CN101580515B - Method for extracting and purifying staurosporin - Google Patents

Method for extracting and purifying staurosporin Download PDF

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CN101580515B
CN101580515B CN200810037512XA CN200810037512A CN101580515B CN 101580515 B CN101580515 B CN 101580515B CN 200810037512X A CN200810037512X A CN 200810037512XA CN 200810037512 A CN200810037512 A CN 200810037512A CN 101580515 B CN101580515 B CN 101580515B
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organic solvent
solution
hydrophilic organic
extraction
aqueous solution
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CN200810037512XA
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CN101580515A (en
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胡海峰
张海红
张琴
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上海医药工业研究院
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Abstract

The invention discloses a method for extracting and purifying staurosporin, which comprises the following steps: firstly, adding acid solution until hydrophilic organic solvent or extract solution of aqueous solution of the hydrophilic organic solvent is acid after the organic solvent of the hydrophilic organic solvent or the extract solution of the aqueous solution of the hydrophilic organic solvent of producing bacteria bodies of the staurosporin is removed, and then centrifuging, getting supernatant fluid; secondly, extracting the supernatant fluid by lipophilic organic solvent under alkalicondition; and thirdly, performing the silicon column chromatography after condensing the extract solution. The method has low cost, short period, simple operation, easy holding, high product purity and high product yield.

Description

A kind of method of extracting and purifying staurosporin

Technical field

The present invention relates to a kind of method of extracting and purifying staurosporin.

Background technology

A kind of wide spectrum nonspecific proteins kinase c of Staurosporine (staurosporine is hereinafter to be referred as STS) inhibitor, arrestin kinase c and other most of kinases (comprising tyrosine protein kinase) forcefully.Can be used for resisting yeast and fungus-caused many infectious diseases, suppress cell proliferation, the inducing cell programmed death is abolished the cell cycle check point, suppresses blood vessel hyperplasia etc.Also has extremely strong anti-tumor activity, clinically to 12 kinds of average IC of human tumor cells 50Be 0.016 μ g/ml (U.S.Patent 4735039).In addition, derivative UCN-01 of STS etc. has entered the clinical second phase (EP 0 238 011 B1, EP 0 575 955 A1) as antitumor drug.

U.S.Pat.No.4,107,297 have described the technology of extracting STS from actinomycetes AM-2282 fermented liquid.Method is: fermented liquid is regulated fermented liquid pH10.0 with ammoniacal liquor, use n-butyl acetate extraction again, the butylacetate phase transition is in 0.1N hydrochloric acid, after the extraction, regulating water pH with ammoniacal liquor is 10.0, use twice of ethyl acetate extraction then, merge extraction phase and add anhydrous sodium sulfate drying, vacuum concentration then, silicagel column (Merk, Kieselgel G) chromatographic separation, eluent is a chloroform: methyl alcohol (60: 1, v/v), alkaloid utilizes thin-layer chromatography to detect (chloroform: methyl alcohol=10: 1) with bismuth potassium iodide generation color reaction.Collection of biological alkali part, and the vacuum concentration drying obtains pale yellow powder.Powder utilizes chloroform: (50: 1, v/v) recrystallization obtained faint yellow needle-like crystal to methyl alcohol.This technological operation complexity, yield is very low, and the final product that obtains is seldom.

Morioka etc. have described technology (reference: Morioka, H., Ishihara, M., Shibai, the H.﹠amp that extracts STS from fermented liquid; Suzuki, T.Staurosporine-induced differentiation in ahuman neuroblastoma cell line, NB-1.Agric.Biol.Chem.1985,49,1959-1963).

Fermented liquid is centrifugal, the filter cake methanol extraction, and the extraction liquid vacuum concentration, the enriched material ethyl acetate extraction is gone up purification by silica gel column chromatography then twice, and twice recrystallization obtains STS.This method operation capacity is limited, and consuming time many, yield is low, does not also fit into production.

Summary of the invention

Therefore, the technical problem to be solved in the present invention is exactly at the high purity of the method existence of existing extracting and purifying staurosporin and the deficiency that high yield can not get both, a kind of not only product purity height is provided, and the method for the also higher extracting and purifying staurosporin of yield.

The present invention solves the problems of the technologies described above the technical scheme that is adopted, and a kind of method of extracting and purifying staurosporin can comprise following steps:

1) the extraction with aqueous solution liquid that Staurosporine is produced the hydrophilic organic solvent of bacterium thalline or hydrophilic organic solvent remove add behind the organic solvent acid solution to acid, centrifugal then, get supernatant;

2) supernatant is used the lipotropy organic solvent extraction under alkaline condition;

3) after extraction liquid concentrates, carry out silica gel column chromatography.

According to the present invention, the extraction with aqueous solution liquid that step 1) produces the hydrophilic organic solvent of bacterium thalline or hydrophilic organic solvent with Staurosporine remove add behind the organic solvent acid solution to acid, centrifugal then, get supernatant.Described extracting solution preferable for Staurosporine produce the bacterium thalline under alkaline condition with the extraction with aqueous solution gained of hydrophilic organic solvent or hydrophilic organic solvent, this step can adopt prior art, as the technology of above-mentioned Morioka.Wherein, described alkaline condition is pH 8.0~14.0, and that preferable is pH 10.0~13.0, and that better is pH 12.0, can add ammoniacal liquor or sodium hydroxide and reach above-mentioned alkaline condition.Staurosporine produce the bacterium thalline preferable can to produce the fermented liquid of bacterium by Staurosporine centrifugal and get, select for use wet thallus to get final product usually.More than 0.5 times of fermentating liquid volume for Staurosporine generation bacterium that the consumption of the hydrophilic organic solvent that adopts during extraction or the aqueous solution of hydrophilic organic solvent is preferable, perhaps its consumption can make Staurosporine produce bacterium thalline concentration therein and be no more than 1g/ml.Be selected from alcohol, ketone and tetrahydrofuran (THF) that described hydrophilic organic solvent is preferable.That described alcohol is preferable is C 1-3Lower aliphatic alcohols, more preferably from methyl alcohol and ethanol.What described ketone was preferable is acetone.The aqueous solution of described hydrophilic organic solvent is preferable can be 85~100% methanol aqueous solutions, 85~100% aqueous ethanolic solutions or 85~100% aqueous acetone solutions, better 90% methanol aqueous solution, 90% aqueous ethanolic solution or 95% the aqueous acetone solution of can be, above-mentioned per-cent is weight percentage.Described extracting solution is better can be Staurosporine produce the bacterium thalline under alkaline condition with twice of the extraction with aqueous solution of hydrophilic organic solvent or hydrophilic organic solvent or gained repeatedly.This extracting solution adds acid solution to acid behind the hydrophilic organic solvent of removing wherein, be selected from hydrochloric acid that described acid solution is preferable and oxalic acid, preferred 0.1N hydrochloric acid.That described acidity is preferable is pH 1~5, preferred pH2~3.

According to the present invention, step 2) supernatant that obtains is used the lipotropy organic solvent extraction under alkaline condition.Preferable described lipotropy organic solvent can be selected from ethyl acetate, butylacetate, chloroform, methylene dichloride, propyl acetate, ethyl propionate and methyl propionate.Described alkaline condition is pH 8.0~14.0, and that preferable is pH 10.0~13.0, and that better is pH 12.0.Can add ammoniacal liquor or sodium hydroxide to above-mentioned alkaline condition.

According to the present invention, step 3) is carried out silica gel column chromatography after the extraction liquid of gained is concentrated.Preferable described extraction liquid adds anhydrous sodium sulphate and removes moisture, carries out silica gel column chromatography after organic solvent is removed in distillation.Described silica gel column chromatography is preferable comprises step: with volume ratio is that 100: 1~50: 1 chloroform-methanol mixed solution is that eluent carries out gradient elution, and it is 60: 1 target compound that substep is collected gradient.Preferable following the tracks of with thin-layer chromatography-bismuth potassium iodide detects.

What the method for extracting and purifying staurosporin of the present invention was preferable can also comprise that the target compound that silica gel column chromatography is obtained concentrates or the step of recrystallization.

The method of lipotropy organic solvent extraction above-mentioned steps 2 of the present invention), step 3) silica gel column chromatography and concentrated or recrystallization etc. all can adopt prior art, as the relevant art in the disclosed Staurosporine separation and purification process in two parts of documents mentioning in the background technology.

Above-mentioned each step of the present invention is as step 2) the lipotropy organic solvent extraction, the silica gel column chromatography of step 3), with and subsequent concentrate or re-crystallization step etc. can repeat twice or repeatedly, to obtain better result.

Each raw material of the present invention or reagent are all commercially available to be got.

Than prior art, advantage of the present invention is: the method cost of extracting and purifying staurosporin of the present invention is low, and the cycle is short, and method is simple, is easy to grasp, and not only product purity height, and product yield is also high.

Embodiment

Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Except that specifying, used per-cent all is weight percent in the following content.

Embodiment 1

Saccharothrix aerocolonigenes subsp.staurosporea CGMCC 4.1708 (purchase in Chinese common micro-organisms DSMZ) seed is taken out activation back inoculation slant medium (ISP 4Substratum: Zulkovsky starch 1.0%, K 2HPO 40.1%, MgSO 47H 2O 0.1%, NaCl 0.1%, (NH 4) 2SO 40.2%, CaCO 30.4%, surplus is a water, pH7.2,121 ℃ of sterilization 20min), the inclined-plane of inoculation bacterial classification is placed 28 ℃ of constant incubators, cultivated 10 days, and obtained sophisticated spore, sophisticated then spore inoculating is in 30ml seed culture medium (glucose 2.0% is housed, peptone 0.5%, extractum carnis 0.5%, yeast powder 0.3%, CaCO 30.4%, surplus is a water, pH7.0,121 ℃ of sterilization 20min) 250ml shakes in the bottle, cultivated 3 days on 28 ℃, 220rpm shaking table, obtain sophisticated seed, the seed that obtains inserts with 5% inoculum size 100ml fermention medium (glucose 3.0% is housed, soybean-cake flour 2%, lime carbonate 0.4%, surplus are water, and 750ml pH7.0) shakes in the bottle, place 28 ℃, 220rpm shaking table to continue to cultivate 60 hours, obtain fermented liquid.

1L fermented liquid centrifugal (rotating speed 4000rpm, 10 minutes time) is handled, and abandons supernatant liquor.Wet thallus 0.45kg adds the methyl alcohol of 1L earlier, regulates pH value 12.0 with 0.1N sodium hydroxide, and stirring at normal temperature is soaked 2 hours after-filtration, and thalline in kind extracts once with the methyl alcohol of 0.5L more again.The filtrate that extracted twice obtains is mixed, and the methyl alcohol in the filtrate is removed in distillation, obtains concentrated solution.Add 200ml 0.1N HCl in concentrated solution, the pH value that makes solution is 3, stirs, and is centrifugal, gets supernatant.And then adding 100ml 0.1N HCl, the pH value that makes solution is 3, repeats aforesaid operations.Merge all supernatant liquors, regulate pH value to 12.0, use 300ml and 200ml ethyl acetate extraction twice then respectively, merge all extraction liquids, add the 10g anhydrous sodium sulphate and remove water.Distillation is removed ethyl acetate to faint yellow oily thing then.Oily matter fully dissolves the back with ethyl acetate goes up silica gel column chromatography, is that 100: 1~100: 20 chloroform-methanol mixed solution is that eluent carries out gradient elution with volume ratio, and flow velocity is 0.3ml/min, the substep collection.Follow the tracks of detection with thin-layer chromatography-bismuth potassium iodide, target compound flows out when gradient is 60: 1.Collection contains the elutriant of target compound, and vacuum concentration obtains pale yellow powder, uses the chloroform thermosol under the room temperature, and 4 ℃ of cool overnight crystallizations obtain purity and be 96.1% compound 19.8mg.Being converted into yield is 61%.

Embodiment 2

Thalline extracts with 1.5L 90% (wt) methanol solution earlier, uses 0.6L 90% (wt) methanol solution solution to extract again, and extracting used lipotropy organic solvent is chloroform, and other obtain the product 17.31mg of 94.5% purity at last with embodiment 1.Being converted into yield is 52.4%.

Embodiment 3

Thalline extracts twice with 95% (wt) ethanolic soln earlier, and consumption is respectively 1.5L, 0.6L, and other obtain the product 19.93mg of purity 89.3% at last with embodiment 1.Being converted into yield is 57.06%.

Embodiment 4

Thalline successively uses 1.5L, 0.8L 95% (wt) acetone soln to extract twice, and other obtain the product 13.17mg of purity 94.1% at last with embodiment 1.Being converted into yield is 39.7%.

Embodiment 5

Thalline extracts twice with 85% (wt) ethanolic soln earlier, and consumption is respectively 1.0L, 0.5L, and other obtain the product 17.93mg of purity 91.3% at last with embodiment 2.Being converted into yield is 52.5%.

Embodiment 6

Thalline extracts twice under pH 8.0 conditions with tetrahydrofuran (THF) earlier.Solution that extraction obtains mixes, and after tetrahydrofuran (THF) in the solution was removed in distillation, adding 0.1N hydrochloric acid soln to acidity was pH3.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is adjusted to pH value 10.0, uses n-butyl acetate extraction.Other obtain the product 9.34mg of purity 94.1% at last with embodiment 1.Being converted into yield is 29.8%.

Embodiment 7

Thalline extracts twice under pH 14.0 conditions with the aqueous ethanolic solution of 90% (wt) earlier.Solution that extraction obtains mixes, and after organic solvent in the solution was removed in distillation, adding 0.1N hydrochloric acid soln to acidity was pH1.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is regulated pH value 14.0, uses chloroform extraction.Other obtain the product 18.67mg of purity 92.24% at last with embodiment 1.Being converted into yield is 55.21%.

Embodiment 8

Thalline extracts twice under pH 10.0 conditions with ethanol earlier.Solution that extraction obtains mixes, and after organic solvent in the solution was removed in distillation, adding oxalic acid solution to acidity was pH4.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is regulated pH value 10.0, uses dichloromethane extraction.Other obtain the product 17.31mg of purity 93.5% at last with embodiment 1.Being converted into yield is 51.89%.

Embodiment 9

Thalline extracts once under the pH13.0 condition with the methanol aqueous solution of 85% (wt) earlier.Solution that extraction obtains mixes, and after organic solvent in the solution was removed in distillation, adding 0.1N hydrochloric acid soln to acidity was pH5.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is regulated pH value 13.0, extracts with propyl acetate.Other obtain the product 15.24mg of purity 92.91% at last with embodiment 1.Being converted into yield is 45.39%.

Embodiment 10

Thalline extracts twice under pH 12.0 conditions with the aqueous acetone solution of 85% (wt) earlier.Solution that extraction obtains mixes, and after organic solvent in the solution was removed in distillation, adding 0.1N hydrochloric acid soln to acidity was pH2.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is regulated pH value 12.0, extracts with ethyl propionate.Other are with embodiment 1.Obtain the product 14.26mg of purity 89.37% at last.Being converted into yield is 40.86%.

Embodiment 11

Thalline extracts twice under pH 12.0 conditions with ethanol earlier.Solution that extraction obtains mixes, and after organic solvent in the solution was removed in distillation, adding 0.1N hydrochloric acid soln to acidity was pH3.0, and stirring is centrifugal, gets supernatant.Supernatant liquor is regulated pH value 12.0, extracts with methyl propionate.Other are with embodiment 1.Obtain the product 14.91mg of purity 89.24% at last.Being converted into yield is 42.66%.

Embodiment 12

4L is divided into 4 parts with the fermented liquid of embodiment 1, gets a copy of it and carries out following operation.

Fermented liquid centrifugal (rotating speed 4000rpm, 10 minutes time) discards supernatant, collects thalline.Add 500ml methyl alcohol, regulate pH12.0 with ammoniacal liquor, stirring at room 1h filters, and relaunders filter cake and filtration with 100ml methyl alcohol, merging filtrate, and vacuum concentration is removed methyl alcohol, obtains 100ml left and right sides concentrated solution.In concentrated solution, add 1/2 volume 0.1N HCl, stir, centrifugal, get supernatant.Regulating supernatant liquor pH is 12.0, adds ethyl acetate extraction, and the combined ethyl acetate extraction phase adds anhydrous sodium sulphate and dewaters.Ethyl acetate is removed in distillation then, obtains faint yellow oily thing.STS content is about 84% (wt) in the oily matter.Oily matter fully dissolves the back with ethyl acetate goes up silica gel column chromatography, is that eluent carries out gradient elution with the chloroform-methanol mixed solution of different ratios, and flow velocity is 0.3ml/min, the substep collection.Follow the tracks of detection with thin-layer chromatography-bismuth potassium iodide, target compound flows out when gradient is 60: 1.The elutriant vacuum concentration of collecting is obtained pale yellow powder, use the chloroform thermosol under the room temperature, 4 ℃ are cooled off and standing over night, obtain faint yellow needle-like crystal.Purity is 96.5%, and yield is 64.9%.

Embodiment 13

Another part of getting among the embodiment 12 in 4 portions of fermented liquids is carried out following operation.

Thalline is successively used 500ml and 100ml acetone extraction, and other steps are with embodiment 1.Be among the embodiment 1, used methyl alcohol was replaced by acetone in the thalline successively step with 500ml and 100ml methanol extraction, other steps were all identical with embodiment 2.

Comparative Examples 1U.S.Pat.No.4,107, the 297 soda acid extraction methods of describing.

The 3rd part that gets among the embodiment 12 in 4 portions of fermented liquids is carried out following operation.

Fermented liquid is regulated pH value 10.0 with ammoniacal liquor, adds the 500ml ethyl acetate extraction, leaves standstill separatory, and is centrifugal, tells organic phase; In organic phase, add 250mL 0.1N HCl, aqueous phase extracted.Transferring aqueous pH values with weak ammonia again is 10.0, and with the ethyl acetate extracting twice of 100mL, separating funnel is removed water, add anhydrous sodium sulfate dehydration after, the concentrated organic phase of underpressure distillation is to the pulpous state crude extract, STS content is about 75% (wt) in the crude extract.Crude extract fully dissolves the back with ethyl acetate goes up silica gel column chromatography, is that eluent carries out gradient elution with the chloroform-methanol mixed solution of different ratios, collects the elutriant that contains target compound, and concentrated, crystallization obtains compound.Purity is 94.5%, and yield is 35.2%.

The methanol extraction method that Comparative Examples 2Morioka describes

The last portion of getting among the embodiment 12 in 4 portions of fermented liquids carries out following operation.

Fermented liquid is centrifugal, thalline is successively used 500ml and 300ml methanol extraction, then all methanol solutions are merged, after concentrating under reduced pressure is removed methyl alcohol, obtain 100ml left and right sides concentrated solution, the concentrated solution ethyl acetate extraction adds anhydrous sodium sulfate dehydration in acetic acid ethyl acetate extract, be evaporated to soup compound.STS content is that impurity is a lot of about 55% (wt) in the soup compound.Soup compound is gone up silica gel column chromatography once after with acetic acid ethyl dissolution, but still has more impurity not separate, so purity is lower.

Embodiment 12 is that methyl alcohol of the present invention-acid-alkali treatment extracts.Embodiment 13 acetone of the present invention-acid-alkali treatment extracts.Comparative Examples 1 is U.S.Pat.No.4,107, the 297 soda acid extraction methods of describing.Comparative Examples 2 is methanol extraction methods that Morioka describes.These four kinds of extracting method the results are shown in Table 1, have the extraction effect of table two kinds of methods of the present invention as can be known significantly to be better than two kinds of existing extracting method.

The comparison of four kinds of extracting method of table 1

Claims (15)

1. the method for an extracting and purifying staurosporin is characterized in that, comprises following steps:
1) the extraction with aqueous solution liquid that Staurosporine is produced the hydrophilic organic solvent of bacterium thalline or hydrophilic organic solvent remove add behind the organic solvent acid solution to acid, centrifugal then, get supernatant;
2) supernatant is used the lipotropy organic solvent extraction under alkaline condition;
3) after extraction liquid concentrates, carry out silica gel column chromatography.
2. method according to claim 1 is characterized in that, the described extracting solution of step 1) is that Staurosporine produces bacterium thalline extraction with aqueous solution gained with hydrophilic organic solvent or hydrophilic organic solvent under alkaline condition.
3. method according to claim 2 is characterized in that, described Staurosporine produces the bacterium thalline is produced bacterium by Staurosporine the centrifugal gained of fermented liquid.
4. method according to claim 3 is characterized in that, the consumption of the hydrophilic organic solvent that adopts during extraction or the aqueous solution of hydrophilic organic solvent is more than 0.5 times of fermentating liquid volume that Staurosporine produces bacterium.
5. method according to claim 1 and 2 is characterized in that described hydrophilic organic solvent is selected from alcohol, ketone and tetrahydrofuran (THF); Described alcohol is selected from methyl alcohol and ethanol, and described ketone is acetone.
6. method according to claim 1 and 2, it is characterized in that, the aqueous solution of the described hydrophilic organic solvent of step 1) be more than 85% less than 100% methanol aqueous solution, more than 85% less than 100% aqueous ethanolic solution or 85% above less than 100% aqueous acetone solution, above-mentioned per-cent is weight percentage.
7. method according to claim 6 is characterized in that, the aqueous solution of described hydrophilic organic solvent is 90% methanol aqueous solution, 90% aqueous ethanolic solution or 95% aqueous acetone solution, and above-mentioned per-cent is weight percentage.
8. method according to claim 1 is characterized in that, the described acidity of step 1) is pH1~5.
9. method according to claim 1 is characterized in that, the described acid solution of step 1) is selected from hydrochloric acid and oxalic acid.
10. method according to claim 1 is characterized in that step 2) described lipotropy organic solvent is selected from ethyl acetate, butylacetate, chloroform, methylene dichloride, propyl acetate, ethyl propionate and methyl propionate.
11. method according to claim 1 and 2 is characterized in that, described alkaline condition is pH 8.0~14.0.
12. method according to claim 11 is characterized in that, described alkaline condition is pH10.0~13.0.
13. method according to claim 12 is characterized in that, described alkaline condition is pH12.0.
14. method according to claim 1, it is characterized in that, the described silica gel column chromatography of step 3) comprises step: with volume ratio is that 100: 1~50: 1 chloroform-methanol mixed solution is that eluent carries out gradient elution, and it is 60: 1 target compound that substep is collected gradient.
15. method according to claim 1 is characterized in that, comprises that also the target compound that silica gel column chromatography is obtained concentrates or recrystallization.
CN200810037512XA 2008-05-16 2008-05-16 Method for extracting and purifying staurosporin CN101580515B (en)

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CN102924479A (en) * 2011-08-09 2013-02-13 山东鲁北药业有限公司 Semisynthetic method of staurosporine derivative
CN102925511B (en) * 2012-06-19 2015-05-13 文才艺 Staurosporine preparation method
CN108272803A (en) * 2017-12-07 2018-07-13 广东省农业科学院动物卫生研究所 Application of the staurosporine in anti-chicken coccidiasis

Citations (2)

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US4107297A (en) * 1976-12-11 1978-08-15 The Kitasato Institute Antibiotic compound
CN1328462A (en) * 1998-11-23 2001-12-26 诺瓦提斯公司 Use of staurosporine derivatives for treating ocular neovascular diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107297A (en) * 1976-12-11 1978-08-15 The Kitasato Institute Antibiotic compound
CN1328462A (en) * 1998-11-23 2001-12-26 诺瓦提斯公司 Use of staurosporine derivatives for treating ocular neovascular diseases

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