CN101153313A - Method of producing methylprednisolone dehydrogenation article - Google Patents
Method of producing methylprednisolone dehydrogenation article Download PDFInfo
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- CN101153313A CN101153313A CNA2007102016358A CN200710201635A CN101153313A CN 101153313 A CN101153313 A CN 101153313A CN A2007102016358 A CNA2007102016358 A CN A2007102016358A CN 200710201635 A CN200710201635 A CN 200710201635A CN 101153313 A CN101153313 A CN 101153313A
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- methylprednisolone
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Abstract
The invention discloses a method for preparing dehydrogenated methyl-prednisone which adopts the medium product of the methyl-prednisone as the fermentation substrate and carries out biological dehydrogenation with the arthrobacter. Compared with the prior art, the invention adopts the medium product of the methyl-prednisone as the fermentation substrate, and substitutes the biological dehydrogenation with arthrobacter for the chemical dehydrogenation technique in the prior art, thereby increasing the harvest rate from 55 to 70-85 percent, decreasing greatly the cost, and improving the purity of the product to more than 97 percent, accomplishing the industrialized production of methyl-prednisone, and completely avoiding the residue of the deadly poison of SeO2 through the green technique.
Description
Technical field:
The present invention relates to a kind of preparation method of methylprednisolone dehydrogenation article, belong to pharmaceutical chemistry and biological pharmacy technical field.
Background technology:
Methylprednisolone is a kind of corticosteroid drug, and it has anti-inflammatory, and antiendotoxin suppresses immunity, and pharmacological actions such as antishock can be made the clinical injection of using, and have important effect clinically.Because methylprednisolone medicine production Technology is very complicated, the production cycle is long, belongs to technological-intensive product.Wherein, 1 dehydrogenation operation of methylprednisolone is a committed step in the methylprednisolone production process, directly has influence on the quality and the yield of methylprednisolone.Original dehydrogenating technology is generally used SeO
2Dehydrogenation, SeO
2Be highly toxic substance, pollute greatly that and reaction yield is low, generally has only 55%, product quality is poor, residual micro-SeO in the product
2Be difficult to eliminate.
By retrieval, the synthetic method of methylprednisolone has kind more than 10 at present, is the exploitation of five sixties of last century, and common drawback is that yield is low, the cost height.Nineteen fifty-nine is published in the synthetic method on the U.S. chemical abstract (seeing CA59P14074), have 10 step chemical reactions, but dehydrogenation wherein and displacement two-step reaction effect are all very poor, the dehydrogenation reaction yield has only 55%, cause cost too high, can't realize suitability for industrialized production.Therefore the applicant optimizes dehydrogenation reaction wherein through experimental study.
Summary of the invention:
The objective of the invention is to: the preparation method that a kind of methylprednisolone dehydrogenation article is provided.The present invention is directed to the deficiencies in the prior art, adopting the methylprednisolone intermediate is fermentation substrate, replaces chemical dehydrogenation with biological dehydrogenation, and its yield reaches 70～85%, and product purity reaches more than 97%, the technology environmental protection.
The present invention is achieved in that a kind of preparation method of methylprednisolone dehydrogenation article: with the methylprednisolone intermediate is fermentation substrate, carries out biological dehydrogenation and gets with Arthrobacter.
Specifically, the methylprednisolone intermediate is made dissolution with solvents or used comminution by gas stream with dioxane, drop in the fermentor tank of having cultivated Arthrobacter and carry out bio-transformation, centrifugal then, the dry crude product that gets, extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, promptly get methylprednisolone dehydrogenation article after the drying.
Described methylprednisolone intermediate is one of following 5 kinds: 1. 6a-methyl isophthalic acid 1 β, and 17a-dihydroxyl-pregnant steroid-4 is rare-3, the 20-diketone; 2. 6a-methyl-17 a-hydroxyl-pregnant steroid-4-is rare-3,11,20-triketone-21-acetic ester; 3. 6a-methyl isophthalic acid 1 β, 17a-dihydroxyl-pregnant steroid-4-is rare-3,20-diketone-21-acetic ester; 4. 6a-methyl-17 a-hydroxyl-pregnant steroid-4-is rare-3,11, the 20-triketone; 5. 6a-methyl isophthalic acid 1 β, 17a, 21-trihydroxy--pregnant steroid-4-is rare-3, the 20-diketone.
The concentration that feeds intake of methylprednisolone intermediate is 0.5～2% (with respect to the fermented liquid volume); Oxidizing temperature in fermentor tank is 30～34 ℃, and oxidization time is 42～55 hours.
The consumption that dissolves solvent dioxane when feeding intake is 7～15 times of substrate weight.
When dry powder feeds intake substrate with comminution by gas stream to accounting for more than 90% below the fineness 10um.
It is as follows that the present invention prepares the technical process of methylprednisolone dehydrogenation article:
Arthrobacter slant culture → first order seed cultivation → secondary seed cultivates → three grades of seed culture → feed intake → heat and puts more than 70 ℃ jar → centrifugal, drying → extraction and making with extra care → product
Compared with prior art, it is fermentation substrate that the present invention adopts the methylprednisolone intermediate, replace traditional chemical dehydrogenating technology with the Arthrobacter biological dehydrogenation, yield brings up to 70～85% from 55%, cost is lower greatly, product purity reaches more than 97%, thereby makes the synthetic suitability for industrialized production that is achieved of methylprednisolone; And avoided highly toxic substance SeO fully
2Residual, the technology environmental protection.
Embodiment:
Embodiments of the invention 1: Arthrobacter carries out slant culture, first order seed cultivation, secondary seed cultivation and three grades of seed culture successively; With 6a-methyl isophthalic acid 1 β, 17a-dihydroxyl-pregnant steroid-4-is rare-3, and the 20-diketone, drops into and cultivated in the fermentor tank of Arthrobacter to accounting for more than 90% below the fineness 10um with comminution by gas stream, concentration 1.5% feeds intake, 30 ℃ of oxidizing temperatures, oxidization time 47 hours, heating is put jar more than 70 ℃, centrifugal then, the dry crude product that gets, transformation efficiency 88.66%, substrate 7.23%, main impurity 2.79%; Extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, get methylprednisolone dehydrogenation article, content 96.29%, maximum contaminant content 1.10%, yield 71.18% after the drying.
Embodiments of the invention 2: Arthrobacter carries out slant culture, first order seed cultivation, secondary seed cultivation and three grades of seed culture successively; With 6a-methyl-17 a-hydroxyl-pregnant steroid-4-rare-3,11,20-triketone-21-acetic ester, drops into and has cultivated in the fermentor tank of Arthrobacter to accounting for more than 90% below the fineness 10um with comminution by gas stream, concentration 0.5% feeds intake, 31 ℃ of oxidizing temperatures, oxidization time 42 hours, heating is put jar more than 70 ℃, centrifugal then, the dry crude product that gets, transformation efficiency 92.16%, substrate 1.56%, main impurity 4.54%; Extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, get methylprednisolone dehydrogenation article, content 96.30%, maximum contaminant content 1.23%, yield 78.75% after the drying.
Embodiments of the invention 3: Arthrobacter places fermentor tank to cultivate; With 6a-methyl isophthalic acid 1 β, 17a-dihydroxyl-pregnant steroid-4-is rare-3, and 20-diketone-21-acetic ester drops into and cultivated in the fermentor tank of Arthrobacter with the dioxane dissolving of 15 times of weight, concentration 1.0% feeds intake, 30 ℃ of oxidizing temperatures, oxidization time 55 hours, heating is put jar more than 70 ℃, centrifugal then, the dry crude product that gets, transformation efficiency 89.17%, substrate 6.46%, main impurity 2.67%; Extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, get methylprednisolone dehydrogenation article, content 96.99%, maximum contaminant content 0.85%, yield 82.36% after the drying.
Embodiments of the invention 4: Arthrobacter carries out slant culture, first order seed cultivation, secondary seed cultivation and three grades of seed culture successively; With 6a-methyl-17 a-hydroxyl-pregnant steroid-4-rare-3,11, the 20-triketone drops into and has cultivated in the fermentor tank of Arthrobacter with the dioxane dissolving of 7 times of weight, concentration 1.1% feeds intake, 34 ℃ of oxidizing temperatures, oxidization time 49 hours, heating is put jar more than 70 ℃, centrifugal then, the dry crude product that gets, transformation efficiency 87.7%, substrate 8.26%, main impurity 2.17%; Extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, get methylprednisolone dehydrogenation article, content 97.05%, maximum contaminant content 0.86%, yield 79.53% after the drying.
Embodiments of the invention 5: Arthrobacter places fermentor tank to cultivate; With 6a-methyl isophthalic acid 1 β, 17a, 21-trihydroxy--pregnant steroid-4-rare-3, the 20-diketone dissolves with the dioxane of 10 times of weight, drop into and cultivated in the fermentor tank of Arthrobacter the concentration 2% that feeds intake, 31 ℃ of oxidizing temperatures, oxidization time 55 hours, heating is put jar more than 70 ℃, centrifugal then, dry crude product, the transformation efficiency 87.7% of getting, substrate 8.26%, main impurity 2.17%; Extract and make with extra care with methyl alcohol, Glacial acetic acid, T reagent and activated carbon again, get methylprednisolone dehydrogenation article, content 97.05%, maximum contaminant content 0.86%, yield 70.58% after the drying.
Claims (6)
1. the preparation method of a methylprednisolone dehydrogenation article is characterized in that: it is to be fermentation substrate with the methylprednisolone intermediate, carries out biological dehydrogenation and gets with Arthrobacter.
2. according to the preparation method of the described methylprednisolone dehydrogenation article of claim 1, it is characterized in that: the methylprednisolone intermediate is made dissolution with solvents or used comminution by gas stream with dioxane, drop in the fermentor tank of having cultivated Arthrobacter and carry out bio-transformation, centrifugal then, dry, extract and make with extra care, promptly get methylprednisolone dehydrogenation article.
3. according to the preparation method of claim 1 or 2 described methylprednisolone dehydrogenation articles, it is characterized in that: described methylprednisolone intermediate is one of following 5 kinds: 1. 6a-methyl isophthalic acid 1 β, and 17a-dihydroxyl-pregnant steroid-4-is rare-3, the 20-diketone; 2. 6a-methyl-17 a-hydroxyl-pregnant steroid-4-is rare-3,11,20-triketone-21-acetic ester; 3. 6a-methyl isophthalic acid 1 β, 17a-dihydroxyl-pregnant steroid-4-is rare-3,20-diketone-21-acetic ester; 4. 6a-methyl-17 a-hydroxyl-pregnant steroid-4-is rare-3,11, the 20-triketone; 5. 6a-methyl isophthalic acid 1 β, 17a, 21-trihydroxy--pregnant steroid-4-is rare-3, the 20-diketone.
4. according to the preparation method of the described methylprednisolone dehydrogenation article of claim 2, it is characterized in that: the concentration that feeds intake of methylprednisolone intermediate is 0.5～2%; Oxidizing temperature in fermentor tank is 30～34 ℃, and oxidization time is 42～55 hours.
5. according to the preparation method of the described methylprednisolone dehydrogenation article of claim 2, it is characterized in that: the consumption that dissolves solvent dioxane when feeding intake is 7～15 times of substrate weight.
6. according to the preparation method of the described methylprednisolone dehydrogenation article of claim 2, it is characterized in that: when dry powder feeds intake substrate with comminution by gas stream to accounting for more than 90% below the fineness 10um.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007102016358A CN101153313A (en) | 2007-09-10 | 2007-09-10 | Method of producing methylprednisolone dehydrogenation article |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101760496A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Biological dehydrogenation preparation method of steroid drug intermediate |
| CN101372706B (en) * | 2008-09-04 | 2011-08-31 | 浙江工业大学 | Biological dehydrogenation method of 11 beta-hydroxy edroxyprogesteroneC1,2 site |
| CN107338281A (en) * | 2017-06-26 | 2017-11-10 | 浙江仙琚制药股份有限公司 | The method for preparing methylprednisolone |
-
2007
- 2007-09-10 CN CNA2007102016358A patent/CN101153313A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372706B (en) * | 2008-09-04 | 2011-08-31 | 浙江工业大学 | Biological dehydrogenation method of 11 beta-hydroxy edroxyprogesteroneC1,2 site |
| CN101760496A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Biological dehydrogenation preparation method of steroid drug intermediate |
| CN107338281A (en) * | 2017-06-26 | 2017-11-10 | 浙江仙琚制药股份有限公司 | The method for preparing methylprednisolone |
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Application publication date: 20080402 |