CN104974208B - A kind of preparation method of high-purity Methylprednisolone Aceponate - Google Patents
A kind of preparation method of high-purity Methylprednisolone Aceponate Download PDFInfo
- Publication number
- CN104974208B CN104974208B CN201410136626.5A CN201410136626A CN104974208B CN 104974208 B CN104974208 B CN 104974208B CN 201410136626 A CN201410136626 A CN 201410136626A CN 104974208 B CN104974208 B CN 104974208B
- Authority
- CN
- China
- Prior art keywords
- methylprednisolone aceponate
- mixed solvent
- volume
- methylprednisolone
- aceponate
- 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.)
- Active
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
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 present invention relates to a kind of process for purification of Methylprednisolone Aceponate, it is characterized in that being recrystallized to give using mixed solvent A, the mixed solvent A is by the acetone of 1 parts by volume, the n-hexane of 0.5 ~ 1.5 parts by volume, the water composition of 0 ~ 0.5 parts by volume.Can be readily available content more than 99.5% using method provided by the invention, it is maximum it is single it is miscellaneous be less than 0.15% high-purity Methylprednisolone Aceponate.
Description
Technical field：
The present invention relates to a kind of preparation method of high-purity Steroidal anti-inflammatory medicine Methylprednisolone Aceponate.
Background technology：
Methylprednisolone Aceponate (Methylprednisolone aceponate, MPA, CAS：86401-95-8) its chemistry knot
Structure formula is as follows：
Methylprednisolone Aceponate is developed by German Schring AG as a kind of derivative of methylprednisolone, is that one kind has
The glucocorticoid of very strong local anti-inflammatory activity, for the treatment to scytitis, at present, commercially available Methylprednisolone Aceponate skin
Skin is that German Schring AG are produced with preparation, trade name Advantan 0.1% Methylprednisolone Aceponate emulsifiable paste, be can be used for
Suppress inflammation and the reaction of allergic skin, while also suppress to accelerate the related reaction of regeneration with cell and cause symptom, such as
The coarse decline of erythema, oedema, skin thicknessization, skin surface, and the problems such as mitigation itch, burning heat sensation and pain.The first of vinegar third
Prednisolone cream is current superpower external application corticosteroid formulations, and its curative effect is superior to known corticosteroid, and wherein
Methylprednisolone Aceponate emulsifiable paste is the efficient corticosteroid of no halide groups again, and side effect is light, is that a kind of can be used for children
Corticosteroid external preparation.The market prospects of said preparation are very wide.But at present on Methylprednisolone Aceponate synthesis and essence
The document of method report processed is few.
US4587236 embodiments 15 are reported using the β of 21- acetoxyl groups-11, and 17-6 Alpha-Methyls of alpha-dihydroxy-Isosorbide-5-Nitraes-are pregnant-
3,20- diketone are the method that starting material prepares Methylprednisolone Aceponate, and reaction scheme is as shown in following formula 1.The first of final products vinegar third is sprinkled
Nylon is isolated and purified (mobile phase dichloromethane-acetone gradient elution, 0-15% acetone) using with column chromatography, is not suitable for work
Industry metaplasia is produced.
DE3427486 is reported using the α of 21- acetoxyl groups-9-- 17 α of Alpha-Methyl of bromo- 11 beta-hydroxy-6-propionyloxy-1,
4- is pregnant -3,20- diketone is that starting material reduces to obtain Methylprednisolone Aceponate by tri-n-butyltin hydride, but do not refer to it is refined just
Method, reaction scheme is as shown in following formula 2：
Document 1 (Chemical＆Pharmaceutical Bulletin, Volume:33,Issue:5,Pages:1889-
98, Journal, 1985), United States Patent (USP) US4587236 embodiments 2, United States Patent (USP) US4567172 embodiments 7, Chinese patent Shen
Please CN200610053788 report the synthetic method of Methylprednisolone Aceponate, reaction scheme is as shown in following formula 3：
Document 1 reports final products Methylprednisolone Aceponate and utilizes column chromatography (mobile phase is dichloroethanes) or thin-layer chromatography
(mobile phase is dichloroethanes：Ether=4-5:1) isolate and purify, be not suitable for industrialized production.US4587236 embodiments 2 are with
State patent application CN200610053788 does not refer to process for purification.United States Patent (USP) US4567172 embodiments 7 report final products
Methylprednisolone Aceponate purifies first with TLC separation, is then obtained using Diethyl ether recrystallization.But we pass through experiment
It was found that final products Methylprednisolone Aceponate is refined using Diethyl ether recrystallization, purity can only achieve 98% or so, still there is 2% or so
Impurity is difficult to remove.According to international working standard ICH Tripartite Coordination guidelines, needed for the impurity of content more than 0.2%
Structure is identified, the impurity of content more than 0.5% needs to carry out pharmacological evaluation, while is controlled generally for the single impurity of bulk drug
Below 0.5%.Therefore, high-purity Methylprednisolone Aceponate bulk drug prepare it is extremely important.
The content of the invention
Present invention aims at provide a kind of method of purification of simple, high income, good product purity Methylprednisolone Aceponate.
Can be readily available content more than 99.5% using method provided by the invention, it is maximum it is single it is miscellaneous be less than 0.15% high-purity vinegar
Third methylprednisolone.
The present invention relates to a kind of process for purification of Methylprednisolone Aceponate, it is characterized in that be recrystallized to give using mixed solvent A,
The mixed solvent A is by the acetone of 1 parts by volume, the n-hexane of 0.5~1.5 parts by volume, the water composition of 0~0.5 parts by volume.
The process for purification of described a kind of Methylprednisolone Aceponate, it is characterized in that the mixed solvent A is by the third of 1 parts by volume
Ketone, the n-hexane composition of 0.5~1.5 parts by volume.
The process for purification of described a kind of Methylprednisolone Aceponate, it is characterized in that Methylprednisolone Aceponate and the mixed solvent A
The rate of charge of middle acetone solvent is 1:0.5—2g/ml.
The process for purification of described a kind of Methylprednisolone Aceponate, it is characterized in that Methylprednisolone Aceponate is dissolved by heating described
In mixed solvent A, heating-up temperature, then with 9~11 DEG C per hour of speed, has been cooled to no more than the reflux temperature of solvent
Crystal separates out, and is filtrated to get.
Through experiment find, using only Methylprednisolone Aceponate good solvent for example, acetone, ethanol, methanol, ethyl acetate,
In the case that dichloromethane, tetrahydrofuran etc. refine to Methylprednisolone Aceponate, if the solvent amount used is more, yield
Very low, main cause is that the solubility of Methylprednisolone Aceponate in a solvent is very big, and loss of material is serious；If reduce solvent to use
Amount, after product under low temperature separates out, system becomes sticky, and is not easy to filter；If used using only atent solvent such as n-hexane
Quantity of solvent is big, and Methylprednisolone Aceponate and relevant material are difficult separation, and product purity is difficult to increase.By test of many times
It was found that technical scheme effect is best.
Embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Methylprednisolone Aceponate crude product bibliography US4587236 embodiments 15 in inventive embodiments 1 and comparative examples
Prepared by method, Methylprednisolone Aceponate content in crude product is 98%.Methylprednisolone Aceponate crude product bibliography in inventive embodiments 2
Prepared by DE3427486 method, Methylprednisolone Aceponate content in crude product is 98%.Methylprednisolone Aceponate crude product in inventive embodiments 3
Prepared by the method for references to U.S. patent US4567172 embodiments 7, Methylprednisolone Aceponate content in crude product is 98%.Invention is real
Prepared by the method for applying Methylprednisolone Aceponate crude product bibliography US4587236 embodiments 15 in example 4, Methylprednisolone Aceponate crude product contains
Measure as 90%.In inventive embodiments 5 prepared by Methylprednisolone Aceponate crude product bibliography DE3427486 method, and the first of vinegar third sprinkles Buddhist nun
Imperial content in crude product is 90%.Methylprednisolone Aceponate crude product references to U.S. patent US4567172 embodiments in inventive embodiments 6
Prepared by 7 method, Methylprednisolone Aceponate content in crude product is 90%.
Implement in following examples in the assay method bibliography CN201010564439.9 of Methylprednisolone Aceponate content
The method of example two is measured.
Brief description of the drawings：
Fig. 1：The HPLC spectrograms of starting material Methylprednisolone Aceponate crude product (content 98%) in inventive embodiments 1
Fig. 2：The HPLC spectrograms of product Methylprednisolone Aceponate fine work (content 99.8%) in inventive embodiments 1-1
Fig. 3：The HPLC spectrograms of product Methylprednisolone Aceponate (content 98.6%) in comparative examples 1-13
Fig. 4：Make the HPLC spectrograms of Methylprednisolone Aceponate standard items (content 99.9%) by oneself
Inventive embodiments 1
Inventive embodiments 1-1
It will be dissolved at 50 DEG C of the Methylprednisolone Aceponate of 100g contents 98% in mixed solvent A, mixed solvent A is by 100ml third
Ketone, 50ml n-hexanes composition, stirs dissolved clarification.Cool 10 DEG C per 1h, be cooled to 20 DEG C, insulation aging 2h.Filtering, acetone with just oneself
Alkane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder 88g, yield 88%, content 99.8% is maximum single miscellaneous
0.10%.
Inventive embodiments 1-2~1-6 mixed solvents A ratio see the table below, and other conditions and operating procedure are real with reference to invention
Apply a 1-1.
Inventive embodiments 2
Inventive embodiments 2-1
It will be dissolved at 50 DEG C of the Methylprednisolone Aceponate of 200g contents 98% in mixed solvent A, mixed solvent A is by 100ml third
Ketone, 50ml n-hexanes composition, stirs dissolved clarification.Cool 11 DEG C per 1h, be cooled to 10 DEG C, insulation aging 2h.Filtering, acetone with just oneself
Alkane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder 180g, yield 90%, content 99.7% is maximum single miscellaneous
0.10%.
Inventive embodiments 2-2
It will be dissolved at 50 DEG C of the Methylprednisolone Aceponate of 200g contents 98% in mixed solvent A, mixed solvent A is by 100ml third
Ketone, 50ml n-hexanes composition, stirs dissolved clarification.Cool 5 DEG C per 1h, be cooled to 10 DEG C, insulation aging 2h.Filtering, acetone with just oneself
Alkane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder 182g, yield 91%, content 99.6% is maximum single miscellaneous
0.13%.
Inventive embodiments 2-3
It will be dissolved at 50 DEG C of the Methylprednisolone Aceponate of 200g contents 98% in mixed solvent A, mixed solvent A is by 100ml third
Ketone, 50ml n-hexanes composition, stirs dissolved clarification.Cool 15 DEG C per 1h, be cooled to 10 DEG C, insulation aging 2h.Filtering, acetone with just oneself
Alkane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder 182g, yield 91%, content 99.5% is maximum single miscellaneous
0.14%.
Inventive embodiments 3
It will be dissolved at 50 DEG C of the Methylprednisolone Aceponate of 50g contents 98% in mixed solvent A, mixed solvent A is by 100ml third
Ketone, 150ml n-hexanes composition, stirs dissolved clarification.Cool 9 DEG C per 1h, be cooled to 5 DEG C, insulation aging 2h.Filtering, acetone with just oneself
Alkane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder 47g, yield 94%, content 99.5% is maximum single miscellaneous
0.13%.
Inventive embodiments 4
It will be dissolved at 55 DEG C of the Methylprednisolone Aceponate of 100g contents 90% in mixed solvent A, mixed solvent A is by 200ml third
Ketone, 200ml n-hexanes composition, stirs dissolved clarification.Cool 5 DEG C per 1h, be cooled to 10 DEG C, insulation aging 1.5h.Filtering, acetone with just
Hexane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder (content 98.0%), repeat aforesaid operations once,
Obtain the Methylprednisolone Aceponate 80g of content 99.5%, maximum list miscellaneous 0.14%.
Inventive embodiments 5
It will be dissolved at 55 DEG C of the Methylprednisolone Aceponate of 100g contents 90% in mixed solvent A, mixed solvent A is by 200ml third
Ketone, 200ml n-hexanes composition, stirs dissolved clarification.Cool 10 DEG C per 1h, be cooled to 10 DEG C, insulation aging 1.5h.Filtering, acetone with
N-hexane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder (content 97.9%), repeat aforesaid operations one
It is secondary, obtain the Methylprednisolone Aceponate 79g of content 99.7%, maximum list miscellaneous 0.11%.
Inventive embodiments 6
It will be dissolved at 55 DEG C of the Methylprednisolone Aceponate of 100g contents 90% in mixed solvent A, mixed solvent A is by 200ml third
Ketone, 200ml n-hexanes composition, stirs dissolved clarification.Cool 15 DEG C per 1h, be cooled to 5 DEG C, insulation aging 1.5h.Filtering, acetone with just
Hexane 1:1 0.5 times of mixed solvent washs.Drain, obtain white crystalline powder (content 97.8%), repeat aforesaid operations once,
Obtain the Methylprednisolone Aceponate 80g of content 99.5%, maximum list miscellaneous 0.13%.
Comparative examples
Comparative examples 1-1~1-13 solvent for use see the table below, and other conditions and operating procedure refer to inventive embodiments 1-1.
Claims (4)
1. a kind of process for purification of Methylprednisolone Aceponate, it is characterized in that being recrystallized to give using mixed solvent A, the mixing is molten
Agent A is by the acetone of 1 parts by volume, the n-hexane of 0.5~1.5 parts by volume, the water composition of 0~0.5 parts by volume.
A kind of 2. process for purification of Methylprednisolone Aceponate as described in claim 1, it is characterized in that the mixed solvent A is by 1
The acetone of parts by volume, the n-hexane composition of 0.5~1.5 parts by volume.
A kind of 3. process for purification of Methylprednisolone Aceponate as described in claim 1 or 2, it is characterized in that Methylprednisolone Aceponate
Rate of charge with acetone solvent in the mixed solvent A is 1:0.5—2g/ml.
A kind of 4. process for purification of Methylprednisolone Aceponate as described in claim 3, it is characterized in that Methylprednisolone Aceponate is heated
Be dissolved in the mixed solvent A, heating-up temperature no more than solvent reflux temperature, then with 9~11 DEG C per hour
Speed, crystal precipitation is cooled to, has been filtrated to get.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410136626.5A CN104974208B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method of high-purity Methylprednisolone Aceponate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410136626.5A CN104974208B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method of high-purity Methylprednisolone Aceponate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104974208A CN104974208A (en) | 2015-10-14 |
| CN104974208B true CN104974208B (en) | 2018-01-19 |
Family
ID=54271212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410136626.5A Active CN104974208B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method of high-purity Methylprednisolone Aceponate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104974208B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111380970A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Method for detecting content of methylprednisolone aceponate and related substances |
| CN111748010B (en) * | 2019-03-29 | 2023-12-08 | 天津药业研究院股份有限公司 | Methylprednisolone aceponate anhydrous crystal type and composition thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759743A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Methylprednisolone aceponate monohydrate, crystal form and preparation method thereof |
| CN101804061A (en) * | 2010-04-01 | 2010-08-18 | 天津金耀集团有限公司 | New methylprednisolone tablets and crystal form and preparation method thereof |
-
2014
- 2014-04-08 CN CN201410136626.5A patent/CN104974208B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759743A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Methylprednisolone aceponate monohydrate, crystal form and preparation method thereof |
| CN101804061A (en) * | 2010-04-01 | 2010-08-18 | 天津金耀集团有限公司 | New methylprednisolone tablets and crystal form and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104974208A (en) | 2015-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1158300C (en) | Process for producing drospirenone (6 beta, 7 beta, 15 beta, 16 beta-dimethylene-3-oxo-17 alpha-pregn-4-en-21, 17-carbolactone, <u> DRSP <1u>) | |
| EP3218353B1 (en) | Continuous process for producing a tenside in a tube reactor | |
| CA2609021C (en) | Compounds useful for treating neurodegenerative disorders | |
| CN104974208B (en) | A kind of preparation method of high-purity Methylprednisolone Aceponate | |
| CN108218951B (en) | Preparation method of high-purity fluocinolone acetonide | |
| CN102070699B (en) | Trihydroxy-substituted pentacyclic triterpene compounds and preparation method and application thereof | |
| CN104983767B (en) | A kind of preparation method of Cynanchum Wallichii total saposins | |
| DE2426779A1 (en) | 1,3-disubstd. 8 alpha oestratrienes - oestrogens with minimal uterotropic activity | |
| CN106890200A (en) | Extract method and the medicine containing squalene of plant source spiny dogfish ene compositions and its preparation method and application | |
| CN106117281B (en) | The method that rhodioside is extracted from rhodiola root | |
| CN112358522B (en) | Method for refining betamethasone dipropionate and betamethasone dipropionate | |
| EA037842B1 (en) | Industrial process for the synthesis of nomegestrol-acetate | |
| Kikuchi et al. | Effective separation and C-24 stereochemical assignment of epimeric 24-isopropenylcholesterols | |
| EP3555057B1 (en) | Process for the preparation of tocols and squalene | |
| DE1468988B1 (en) | 17alpha-chloroethynyl-13beta-ethyl-4- or -5 (10) -gon-3-ketones | |
| DE69826356T2 (en) | Sulfation of estrogen mixtures | |
| US2848497A (en) | Process for isomerizing 8alpha-methyl-1, 2, 3, 4, 6, 7, 8, 8alpha-octahydro-1-ethynyl-1beta-hydroxy-6-oxonaphthalene and isomer obtained thereby | |
| DE3144049A1 (en) | 16 beta -Methyl-8 alpha -oestradiols, process for their preparation and pharmaceutical products containing these | |
| DE1493165C3 (en) | 1-hydroxyestradiol derivatives, processes for their preparation and agents containing them | |
| EP1163257B1 (en) | Method for producing 4,4-dimethyl-3beta-hydroxypregna-8,14-diene-21-carboxylic acid esters and intermediate products obtained by said method | |
| DE959187C (en) | Process for the preparation of 11-keto-17 ª ‡ -aethynyltestosterone or 11ª ‰ -oxy-17-ª ‡ -aethynyltestosterone | |
| CN104628588B (en) | (3-hydroxyl) propionyloxy anil and preparation method thereof | |
| CN116283583A (en) | Tetrahydrocurcumin dipalmitate and synthesis method thereof | |
| DE1468988C (en) | Alpha-chloroethinyl-1-beta-ethyl-4-or-5 (10) -gon-3-ketone. ' | |
| DE1668687B2 (en) | NEW 18-METHYL-5ALPHA-H-ANDROSTANES, THE METHOD OF MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINED |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |