CN104341377B - The method reclaiming lovastatin from lovastatin crystalline mother solution - Google Patents
The method reclaiming lovastatin from lovastatin crystalline mother solution Download PDFInfo
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- CN104341377B CN104341377B CN201310337260.3A CN201310337260A CN104341377B CN 104341377 B CN104341377 B CN 104341377B CN 201310337260 A CN201310337260 A CN 201310337260A CN 104341377 B CN104341377 B CN 104341377B
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- lovastatin
- organic facies
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Abstract
The invention provides a kind of method reclaiming lovastatin from lovastatin crystalline mother solution.The method includes: 1) mixed with alkaline aqueous solution by lovastatin crystalline mother solution, to wash, and isolated organic facies；2) organic facies that step 1) obtains is mixed with acidic aqueous solution, to wash, isolated organic facies；3) by step 2) organic facies that obtains carries out cyclization；And 4) organic facies after the cyclisation that step 3) obtained concentrates, crystallization, thus obtain lovastatin.The method operating procedure of the present invention is simple, improves mother solution product recovery rate, reduces the solvent consumption in removal process, safer environmental protection, and less demanding to equipment of remanufacture condition, be suitable to industrialization and produce continuously, and the collection process in producing can be accelerated.
Description
Technical field
The present invention relates to lovastatin production technology field, cut down from Lip river in particular to one
The method reclaiming lovastatin in statin crystalline mother solution.
Background technology
Lovastatin (Lovastatin) be microbe-derived hydroxy-methyl-glutaryl coenzyme A also
Reductase inhibitor class anticholesteremic agent, because its mechanism of action is clear and definite, clinical efficacy is notable, is
The most important preventing and treating cardiovascular and cerebrovascular disease (such as atherosclerosis and coronary heart disease) medicine
Thing.Lovastatin is the secondary metabolite of fungus, and industrial main producing strains has aspergillus terreus
(Aspergillus terreus), Aspergillus citrimum (Penicillium citrinum) and monascus
(Monascus ruber).
The chemical name of lovastatin is: (S)-2-Methyl Butyric Acid-(1S, 3R, 7S, 8S, 8aR)
-1,2,3,7,8,8a-6H-3,7-dimethyl-8-(2-((2R, 4R)-4-hydroxyl-6 oxo-2H-Pentamethylene oxide.
Base)-ethyl)-1-naphthalene ester.The molecular formula of lovastatin is C24H36O5, molecular weight is 404.55,
Structural formula is:
Lovastatin is white or off-white color crystalline powder, odorless, tasteless, slightly draws moist,
Being soluble in chloroform, the most molten in ethanol, ethyl acetate, acetonitrile, insoluble in water, fusing point is
174.5℃。
From lovastatin fermentation liquid, extract lovastatin at present mainly have two kinds of extraction process roads
Line:
1. by lovastatin fermentation liquid is acidified, the pretreatment such as flocculation, make Lip river cut down him
Spit of fland is retained in mycelium, by filtering the dreg obtained containing lovastatin；Utilize organic solvent
Dreg is extracted, it is thus achieved that extract, extract is concentrated, crystallize, separate to obtain Lip river
Cut down statin crude product and crystalline mother solution；Crude product is carried out recrystallization and obtains lovastatin finished product.
2., by lovastatin fermentation liquid is carried out basic hydrolysis process, make mycelia wall destroy,
Lovastatin is hydrolyzed to the Lip river of open loop and cuts down acid structure, is changed into water solublity, enters aqueous phase；Pass through
Filter, collect filtrate, filtrate is carried out acid precipitation process, precipitate is collected by filtration；Utilize
Precipitation is extracted by organic solvent, it is thus achieved that extract, extract is concentrated, crystallize,
Separate to obtain lovastatin crude product and crystalline mother solution；Crude product is carried out recrystallization and obtains lovastatin
Product.
Extract is not all carried out at effective purification by the extraction process of both the above lovastatin
Reason, and substantial amounts of oil-soluble impurities enters in organic crystal mother solution.Often produce one ton of Lip river to cut down
Statin finished product can produce 4.5-5.5m3Crystalline mother solution, simultaneously containing substantial amounts of in crystalline mother solution
Lovastatin, lovastatin unit is at more than 30000U/ml.And by crystalline mother solution is entered
Row simple secondary concentration crystallization, can only reclaim few part lovastatin.The most current carries
Crystalline mother solution is fallen by taking technique as producing offal treatment, does not reaches the purpose of efficient recovery,
Extract yield is low.If able to the lovastatin in lovastatin crystalline mother solution is carried out effectively
Reclaim, just can significantly improve extraction efficiency, be substantially reduced the production cost of lovastatin.
In the current patent documentation about lovastatin production technology, only Chinese patent
CN103012344A describes the recovery of lovastatin, technical essential in lovastatin mother solution
It is to add two kinds of precipitant under the conditions of alkalescence after open loop to precipitate and carry out extracting, concentrate and crystallization reaches
To reclaiming purpose.Specifically describe is mother solution after reclaiming organic solvent, open loop under the conditions of alkalescence
Add two kinds of precipitant to precipitate and carry out extracting, concentrate and crystallization reaches to reclaim purpose.
In other scientific and technical literatures, only two discussions to lovastatin mother liquid recovery process: (1)
The science that North China pharmacy group Wang Jian et al. delivered on Chinese Pharmaceutical Association Annual Conference in 2008
Paper: lovastatin mother liquid recovery process is studied；Described in it is that crystalline mother solution open loop processes
After be translated into the organic salt being dissolved in water, then use the method for macroporous resin adsorption to remove
Remove major part impurity, then carry out solvent crystal.(2) Yang Junfa et al. delivered in 2011
Scientific paper: lovastatin disposing mother liquor utilizes process modification research.Described in it is open loop
It is translated into the organic salt being dissolved in water after process, then uses the method for stratification to remove big
Part oil-soluble impurities, acidified rear extraction applies mechanically crystallization.
Above method has all referred to the technique being cyclized again after the open loop to crystalline mother solution processes,
The tediously long complexity of operating process, the operating procedure relating to equipment is the most more, and him is cut down in scientific and technical literature Lip river
The method of spit of fland mother liquid recovery process employs substantial amounts of macroporous resin, substantial amounts of ethyl acetate etc.
Organic solvent, removal process solvent consumption is high, and safety and environmental protection pressure is big.
Therefore, need that a kind of technique is relatively easy at present badly and the crystallizing from lovastatin of safety and environmental protection
The method reclaiming lovastatin in mother solution.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides one and cut down him from Lip river
The method reclaiming lovastatin in the crystalline mother solution of spit of fland.
Specifically, the present invention provides:
(1) a kind of method reclaiming lovastatin from lovastatin crystalline mother solution, comprising:
1) lovastatin crystalline mother solution is mixed with alkaline aqueous solution, to wash, separate
Obtain organic facies；
2) organic facies that step 1) obtains is mixed with acidic aqueous solution, to wash,
Isolated organic facies；
3) by step 2) organic facies that obtains carries out cyclization；And
4) organic facies after cyclisation step 3) obtained concentrates, crystallizes, thus obtains Lip river
Cut down statin.
(2) according to the method described in (1), wherein, in step 1), described alkalescence
Alkali used in aqueous solution is one or more in sodium bicarbonate, sodium carbonate, sodium hydroxide.
(3) according to the method described in (1), wherein, in step 1), described alkalescence
Aqueous solution is (0.3-0.5) with the volume ratio of described lovastatin crystalline mother solution: 1, is preferably
0.4:1。
(4) according to the method described in (1), wherein, in step 1), carry out described
The number of times of washing is 1-4 time；It is preferably 2 times.
(5) according to the method described in (1), wherein, in step 2) in, described acidity
Acid used in aqueous solution is one or more in hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid and oxalic acid.
(6) according to the method described in (1), wherein, in step 2) in, described acidity
The volume ratio of the organic facies that aqueous solution and step 1) obtain is (0.5-2.5): 1, preferably 1:1.
(7) according to the method described in (1), wherein, in step 3), by step 2)
The organic facies obtained is acidified, and then reflux under conditions of temperature is 70-90 DEG C 1.5-4.5
Hour；Reflux 2 hours under conditions of being preferably 80 DEG C.
(8) according to the method described in (7), wherein, in step 3), described acidifying
Acid be one or more in phosphoric acid, acetic acid and oxalic acid.
(9) according to the method described in (8), wherein, described acid is dissolved in alcoholic solvent
, described alcoholic solvent is the one in methanol, ethanol, butanol, preferably ethanol；And
Described acid concentration in described alcoholic solvent is 1%-5%(w/v).
(10) according to the method described in (1), wherein, in step 4), in temperature it is
It is concentrated in vacuo under conditions of 70-90 DEG C.
(11) according to the method described in (1), wherein, in step 4), Crystallization Separation
Temperature is less than 20 DEG C.
(12) according to the method described in (1), wherein, described method also includes:
5) the lovastatin crystal crude product obtained by step 4) is carried out recrystallization, be dried
Lovastatin finished product.
(13) according to the method described in (12), wherein, in step 5), described weight
Crystallization can be repeatedly recrystallization；Preferably, for the first time the solvent of recrystallization be butyl acetate or
Ethyl acetate；Crystallization Separation temperature is less than 20 DEG C；Recrystallization and later recrystallization for the second time
The ethanol that solvent is more than 95%；Crystallization Separation temperature is less than 20 DEG C.
(14) according to the method described in (1), wherein, described lovastatin crystalline mother solution is
The crystalline mother solution obtained after lovastatin fermentation liquor primary crystallization is processed.
The method of the present invention compared with prior art has the advantages that:
The method operating procedure of the present invention is simple, improves mother solution product recovery rate, reduces and reclaims
During solvent consumption, safer environmental protection, reduce the health risk to operator, and
Less demanding to equipment of remanufacture condition, is suitable to industrialization and produces continuously, and can accelerate
Collection process in production.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is also
Non-is limitation of the present invention, and those skilled in the art are according to the basic thought of the present invention, permissible
Make various amendment or improvement, but without departing from the basic thought of the present invention, all at this
Within the scope of bright.
" lovastatin crystalline mother solution " of the present invention is by lovastatin fermentation liquor once
The crystalline mother solution obtained after crystallization treatment.This crystallization treatment can be commonly employed in the art
Method.
For example, it is possible to be acidified by the fermentation liquid of lovastatin, it is filtrated to get the bacterium containing lovastatin
Slag；Utilize organic solvent that dreg is extracted, it is thus achieved that extract, extract is concentrated,
Crystallization, obtains lovastatin crude product, and separating the liquid after lovastatin crude product is crystalline mother solution,
I.e. lovastatin crystalline mother solution.Preferably, the fermentation liquid hydrochloric acid of lovastatin is adjusted pH value
To 2.5-3.5, dreg is collected by filtration；Dreg butyl acetate is extracted, separates and collects organic facies,
Organic facies is concentrated, decrease temperature crystalline, be centrifugally separating to obtain lovastatin crude product, Yi Jiluo
Cut down statin crystalline mother solution.
Further for example, lovastatin fermentation liquid can be carried out basic hydrolysis process, mycelia wall is made to break
Bad, and make lovastatin hydrolysis；Filtrate is collected by filtration, filtrate is carried out at acid precipitation
Reason, is collected by filtration precipitate；Utilize organic solvent that precipitation is extracted, it is thus achieved that extract,
Extract is concentrated, crystallizes, obtain lovastatin crude product, after separating lovastatin crude product
Liquid be lovastatin crystalline mother solution.
Containing substantial amounts of impurity in lovastatin crystalline mother solution, contain substantial amounts of Lip river simultaneously and cut down him
Spit of fland and organic solvent (such as butyl acetate).Owing to there is the shortcoming reclaiming difficulty, therefore giving birth to
Product falls as offal treatment.
" lovastatin fermentation liquid " as herein described refers to by any one can mainly be produced
(such as, the soil in China typical culture collection center preservation is bent for the aspergillus terreus of raw lovastatin
Mould CCTCC AF93208), that the bacterial strain such as Aspergillus citrimum and monascus or its mutation carry out fermentation is raw
The fermentation liquid produced and obtain.
" cyclization " as herein described is to instigate the lovastatin of open loop in acid condition
Make the reaction of its closed loop.Wherein the lovastatin of open loop is difficult to crystallization and forms crystal, and closed loop
Lovastatin is prone to crystallization and forms crystal.
It is an object of the invention to provide a kind of more easy and safety and environmental protection from lovastatin
The method reclaiming lovastatin in crystalline mother solution.The present inventor, by substantial amounts of experiment, goes out people's will
The discovery of material, optionally passes sequentially through alkaline aqueous solution, acid by the crystalline mother solution of lovastatin
Property aqueous solution washs, and can remove a large amount of pigments, alkaline impurities and the acidity in material
Impurity, and after the organic facies obtained after washing carries out cyclization, it is possible to easily by crystallization
Separate.The present inventor on this basis, has obtained technical scheme further.
Such as, the purpose of the present invention can be realized by following steps:
(1) by alkaline aqueous solution, lovastatin crystalline mother solution is washed, with removing unit
Color separation element and alkaline impurities, in this step, sub-fraction lovastatin can be because occurring open loop anti-
Emulsifying is answered to enter emulsion layer；
(2) the organic facies mother solution obtained (1) by acidic aqueous solution (preferably comprises described
Emulsion layer) wash, to remove partial pigment and acid impurities, in this step, (1)
The lovastatin of middle emulsifying can occur ring-closure reaction and demulsification；
(3) organic facies that (2) obtain is carried out cyclization, such as, add solid weak acid
Alcoholic solution or liquid weak acid, make (1) there occurs, the lovastatin of ring-opening reaction closes again
Ring；
(4) organic facies (3) obtained concentrates, crystallization, thus obtains lovastatin.
Specifically, the invention provides a kind of Lip river of reclaiming from lovastatin crystalline mother solution and cut down him
The method in spit of fland, comprising:
1) lovastatin crystalline mother solution is mixed with alkaline aqueous solution, to wash, separate
Obtain organic facies；
2) organic facies that step 1) obtains is mixed with acidic aqueous solution, to wash,
Isolated organic facies；
3) by step 2) organic facies that obtains carries out cyclization；And
4) organic facies after cyclisation step 3) obtained concentrates, crystallizes, thus obtains Lip river
Cut down statin.
Preferably, in step 1), alkali used in described alkaline aqueous solution is carbonic acid
One or more in hydrogen sodium, sodium carbonate, sodium hydroxide.
Preferably, in step 1), described alkaline aqueous solution and described lovastatin
The volume ratio of crystalline mother solution is (0.3-0.5): 1, preferably 0.4:1；During washing,
The pH value of the mixed liquor preferably controlling gained is 6.5-8.0, preferably 7.0.
Preferably, in step 1), the number of times carrying out described washing is 1-4 time；Excellent
Elect 2 times as.
Preferably, in step 2) in, acid used in described acidic aqueous solution be hydrochloric acid,
One or more in sulphuric acid, phosphoric acid, acetic acid and oxalic acid.
Preferably, in step 2) in, described acidic aqueous solution and step 1) obtain
The volume ratio of organic facies is (0.5-2.5): 1, preferably 1:1.
Preferably, in step 3), by step 2) organic facies that obtains is acidified,
Then reflux 1.5-4.5 hour under conditions of temperature is 70-90 DEG C；It is preferably the condition of 80 DEG C
Lower backflow 2 hours.
It is further preferred that in step 3), the alcohol that acid is solid weak acid of described acidifying
Solution or liquid weak acid.
It is further preferred that in step 3), the acid of described acidifying be phosphoric acid, acetic acid and
One or more in oxalic acid.
It is further preferred that the alcoholic solution that described acid is solid weak acid；Described alcoholic solvent is first
One in alcohol, ethanol, butanol, preferably ethanol.It is further preferred that described solid is weak
Acid concentration in described alcoholic solvent is 1%-5%(w/v).
It is further preferred that the alcoholic solution of described solid weak acid and step 2) organic facies that obtains
Volume ratio be (6-12): 100, preferably 10:100；Described liquid weak acid and step 2)
The volume ratio of the organic facies obtained is (1-5): 100, preferably 3:100.
Preferably, in step 4), under conditions of temperature is 70-90 DEG C, carry out vacuum
Concentrate.
Preferably, in step 4), Crystallization Separation temperature is less than 20 DEG C.
Preferably, described method also includes: 5) Lip river obtained by step 4) is cut down him
Spit of fland crystal crude product carries out recrystallization, is dried to obtain lovastatin finished product.
Preferably, the recrystallization described in step 5) can be repeatedly recrystallization.More preferably
, the solvent of recrystallization is butyl acetate or ethyl acetate for the first time；Crystallization Separation temperature is
Less than 20 DEG C；The solvent of recrystallization and later recrystallization is the ethanol of more than 95% for the second time；
Crystallization Separation temperature is less than 20 DEG C.
A kind of preferred embodiment of the present invention may is that
A kind of method reclaiming lovastatin from lovastatin mother solution, the method includes:
1) a kind of method reclaiming lovastatin from lovastatin mother solution, takes lovastatin thick
The sodium bicarbonate solution of the 0.4mol/L that crystalline mother solution adds mother solution 0.3-0.5 times of volume of volume stirs
Mix washing 30 minutes, stratification, separate to obtain organic facies mother solution, wash twice；
2) above-mentioned 1) after washing, organic facies mother solution adds isopyknic weak acid solution to stir
Mix washing 1h, stratification；
3) organic facies mother solution above-mentioned 2) adds after washing ethanol solution or the liquid of solid weak acid
Weak acid carries out 80 DEG C and refluxes 2 hours；And
4) suitably concentrate under vacuum condition after having refluxed, decrease temperature crystalline, separate back
Receipts obtain crude product.
Preferably, in step 2) in, to 1) solution after washing selects a kind of weak acid to enter
Row secondary washing, the acid used by washing is in hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid and oxalic acid
One or more.
Preferably, in step 3), solid weak acid used is selected from: phosphoric acid, acetic acid and
A kind of in oxalic acid or their mixture, in the ethanol solution of solid weak acid acid concentration between
Between 1% to 5%；Liquid weak acid is selected from acetic acid.
Preferably, in step 4), described in be concentrated in temperature 70-80 DEG C condition and carry out very
Empty concentration.
Preferably, described lovastatin crystalline mother solution is by lovastatin fermentation liquor once
The crystalline mother solution obtained after crystallization treatment.
Present invention is further explained and described below by way of the mode of example, but these examples
Son is not to be construed as limiting the scope of the invention.
In example below, if no special instructions, each reagent the most commercially, such as, can obtain
From Tianjin Qing Sheng Chemical trade company limited.
Chromatograph of liquid used in example below is purchased from Shimadzu Corp, and model is
LC-2010AHT；Rotary evaporator is purchased from Shanghai Yarong Biochemical Instrument Plant, and model is
RE5220；JJ-1 motor stirrer is purchased from Community of Jin Tan County Rong Hua instrument manufacturing company.
Lovastatin crystalline mother solution used in following example can be by the method for test example 1
Prepare, but the invention is not restricted to this.
Test example 1
Lovastatin crystalline mother solution can be prepared by the following method and to obtain:
1. the sweat of lovastatin
Aspergillus terreus seed liquor 3-5L is accessed first class seed pot, is wherein loaded with aseptic first order seed
Culture fluid 1000L, comprises peptone, Semen sojae atricolor powder, maltose, glucose, cottonseed meal,
PH value 6.6-7.0；Cultivate 80-150 hour at 25-28 DEG C, move in secondary seed tank and train
Support.
Secondary seed tank is loaded with aseptic secondary seed culture fluid 4000-5000L, comprises albumen
Peptone, Semen sojae atricolor powder, maltose, glucose, cottonseed meal, pH value 6.6-7.0；At 25-28
Cultivate 40-120 hour at DEG C, move in fermentation tank and cultivate.
Fermentation tank is loaded with aseptic fermentation culture 38000-42000L, comprises peptone, big
Semen Glycines powder, maltose, glucose, cottonseed meal, pH value 6.6-7.0；At 25-28 DEG C of bottom fermentation
Cultivating 160-180 hour, mycelia puts tank when being in metabolism latter stage.
2. the extraction process of lovastatin
Filter pressing:
After connecing fermentation liquid, start acidifying bucket stirring, with 5-6mol × L-1HCl adjust pH extremely
2.5-3.5, is passed through air stirring more than 0.5 hour, and after filter pressing, filter cake extracts.
Extraction:
Dreg is put into extraction bucket, by the butyl acetate dosage of 5-15L/Kg, butyl acetate is put
Enter and extract in bucket, insulated and stirred 2-6 hour at 45-50 DEG C.It is then pumped into automatic bottom to unload
Material seperator carries out solid-liquid separation, and extract concentrates.
Concentrate:
Feed limit below at vacuum≤-0.07Mpa to concentrate, concentration heating steam pressure≤
0.2Mpa, temperature≤70 DEG C.Material is concentrated into crystallization in concentration tank and just separates out, and is immediately placed in
Crystallizer crystallizes.
Crystallization Separation:
Material after concentration enters crystallizer, is cooled to less than 30 DEG C by water at low temperature, stirring knot
Crystalline substance, 8-24 hour time.Material is put into link-suspended basket centrifuge separate, respectively obtain Lip river and cut down
Statin crude product and lovastatin crystalline mother solution.
3. the unit of lovastatin and content assaying method:
The preparation of Working Control product solution
Take lovastatin Working Control product 10mg in 25ml volumetric flask, accurately weighed, use
After proper amount of methanol is dissolved, and it is settled to scale, shakes up and get final product.
The preparation of need testing solution
Take uniform lovastatin test liquid or finished product (seed liquor, fermentation liquid, filter pressing waste liquid,
Crystalline mother solution) 10ml or weigh the appropriate methanol of appropriate finished product and dissolve, mixing, filter i.e.
?.
Measure
Opening chromatograph of liquid, the methanol aqueous solution with 40% is flowing phase, flow velocity 1ml/min,
After system stability, accurately draw in reference substance solution 10 μ l injecting chromatograph, record chromatograph
Figure.Parallel sample introduction three times, takes the meansigma methods peak area as reference substance solution of three peak areas.
Separately take in need testing solution injecting chromatograph, record chromatogram, be calculated as follows in each test liquid
The content of lovastatin effective ingredient.
Calculate
Lovastatin active constituent content (μ g/ml)=(A1+A2)/A × C × diluted sample times
Number
In formula: A1The peak area of lovastatin acid in need testing solution；
A2The peak area of lovastatin in need testing solution；
The peak area of A Working Control product solution.
C Working Control product solution concentration (μ g/ml)
Embodiment 1
Taking lovastatin crystalline mother solution 1000ml, lovastatin unit therein is 54666
U/ml, the sodium bicarbonate solution agitator treating of addition 400ml0.4mol/L 30 minutes, stirring
After having washed, stand, separate aqueous phase, obtain organic facies 975ml；Organic facies adds again
Enter the sodium bicarbonate solution 400ml agitator treating 30 minutes of 0.4mol/L, stand, separate water
Phase, obtains organic facies 965ml；Add 965ml1%(w/v, i.e. 1g oxalic acid and be dissolved in 100ml
Water is configured to the oxalic acid aqueous solution of 1%, lower with) oxalic acid aqueous solution be stirred washing 1
Hour, stand, separate aqueous phase, obtain organic facies 963ml.Organic facies after washing adds
Enter the oxalic acid ethanol solution 100ml(2g oxalic acid constant volume of 2% in 100ml dehydrated alcohol) in
Under the conditions of 80 DEG C cyclisation process 2 hours, in 73 DEG C, vacuum≤-0.09Mpa suitably concentrate,
After standing crystallization 8 hours, sucking filtration obtains lovastatin crude product 41.5g, and content is 76.9%,
Yield is 75.91%.
Embodiment 2
Taking lovastatin crystalline mother solution 2000ml, lovastatin unit therein is
54696U/ml, the sodium bicarbonate solution agitator treating of addition 750ml0.4mol/L 30 minutes,
After agitator treating completes, stand, separate aqueous phase, obtain organic facies 1980ml；Add 1980ml
The oxalic acid aqueous solution of 1% is stirred washing 1 hour, stands, and separates aqueous phase, obtains organic
Phase 1960ml.Organic facies after washing adds 58.8ml glacial acetic acid ring under the conditions of 80 DEG C
Change processes 2 hours, in 75 DEG C, suitably concentrate under vacuum≤-0.09Mpa, stand crystallization 8
After hour, sucking filtration obtains lovastatin crude product 87.8g, and content is 73.2%, and yield is 80.26%.
Embodiment 3
Taking lovastatin crystalline mother solution 1000ml, lovastatin unit therein is
50696U/ml, the sodium bicarbonate solution agitator treating of addition 300ml0.4mol/L 30 minutes,
After agitator treating completes, stand, separate aqueous phase, obtain organic facies 980ml；Add 980ml1%
Oxalic acid aqueous solution be stirred washing 1 hour, stand, separate aqueous phase, obtain organic facies
965ml.Organic facies after washing adds 9.7ml acetic acid, under the conditions of 80 DEG C at cyclisation
Under the conditions of managing 2 hours, with 75 DEG C of vacuum≤-0.09Mpa, lower suitably concentration, stands crystallization 8
After hour, sucking filtration obtains lovastatin crude product 39.62g, and content is 73.8%, and yield is
78.15%。
Embodiment 4
Taking lovastatin crystalline mother solution 1000ml, lovastatin unit therein is
50696U/ml, the sodium bicarbonate solution agitator treating of addition 300ml0.4mol/L 30 minutes,
After agitator treating completes, stand, separate aqueous phase, obtain organic facies 980ml；Add 980ml1%
Oxalic acid aqueous solution be stirred washing 1 hour, stand, separate aqueous phase, obtain organic facies
965ml.Organic facies after washing adds oxalic acid ethanol solution (the 1g oxalic acid constant volume of 1%
In 100ml dehydrated alcohol) 57.9ml cyclisation process 2 hours under the conditions of 80 DEG C, in 73
DEG C, suitably concentrate under the conditions of vacuum≤-0.09Mpa, after standing crystallization 8 hours, sucking filtration obtains
To lovastatin crude product 37.82g, content is 75.6%, and yield is 74.6%.
Embodiment 5
Taking lovastatin crystalline mother solution 1000ml, lovastatin unit therein is
49896U/ml, the sodium bicarbonate solution agitator treating of addition 500ml0.4mol/L 30 minutes,
After agitator treating completes, stand, separate aqueous phase, obtain organic facies 970ml；Add 970ml1%
Oxalic acid aqueous solution be stirred washing 1 hour, stand, separate aqueous phase, obtain organic facies
950ml.Organic facies after washing adds the cyclisation under the conditions of 80 DEG C of 47.5ml acetic acid process
2 hours, in 75 DEG C, suitably concentrate under the conditions of vacuum≤-0.09Mpa, stand crystallization 8
After hour, sucking filtration obtains lovastatin crude product 39.87g, and content is 75.87%, and yield is
79.9%。
Embodiment 6
Taking lovastatin crystalline mother solution 1000ml, lovastatin unit therein is
49896U/ml, the sodium bicarbonate solution agitator treating of addition 500ml0.4mol/L 30 minutes,
After agitator treating completes, stand, separate aqueous phase, obtain organic facies 970ml；Add 970ml1%
Oxalic acid aqueous solution be stirred washing 1 hour, stand, separate aqueous phase, obtain organic facies
950ml.Organic facies after washing adds oxalic acid ethanol solution (the 5g oxalic acid constant volume of 5%
In 100ml dehydrated alcohol) 114ml cyclisation process 2 hours under the conditions of 80 DEG C, in 73
DEG C, suitably concentrate under the conditions of vacuum≤-0.09Mpa, after standing crystallization 8 hours, sucking filtration obtains
To lovastatin crude product 39.2g, content is 78.86%, and yield is 78.56%.
Claims (16)
1. the method reclaiming lovastatin from lovastatin crystalline mother solution, comprising:
1) lovastatin crystalline mother solution is mixed with sodium bicarbonate aqueous solution, to wash,
Isolated organic facies；
2) by step 1) organic facies that obtains mixes with acidic aqueous solution, to wash,
Isolated organic facies, acid used in wherein said acidic aqueous solution is oxalic acid；
3) by step 2) organic facies that obtains carries out cyclization,
Wherein, in step 3) in, by step 2) organic facies that obtains is acidified, then
Reflux 1.5-4.5 hour under conditions of temperature is 70-90 DEG C, the acid of wherein said acidifying
For one or more in phosphoric acid, acetic acid and oxalic acid；And
4) by step 3) organic facies after the cyclisation that obtains concentrates, crystallization, thus obtain Lip river
Cut down statin.
Method the most according to claim 1, wherein in step 3) in, in temperature it is
Reflux 2 hours under conditions of 80 DEG C.
Method the most according to claim 1, wherein, in step 1) in, described carbon
Acid hydrogen sodium water solution is (0.3-0.5) with the volume ratio of described lovastatin crystalline mother solution: 1.
Method the most according to claim 1, wherein, in step 1) in, described carbon
Acid hydrogen sodium water solution is 0.4:1 with the volume ratio of described lovastatin crystalline mother solution.
Method the most according to claim 1, wherein, in step 1) in, carry out described
The number of times of washing be 1-4 time.
Method the most according to claim 1, wherein, in step 1) in, carry out described
The number of times of washing be 2 times.
Method the most according to claim 1, wherein, in step 2) in, described acid
Property aqueous solution and step 1) volume ratio of organic facies that obtains is (0.5-2.5): 1.
Method the most according to claim 1, wherein, in step 2) in, described acid
Property aqueous solution and step 1) volume ratio of organic facies that obtains is 1:1.
Method the most according to claim 1, wherein in step 3) in, described acid is
Being dissolved in alcoholic solvent, described alcoholic solvent is the one in methanol, ethanol, butanol；With
And the concentration that described acid is in described alcoholic solvent is 1%-5% (w/v).
Method the most according to claim 9, wherein, described alcoholic solvent is ethanol.
11. methods according to claim 1, wherein, in step 4) in, in temperature
It is concentrated in vacuo under conditions of 70-90 DEG C.
12. methods according to claim 1, wherein, in step 4) in, crystallization point
It is less than 20 DEG C from temperature.
13. methods according to claim 1, wherein, described method also includes:
5) by step 4) obtained by lovastatin crystal crude product carry out recrystallization, be dried
Lovastatin finished product.
14. methods according to claim 13, wherein, in step 5) in, described
Recrystallization can be repeatedly recrystallization.
15. methods according to claim 14, wherein, in step 5) in, for the first time
The solvent of recrystallization is butyl acetate or ethyl acetate；Crystallization Separation temperature is less than 20 DEG C；The
The solvent of secondary recrystallization and later recrystallization is the ethanol of more than 95%；Crystallization Separation temperature
For less than 20 DEG C.
16. methods according to claim 1, wherein, described lovastatin crystalline mother solution
For the crystalline mother solution obtained after lovastatin fermentation liquor primary crystallization is processed.
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| CN108976190B (en) * | 2017-12-21 | 2020-09-04 | 北大方正集团有限公司 | Method for recovering lovastatin from lovastatin crystallization mother liquor |
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| CN102344426A (en) * | 2010-07-30 | 2012-02-08 | 北大方正集团有限公司 | Method for extracting and purifying lovastatin |
| CN103012344A (en) * | 2011-09-28 | 2013-04-03 | 北大方正集团有限公司 | Method of recovering lovastatin from lovastatin crystal mother liquor |
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| CN102344426A (en) * | 2010-07-30 | 2012-02-08 | 北大方正集团有限公司 | Method for extracting and purifying lovastatin |
| CN103012344A (en) * | 2011-09-28 | 2013-04-03 | 北大方正集团有限公司 | Method of recovering lovastatin from lovastatin crystal mother liquor |
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| 洛伐他汀母液回收利用工艺改进研究;杨俊法 等;《科技风》;20111031;第98页 * |
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