CN101979399A - Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate - Google Patents
Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate Download PDFInfo
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- CN101979399A CN101979399A CN2010102785569A CN201010278556A CN101979399A CN 101979399 A CN101979399 A CN 101979399A CN 2010102785569 A CN2010102785569 A CN 2010102785569A CN 201010278556 A CN201010278556 A CN 201010278556A CN 101979399 A CN101979399 A CN 101979399A
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Abstract
The invention discloses a method for producing an important steroid hormone dexamethasone methyl tetraenes (5ST) intermediate, which comprises the following steps of: dissolving a methyl dehydrate into an organic solvent, adding a reducing agent into the solution at the temperature of between 5 DEG C below zero and 20 DEG C, and performing one-step reaction to obtain methyl tetraenes with less than 0.8 percent of single impurity, wherein the reducing agent is a mixed reducing agent of 1 to 15 weight parts of chromium trichloride and 0.2 to 8 weight parts of zinc powder. The method for producing the 5ST shortens the reduction reaction into one-step reaction from three-step reaction so as to save the reaction time and facilitate the operation. The method reduces the consumption of chemical raw materials and dangerous goods, reduces the environmental pollution, and reflects the environment-friendly idea of green chemistry.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of production method of important intermediate methyl tetraene thing (5ST) of steroid hormone dexamethasone product.
Background technology
Dexamethasone is the same with other glucocorticosteroids, has pharmacological actions such as anti-inflammatory, antiendotoxin, inhibition immunity, antishock and enhancing stress reaction, treats multiple disease so be widely used in each section, as autoimmune disorder, allergy, inflammation, asthma and Dermatology Department, ophthalmic diseases.The Decameth indispensable first-aid medicine that gives emergency treatment to a dying patient especially, in recent ten years, the clinicist uses dexamethasone sodium phosphate treatment and prevents drug allergy that all kinds of Chinese-western medicine cause and diseases such as fever that the treatment viral cold causes, dexamethasone clinical application amount is increased year by year, and China has become maximum in the world dexamethasone market so far.
Dexamethasone (dexamethasone) is made the steroid hormone dexamethasone by the mould dehydrogen substance through polystep reaction, and methyl tetraene thing is the 1st step of entire reaction.Prepare methyl tetraene thing by the mould dehydrogen substance and be divided into two-step reaction: the first step dewater the methyl dehydrate, second the step through reduce methyl tetraene thing (5ST).
At present, mainly contain in the suitability for industrialized production of steroid hormone dexamethasone important intermediate methyl tetraene thing both at home and abroad:
(1) Δ
9,11Dehydrating step is mainly used sulfonation and is taken off this technology of ester and produce, takes off in this operation process of ester in the sulphur esterification, and be solvent with the pyridine, carry out esterification with Methanesulfonyl chloride, and then reflux in acetic acid with sodium-acetate and to take off ester.Eliminate formation Δ 9 at 11 α hydroxyls, 11 pairs of these processes of key, wherein inevasiblely can produce Δ 11 (12) these isomer of two keys of about 10% and since this impurity in follow-up reaction, treating process all difficulty remove, cause final product quality obviously to descend.
(2) reduction reaction is at steroid hormone 16,17 epoxy bridgings to be become Δ
16,17The reaction of two keys, traditional preparation process methyl tetraene thing, existing reduction reaction needed through three steps: open loop, debrominate, dehydration, reaction process is as follows:
Its production method, condition is violent, and explosives, inflammable items are more, and dangerous high, environmental pollution is serious, and yield is low, and poor product quality is not suitable for large-scale industrial production.
Summary of the invention
Shortcoming and deficiency at aforesaid method the invention provides the new production technique of a kind of steroid hormone important intermediate methyl tetraene thing (5ST), thereby have guaranteed the quality of product to greatest extent.
Technical scheme of the present invention is as follows:
A kind of production method of steroid hormone dexamethasone important intermediate methyl tetraene thing is characterized in that: the methyl dehydrate is dissolved in the organic solvent, and in-5 ℃～20 ℃ adding reductive agents, single step reaction makes single methyl tetraene thing of assorted＜0.8%; Wherein said reductive agent is chromium trichloride 1-15 part and 0.2-8 part zinc powder mixing reductive agent of parts by weight; Described organic solvent is an ethanol.
Production method of the present invention, the parts by weight of preferred reductive agent chromium trichloride and zinc powder are 2-12 part, 0.2-6 part.
Industrial process of the present invention, its reduction reaction time is 1～8 hour.
The present invention is a reductive agent with chromium trichloride, zinc powder, is solvent with ethanol, changes three-step reaction into single step reaction, obtains methyl tetraene thing, and yield has improved 9.4%,, reach product maximum single assorted＜0.8%.Improve quality product, shortened reaction time, saved raw material, strengthened the security of producing.
The present invention is dissolved in the methyl dehydrate in the ethanol through single step reaction, reductive agent is selected chromium trichloride and zinc powder reduction agent for use, it is more stable to carry out reduction reaction, adds reductive agents low temperature-5 ℃～20 ℃, keeps temperature, reacted 1～8 hour, concentrating under reduced pressure reclaims ethanol then, leaves standstill, gets rid of material, drying, methyl tetraene thing crude product, make with extra care again the 5ST elaboration.
The present invention shortens to single step reaction with reduction reaction by three-step reaction, has saved the reaction times, and the operation of being more convenient for.Reduce the use of industrial chemicals and hazardous substance, reduced pollution on the environment, more embodied the environmental protection concept of my company's Green Chemistry.
Embodiment
For simple and purpose clearly, hereinafter appropriate omission the description of known technology, in order to avoid those unnecessary details influences are to the description of the technical program.The present invention is described further below in conjunction with example.Mould dehydrogen substance market is on sale.
Embodiment 1:
With mould dehydrogen substance 30g, solvents tetrahydrofurane 280ml, join in the reactor, be cooled to-50 ℃, keep this temperature, add dewatering agent phosphorus pentachloride 30g, insulation reaction 3.5 hours is identified (TLC) no raw material point to thin-layer chromatography, reaction solution is scattered in 50 times the frozen water, with in the alkali and pH ≈ 7, leave standstill, filter, dry dehydrate.The methyl dehydrate is dissolved in the ethanol, reductive agent is selected 2 times of chromium trichlorides and 0.4 times of zinc powder for use, at low temperature-5 ℃ adding reductive agent, keeps temperature, reacted 1 hour, concentrate then, reclaim ethanol, leave standstill, get rid of material, drying, get methyl tetraene thing crude product, the dehydration yield is 85.2%, make with extra care again the 5ST elaboration, maximum single assorted 0.75%.
Embodiment 2:
With mould dehydrogen substance 30g, solvents tetrahydrofurane 180ml, join in the reactor, be cooled to-50 ℃, keep this temperature, add dewatering agent phosphorus pentachloride 30g, insulation reaction 3.5 hours is identified (TLC) no raw material point to thin-layer chromatography, reaction solution is scattered in 50 times the frozen water, with in the alkali and pH ≈ 7, leave standstill, filter, dry dehydrate.The methyl dehydrate is dissolved in the ethanol, reductive agent is selected 5 times of chromium trichlorides and 0.4 zinc powder for use, at low temperature-15 ℃ adding reductive agent, keeps temperature, reacted 8 hours, concentrate then, reclaim ethanol, leave standstill, get rid of material, drying, get methyl tetraene thing crude product, the dehydration yield is 85.8%, make with extra care again the 5ST elaboration, maximum single assorted 0.82%.
Embodiment 3:
With mould dehydrogen substance 30g, solvents tetrahydrofurane 220ml, join in the reactor, be cooled to-60 ℃, keep this temperature, add dewatering agent phosphorus pentachloride 42g, insulation reaction 3.5 hours is identified (TLC) no raw material point to thin-layer chromatography, reaction solution is scattered in 50 times the frozen water, with in the alkali and pH ≈ 7, leave standstill, filter, dry dehydrate.The methyl dehydrate is dissolved in the ethanol, and reductive agent is selected 9 times of chromium trichlorides and 4 times of zinc powders for use, in low temperature～20 ℃, add reductive agent, keep temperature, reacted 5 hours, concentrate then, reclaim ethanol, leave standstill, get rid of material, drying in 20 times of dilution waters, get methyl tetraene thing crude product, the dehydration yield is 86.3%, make with extra care again the 5ST elaboration, maximum single assorted 0.76%.
Embodiment 1-3
Methyl tetraene amount standard:
| Project | Quality standard |
| Outward appearance | White or off-white color crystalline powder |
| Weight loss on drying | ≤0.5％? |
| Chromatographic purity | ≥98％? |
| Fusing point | ≥198℃? |
| Single assorted | ≤1％? |
| Specific optical rotation | +122°～+129°? |
The present invention with prepared methyl tetraene thing through reaction qualified product to the end.
Claims (3)
1. the production method of a steroid hormone dexamethasone important intermediate methyl tetraene thing is characterized in that: the methyl dehydrate is dissolved in the organic solvent, adds reductive agents in-5 ℃～20 ℃, single step reaction makes single methyl tetraene thing of assorted＜0.8%; Wherein said reductive agent is chromium trichloride 1-15 part and 0.2-8 part zinc powder mixing reductive agent of parts by weight; Described organic solvent is an ethanol.
2. the described production method of claim 1, the parts by weight of its described reductive agent chromium trichloride and zinc powder are 2-12 part, 0.2-6 part.
4. the described industrial process of claim 1, its reduction reaction time is 1～8 hour.
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| CN2010102785569A CN101979399A (en) | 2010-09-10 | 2010-09-10 | Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate |
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| CN2010102785569A CN101979399A (en) | 2010-09-10 | 2010-09-10 | Method for producing important steroid hormone dexamethasone methyl tetraenes intermediate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628808A (en) * | 2015-02-28 | 2015-05-20 | 苏州汉酶生物技术有限公司 | Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone |
| 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 |
| CN105440094A (en) * | 2015-11-27 | 2016-03-30 | 江苏佳尔科药业集团有限公司 | Preparation method of dexamethasone intermediate |
| CN105622700A (en) * | 2016-01-29 | 2016-06-01 | 山东赛托生物科技股份有限公司 | Method for synthesizing steroid intermediate 17-Acetyl-10, 13-dimethyl-6, 7, 8, 10, 12, 13, 14, 15octahydro-cyclopenta[a]phenathren-3 |
| CN113980818A (en) * | 2021-09-13 | 2022-01-28 | 丽江映华生物药业有限公司 | Fungus dehydrogenation seed liquid culture method |
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| CN1824671A (en) * | 2005-02-24 | 2006-08-30 | 天津天药药业股份有限公司 | Production method of dexamethasone series product 16,17-bibone intermediate |
| CN1951951A (en) * | 2006-01-20 | 2007-04-25 | 浙江仙琚制药股份有限公司 | Synthesis process of a pregnane compound |
| CN101759745A (en) * | 2008-11-28 | 2010-06-30 | 天津金耀集团有限公司 | Production process method of 16, 17 doublebond steroidal pharmaceutical intermediate |
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| CN1824671A (en) * | 2005-02-24 | 2006-08-30 | 天津天药药业股份有限公司 | Production method of dexamethasone series product 16,17-bibone intermediate |
| CN1951951A (en) * | 2006-01-20 | 2007-04-25 | 浙江仙琚制药股份有限公司 | Synthesis process of a pregnane compound |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628808A (en) * | 2015-02-28 | 2015-05-20 | 苏州汉酶生物技术有限公司 | Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone |
| 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 |
| CN105440094A (en) * | 2015-11-27 | 2016-03-30 | 江苏佳尔科药业集团有限公司 | Preparation method of dexamethasone intermediate |
| CN105440094B (en) * | 2015-11-27 | 2017-08-25 | 江苏佳尔科药业集团有限公司 | The preparation method of Dexamethasone Intermediate |
| CN105622700A (en) * | 2016-01-29 | 2016-06-01 | 山东赛托生物科技股份有限公司 | Method for synthesizing steroid intermediate 17-Acetyl-10, 13-dimethyl-6, 7, 8, 10, 12, 13, 14, 15octahydro-cyclopenta[a]phenathren-3 |
| CN113980818A (en) * | 2021-09-13 | 2022-01-28 | 丽江映华生物药业有限公司 | Fungus dehydrogenation seed liquid culture method |
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Application publication date: 20110223 |