CN104974208A - Preparation method of high-purity methylprednisolone aceponate - Google Patents
Preparation method of high-purity methylprednisolone aceponate Download PDFInfo
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- CN104974208A CN104974208A CN201410136626.5A CN201410136626A CN104974208A CN 104974208 A CN104974208 A CN 104974208A CN 201410136626 A CN201410136626 A CN 201410136626A CN 104974208 A CN104974208 A CN 104974208A
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- methylprednisolone aceponate
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- 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
Abstract
The invention relates to a refining method of methylprednisolone aceponate. The refining method is characterized in that methylprednisolone aceponate is obtained by virtue of recrystallization of a mixed solvent A, wherein the mixed solvent A consists of 1 part by volume of acetone, 0.5-1.5 parts by volume of normal hexane and 0-0.5 part by volume of water. By virtue of the refining method, high-purity methylprednisolone aceponate can be easily prepared, the content of high-purity methylprednisolone aceponate is more than or equal to 9.5%, and the maximal individual impurity of high-purity methylprednisolone aceponate is smaller than 0.15%.
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 chemical structural formula is as follows:
Methylprednisolone aceponate is as a kind of derivative of methylprednisolone, developed by German Schring AG, it is a kind of glucocorticosteroid with very strong local anti-inflammatory activity, for the treatment to skin inflammation, at present, commercially available methylprednisolone aceponate skin-use preparation is that German Schring AG produces, commodity are called the 0.1% methylprednisolone aceponate emulsifiable paste of Advantan, can be used for the reaction suppressing inflammation and allergic skin, also suppress add the related reaction of rapid regeneration with cell and cause symptom simultaneously, such as erythema, oedema, skin thickization, coarse the going down of skin surface, and alleviate itch, the problem such as burning sensation and pain.Methylprednisolone aceponate emulsifiable paste is current superpower external application corticosteroid formulations, its curative effect is all better than known reflunomide, and wherein methylprednisolone aceponate emulsifiable paste is the efficient reflunomide without halide groups, side effect is light, is a kind of reflunomide external preparation that may be used for children.The market outlook of said preparation are very wide.But the document at present about methylprednisolone aceponate synthesis and process for purification report is few.
US4587236 embodiment 15 reports and utilizes 21-acetoxyl group-11 β, and 17 alpha-dihydroxy--6 Alpha-Methyls-Isosorbide-5-Nitraes-pregnant-3,20-diketone are the method that initiator prepares methylprednisolone aceponate, and reaction scheme is as shown in the formula shown in 1.The finished product methylprednisolone aceponate utilization column chromatography carries out separation and purification (mobile phase dichloromethane-acetone gradient elution, 0-15% acetone), is not suitable for suitability for industrialized production.
DE3427486 reports and utilizes 21-acetoxyl group-9 α-bromo-11 beta-hydroxy-6 Alpha-Methyl-17 α-propionyloxies-1,4-pregnant-3,20-diketone is that initiator obtains methylprednisolone aceponate through tri-n-butyltin hydride reduction, but not mentioned process for purification, reaction scheme is as shown in the formula shown in 2:
Document 1 (Chemical & Pharmaceutical Bulletin, Volume:33, Issue:5, Pages:1889-98, Journal, 1985), US Patent No. 4587236 embodiment 2, US Patent No. 4567172 embodiment 7, Chinese patent application CN200610053788 report the synthetic method of methylprednisolone aceponate, and reaction scheme is as shown in the formula shown in 3:
Document 1 reports the finished product methylprednisolone aceponate and utilizes column chromatography (moving phase is ethylene dichloride) or thin-layer chromatography (moving phase is ethylene dichloride: ether=4-5:1) separation and purification, is not suitable for suitability for industrialized production.US4587236 embodiment 2 and the not mentioned process for purification of Chinese patent application CN200610053788.US Patent No. 4567172 embodiment 7 reports the finished product methylprednisolone aceponate and first utilizes TLC separation purifying, then utilizes Diethyl ether recrystallization to obtain.But by test, we find that the finished product methylprednisolone aceponate adopts Diethyl ether recrystallization to refine, purity can only reach about 98%, the impurity of about 2% is still had to be difficult to remove.According to international working standard ICH Tripartite Coordination governing principle, the impurity for content more than 0.2% needs to identify structure, and the impurity of content more than 0.5% needs to carry out pharmacological evaluation, simultaneously generally all controls below 0.5% for the single impurity of bulk drug.Therefore, the preparation of high purity methylprednisolone aceponate bulk drug is extremely important.
Summary of the invention
The object of the invention be to provide a kind of simple, yield is high, the method for purification of the methylprednisolone aceponate of good product purity.Utilize method provided by the invention can be easy to obtain content more than 99.5%, maximum list mix be less than 0.15% high-purity methylprednisolone aceponate.
The present invention relates to a kind of process for purification of methylprednisolone aceponate, it is characterized in that utilizing mixed solvent A recrystallization to obtain, described mixed solvent A is by the acetone of 1 parts by volume, and the normal hexane of 0.5 ~ 1.5 parts by volume, the water of 0 ~ 0.5 parts by volume forms.
The process for purification of described a kind of methylprednisolone aceponate, is characterized in that the acetone of described mixed solvent A by 1 parts by volume, the normal hexane composition of 0.5 ~ 1.5 parts by volume.
The process for purification of described a kind of methylprednisolone aceponate, is characterized in that the feed ratio of acetone solvent in methylprednisolone aceponate and described mixed solvent A is 1:0.5-2g/ml.
The process for purification of described a kind of methylprednisolone aceponate, it is characterized in that Heating temperature can not exceed the reflux temperature of solvent by methylprednisolone aceponate heating for dissolving in described mixed solvent A, then with the speed of 9 ~ 11 DEG C per hour, be cooled to crystal to separate out, filtration obtains.
Find through experiment, only use the good solvent of methylprednisolone aceponate such as, when acetone, ethanol, methyl alcohol, ethyl acetate, methylene dichloride, tetrahydrofuran (THF) etc. are refined methylprednisolone aceponate, if the solvent amount used is more, then productive rate is very low, major cause is that methylprednisolone aceponate solubleness is in a solvent very large, and loss of material is serious; If reduce solvent consumption, after product under low temperature is separated out, system becomes sticky, and not easily filters; If only use inert solvent such as normal hexane etc., the quantity of solvent of use is large, and methylprednisolone aceponate is difficult to be separated with related substance, and product purity is difficult to increase.Find that technical scheme effect of the present invention is best through test of many times.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
The method preparation of methylprednisolone aceponate crude product reference US4587236 embodiment 15 in inventive embodiments 1 and comparative examples, methylprednisolone aceponate content in crude product is 98%.The method preparation of methylprednisolone aceponate crude product reference DE3427486 in inventive embodiments 2, methylprednisolone aceponate content in crude product is 98%.The method preparation of methylprednisolone aceponate crude product references to U.S. patent US4567172 embodiment 7 in inventive embodiments 3, methylprednisolone aceponate content in crude product is 98%.The method preparation of methylprednisolone aceponate crude product reference US4587236 embodiment 15 in inventive embodiments 4, methylprednisolone aceponate content in crude product is 90%.The method preparation of methylprednisolone aceponate crude product reference DE3427486 in inventive embodiments 5, methylprednisolone aceponate content in crude product is 90%.The method preparation of methylprednisolone aceponate crude product references to U.S. patent US4567172 embodiment 7 in inventive embodiments 6, methylprednisolone aceponate content in crude product is 90%.
In following examples methylprednisolone aceponate content measuring method reference CN201010564439.9 in the method for embodiment two measure.
Accompanying drawing illustrates:
Fig. 1: the HPLC spectrogram of initiator methylprednisolone aceponate crude product (content 98%) in inventive embodiments 1
Fig. 2: the HPLC spectrogram of product methylprednisolone aceponate fine work (content 99.8%) in inventive embodiments 1-1
Fig. 3: the HPLC spectrogram of product methylprednisolone aceponate (content 98.6%) in comparative examples 1-13
Fig. 4: the HPLC spectrogram of self-control methylprednisolone aceponate standard substance (content 99.9%)
Inventive embodiments 1
Inventive embodiments 1-1
To be dissolved in mixed solvent A at the methylprednisolone aceponate 50 DEG C of 100g content 98%, mixed solvent A be by 100ml acetone, and 50ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 10 DEG C, is cooled to 20 DEG C, is incubated aging 2h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder 88g, yield 88%, content 99.8%, maximum list assorted 0.10%.
The ratio of inventive embodiments 1-2 ~ 1-6 mixed solvent A sees the following form, and other conditions and operation steps are with reference to inventive embodiments 1-1.
Inventive embodiments 2
Inventive embodiments 2-1
To be dissolved in mixed solvent A at the methylprednisolone aceponate 50 DEG C of 200g content 98%, mixed solvent A be by 100ml acetone, and 50ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 11 DEG C, is cooled to 10 DEG C, is incubated aging 2h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder 180g, yield 90%, content 99.7%, maximum list assorted 0.10%.
Inventive embodiments 2-2
To be dissolved in mixed solvent A at the methylprednisolone aceponate 50 DEG C of 200g content 98%, mixed solvent A be by 100ml acetone, and 50ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 5 DEG C, is cooled to 10 DEG C, is incubated aging 2h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder 182g, yield 91%, content 99.6%, maximum list assorted 0.13%.
Inventive embodiments 2-3
To be dissolved in mixed solvent A at the methylprednisolone aceponate 50 DEG C of 200g content 98%, mixed solvent A be by 100ml acetone, and 50ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 15 DEG C, is cooled to 10 DEG C, is incubated aging 2h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder 182g, yield 91%, content 99.5%, maximum list assorted 0.14%.
Inventive embodiments 3
To be dissolved in mixed solvent A at the methylprednisolone aceponate 50 DEG C of 50g content 98%, mixed solvent A be by 100ml acetone, and 150ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 9 DEG C, is cooled to 5 DEG C, is incubated aging 2h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder 47g, yield 94%, content 99.5%, maximum list assorted 0.13%.
Inventive embodiments 4
To be dissolved in mixed solvent A at the methylprednisolone aceponate 55 DEG C of 100g content 90%, mixed solvent A be by 200ml acetone, and 200ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 5 DEG C, is cooled to 10 DEG C, is incubated aging 1.5h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder (content 98.0%), repeat aforesaid operations once, obtain the methylprednisolone aceponate 80g of content 99.5%, maximum list assorted 0.14%.
Inventive embodiments 5
To be dissolved in mixed solvent A at the methylprednisolone aceponate 55 DEG C of 100g content 90%, mixed solvent A be by 200ml acetone, and 200ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 10 DEG C, is cooled to 10 DEG C, is incubated aging 1.5h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder (content 97.9%), repeat aforesaid operations once, obtain the methylprednisolone aceponate 79g of content 99.7%, maximum list assorted 0.11%.
Inventive embodiments 6
To be dissolved in mixed solvent A at the methylprednisolone aceponate 55 DEG C of 100g content 90%, mixed solvent A be by 200ml acetone, and 200ml normal hexane forms, and stirs clearly molten.Every 1h lowers the temperature 15 DEG C, is cooled to 5 DEG C, is incubated aging 1.5h.Filter, acetone and normal hexane 1:1 mixed solvent 0.5 times wash.Drain, obtain white crystalline powder (content 97.8%), repeat aforesaid operations once, obtain the methylprednisolone aceponate 80g of content 99.5%, maximum list assorted 0.13%.
Comparative examples
Comparative examples 1-1 ~ 1-13 solvent for use sees the following form, and other conditions and operation steps are with reference to inventive embodiments 1-1.
Claims (4)
1. a process for purification for methylprednisolone aceponate, is characterized in that utilizing mixed solvent A recrystallization to obtain, and described mixed solvent A is by the acetone of 1 parts by volume, and the normal hexane of 0.5 ~ 1.5 parts by volume, the water of 0 ~ 0.5 parts by volume forms.
2. the process for purification of a kind of methylprednisolone aceponate as claimed in claim 1, is characterized in that the acetone of described mixed solvent A by 1 parts by volume, the normal hexane composition of 0.5 ~ 1.5 parts by volume.
3. the process for purification of a kind of methylprednisolone aceponate as described in claim 1 ~ 2, is characterized in that the feed ratio of acetone solvent in methylprednisolone aceponate and described mixed solvent A is 1:0.5-2g/ml.
4. the process for purification of a kind of methylprednisolone aceponate as claimed in claim 3, it is characterized in that Heating temperature can not exceed the reflux temperature of solvent by methylprednisolone aceponate heating for dissolving in described mixed solvent A, then with the speed of 9 ~ 11 DEG C per hour, be cooled to crystal to separate out, filtration obtains.
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Cited By (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 |
| CN111748010A (en) * | 2019-03-29 | 2020-10-09 | 天津药业研究院有限公司 | Methylprednisolone aceponate anhydrous crystal form 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 |
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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 |
Cited By (3)
| 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 |
| CN111748010A (en) * | 2019-03-29 | 2020-10-09 | 天津药业研究院有限公司 | Methylprednisolone aceponate anhydrous crystal form and composition thereof |
| 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 |
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