CN101759745A - Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate - Google Patents
Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate Download PDFInfo
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- CN101759745A CN101759745A CN200810153609A CN200810153609A CN101759745A CN 101759745 A CN101759745 A CN 101759745A CN 200810153609 A CN200810153609 A CN 200810153609A CN 200810153609 A CN200810153609 A CN 200810153609A CN 101759745 A CN101759745 A CN 101759745A
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Abstract
A production process method of a 16, 17 doublebond steroidal pharmaceutical intermediate is characterized by taking 16, 17 epoxy intermediate (II) as raw material, reacting with reducing agent of chromous salt, adopting ethanol as solvent, diluting reaction liquid with large amount of water after the reaction, filtering, drying and obtaining reducer. The process can reduce the reaction step, shortens the process route, and greatly improves the quality and yield of the reducer (I).
Description
Technical field:
The present invention relates to the production method of steroid drugs intermediate.The production method of 16,17 pairs of key steroid drugs intermediates particularly.
Background technology:
The steroidal glucocorticosteroid is the important medicine of a class, and prior art shows, introduces 16 Alpha-Methyls and can significantly reduce its sodium ion retention effect (steroidal chemical fundamentals, Lin Jiwen, Chemical Industry Press, 1989.9 on the steroidal parent nucleus; 149～151), the steroid hormone with 16 Alpha-Methyls mainly contains dexamethasone etc.
16,17 pairs of key intermediates (I) are a kind of important intermediate in steroid drugs synthetic with 16 Alpha-Methyls
Traditional preparation process 16, the method of the two key intermediates (I) of 17-, need be raw material with 16,17 epoxy intermediate (II) through three step chemical reactions, through the open loop of bromine hydroxyl, debrominate, dehydration reaction, reactions steps is many, and the products obtained therefrom yield is low, and by product is many, and when carrying out debromination, to adopt the debrominate of nickel catalytic hydrogenation, need use SO during dehydration reaction
2, POCl
3Deng reagent, hydrogenation need be used highly inflammable and explosive hydrogen, and safety is not easy to guarantee, and POCl
3Instability, and can produce HCl gas excitatory, environmental pollution is serious.
Reaction process is as follows:
Summary of the invention:
The present invention is directed to the problems and shortcomings that prior art exists, a kind of new steroidal 16 is provided, the producing and manufacturing technique of the two key intermediates (I) of 17-is a raw material with 16,17 epoxy intermediate (II), reacts with the chromous salt reductive agent:
R1 is=O or-OCOCH
3
R2 is halogen or H, preferred F, Cl, Br or H; Preferred especially F, Cl or H
R3 is halogen or H, preferred F, Cl, Br or H; Preferred especially F, Cl or H
R4 is H ,-OH, or-OCOCH
3
R5 is-OH or H;
This is reflected in the organic solvent and carries out, described solvent preferred alcohol.
Temperature of reaction is 0～60 ℃, preferred 10～40 ℃, and one or more in the preferred chromous acetate of described chromous salt, chromous chloride, the chromous sulfate, the mol ratio of described chromous salt and raw material is 2～10: 1.Described ethanol as solvent can be dehydrated alcohol, also can be the industrial alcohol of content 94%～96%.The envelope-bulk to weight ratio of described solvent and substrate is 5～20: 1,
Above-mentioned processing method reaction process is: compound (II) is dissolved in the organic solvent; logical protection of inert gas; under protection of inert gas, add water-soluble chromous acetate 0.05mol; react, temperature of reaction is 10～20 ℃, and reaction is after fully under protection of inert gas; reaction solution dilutes with big water gaging; filter, drying gets compound (I).
Described rare gas element is selected nitrogen, carbonic acid gas.
Adopt processing method of the present invention synthetic 16, the two key intermediates (I) of 17-, compared with prior art, the reaction conditions gentleness, avoided having the hydrogen of high risk and environment is caused severe contamination and has the application of irritating sulfurous gas, reduce reactions steps, shortened operational path, helped the raising of reaction yield and product quality simultaneously.
Embodiment:
Raw materials used content with product adopts high performance liquid chromatography to detect chromatographic column: ODS-C in the present embodiment
18, 10 μ, the stainless steel column of 4.6 * 250mm; Chromatogram column temperature: room temperature; Detect wavelength: 254nm; Moving phase: acetonitrile: water=1: 1; Flow velocity: 0.8ml/min; Sample concentration: 3mg/ml; Sample size: 2 μ L.
Embodiment 1: Compound I a's is synthetic,
Get compound (IIa) 10g, content 95% is dissolved in the 50ml dehydrated alcohol; nitrogen protection; add water-soluble chromous acetate 0.05mol under nitrogen protection, react, temperature of reaction is 10～20 ℃; after under nitrogen protection, reacting extremely fully; reaction solution dilutes with big water gaging, filters drying; get compound (Ia) 8.2g, content 90.1%
Embodiment 2: compounds ib synthetic
Get compound (IIb) 10g, content 95% is dissolved in the 100ml95% ethanol; nitrogen protection; add water-soluble chromous chloride 0.1mol under nitrogen protection, react, temperature of reaction is 20～30 ℃; after under nitrogen protection, reacting extremely fully; reaction solution dilutes with big water gaging, filters drying; get compound (Ib) 8.1g, content 90.5%
Embodiment 3: Compound I c's is synthetic
Get compound (IIc) 10g, content 95% is dissolved in the 150ml95% ethanol; nitrogen protection; add water-soluble chromous chloride 0.15mol under nitrogen protection, react, temperature of reaction is 0～10 ℃; after under nitrogen protection, reacting extremely fully; reaction solution dilutes with big water gaging, filters drying; get compound (Ic) 8.3g, content 91%
Embodiment 4: Compound I d's is synthetic
Get compound (IId) 10g, content 95% is dissolved in the 200ml95% ethanol; nitrogen protection; add water-soluble chromous sulfate 0.2mol under nitrogen protection, react, temperature of reaction is 30～40 ℃; after under nitrogen protection, reacting extremely fully; reaction solution dilutes with big water gaging, filters drying; compound (Id) 8.0g, content 90.3%.
Claims (9)
1. steroidal 16, the producing and manufacturing technique of the two key intermediates (I) of 17-, (II) is raw material with 16,17 epoxy intermediate, it is characterized in that, reacts as reductive agent with chromous salt in organic solvent
R1 is=O or-OAc;
R2 is halogen or H,
R3 is halogen or H,
R4 is H ,-OH, or-OAc;
R5 is-OH or H;
2. processing method as claimed in claim 1 is characterized in that, the preferred F of R2, Cl, Br or H, the preferred F of R3, Cl, Br or H.
3. processing method as claimed in claim 1 or 2 is characterized in that described organic solvent preferred alcohol.
4. as claim 1 or 3 described processing methodes, it is characterized in that the envelope-bulk to weight ratio of described solvent and formula (I) compound is 5～20: 1.
5. as arbitrary described processing method in the claim 1 to 4, it is characterized in that described temperature of reaction is 0～60 ℃.
6. as arbitrary described processing method in the claim 1 to 5, it is characterized in that described temperature of reaction is 10～40 ℃.
7. as arbitrary described processing method in the claim 1 to 6, the mol ratio that it is characterized in that described chromous salt and formula (I) is 2～10: 1.
8. as arbitrary described processing method in the claim 1 to 7; described reaction process is: compound (II) is dissolved in the organic solvent logical protection of inert gas; under protection of inert gas, add water-soluble chromous acetate 0.05mol; react, temperature of reaction is 10～20 ℃, and reaction is after fully under protection of inert gas; reaction solution dilutes with big water gaging; filter, drying gets compound (I).
9. as arbitrary described processing method in the claim 1 to 8, it is characterized in that described rare gas element selection nitrogen, carbonic acid gas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810153609A CN101759745A (en) | 2008-11-28 | 2008-11-28 | Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810153609A CN101759745A (en) | 2008-11-28 | 2008-11-28 | Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate |
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| CN101759745A true CN101759745A (en) | 2010-06-30 |
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| CN200810153609A Pending CN101759745A (en) | 2008-11-28 | 2008-11-28 | Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101979399A (en) * | 2010-09-10 | 2011-02-23 | 天津金汇药业集团有限公司 | Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate |
| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
-
2008
- 2008-11-28 CN CN200810153609A patent/CN101759745A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101979399A (en) * | 2010-09-10 | 2011-02-23 | 天津金汇药业集团有限公司 | Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate |
| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
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Application publication date: 20100630 |