide intermediate |
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| CN201710320686.6A CN107417755A (en) | 2017-05-09 | 2017-05-09 | A kind of synthetic method of Fluocinonide intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113896759A (en) * | 2021-12-10 | 2022-01-07 | 山东谷雨春生物科技有限公司 | Synthesis method of fluocinonide |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3210341A (en) * | 1963-03-29 | 1965-10-05 | Upjohn Co | 9, 11-epoxy-6-fluoro-delta4, 16-pregnadienes and products produced therefrom |
| CN101250213A (en) * | 2008-03-24 | 2008-08-27 | 天津太平洋化学制药有限公司 | Technique for producing fluocinonide intermediate 6 alpha F |
| CN101759761A (en) * | 2008-11-28 | 2010-06-30 | 天津金耀集团有限公司 | Method for preparing steroid compounds containing 6alpha-F |
| CN101928318A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Preparation of fluorine-containing steroid hormone |
| WO2016120891A1 (en) * | 2015-01-30 | 2016-08-04 | Coral Drugs Pvt. Ltd. | Novel process for preparation of glucocorticoid steroids |
-
2017
- 2017-05-09 CN CN201710320686.6A patent/CN107417755A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3210341A (en) * | 1963-03-29 | 1965-10-05 | Upjohn Co | 9, 11-epoxy-6-fluoro-delta4, 16-pregnadienes and products produced therefrom |
| CN101250213A (en) * | 2008-03-24 | 2008-08-27 | 天津太平洋化学制药有限公司 | Technique for producing fluocinonide intermediate 6 alpha F |
| CN101759761A (en) * | 2008-11-28 | 2010-06-30 | 天津金耀集团有限公司 | Method for preparing steroid compounds containing 6alpha-F |
| CN101928318A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Preparation of fluorine-containing steroid hormone |
| WO2016120891A1 (en) * | 2015-01-30 | 2016-08-04 | Coral Drugs Pvt. Ltd. | Novel process for preparation of glucocorticoid steroids |
Non-Patent Citations (1)
| Title |
|---|
| 陈勇攀等: "醋酸肤轻松合成工艺综述", 《中国医药导刊》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113896759A (en) * | 2021-12-10 | 2022-01-07 | 山东谷雨春生物科技有限公司 | Synthesis method of fluocinonide |
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Application publication date: 20171201 |