CN104744543A - Preparation method of pregnenolone phosphate derivatives and their salts - Google Patents
Preparation method of pregnenolone phosphate derivatives and their salts Download PDFInfo
- Publication number
- CN104744543A CN104744543A CN201310731731.9A CN201310731731A CN104744543A CN 104744543 A CN104744543 A CN 104744543A CN 201310731731 A CN201310731731 A CN 201310731731A CN 104744543 A CN104744543 A CN 104744543A
- Authority
- CN
- China
- Prior art keywords
- formula
- phase system
- organic solvent
- compound
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07J5/0053—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 not substituted in position 16
-
- 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
- C07J5/0069—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 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 by a saturated or unsaturated hydrocarbon group by an alkyl group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing pregnenolone phosphate shown in the formula I from sodium pregnenolone phosphate as a raw material. The method utilizes a two-phase acidification crystallization method and comprises the following steps of 1, preparing an aqueous solution of a compound shown in the formula II, 2, adding a hydrophobic organic solvent into the aqueous solution to obtain a two-phase system comprising water and the organic solvent, and 3, adjusting pH of the two-phase system to less than 7 so that the compound shown in the formula I is precipitated. The product has good quality, less impurities, and solution clarification degree and color satisfying pharmacopeia requirements. The method is efficient, can remove water-soluble impurities and fat-soluble impurities by one step, improves efficiency, has simple processes, is free of reworking, realizes one-step production of the high-quality qualified product, has low energy consumption and reduces a cost.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the preparation method of a kind of pregnene ketone phosphate derivative and salt thereof.
Background technology
Pregnene ketone is a class take pregnane as parent nucleus, and the compound of ketone group containing and carbon-carbon double bond, 16 carbon of its pregnane parent nucleus may have steric configuration.Pregnene ketone phosphate derivative refers to the ester that 21 hydroxyls of pregnene ketone and phosphoric acid are formed.Particular compound is as dexamethasone phosphate (formula III), prednisolone phosphoric acid ester (formula IV), Betamethasone Valerate phosphoric acid ester (formula V) etc.
Pregnene ketone phosphate derivative and pharmacologically acceptable salt thereof as adrenal cortex hormones drug, Clinical practice formulation mainly injection.Therefore, the bulk drug of country to this type of pharmaceutical preparation of preparation has higher specification of quality.Such as, for betamethasone sodium phosphate, Chinese Pharmacopoeia 2010 editions not only defines the limit of related substance, and (single foreign matter content is not more than 1%, total impurities content is not more than 3%), and newly-increased define clarity of solution and color, that is: by bulk drug with after the cold-water solution newly boiled, solution answers clear, colorless, as colour developing, compare with yellow or orange-yellow No. 2 standard color solutions, must not be darker.
Quality and its preparation method of bulk drug are closely related.Technically, pregnene ketone phosphate derivative, salify and obtaining again after phosphoric acid ester can being generated with sodium phosphate salt.To this, some in prior art, are had to report, as:
CN200710061254.4 discloses a kind of preparation method of Betamethasone Valerate phosphoric acid ester: in the aqueous solution of betamethasone sodium phosphate, add hydrochloric acid, makes pH value be 1-2, filters, dry, obtains Betamethasone Valerate phosphoric acid ester.This method directly carries out acidifying precipitation of phosphorus acid esters, but even if separate out quite lentamente, also can make to wrap up a large amount of organic impurity in product.
CN00136585.1 discloses a kind of preparation method of dexamethasone phosphate: with the dexamethasone sodium phosphate mother liquor of output aborning for raw material, and extract repeatedly by ethyl acetate, it is 0.5-1.5 that aqueous phase adds hydrochloric acid adjust pH again, leave standstill, filter, dry, obtain Betamethasone Valerate phosphoric acid ester.This method needs repeatedly to use organic solvent extraction, very loaded down with trivial details, even and if like this, be also difficult to impurity well to extract from product, the clarity of solution of product and color also differ and reach requirement surely.
With pregnene ketone sodium phosphate for raw material is prepared in the art methods of pregnene ketone phosphoric acid ester, the present inventor finds, no matter be that direct acidifying is separated out, still first with acidifying precipitation again after organic solvent extraction, be all difficult to make the clarity of solution of pregnene ketone phosphoric acid ester and color reach the standard of Chinese Pharmacopoeia.
Therefore, need the preparation method providing a kind of better pregnene ketone phosphate derivative, make the foreign matter content of product few, solution colour and clarity can reach pharmacopoeial requirements.
Summary of the invention
The object of this invention is to provide a kind of with pregnene ketone sodium phosphate for the novel method of pregnene ketone phosphoric acid ester prepared by raw material, the product impurity content obtained is few, and clarity is high, can reach the requirement of Chinese Pharmacopoeia.
Another object of the present invention is to provide the process for purification of raw material pregnene ketone sodium phosphate.
Contriver is through exploring Late Cambrian, and by adopting a kind of method of crystallization after acidifying in a two-phase system, obtain foreign matter content few, clarity of solution is high, the product that solution colour is qualified, reaches goal of the invention.
Concrete technical scheme of the present invention is:
With the method for pregnene ketone sodium phosphate for raw material preparation formula I pregnene ketone phosphoric acid ester, its feature adopts the method for crystallization after acidifying in a two-phase system, comprises the following steps:
1) starting materials of formulae II compound is made the aqueous solution;
2) in formula II compound water solution, add hydrophobic organic solvent, form the two-phase system of water and organic solvent;
3) regulate the pH value of described two-phase system to acid, separate out formula I.
In formula I or formula II, R1 is selected from the alkyl of H or C1-C6, preferred H or methyl; When R1 is the alkyl of C1-C6, what connect 16 carbon of R1 is configured as R or S type.
On this basis, present invention also offers a kind of method of refining above-mentioned formula II pregnene ketone sodium phosphate:
A process for purification for formula II compound, comprises the following steps:
1) starting materials of formulae II compound is made the aqueous solution;
2) in formula II compound water solution, add hydrophobic organic solvent, form the two-phase system of water and organic solvent;
3) regulate the pH value of described two-phase system to acid, separate out formula I.
4) collect the formula I separated out, dissolve with alcohol, form alcoholic solution;
5) with ionizable go out the alkali of sodium ion regulate the pH value of described alcoholic solution to alkalescence, separate out the highly finished product of formula II compound.
Described ionizable go out the alkali of sodium ion be selected from sodium methylate, sodium hydroxide, sodium carbonate or sodium bicarbonate.
A kind of preparation method of above-mentioned raw materials formula II compound is:
I) formula III compound and pyrophosphoryl chloride react;
Ii) reaction product and ionizable go out the alkali of sodium ion carry out salt-forming reaction, obtain the crude product of formula II compound.
In formula III, R1 is selected from the alkyl of H or C1-C6; When R1 is the alkyl of C1-C6, the steric configuration connecting 16 carbon of R1 is R or S type.
Described ionizable go out sodium ion alkali as previously mentioned.
" two-phase acidizing crystal method " of the present invention is a kind of method that the present invention develops voluntarily.Contriver finds, why the limit of impurities of product can reach requirement, but clarity of solution and color are not good, be probably because of exist in pregnene ketone phosphoric acid ester bulk drug usual way (as HPLC method) be difficult to the inorganic or organic impurity detected cause.
Contriver creatively forms the two-phase system of aqueous phase and organic phase in the present invention, and sodium salt is converted into ester in a two-phase system, and impels its crystallization simultaneously.Pregnene ketone sodium phosphate is converted in the process that pregnene ketone phosphoric acid ester separates out again, product has carried out repeatedly exchanging in a two-phase system, make two-phase system be provided with very strong impurity Scavenging activity, can remove and pregnene ketone phosphoric acid ester or the very close impurity of salt character.In conversion process, not only eliminate water-soluble and fat-soluble two class impurity simultaneously, and eliminate the impurity in ester and salt two kinds of forms simultaneously, thus obtain high-quality pregnene ketone phosphoric acid ester.
After obtaining high-quality pregnene ketone phosphoric acid ester, then dissolve with alcohol, alkalization, can obtain high-quality pregnene ketone sodium phosphate, thus achieves the refining of pregnene ketone sodium phosphate.
After substance dissolves to be purified is formed solution by traditional crystallization process often in a solvent, after leaching insoluble impurity, then crystallize out.Also have a kind of crystallization purifications to be first material to be purified is dissolved in it easily in broad dose, then add indissoluble solvent in system, the solubility property of whole system is declined, thus substance crystallization is separated out.
These methods all can not realize object of the present invention.Because it can only process the material of a kind of form (ester or salt), the impurity larger with this physical property difference can only be removed, in Crystallization Process, the impurity very close with product characteristics and the impurity being difficult to detect often are separated out with product simultaneously, and be difficult to again remove, thus have impact on the quality of product.
The many aspects such as ratio of water and organic solvent can optimize further method of the present invention from the kind of organic solvent kind, alcohol, two-phase system pH value or two-phase system:
In aforesaid method, described organic solvent can be selected from ester class, ethers or hydro carbons (as alkane, naphthenic hydrocarbon, halohydrocarbon, aromatic hydrocarbon), preferred methyl acetate, ethyl acetate, ether, positive propyl ether, isopropyl ether, ethyl-butyl ether, benzene,toluene,xylene, hexanaphthene, normal hexane, methylene dichloride or trichloromethane.
In aforesaid method, described alcohol can be lower aliphatic alcohols, particular methanol or ethanol.
In aforesaid method, in step 3), the pH value of adjustable described two-phase system is to 0.1-6, preferred 0.2-4.
In aforesaid method, in described two-phase system, the volume ratio of water and organic solvent can be 1:0.1-5, preferred 1:0.3-3.
Method of the present invention at least has following beneficial effect:
1, good product quality.Solve in prior art when separating out pregnene ketone phosphoric acid ester or salt and wrap up a more polymictic difficult problem, good product quality, impurity is few, and clarity of solution and color can reach pharmacopoeial requirements.
2, method is efficient.Impurity in disposable removing ester and salt two kinds of forms, disposable removal water-soluble impurity and oil-soluble impurities, improve efficiency.
3, method is easy.Without the need to rework operation, high-quality qualified product disposablely can be produced, compared with traditional method needs repeatedly to do over again, more easy.
4, reduce energy consumption and reduce cost.Because the inventive method has very strong Impurity removal ability, therefore react in the process preparing pregnene ketone phosphoric acid ester crude product at formula III compound and pyrophosphoryl chloride early stage, without the need to the cold condition of less than-40 DEG C required by traditional method, the general cold condition of about-10 DEG C is only needed to reach requirement, thus reduction equipment requirements, decrease energy consumption, save cost.
Embodiment
By embodiment, method of the present invention being specifically described below, by comparative example, art methods being simulated, contrasting using the product of the inventive method and art methods gained by test example.
Embodiment 1
Get 0.3kg dexamethasone (formula III, R1 is methyl, and 18 carbon are R configuration) in dried and clean reactor, add 6kg tetrahydrofuran (THF), dispersed with stirring, open refrigerant and be cooled to-10 DEG C, drip pyrophosphoryl chloride 0.55kg, react after 1 hour at-12 DEG C ~-9 DEG C, add water 6kg, rise to room temperature, abundant stirring, pressure reducing and steaming tetrahydrofuran (THF), filters and obtains dexamethasone phosphate (formula I, R1 is methyl, and 18 carbon are R configuration) crude product.Be scattered in by products therefrom in purified water, adding sodium carbonate adjust ph is 6 ~ 8, filters, and collects filtrate, obtains dexamethasone sodium phosphate (formula II, R1 are methyl, and 18 carbon are R configuration) crude product aqueous solution 4.5kg.
Get above dexamethasone sodium phosphate crude product aqueous solution 500ml, add 100ml trichloromethane, obtain two-phase system, then be 0.1 ~ 0.3 with salt acid for adjusting pH value, place and make crystallization, filter, dry, obtain dexamethasone phosphate.
After gained dexamethasone phosphate dissolve with methanol, be 8 ~ 10 with sodium methylate adjust pH, crystallization, filters, dry, obtains the highly finished product of dexamethasone sodium phosphate.
Embodiment 2
Get 120g prednisolone (formula III, R1 is hydrogen) and in dried and clean reactor, add 3000g tetrahydrofuran (THF), dispersed with stirring, open refrigerant and be cooled to-12 DEG C, drip pyrophosphoryl chloride 380g, react after 3 hours at-10 DEG C ~-5 DEG C, add water 2000g, rise to room temperature, fully stir, pressure reducing and steaming tetrahydrofuran (THF), be filled into prednisolone phosphoric acid ester (formula III, R1 is hydrogen) crude product.Be scattered in by products therefrom in purified water, adding sodium bicarbonate adjust ph is 6.5 ~ 7.0, filters, and collects filtrate, obtains the aqueous solution 1800g of prednisolone phosphate disodium (formula III, R1 is hydrogen) crude product.
Get above prednisolone phosphate disodium crude product aqueous solution 1000ml, add 300ml hexanaphthene, obtain two-phase system, then be 3.5 ~ 4.0 with salt acid for adjusting pH value, place and make crystallization, filter, dry, obtain prednisolone phosphoric acid ester.
After gained prednisolone phosphoric acid ester dissolve with ethanol, be 10 ~ 12 with sodium hydroxide adjust pH, crystallization, filters, dry, obtains the highly finished product of prednisolone phosphate disodium.
Embodiment 3
Dexamethasone sodium phosphate crude product aqueous solution 800ml in Example 1, adds 1600ml normal hexane, obtains two-phase system, then is 0.2 ~ 0.4 with salt acid for adjusting pH value, places and makes crystallization, filters, dry, obtains dexamethasone phosphate.
After gained dexamethasone phosphate dissolve with methanol, be 9 ~ 12 with sodium hydroxide adjust pH, crystallization, filters, dry, obtains the highly finished product of dexamethasone sodium phosphate.
Embodiment 4
Get 0.52kg Betamethasone Valerate (formula III, R1 is methyl, and 18 carbon are S configuration) in dried and clean reactor, add 7.0kg tetrahydrofuran (THF), dispersed with stirring, open refrigerant and be cooled to-10 DEG C, drip pyrophosphoryl chloride 0.76kg, react after 2 hours at-15 DEG C ~-10 DEG C, add water 8.0kg, rise to room temperature, abundant stirring, pressure reducing and steaming tetrahydrofuran (THF), is filled into Betamethasone Valerate phosphoric acid ester (formula III, R1 is methyl, and 18 carbon are S configuration) crude product.Be scattered in by products therefrom in purified water, adding sodium carbonate adjust ph is 7.5 ~ 8.5, filters, and collects filtrate, obtains the aqueous solution 6.2kg of betamethasone sodium phosphate (formula III, R1 is methyl, and 18 carbon are S configuration) crude product.
Get above betamethasone sodium phosphate crude product aqueous solution 2000ml, add 6000ml ethyl acetate, obtain two-phase system, then be 2.0 ~ 3.0 with salt acid for adjusting pH value, place and make crystallization, filter, dry, obtain Betamethasone Valerate phosphoric acid ester.
After gained Betamethasone Valerate phosphoric acid ester dissolve with ethanol, be 11 ~ 12 with sodium hydroxide adjust pH, crystallization, filters, dry, obtains the highly finished product of betamethasone sodium phosphate.
Embodiment 5
Dexamethasone sodium phosphate crude product aqueous solution 250ml in Example 1, adds 1250ml isopropyl ether, obtains two-phase system, then is 5 ~ 6 by sulfuric acid adjust ph, places and makes crystallization, filters, dry, obtains dexamethasone phosphate.
Embodiment 6
Prednisolone phosphate disodium crude product aqueous solution 600ml in Example 2, adds 60ml toluene, obtains two-phase system, then is 1.0 ~ 1.2 by sulfuric acid adjust ph, places and makes crystallization, filters, dry, obtains prednisolone phosphoric acid ester.
Comparative example 1
Dexamethasone sodium phosphate crude product aqueous solution 500ml in Example 1 is 0.1 ~ 0.3 with salt acid for adjusting pH value, places and makes crystallization, filters, dry, obtains dexamethasone phosphate.
After gained dexamethasone phosphate dissolve with methanol, be 8 ~ 10 with sodium methylate adjust pH, crystallization, filters, dry, obtains the highly finished product of dexamethasone sodium phosphate.
Comparative example 2
Betamethasone sodium phosphate crude product aqueous solution 2000ml in Example 4, extracts twice, each 3000ml by ethyl acetate; Collect water layer, water layer salt acid for adjusting pH value is 2.0 ~ 3.0, places and makes crystallization, filters, dry, obtains Betamethasone Valerate phosphoric acid ester.
After gained Betamethasone Valerate phosphoric acid ester dissolve with ethanol, be 11 ~ 12 with sodium hydroxide adjust pH, crystallization, filters, dry, obtains the highly finished product of betamethasone sodium phosphate.
Test example 1
In the various embodiments described above and comparative example, gained pregnene ketone phosphoric acid ester and pregnene ketone sodium phosphate highly finished product are as sample; The content of wherein impurity is measured respectively by HPLC method, check the color of each sample solution by solution colour test procedure (Chinese Pharmacopoeia 2010 editions annex IX A first methods), check the clarity of each sample solution by clarity test procedure (Chinese Pharmacopoeia 2010 editions annex IX B).
HPLC testing conditions is, chromatographic column: C
18(4.6 × 250mm, 5 μm); Moving phase: potassium primary phosphate is amine aqueous solution (get potassium primary phosphate 1.36g to mix with amine 0.60g, place after 10 minutes, the 185ml that adds water makes dissolving)-second eyeball=74:26; Determined wavelength: 254nm; Column temperature: 30 DEG C; Flow velocity: 1.0ml/min; Sample size: 20 μ l.
Test-results is in table 1 and table 2.In table, the preparation of " yellow No. 2 standard color solutions " and " orange-yellow No. 2 standard color solutions ", prepares by the relevant regulations of Chinese Pharmacopoeia 2010 editions.
The clarity of solution of table 1 product pregnene ketone phosphoric acid ester, color and foreign matter content
The clarity of solution of table 2 product pregnene ketone sodium phosphate, color and foreign matter content
As can be seen from the test results:
The pregnene ketone phosphoric acid ester that existing method obtains or its salt impurity is more, clarity of solution and color poor.
The pregnene ketone phosphoric acid ester that the inventive method obtains or its salt better quality, foreign matter content is few, and solution colour and clarity can reach pharmacopoeial requirements.
Note: the quality standard of Chinese Pharmacopoeia 2010 editions regulation:
The limit of related substance is: single foreign matter content is not more than 1%, and total impurities content is not more than 3%;
Clarity of solution and color: by bulk drug with after the cold-water solution newly boiled, solution answers clear, colorless, as colour developing, compare with yellow or orange-yellow No. 2 standard color solutions, must not be darker.
Claims (10)
1., with the method for pregnene ketone sodium phosphate for raw material preparation formula I pregnene ketone phosphoric acid ester, it is characterized by the employing method of crystallization after acidifying in a two-phase system, comprise the following steps:
1) starting materials of formulae II compound is made the aqueous solution;
2) in the above-mentioned aqueous solution, add hydrophobic organic solvent, form the two-phase system of water and organic solvent;
3) regulate the pH value of described two-phase system to acid, separate out formula I;
In formula I or formula II, R1 is selected from the alkyl of H or C1-C6; When R1 is the alkyl of C1-C6, what connect 16 carbon of R1 is configured as R or S type.
2. method according to claim 1, the preparation method of wherein said starting materials of formulae II compound is:
I) formula III compound and pyrophosphoryl chloride react;
Ii) reaction product and ionizable go out the alkali of sodium ion carry out salt-forming reaction, obtain formula II compound;
In formula III, R1 is selected from the alkyl of H or C1-C6; When R1 is the alkyl of C1-C6, the steric configuration connecting 16 carbon of R1 is R or S type.
3. the method for claim 1 or 2, in described formula I, formula II or formula III, R1 is selected from H or methyl.
4. the method described in claim 1 or 2, the process for purification of described starting materials of formulae II compound comprises the following steps:
A) by formula II compound water dissolution, the aqueous solution is formed;
B) in the described aqueous solution, add hydrophobic organic solvent, form the two-phase system of water and organic solvent;
C) regulate the pH value of described two-phase system to acid, separate out formula I solid;
D) collect the solid of separating out, dissolve with alcohol, form alcoholic solution, described alcohol is lower aliphatic alcohols;
E) with ionizable go out the alkali of sodium ion regulate the pH value of described alcoholic solution to alkalescence, separate out the highly finished product of formula II compound.
5. the method for claim 1 or 4, described organic solvent is selected from ester class, ethers or hydro carbons, and described hydrocarbon comprises alkane, naphthenic hydrocarbon, halohydrocarbon, aromatic hydrocarbon.
6. the method for claim 1 or 4, described organic solvent is selected from methyl acetate, ethyl acetate, ether, positive propyl ether, isopropyl ether, ethyl-butyl ether, benzene,toluene,xylene, hexanaphthene, normal hexane, methylene dichloride or trichloromethane.
7. the method for claim 1 or 4, the pH value of the described two-phase system of described adjustment, to acid, is that adjust ph is to 0.1-6; In described two-phase system, the volume ratio of water and organic solvent is 1:0.1-5.
8. the method for claim 1 or 4, in described two-phase system, the volume ratio of water and organic solvent is 1:0.3-3.
9. the method described in claim 2 or 4, described ionizable go out the alkali of sodium ion be selected from sodium methylate, sodium hydroxide, sodium carbonate or sodium bicarbonate.
10. method according to claim 4, described alcohol is methyl alcohol or ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310731731.9A CN104744543A (en) | 2013-12-26 | 2013-12-26 | Preparation method of pregnenolone phosphate derivatives and their salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310731731.9A CN104744543A (en) | 2013-12-26 | 2013-12-26 | Preparation method of pregnenolone phosphate derivatives and their salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104744543A true CN104744543A (en) | 2015-07-01 |
Family
ID=53584868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310731731.9A Pending CN104744543A (en) | 2013-12-26 | 2013-12-26 | Preparation method of pregnenolone phosphate derivatives and their salts |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104744543A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109734766A (en) * | 2019-01-07 | 2019-05-10 | 河南利华制药有限公司 | A kind of preparation method of Inflamase intermediate |
| CN110964075A (en) * | 2018-09-30 | 2020-04-07 | 天津药业研究院有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
| CN112094311A (en) * | 2020-10-16 | 2020-12-18 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
| CN112457361A (en) * | 2020-11-26 | 2021-03-09 | 河南利华制药有限公司 | Method for recovering prednisolone sodium phosphate mother liquor |
| CN113773359A (en) * | 2021-09-13 | 2021-12-10 | 山东省药学科学院 | Preparation and separation method of betamethasone sodium phosphate |
| RU2764597C1 (en) * | 2020-12-29 | 2022-01-18 | Федеральное государственное бюджетное образовательное учреждение высшего образования «Московский государственный университет имени М.В.Ломоносова» (МГУ) | Method for synthesising disodium salt of dexamethasone 21-phosphate applied for treating patients with coronavirus infection (covid-19) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1361109A (en) * | 2000-12-27 | 2002-07-31 | 天津药业集团有限公司 | Recovery process of Dexamethazone-sodium phosphate mother liquor |
| CN101397320A (en) * | 2007-09-29 | 2009-04-01 | 天津天药药业股份有限公司 | Method for preparing dexamethasone and series products thereof |
-
2013
- 2013-12-26 CN CN201310731731.9A patent/CN104744543A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1361109A (en) * | 2000-12-27 | 2002-07-31 | 天津药业集团有限公司 | Recovery process of Dexamethazone-sodium phosphate mother liquor |
| CN101397320A (en) * | 2007-09-29 | 2009-04-01 | 天津天药药业股份有限公司 | Method for preparing dexamethasone and series products thereof |
Non-Patent Citations (1)
| Title |
|---|
| 周遂: "地塞米松磷酸钠的合成工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110964075A (en) * | 2018-09-30 | 2020-04-07 | 天津药业研究院有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
| CN110964075B (en) * | 2018-09-30 | 2022-09-06 | 天津药业研究院股份有限公司 | Preparation method of betamethasone phosphate and sodium salt thereof |
| CN109734766A (en) * | 2019-01-07 | 2019-05-10 | 河南利华制药有限公司 | A kind of preparation method of Inflamase intermediate |
| CN109734766B (en) * | 2019-01-07 | 2020-09-04 | 河南利华制药有限公司 | Preparation method of prednisolone sodium phosphate intermediate |
| CN112094311A (en) * | 2020-10-16 | 2020-12-18 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
| CN112094311B (en) * | 2020-10-16 | 2022-04-08 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
| CN112457361A (en) * | 2020-11-26 | 2021-03-09 | 河南利华制药有限公司 | Method for recovering prednisolone sodium phosphate mother liquor |
| CN112457361B (en) * | 2020-11-26 | 2021-12-07 | 河南利华制药有限公司 | Method for recovering prednisolone sodium phosphate mother liquor |
| RU2764597C1 (en) * | 2020-12-29 | 2022-01-18 | Федеральное государственное бюджетное образовательное учреждение высшего образования «Московский государственный университет имени М.В.Ломоносова» (МГУ) | Method for synthesising disodium salt of dexamethasone 21-phosphate applied for treating patients with coronavirus infection (covid-19) |
| CN113773359A (en) * | 2021-09-13 | 2021-12-10 | 山东省药学科学院 | Preparation and separation method of betamethasone sodium phosphate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104744543A (en) | Preparation method of pregnenolone phosphate derivatives and their salts | |
| CA2722496C (en) | Crystalline minocycline base and processes for its preparation | |
| CN102603841B (en) | Preparation method of dehydroisoandrosterone | |
| CN101987860B (en) | Preparation method of ursodesoxycholic acid | |
| CN103087048B (en) | Method for purifying esomeprazole sodium | |
| CN103102384B (en) | Method for extracting high-purity ursolic acid from rosemary | |
| CN113264817B (en) | Curcumin crystallization method and application thereof | |
| CN112441952B (en) | Cannabidiol-3-sulfonic acid, preparation method and application thereof, and cannabidiol derivative | |
| CN103288801B (en) | A kind of preparation method of high-purity esomeprazole sodium | |
| CN102241722B (en) | A kind of purification process synthesizing progesterone receptor modulator gifted zafirlukast | |
| CN103896930A (en) | Method for preparing pharmaceutical crystal form of Canagliflozin hemihydrates | |
| CN103073417B (en) | The preparation method of high-purity trans-crocetin | |
| CN103420979A (en) | Esomeprazole sodium refining method | |
| CN104262421B (en) | The technique extracting salicoside from Populus euphratica fallen leaves | |
| CN103772454B (en) | The process for purification of Clindamycin Phosphate | |
| CN103739619A (en) | Refining and purifying method of high-purity cefotetan acid | |
| CN104844681B (en) | The process for purification of the brilliant type eplerenone of a kind of L | |
| CN1193994C (en) | Method for purifying monomer of epigallocatechingallate (EGCG) | |
| CN102127016A (en) | Hetisin type diterpenoid alkaloid and preparation method and application thereof | |
| CN110818767B (en) | Preparation and purification method of 3-O-cyclohexanecarboxyl-11-carbonyl-beta-boswellic acid or analogue thereof | |
| CN116199729A (en) | Crystal form B of acetamiprid and preparation method thereof | |
| CN110759960B (en) | Refining method of fluticasone propionate | |
| CN104650165B (en) | A kind of preparation method of scutelloside | |
| CN103720720A (en) | Natural pregnant mare conjugated estrogen purification and refinement method and application of nonionic nonpolar fine separation resin used by same | |
| CN105017051A (en) | Method for refining bromfenac sodium sesquicarbonate hydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150701 |
|
| RJ01 | Rejection of invention patent application after publication |