CN104496872A - Separating and purifying method for steroid ethyl hydroxide - Google Patents
Separating and purifying method for steroid ethyl hydroxide Download PDFInfo
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- CN104496872A CN104496872A CN201410829381.4A CN201410829381A CN104496872A CN 104496872 A CN104496872 A CN 104496872A CN 201410829381 A CN201410829381 A CN 201410829381A CN 104496872 A CN104496872 A CN 104496872A
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Abstract
The invention relates to the separating and purifying technology and particular relates to a separating and purifying method for steroid ethyl hydroxide. The separating and purifying method comprises the following steps: extracting by an organic solvent, and then performing elutriation and crystallization. The invention provides the separating and purifying method for the steroid ethyl hydroxide, and the method is high in separating and purifying efficiency, high in yield, convenient in production operation, relatively low in requirements on equipment and staff, and suitable for large-scale production.
Description
Technical field
The present invention relates to separating and purifying technology, be specifically related to the separation purification method of steroidal ethyl hydroxylate.
Background technology
Steroid intermediate often can be used for producing various medicine clinically.13 β-ethyl-3-methoxyl group-8,14-open chain-1,3,5 (10), 9 (11)-female tetraene-17 β-ol-14-ketone (after referred to as ethyl hydroxylate) is exactly a kind of important steroidal intermediate, the activeconstituents Levonorgestrel that oral contraceptive is given birth graceful is many by its synthesis, and its structural formula is as follows:
In steroid hormone, people are decided to be D-form the configuration of natural estrogen, and all hormones identical with natural estrogen configuration all belong to D-form.Only have the steroid hormone of native configurations to be only to have bioactive through clinical proof.But chemically often can only obtain the mixture of racemism during synthesizing steroid compound, namely comprise DL-two kinds of isomer, one of them is unwanted, has to pass through separation, and this is industrially uneconomic.
Proved that microorganism has stereospecificity to Steroid Transformation, converted product is the optically active compound of tool of single configuration.Just because of the peculiar advantage of microbial transformation, current microbial transformation has critical role in the synthesis of steroid drugs, and several important steroidal microbial transformation reaction such as hydroxylation, dehydrogenation and side chain cleavage have become the important method of industrial production steroid hormone and analogue thereof.Levonorgestrel intermediate ethyl hydroxylate is industrial is also formed by microbial transformation.But microbial transformation also exists complicated components, product separation extracts the problem of difficulty.
Method children China waits (microorganism journal .18 (3): 232-238,1978) report cereuisiae fermentum (Saccharomycescerevisiae AS2.346) and transform generation ethyl hydroxylate, its extraction and purification process is ethyl acetate or extraction using alcohol thalline 4-5 time, extracting solution concentrating under reduced pressure, concentrated solution cooling after fixing, with hexanaphthene or sherwood oil: ethyl acetate (50: 1) is washed, product crystallization is obtained after filtering drying, yield is lower than 90%, and must refine further if desired, after refining, purity is less than 95%.Current industrial production method is all similar, ubiquity after extracting solution concentrates and is formed bulk, be mingled with impurity more and operation inconvenience, washing process is often because washing organic solvent can not evenly drip washing cause product purity lower simultaneously, fluctuate between batch comparatively large, the part batch problem that need repeatedly refine.
Summary of the invention
Direct crystallization after extracting owing to adopting organic solvent in prior art, the yield obtained is low, and purity is low, need refining further, and there is the problem that extracting solution concentrates rear caking, the present invention carries out the method for elutriation crystallization again after adopting organic solvent to extract in a creative way, solve problems of the prior art.
The invention provides a kind of separation and purification efficiency high, yield is high, and production operation is convenient, lower to equipment, personnel requirement, is suitable for the separation purification method of the steroidal ethyl hydroxylate of scale operation.
Realizing technical scheme of the present invention is:
A separation purification method for steroidal ethyl hydroxylate, comprises the steps:
1) broth extraction concentrates
Through the centrifugal acquisition thalline of fermentation liquor of bio-transformation, adopt the organic solvent of the alcohol containing C1-C6 or ketone to extract and obtain extracting solution, extracting solution obtains concentrated solution through concentrating under reduced pressure, and the weight ratio that organic solvent concentrates contained ethyl hydroxylate in rear volume and fermented liquid is 0-10: 1;
2) concentrated solution elutriation
Under heated and stirred state, in concentrated solution, add water, a large amount of particulate state elutriation crude product after adding water, can be obtained;
3) the full dissolved of crude product is brilliant
Adding in crude product with the envelope-bulk to weight ratio of crude product is the organic solvent of the alcohol of the C1-C6 of 0-10: 1, ester or ketone, heated and stirred is dissolved completely to crude product, fat or ring-shaped fat hydrocarbon cosolvent is added in solution, stir ice bath crystallization simultaneously and be incubated 0.5 hour, filter post-drying and can obtain highly finished product.
Above-mentioned steps 1) in the alcohol of C1-C6 or alcohol in the organic solvent of ketone be methyl alcohol, ethanol or propyl alcohol, ketone is acetone or butanone.
Above-mentioned steps 3) in the alcohol of C1-C6, ester or ketone organic solvent in alcohol be methyl alcohol, ethanol or propyl alcohol, ester is ethyl acetate or butylacetate, and ketone is acetone or butanone.
Above-mentioned steps 3) in fat or ring-shaped fat hydrocarbon cosolvent be normal hexane, hexanaphthene or methylcyclohexane.
Above-mentioned steps 1) in the organic solvent weight ratio that to concentrate in rear volume and fermented liquid contained ethyl hydroxylate be 0.6-5: 1.
Above-mentioned steps 3) in the organic solvent envelope-bulk to weight ratio that adds volume and crude product be 0.4-5: 1.
Beneficial effect of the present invention is:
1, adopt method elutriation crude yield of the present invention high (>=98%), Impurity removal is good, purity high (more than 98%), steady quality.Organic solvent after extracting directly crystallization there is crude yield not high (lower than 90%) then due to organic solvent, purity difference (lower than 95%), organic solvent concentrating degree high retention volume then has the many one-tenth of crude product large bulk parcel impurity time less, color is comparatively dark, there is the problem that end is molten unclear.
2, method process for refining of the present invention is the complete molten rear crystallization of crude product, fine work uniform particle diameter, steady quality, avoids the problem that organic solvent washing is uneven, it also avoid the problem that block crude product middle portion is difficult to refine simultaneously.
3, equipment requirements is simple: the equipment used by method of the present invention is all fairly simple and conventional equipment, is easy to suitability for industrialized production.
4, easy and simple to handle: elutriation crude product is fine particle shape, does not need refinement before crude product refining, easy and simple to handle; Refine and do not need hand washing, time and labour saving.
Embodiment
Embodiment 1
Get 1L thalline methanol extract liquid (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 200ml (now residual methyl alcohol volume is about 100ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 99.37%.In crude product, add 70ml ethyl acetate 60 DEG C is heated to entirely molten, adds 280ml hexanaphthene, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 76.15%, purity 99.15%.
Embodiment 2
Get 1L thalline ethanol extract (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 200ml (now residual ethanol contend is about 100ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 99.25%.In crude product, add 40ml ethyl acetate 60 DEG C is heated to entirely molten, adds 160ml hexanaphthene, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 77.70%, purity 98.85%.
Embodiment 3
Get 1L thalline ethanol extract (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 160ml (now residual ethanol contend is about 60ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 100.32%.In crude product, add 50ml butylacetate 60 DEG C is heated to entirely molten, adds 200ml hexanaphthene, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 79.21%, purity 99.10%.
Embodiment 4
Get 1L thalline acetone extract (containing ethyl hydroxylate 100g), 50 DEG C of heating under reduced pressure are concentrated into about 200ml (now residual acetone volume is about 100ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 99.37%.In crude product, add 50ml ethanol 60 DEG C is heated to entirely molten, adds 200ml hexanaphthene, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 80.04%, purity 98.95%.
Embodiment 5
Get 1L thalline ethanol extract (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 200ml (now residual ethanol contend is about 100ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 99.50%.In crude product, add 60 DEG C, 40ml acetone is heated to entirely molten, adds 160ml normal hexane, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 81.20%, purity 99.66%.
Embodiment 6
Get 1L thalline ethanol extract (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 600ml (now residual ethanol contend is about 500ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 97.32%.In crude product, add 500ml ethyl acetate 60 DEG C is heated to entirely molten, adds 2000ml normal hexane, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 74.16%, purity 98.34%.
Embodiment 7
Get 2L thalline ethanol extract (containing ethyl hydroxylate 100g), 60 DEG C of heating under reduced pressure are concentrated into about 1100ml (now residual ethanol contend is about 1000ml), water is added fast under whipped state, heating is stopped to be cooled to room temperature, suction filtration obtains particulate state crude product, crude yield 92.38%.In crude product, add 1000ml ethyl acetate 60 DEG C is heated to entirely molten, adds 4000ml normal hexane, and stop heating ice bath crystallization 0.5h, suction filtration, product is dried can obtain fine work.Yield 69.59%, purity 98.45%.
Claims (6)
1. a separation purification method for steroidal ethyl hydroxylate, comprises the steps:
1) broth extraction concentrates
Through the centrifugal acquisition thalline of fermentation liquor of bio-transformation, adopt the organic solvent of the alcohol containing C1-C6 or ketone to extract and obtain extracting solution, extracting solution obtains concentrated solution through concentrating under reduced pressure, and the weight ratio having organic solvent to concentrate contained ethyl hydroxylate in rear volume and fermented liquid is 0-10: 1;
2) concentrated solution elutriation
Under heated and stirred state, in concentrated solution, add water, obtain particulate state elutriation crude product;
3) the full dissolved of crude product is brilliant
Adding in crude product with the envelope-bulk to weight ratio of crude product is the organic solvent of the alcohol of the C1-C6 of 0-10: 1, ester or ketone, heated and stirred is dissolved completely to crude product, fat or ring-shaped fat hydrocarbon cosolvent is added in solution, stir ice bath crystallization simultaneously and be incubated 0.5 hour, filter post-drying and can obtain highly finished product.
2. method according to claim 1, is characterized by: step 1) in the alcohol of C1-C6 or alcohol in the organic solvent of ketone be methyl alcohol, ethanol or propyl alcohol, ketone is acetone or butanone.
3. method according to claim 2, is characterized by: step 1) in the organic solvent weight ratio that to concentrate in rear volume and fermented liquid contained ethyl hydroxylate be 0.6-5: 1.
4. method according to claim 3, is characterized by: step 3) in the alcohol of C1-C6, ester or ketone organic solvent in alcohol be methyl alcohol, ethanol or propyl alcohol, ester is ethyl acetate or butylacetate, and ketone is acetone or butanone.
5. method according to claim 4, is characterized by: step 3) in fat or ring-shaped fat hydrocarbon cosolvent be normal hexane, hexanaphthene or methylcyclohexane.
6. method according to claim 5, is characterized by step 3) in the organic solvent envelope-bulk to weight ratio that adds volume and crude product be 0.4-5: 1.
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| CN201410829381.4A CN104496872B (en) | 2014-12-29 | 2014-12-29 | A kind of isolation and purification method of steroidal ethyl hydroxylate |
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| CN201410829381.4A CN104496872B (en) | 2014-12-29 | 2014-12-29 | A kind of isolation and purification method of steroidal ethyl hydroxylate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014934A2 (en) * | 2002-08-02 | 2004-02-19 | Poli Industria Chimica Spa | Process and new intermediates for the preparation of steroids with a progestogen activity |
| CN102532233A (en) * | 2010-12-17 | 2012-07-04 | 北京紫竹药业有限公司 | Preparation process for desogestrel and novel intermediate compound thereof |
| CN104119421A (en) * | 2014-06-27 | 2014-10-29 | 华润紫竹药业有限公司 | Method for removing steroid hydroxylation impurities |
-
2014
- 2014-12-29 CN CN201410829381.4A patent/CN104496872B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014934A2 (en) * | 2002-08-02 | 2004-02-19 | Poli Industria Chimica Spa | Process and new intermediates for the preparation of steroids with a progestogen activity |
| CN102532233A (en) * | 2010-12-17 | 2012-07-04 | 北京紫竹药业有限公司 | Preparation process for desogestrel and novel intermediate compound thereof |
| CN104119421A (en) * | 2014-06-27 | 2014-10-29 | 华润紫竹药业有限公司 | Method for removing steroid hydroxylation impurities |
Non-Patent Citations (1)
| Title |
|---|
| 法幼华等: "制备13β-乙基-3-甲氧基-8,14-开链-1,3,5（10），9（11）-雌四烯-17β-醇-14-酮的微生物学研究", 《微生物学报》 * |
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| CN104496872B (en) | 2018-04-20 |
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