CN101948503A - Method for preparing betamethasone ketal by homogeneous reaction at normal temperature - Google Patents
Method for preparing betamethasone ketal by homogeneous reaction at normal temperature Download PDFInfo
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- CN101948503A CN101948503A CN 201010278528 CN201010278528A CN101948503A CN 101948503 A CN101948503 A CN 101948503A CN 201010278528 CN201010278528 CN 201010278528 CN 201010278528 A CN201010278528 A CN 201010278528A CN 101948503 A CN101948503 A CN 101948503A
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Abstract
The invention provides a novel method for preparing betamethasone ketal by homogeneous reaction at normal temperature, which comprises the steps of: adding reagents of dichloromethane, triethyl orthoformate and boron fluoride etherate in a normal temperature homogeneous system; carrying out condensation reaction through Platts oxides and ethanediol to prepare betamethasone ketal; reacting for 2-15h, condensing filtrate again, extracting semi-condensed materials, and again putting the materials. The product content is not less than 90 percent and the yield is 115-118 percent. Compared with the traditional process, the method has the advantages of shortening the reaction time, improving the content and the yield of the betamethasone ketal, reducing the environment pollution, discarding the benzene with huge hurt on the human body and the environment, ensuring that the production process is more environmentally friendly, lowering the labor intensity of workers, generating better social benefit, and being more beneficial to the massive industrialized production.
Description
Technical field
The invention belongs to steroid hormone class technical field of medicine synthesis, relate to the production method of steroid hormone Betamethasone Valerate product important intermediate ketal thing.
Background technology
Betamethasone Valerate is important glucocorticoid medicine, have anti-inflammatory, antianaphylaxis, toxinicide, Antishock function, can improve the adaptive faculty and the tolerance of antibody during stress reaction, to reduce the infringement of various factors antagonist, the inflammation that a variety of causes is caused all has restraining effect, can alleviate immunoreactive symptom, antagonism bacterial endotoxin infringement body, and can increase the reactivity of blood vessel to adrenomimetic drug, make elevation of blood pressure and microcirculation improvement.Act on dexamethasone on year-on-year basis, its anti-inflammatory action is stronger than dexamethasone, triamcinolone, hydrocortisone, and side effect is little.
Betamethasone Valerate (Betamethasone), chemical name: 16 Beta-methyls-11 β, 17 α, 21-trihydroxy--9 α-pregna-fluoride-1,4-diene-3,20-diketone.Make Betamethasone Valerate from the Pu Shi oxide compound through polystep reaction, the ketal thing is second step that whole Betamethasone Valerate is produced.Midbody product ketal thing wherein (Betamethasone Ketal structures) chemical name: 16, the pregnant steroid of 17-epoxy-11-ketone-5-alkene-3,20-Diethylene Glycol ketal is an important intermediate of making Betamethasone Valerate, carbonyl and ethylene glycol condensation by the Pu Shi oxide compound form, be second step that Betamethasone Valerate is produced,, make side reaction increase quality and descend because prior preparation method is undesirable, yield reduces, and has directly influenced ultimate yield and quality.Structural formula is as follows:
Though the ketal thing has followed traditional technology mostly in the research that there is preparation technology in China.Traditional preparation process technology is to be raw material with the Pu Shi oxide compound, is solvent and band aqua with benzene, to be catalyzer to toluene sulfonation acid, carries out condensation reaction with ethylene glycol.For the water that makes generation constantly shifts out from reaction system, reaction system need be in the reflux state about 80 ℃, be heterogeneous reversible reaction because of this reaction again, the probability of Pu Shi oxide compound and ethylene glycol collision is little, reaction needed for up to 42-45 hour, so side reaction is many, transformation efficiency is low, product content has only about 80%, and optically-active is overproof very high, and weight yield also can only reach 96%-105%.
Some defectives that traditional preparation method exists: the band water efficient that at first is benzene is low, must use and be equivalent to substrate 25-40 benzene doubly, and must under the high temperature reflux state about 80 ℃, carry out, will react the water that generates with the form of azeotrope and take out of outside the system.This has just caused a lot of negative results: the one, have a large amount of benzene leak into production plant and around atmospheric environment in go, human body and environment are caused great harm; The 2nd, benzene can only dissolve substrate and can not be well and ethylene glycol miscible, make reaction system become nonhomogeneous system, and then make speed of response slack-off, the reaction times prolongs, reaction is not exclusively; The 3rd, reflux temperature is higher, considerably beyond the temperature of condensation reaction needs, makes side reaction increase quality and descends, and yield reduces; The 4th, though resultant mainly is dissolved in the benzene layer, also there is small part to be dissolved in ethylene glycol, this part product can not be recovered, and causes reaction yield further to reduce; The 5th, lost time is long, and power consumption is big; The 6th, the catalytic effect of p-methyl benzenesulfonic acid is undesirable, is not best catalyzer.Mainly to be present in the ethylene glycol probability with the substrate contact-impact in above nonhomogeneous system very little in addition, causes catalytic effect further to reduce.Be that aftertreatment technology is very loaded down with trivial details at last, operability is relatively poor, and the labour intensity height causes every index fluctuation bigger.
Summary of the invention
Because there is certain limitation in traditional ketal preparation technology on design concept, carries out process optimization on the original basis and do not had a realistic meaning.Set up the project team specially at this problem the applicant and carry out monographic study, at first carried out investigating again from the reaction system design concept, designed brand-new preparation method: in reaction system, add reagent methylene dichloride, triethyl orthoformate, boron trifluoride diethyl etherate, realize the condensation reaction under Pu Shi oxide compound and the ethylene glycol normal temperature.Thereby overcome the deficiency of above-mentioned background technology to greatest extent.
Technical solution of the present invention is: the production method of steroid hormone Betamethasone Valerate product important intermediate ketal thing, it is characterized in that at room temperature, and with substrate and reaction reagent, methylene dichloride, triethyl orthoformate, boron trifluoride diethyl etherate, carry out condensation reaction; The raw material of its parts by weight is composed as follows:
1 part of substrate
Methylene dichloride 0.2-14 part
Boron trifluoride diethyl etherate 0.04-10 part
Triethyl orthoformate 0.5-12 part
Ethylene glycol 1-11 part
Triethylamine 0.5-18 part;
Wherein substrate refers to: Pu Shi oxide compound or Pu Shi oxide compound and its thing that partly contracts.
Production method of the present invention, condensation reaction wherein are to carry out in room temperature, homogeneous system, and the reaction times is 2-15 hour.
Production method of the present invention, wherein the condensation reaction rear filtrate concentrates again, gets rid of filter, gets the thing that partly contracts, and carries out ketal reaction then again.
Add reagent methylene dichloride, triethyl orthoformate, boron trifluoride diethyl etherate in the reaction system of the present invention, realize the condensation reaction under Pu Shi oxide compound and the ethylene glycol normal temperature.This reaction system, its advantage are can react under the normal temperature condition, can form homogeneous system well again, and methylene dichloride is as the good auxiliary agent of condensation reaction, because of it has positive contribution to condensation reaction.Optimized technical scheme of the present invention is as follows:
In retort, drop into the Pu Shi oxide compound successively and (1-11) times ethylene glycol of the thing (parts by weight) that partly contracts, (0.5-12) times triethyl orthoformate, (0.04-10) times boron trifluoride diethyl etherate, (0.2-14) times methylene dichloride, Pu Shi oxide compound and the thing that partly contracts thereof at room temperature reacted 2-15 hour, add triethylamine, terminal point is as the criterion with chromatography, concentrate, leave standstill, get rid of material then, oven dry gets the ketal thing.
After getting rid of material, filtrate is concentrated again, leave standstill, get rid of filter again, get the thing that partly contracts, can heavily knock down capable ketal reaction.
The positively effect that the production method of ketal thing of the present invention is compared with prior art had is:
(1) the present invention removes the water of condensation course generation and balanced reaction is constantly moved right.Its advantage is: the one, except reacting with water can any chemical reaction not take place with other materials in substrate or the system; The 2nd, can well dissolve each other with reaction system is homogeneous system to play the effect of solvent simultaneously; The 3rd, in last handling process, be easier to separate with product; The 4th, storing is convenient, and is cheap and easy to get.
(2) the new preparation method of the present invention promotes product quality comprehensively, and sound ketal thing preparation method's quality assurance system has been set up in ketal amount standard corresponding perfect raising, produces more safe and reliable.
(3) the present invention has got rid of human body and the huge benzene of environmental hazard, makes production process environmental protection more, has reduced working strength of workers, has produced fabulous social benefit.
(4) when significantly having improved product quality and yield, significantly reduce solvent consumption and various material, power consumption, shortened man-hour, improved production capacity, significantly reduced production cost, produced good economic benefits.
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.Raw materials used market is on sale.
Embodiment 1:
In retort, drop into ethylene glycol 20kg, triethyl orthoformate 5kg, boron trifluoride diethyl etherate 0.6kg, after stirring, add Pu Shi oxide compound 10kg, methylene dichloride 10kg, at room temperature reacted 2-15 hour, add triethylamine, terminal point is as the criterion with chromatography, concentrates, lowers the temperature, leaves standstill, gets rid of material then, oven dry gets the ketal thing.
After getting rid of material, filtrate is concentrated again, leave standstill, get rid of filter again, get the thing that partly contracts, can heavily knock down capable ketal reaction, yield 118%, content 93.72%
Embodiment 2:
In retort, drop into ethylene glycol 30kg, triethyl orthoformate 30kg, boron trifluoride diethyl etherate 1kg, after stirring, add Pu Shi oxide compound and the thing 10kg that partly contracts, methylene dichloride 6kg, at room temperature reacted 2-15 hour, add triethylamine, terminal point is as the criterion with chromatography, concentrates, lowers the temperature, leaves standstill, gets rid of material then, oven dry gets the ketal thing.
After getting rid of material, filtrate is concentrated again, leave standstill, get rid of filter again, get the thing that partly contracts, can heavily knock down capable ketal reaction, yield 116%, content 91.7%.
Embodiment 3:
In retort, drop into ethylene glycol 60kg, triethyl orthoformate 20kg, boron trifluoride diethyl etherate 6kg, after stirring, add Pu Shi oxide compound and the thing 10kg that partly contracts, methylene dichloride 15kg, at room temperature reacted 2-15 hour, add triethylamine, terminal point is as the criterion with chromatography, concentrates, lowers the temperature, leaves standstill, gets rid of material then, oven dry gets the ketal thing.
After getting rid of material, filtrate is concentrated again, leave standstill, get rid of filter again, get the thing that partly contracts, can heavily knock down capable ketal reaction, yield 115%, content 92.3%.
The ketal rerum natura shape of embodiment of the invention 1-3 preparation: the crystalline powder of white or off-white color.The quality standard of ketal thing:
| Project | Quality standard |
| Outward appearance | White or off-white color crystalline powder |
| Weight loss on drying | ≤0.5％ |
| Chromatographic purity | HPLC≥92％ |
| Fusing point | ≥160℃ |
| Single assorted | ≤1％ |
| Specific optical rotation | ≤+25°～+35° |
With prepared ketal thing through reaction qualified product to the end.
Claims (3)
1. the production method of a steroid hormone Betamethasone Valerate product important intermediate ketal thing is characterized in that at room temperature, and substrate and reaction reagent are carried out condensation reaction; The raw material of its parts by weight is composed as follows:
1 part of substrate
Methylene dichloride 0.2-14 part
Boron trifluoride diethyl etherate 0.04-10 part
Triethyl orthoformate 0.5-12 part
Ethylene glycol 1-11 part
Triethylamine 0.5-18 part;
Wherein substrate refers to: Pu Shi oxide compound or Pu Shi oxide compound and its thing that partly contracts.
2. the described production method of claim 1, condensation reaction wherein is to carry out in room temperature, homogeneous system, the reaction times is 2-15 hour.
3. the described production method of claim 1, wherein the condensation reaction rear filtrate concentrates again,---get rid of filter, the thing that partly contract, carry out ketal reaction then again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201010278528 CN101948503B (en) | 2010-09-10 | 2010-09-10 | Method for preparing betamethasone ketal by homogeneous reaction at normal temperature |
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| CN 201010278528 CN101948503B (en) | 2010-09-10 | 2010-09-10 | Method for preparing betamethasone ketal by homogeneous reaction at normal temperature |
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| CN101948503A true CN101948503A (en) | 2011-01-19 |
| CN101948503B CN101948503B (en) | 2013-01-02 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102367262A (en) * | 2011-07-19 | 2012-03-07 | 浙江仙琚制药股份有限公司 | Preparation method of hydrocortisone |
| CN110396040A (en) * | 2019-09-09 | 2019-11-01 | 东南大学 | A kind of method of one pot process diaryl first ketal |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1763066A (en) * | 2005-11-17 | 2006-04-26 | 台州百大药业有限公司 | Methylprednisolone chemical synthesis method |
| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101560238A (en) * | 2009-05-22 | 2009-10-21 | 河南利华制药有限公司 | Intermediates of betamethasone products-3, 20-double ethylene glycol production process |
-
2010
- 2010-09-10 CN CN 201010278528 patent/CN101948503B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1763066A (en) * | 2005-11-17 | 2006-04-26 | 台州百大药业有限公司 | Methylprednisolone chemical synthesis method |
| CN101230084A (en) * | 2008-02-04 | 2008-07-30 | 台州百大药业有限公司 | Chemical synthesis method of methylprednisolone |
| CN101560238A (en) * | 2009-05-22 | 2009-10-21 | 河南利华制药有限公司 | Intermediates of betamethasone products-3, 20-double ethylene glycol production process |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102367262A (en) * | 2011-07-19 | 2012-03-07 | 浙江仙琚制药股份有限公司 | Preparation method of hydrocortisone |
| CN102367262B (en) * | 2011-07-19 | 2013-01-02 | 浙江仙琚制药股份有限公司 | Preparation method of hydrocortisone |
| CN110396040A (en) * | 2019-09-09 | 2019-11-01 | 东南大学 | A kind of method of one pot process diaryl first ketal |
| CN110396040B (en) * | 2019-09-09 | 2020-12-15 | 东南大学 | Method for synthesizing diaryl methyl ketal by one-pot method |
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Granted publication date: 20130102 Termination date: 20160910 |