CN106518824B - A kind of extraction process of Lovastatin - Google Patents
A kind of extraction process of Lovastatin Download PDFInfo
- Publication number
- CN106518824B CN106518824B CN201610883511.1A CN201610883511A CN106518824B CN 106518824 B CN106518824 B CN 106518824B CN 201610883511 A CN201610883511 A CN 201610883511A CN 106518824 B CN106518824 B CN 106518824B
- Authority
- CN
- China
- Prior art keywords
- bacteria residue
- lovastatin
- fermentation liquid
- filtrate
- concentrated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
It is of the present invention from fermentation liquid from or purifying Lovastatin or its pharmaceutically acceptable salt method, it the described method comprises the following steps: (1) taking Lovastatin fermentation liquid, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 1.0-5.0；(2) it filters, it is 10%-70% that bacteria residue, which is dried up to bacteria residue water content,；(3) organic solvent is added in bacteria residue, impregnates, the NaHCO3 solution of the 1.0%-5.0% of filtrate volume 10% is added into filtrate for filtering, separates water layer, retains organic layer；(4) organic layer is concentrated, concentrate cooling stirring, crystallization；The cyclization of Lovastatin is carried out in concentration；(5) it filters, and washs the crude crystalline being obtained by filtration with 10-20 DEG C of cold ethyl acetate, obtain Lovastatin crude product in 40 DEG C of -50 DEG C or so drying crude crystallines.Method high income provided by the invention, adapts to large-scale production at energy conservation.
Description
Technical field
The present invention relates to one kind from microbial fermentation solution isolated or purified Lovastatin or its pharmaceutically acceptable salt
Method.
Background technique
Lovastatin (Lovastatin), which is called, is Ai Leting, the entitled chemical name of chemistry: (S) -2-Methyl Butyric Acid -
(1S, 3S, 7S, 8S, 8aR) -1,2,3,7,8,8a- hexahydro -3,7- dimethyl -8- { 2- [- 6 oxo -2- of (2R, 4R) -4- hydroxyl
Tetrahydro, concrete structure formula are as follows:
Lovastatin is first generation statin substance, before being used as Statins active medicine Pravastatin now more
Body, therefore the yield of Lovastatin and quality directly affect the cost and purity of Pravastatin.
The method that existing extraction prepares Lovastatin mainly filters fermentation liquid heating, alkalization, then carries out to filtrate
Extraction or to filtrate carry out resins exchange extraction, using macroporous resin adsorption column chromatography technique there are it is cumbersome, mention
The problems such as at high cost, the production cycle is long, yield is low is taken, gradually replaced the method by solvent extraction.
But there is also defects for solvent extraction.PCT Patent Application WO 9720834 elaborates that a kind of Lovastatin mentions
Method is taken, fermentation liquid is transferred to alkalinity with NaOH, is then extracted under stiring with toluene and ethyl alcohol mixed solvent, in extract liquor
It is middle that a large amount of toluene and perlite is added, be acidified with nitric acid, it is imitative to stir lower chlorination, filters pressing, concentration, crystallize crude product is tied again again
It is brilliant.This method uses mixed solvent, and recycling is difficult, so that production operation is become complicated using a variety of solvents；Simultaneously during the extraction process
2 times pH is adjusted to 11 or more, and once to pH value 2 or so, adjusting is excessively frequent, and the acidproof and alkaline-resisting proposition for equipment
Excessive demand, easily corrodes equipment.
A kind of new method is provided in PCT Patent Application WO 0063411: readjusting the distribution zymotic fluid to alkalinity, at low temperature with NaOH
Stirring, centrifuge separation collect supernatant with sulfuric acid and are adjusted to acidity, and the mixed solvent extraction of butyl ester and normal octane, centrifugation point is added
From extract liquor is concentrated in vacuo low temperature crystallization.It is still extracted using mixed solvent in the invention, recycling is difficult, alkaline extraction emulsification
Seriously, a large amount of demulsifier need to be used, brings difficulty to subsequent subtractive process；And the number for adjusting pH value is reduced
To 2 times, but it is still that strong acid and highly basic all occur, excessive demand still is proposed for the acidproof and alkaline-resisting of equipment, is easy
Corrode equipment.
The Lovastatin extracting method that United States Patent (USP) US 2003215932 (A1) is illustrated is to be acidified fermentation liquid sulfuric acid simultaneously
Heating, stirring cyclisation, then extracts fermentation liquid with toluene, filter residue soda solution and salt-free water washing, so at high temperature
After be concentrated in vacuo, low temperature crystallization separation, washing.Cyclisation operation is just just initially carried out to fermentation liquid in extraction process, is needed
The fermentating liquid volume to be heated is huge, almost in the whole extraction process volume maximum stage, and also contains in fermentation liquid
Strong oxidizing property sulfuric acid needs to consume a large amount of energy and easily corrodes equipment.
Summary of the invention
The object of the present invention is to provide in slave microbial fermentation solution that is a kind of high income, energy saving, adapting to large-scale production
The method of separation and Extraction Lovastatin or its pharmaceutically acceptable salt.
The invention before extracting bacteria residue, introduce drying bacteria residue the step of, it is found that the step can be mentioned significantly
The yield of high Lovastatin crude product.Filtered bacteria residue residual water, some hydrophilic impurity and readily volatilized impurity for being dissolved in water
It will have a direct impact on the extraction and cyclisation efficiency in later period Deng, these impurity, extend the time of cyclisation and extraction process.Bacteria residue drying
In the process, some hydrophilic impurity and readily volatilized impurity etc. for being dissolved in water are as vapor is removed, in addition, after drying
Bacteria residue weight is reduced, it is possible to reduce the dosage of organic solvent and the solution for washing is used in subsequent extraction.
Specifically, present invention method packet of isolated or purified Lovastatin or its pharmaceutically acceptable salt from fermentation liquid
Include following steps:
(1) Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 1.0-
5.0；
(2) it filters, it is 10%-70% that bacteria residue, which is dried up to bacteria residue water content,；
(3) organic solvent is added in bacteria residue, impregnates, the 1.0%- of filtrate volume 10% is added into filtrate for filtering
5.0% NaHCO3Solution separates water layer, retains organic layer；
(4) organic layer is concentrated, concentrate cooling stirring, crystallization；The cyclization of Lovastatin concentration when into
Row；
(5) it filters, and washs the crude crystalline being obtained by filtration with 10-20 DEG C of cold ethyl acetate, at 40 DEG C -50 DEG C or so
Drying crude crystalline obtains Lovastatin crude product.
Preferably, the concentrated sulfuric acid adjusts fermentation liquid pH to 3.0-4.0 in the step (1).
It is furthermore preferred that the concentrated sulfuric acid adjusts fermentation liquid pH to 3.5-4.0 in the step (1).
Preferably, bacteria residue drying uses air at room temperature to dry up in step (2).
Preferably, in the step (3) organic solvent be hydrophobic organic solvent, be selected from but be not limited to butyl acetate,
Ethyl acetate, propyl acetate, Ethyl formate, hexanone, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, toluene, benzyl alcohol
One of or it is several.
Preferably, the additional amount of organic solvent and the dispensing ratio of bacteria residue are total throwing of organic solvent in the step (3)
Enter 1.0-10.0 times (V/W) that amount is equivalent to the total input amount of bacteria residue.
It is furthermore preferred that the additional amount of organic solvent and the dispensing ratio of bacteria residue are in the step (3), organic solvent it is total
Input amount is equivalent to 4.0-6.0 times (V/W) of the total input amount of bacteria residue.
Most preferably, the additional amount of organic solvent and the dispensing ratio of bacteria residue are in the step (3), organic solvent it is total
Input amount is equivalent to 4.5 times (V/W) of the total input amount of bacteria residue.
Preferably, the temperature that organic layer is concentrated in the step (4) is controlled at 40 DEG C -85 DEG C.
Preferably, the condition control that organic layer is concentrated in the step (4) is that air pressure is -0.080MPa, and temperature is 55 DEG C,
Concentration time is 10 hours.
Preferably, when be air pressure be atmospheric pressure, temperature is 85 DEG C for the condition control that organic layer is concentrated in the step (4),
Concentration time is 40 hours.
Preferably, in the step (4) when concentrate cooling stirring, mixing speed 150rpm, mixing time is 6-8
Hour.Mixing speed is controlled in lower range, extends mixing time so that crystal growth is slack-off and obtains bulky crude product
Crystal, convenient for following filtration step.
Present invention method of isolated or purified Lovastatin or its pharmaceutically acceptable salt from fermentation liquid includes following
Step:
(1) Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0；
(2) it filters, it is 40-50% that bacteria residue, which is dried up to bacteria residue water content,；
(3) ethyl acetate that 4.0-6.0 times of bacteria residue weight is added in bacteria residue, which impregnates 5-6 hours, to be filtered, to filtrate
Middle 1% NaHCO that filtrate volume 10% is added3Solution, filtrate separate water layer after standing；
(4) extraction filtrate is concentrated, air pressure is -0.080MPa or more when concentration, and temperature is 55 DEG C, and concentration carries out 10
A hour is concentrated into 5-7 times of product volume of small size, and then concentrate cools down and stirs, crystallization；
(5) it filters, and washs crude crystalline with 10-20 DEG C of cold ethyl acetate, drying crude crystalline obtains Lovastatin
Crude product.
When existing documents and materials disclose fermentation liquor pretreatment, with acid adding or alkali can be added, pH value is adjusted to when acid adding
1.0-5.0 or so, pH value is adjusted to 12.0 or so when adding alkali.According to actual production status of equipment, inventor selects to carry out acid adding
Processing, and it is lower by repetition test discovery pH value, and Lovastatin dissolution increases, but when pH is lower than 3.5, Lovastatin
Dissolution increase become slowly, and pH value is lower bigger to the corrosivity of equipment, increases equipment depreciation, increases production cost.
Therefore pH value is adjusted to 3.5-4.0 or so, the relationship of Equilibrium yield and production cost by inventor's selection.
The method of isolated or purified Lovastatin or its pharmaceutically acceptable salt of the present invention from fermentation liquid,
Extraction initial stage has carried out pH value adjusting to fermentation liquid, and extraction step later is carried out under conditions of pH value is close neutral,
A pH value is only adjusted in entire work flow, has not only saved acid-base reagent, and alleviates the corrosion to equipment.In addition, extracting
Single solvent ethyl acetate is used in the process, convenient for the recycling of solvent: while ethyl acetate addition only occurs in extraction and washing
Crude crystalline, and ethyl acetate is added again after bacteria residue drying, the whole additive amount of ethyl acetate is few.
Of the invention is creative in fermentation liquid adjusting pH value to acidity or when extraction, does not carry out heating cyclisation step
Suddenly, the step of but removing heating cyclisation, time needed for shortening extraction.
Specific embodiment
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.
Embodiment 1
Experimental group 1 (referring to CN 102344426)
Fermentation liquid lL, is adjusted to pH1.5 with 5mol/L HCl, stirs precipitation 1 hour, and filtering collects bacteria residue, in bacteria residue
0.25L butyl ester is added, extract liquor is collected in stirring extraction bacteria residue 3 hours, separation under the conditions of 55 DEG C of temperature, is kept the temperature at 30 DEG C, is added
50ml 0.5mol/L NaOH agitator treating 30 minutes, 15 minutes removal water phases are stood, it is organic to be added to 50ml 0.5mol/L
HCl agitator treating 30 minutes, stands 15 minutes removal water phases, organic to be added to 50ml deionized water, and agitator treating 30 minutes,
Stand 15 minutes removal water phases, organic phase is concentrated in vacuo (65-70 DEG C of temperature, vacuum degree is less than 0.08MPa) to volume about
30ml, cools to 12 DEG C, keeps the temperature 3 hours, is centrifugated and dry crude product.
Experimental group 2 (referring to US5712130)
The fermentation liquid of lL Lovastatin is reduced temperature to being lower than 20 degree, 500ml second is added with salt acid for adjusting pH value to 3-5
Acid butyl ester extracts 4 hours, and centrifugation retains organic phase, abandons water phase and bacteria residue.Organic phase at reduced pressure conditions 40 degree or so it is dense
Being reduced to volume is 50ml, is cyclized while concentration, and concentrate is cooled below 20 degree, and standing a few hours obtain
The Lovastatin of crystallization, Lovastatin is recrystallized.
Experimental group 3 (referring to US2003215932A)
63.5ml 2N sulfuric acid is added in 1L fermentation liquid, pH to 2.0 is warming up to 50-55 degree, stirs 22 hours.
894.1mL toluene extractive fermentation liquid, organic extractant phase liquid 5% sodium bicarbonate of 157.6mL and 78.8mL distilled water
Washing, washed organic extractant phase liquid are concentrated in vacuo to 23.5mL under 40-60 degree；Concentrate is cooled to 5-8 degree, stirring
2h, filtering, the toluene that filter cake is cooled to 5-10 degree with 15.3mL in advance wash, and filtration cakes torrefaction obtains Lovastatin.
Experimental group 4
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0。
Filtering, it is 50% that bacteria residue, which is dried up to bacteria residue water content,.
4.5 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO3 solution of filtrate volume 10% is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic
Phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
5 times of small sizes of amount, are then down to 10 DEG C for the temperature of concentrate, and stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Experimental group 5
10L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0
Filtering, it is 50% that bacteria residue, which is dried up to bacteria residue water content,.
5.0 times of bacteria residue weight of ethyl acetate is added in bacteria residue, is warming up to 85 DEG C, heat preservation is cyclized, after the completion of cyclisation, into
Row filtering, separates water layer after filtrate is stood, retain organic phase.
Organic phase is concentrated, the temperature of concentrate is then down to 10 DEG C, stirring keeps the temperature 6 hours, and mixing speed is
150rpm, crystallization.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lovastatin is obtained in 40 DEG C of right thick wet products of drying
Crude product.
Experimental group 6
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0
Filtering, it is 50% that bacteria residue, which is dried up to bacteria residue water content,.
It 5.0 times of bacteria residue weight of ethyl acetate is added in bacteria residue impregnates and be filtered for 5 hours, and with a small amount of ethyl acetate
Bacteria residue is washed, after the completion of filtering, water layer is separated after filtrate is stood 1 hour, retains organic phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
5 times of small sizes of amount, the temperature of concentrate is then down to 10 DEG C, stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
The experimental result of experiment 1-6 is shown in Table 1.
Table 1, experiment 1-6 Lovastatin crude yield list
Conclusion: it is cut down from the Lip river that the experimental data of above table crude product Lovastatin yield and purity can be seen that experimental group 4
Statin crude yield has reached 86%, much higher than the Lovastatin crude yield of experimental group 1-3,5-6.Experimental group 1-3,5-6 is
Comparative example, wherein experimental group 6 is to remove on the basis of experimental group 4 and " the 1% of filtrate volume 10% is added into filtrate
NaHCO3 solution " step, for illustrate be added NaHCO3 solution washing beneficial effect；And experimental group 5 is in experimental group 6
On the basis of further by the cyclisation step of enriching stage move to extraction simultaneously progress experimental program, to illustrate cyclisation step
Influence of the position change to experimental program, and experimental group 4 be the method for the invention, therefore, the method for the invention better than pair
Than the method for embodiment, mevastatin crude yield is significantly improved.
Embodiment 2
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0。
Filtering, bacteria residue drying.
5.0 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO3 solution of filtrate volume 10% is added in liquid, water layer is separated after filtrate is stood 1 hour, retains organic phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
5 times of small sizes of amount, are then down to 10 DEG C for the temperature of concentrate, and stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Bacteria residue water content is dried up to 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90% (without drying
Bacteria residue), experimental result is shown in Table 2.
The influence that table 2, bacteria residue water content extract Lovastatin
Conclusion: as can be seen from the table above, bacteria residue drying, addition ethyl acetate can be reduced by reducing bacteria residue water content
Amount, extraction time, and yield and purity can be improved.Drying bacteria residue is conducive to improve extraction efficiency.
When bacteria residue water content falls further below 50%, ethyl acetate additional amount and extraction time still will continue to
Bacteria residue water content is reduced and is reduced, and yield and purity increase slowly with the reduction of bacteria residue water content or do not increase.Illustrate bacterium
When slag water content is not higher than 50%, ethyl acetate additional amount and extraction time can only be reduced by further decreasing bacteria residue water content, be received
Rate and purity can't be obviously improved again；And water content is lower, the time for needing to dry up extends, and will increase the production time, therefore
Inventor determines that drying up bacteria residue be 40-50% to bacteria residue water content is optimal working condition.
Embodiment 3
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5.
Filtering, bacteria residue are dried up to bacteria residue water content 40%.
4.0 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO of filtrate volume 10% is added in liquid3Solution separates water layer after filtrate is stood 1 hour, retain organic phase.
Organic phase is concentrated, 55 degree or so progress 10h under reduced pressure are concentrated, the temperature of concentrate is then down to 5
DEG C, stirring heat preservation 6 hours, mixing speed 150rpm, crystallization.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Embodiment 4
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5.
Filtering, bacteria residue are dried up to bacteria residue water content 50%.
6.0 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO of filtrate volume 10% is added in liquid3Solution separates water layer after filtrate is stood 1 hour, retain organic phase.
Organic phase is concentrated, 40 degree or so progress 10h under reduced pressure are concentrated, the temperature of concentrate is then down to 5
DEG C, stirring heat preservation 6 hours, mixing speed 150rpm, crystallization.
Filtering, and crude crystalline is washed with 10 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 50 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Embodiment 5
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 4.0.
Filtering, it is 50% that bacteria residue, which is dried up to bacteria residue water content,.
5.0 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO3 solution of filtrate volume 10% is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic
Phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
5 times of small sizes of amount, the temperature of concentrate is then down to 10 DEG C, stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Embodiment 6
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0。
Filtering, it is 10% that bacteria residue, which is dried up to bacteria residue water content,.
1.0 times of bacteria residue weight of butyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
5.0% NaHCO3 solution of filtrate volume 10% is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic
Phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
7 times of small sizes of amount, the temperature of concentrate is then down to 10 DEG C, stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 20 DEG C of cold butyl acetate, Lip river, which must be arrived, in 50 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Embodiment 7
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0。
Filtering, it is 70% that bacteria residue, which is dried up to bacteria residue water content,.
It is added 10.0 times of bacteria residue weight in bacteria residue to be filtered for toluene soak 5 hours, after the completion of filtering, into filtrate
1.0% NaHCO3 solution of filtrate volume 10% is added, water layer is separated after filtrate is stood 1.5 hours, retains organic phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
7 times of small sizes of amount, the temperature of concentrate is then down to 10 DEG C, stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 20 DEG C of cold toluene, it is thick to obtain Lovastatin in 50 DEG C or so the thick wet products of drying
Product.
Embodiment 8
1L Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-
4.0。
Filtering, it is 50% that bacteria residue, which is dried up to bacteria residue water content,.
4.5 times of bacteria residue weight of ethyl acetate immersion is added in bacteria residue to be filtered within 5 hours, after the completion of filtering, to filter
1% NaHCO3 solution of filtrate volume 10% is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic
Phase.
Organic phase is concentrated, air pressure is -0.080Mpa or more when concentration, and 55 DEG C or so progress 10h are concentrated into product
5 times of small sizes of amount, are then down to 10 DEG C for the temperature of concentrate, and stirring heat preservation 6 hours, mixing speed 150rpm is tied
It is brilliant.
Filtering, and crude crystalline is washed with 15 DEG C of cold ethyl acetate, Lip river, which must be arrived, in 40 DEG C or so the thick wet products of drying cuts down him
Spit of fland crude product.
Crude product is dissolved in acetone, is heated to 55 DEG C, and using active carbon decoloring, is filtered to remove active carbon, is cooled to 10
DEG C, 2 hours are kept the temperature, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying, acquisition Lovastatin finished product.The Lovastatin of acquisition
Product yield is 82.0%, chromatographic purity 99.3%.
Claims (8)
1. a kind of method of isolated or purified Lovastatin, it is characterised in that the described method comprises the following steps:
(1) Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-4.0；
(2) it filters, it is 40-50% that bacteria residue, which is dried up to bacteria residue water content,；
(3) organic solvent is added in bacteria residue, impregnates, filtering is added the 1.0%-5.0%'s of filtrate volume 10% into filtrate
NaHCO3Solution separates water layer, retains organic layer；
(4) organic layer is concentrated, concentrate cooling stirring, crystallization；The cyclization of Lovastatin is carried out in concentration；
(5) it filters, and washs the crude crystalline being obtained by filtration with 10-20 DEG C of cold ethyl acetate, in 40 DEG C of -50 DEG C of drying crude products
Crystal obtains Lovastatin crude product.
2. the method for isolated or purified Lovastatin as described in claim 1, it is characterised in that bacteria residue is blown in the step (2)
It is dry that air at room temperature is used to dry up.
3. the method for isolated or purified Lovastatin as described in claim 1, it is characterised in that organic molten in the step (3)
Agent is hydrophobic organic solvent, is selected from butyl acetate, ethyl acetate, propyl acetate, Ethyl formate, hexanone, methylene chloride, chlorine
One of imitative, carbon tetrachloride, dichloroethanes, toluene or benzyl alcohol are several.
4. the method for isolated or purified Lovastatin as described in claim 1, it is characterised in that organic molten in the step (3)
The additional amount of agent and the dispensing ratio of bacteria residue are that total input amount of organic solvent is equivalent to the 1.0-10.0 of the total input amount of bacteria residue
Times, the ratio is volume mass ratio.
5. the method for isolated or purified Lovastatin as claimed in claim 4, it is characterised in that organic molten in the step (3)
The additional amount of agent and the dispensing ratio of bacteria residue are that total input amount of organic solvent is equivalent to 4.0-6.0 times of the total input amount of bacteria residue,
The ratio is volume mass ratio.
6. the method for isolated or purified Lovastatin as claimed in claim 5, which is characterized in that organic in the step (3)
The additional amount of solvent and the dispensing ratio of bacteria residue are that total input amount of organic solvent is equivalent to 4.5 times of the total input amount of bacteria residue, institute
Stating ratio is volume mass ratio.
7. the method for isolated or purified Lovastatin as described in claim 1, it is characterised in that organic layer in the step (4)
The temperature of concentration is controlled at 40 DEG C -85 DEG C.
8. the method for isolated or purified Lovastatin as claimed in claim 4, it is characterised in that the method includes following steps
It is rapid:
(1) Lovastatin fermentation liquid is taken, the concentrated sulfuric acid is slowly added under stirring and adjusts the pH of fermentation liquid to 3.5-4.0；
(2) it filters, it is 40-50% that bacteria residue, which is dried up to bacteria residue water content,；
(3) ethyl acetate that 4.0-6.0 times of volume of bacteria residue quality is added in bacteria residue, which impregnates 5-6 hours, to be filtered, to filtrate
The middle 1% NaHCO3 solution that filtrate volume 10% is added, filtrate separate water layer after standing；
(4) extraction filtrate is concentrated, air pressure is -0.080MPa or more when concentration, and temperature is 55 DEG C, and concentration carries out 10 small
When, it is concentrated into 5-7 times of product volume of small size, then stirs the cooling of concentrate, crystallization；
(5) it filters, and washs crude crystalline with 10-20 DEG C of cold ethyl acetate, drying crude crystalline obtains Lovastatin crude product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610883511.1A CN106518824B (en) | 2016-09-30 | 2016-09-30 | A kind of extraction process of Lovastatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610883511.1A CN106518824B (en) | 2016-09-30 | 2016-09-30 | A kind of extraction process of Lovastatin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106518824A CN106518824A (en) | 2017-03-22 |
| CN106518824B true CN106518824B (en) | 2019-06-04 |
Family
ID=58333085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610883511.1A Active CN106518824B (en) | 2016-09-30 | 2016-09-30 | A kind of extraction process of Lovastatin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106518824B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344426A (en) * | 2010-07-30 | 2012-02-08 | 北大方正集团有限公司 | Method for extracting and purifying lovastatin |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI9300303A (en) * | 1993-06-08 | 1994-12-31 | Krka Tovarna Zdravil | Process for isolation of hypolipemic effective substance |
| IN192861B (en) * | 2000-06-30 | 2004-05-22 | Ranbaxy Lab Ltd |
-
2016
- 2016-09-30 CN CN201610883511.1A patent/CN106518824B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344426A (en) * | 2010-07-30 | 2012-02-08 | 北大方正集团有限公司 | Method for extracting and purifying lovastatin |
Non-Patent Citations (1)
| Title |
|---|
| 重结晶;张昌军 等;《有机化学实验》;20060831;35-38 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106518824A (en) | 2017-03-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109956983B (en) | Method for extracting sucralose-6-ethyl ester | |
| CN107474088B (en) | Extraction process for industrial mass production of spinosad | |
| WO2017080520A1 (en) | Method for extracting avermectin b2 from avermectin ointment | |
| CN102050737B (en) | Method for extracting and purifying pleuromutilin | |
| WO2021036384A1 (en) | Method for purifying vitamin d3 | |
| CN102993134B (en) | A kind of method of purification of Lipstatin | |
| CN102344426A (en) | Method for extracting and purifying lovastatin | |
| CN106518824B (en) | A kind of extraction process of Lovastatin | |
| CN106496174B (en) | A kind of extraction and purification process of Lovastatin | |
| CN103896955B (en) | A kind of method extracting sesamin from sesame oil | |
| CN108976270B (en) | Preparation method of high-purity doramectin | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN110105195A (en) | A method of extracting dihydroartemisinic acid from sweet wormwood wax oil | |
| CN103012535B (en) | Method for preparing refined cholesterol by separating cholesterol from egg oil | |
| CN113366006B (en) | Method for purifying sucralose-6-ethyl ester | |
| CN106543196B (en) | A method of extracting sesamin from sesame oil | |
| CN101284775B (en) | Process for reclaiming 2-keto-L-gulonate by salting out method | |
| CN101417917A (en) | Method for preparing high-purity all-trans lycopene crystal | |
| CN102180781B (en) | Method for extracting and producing high-purity xanthohumol from residues generated by extracting hops by carbon dioxide | |
| CN109928982B (en) | Artemisinin separation and purification process | |
| CN1583736A (en) | Extraction and refinement of lovastatin | |
| CN101560235A (en) | Refining method of adenylic acid | |
| CN101531646A (en) | Method for extracting gibberellin by salting-out method | |
| CN103172602B (en) | Lovastatin purification method | |
| CN103172604B (en) | Lovastatin purification method combining auxiliary magnetic crystallization |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 753401 west side of head rock road south of 301 provincial road, Pingluo Industrial Park, Shizuishan, the Ningxia Hui Autonomous Region Applicant after: Li Zhu group (Ningxia) Pharmaceutical Co.,Ltd. Address before: The north side of Jianzhong Avenue, 301 provincial road, Pingluo Industrial Park, Shizuishan, the Ningxia Hui Autonomous Region Applicant before: LIVZON GROUP NINGXIA FUXING PHARMACEUTICAL CO.,LTD. |
|
| CB02 | Change of applicant information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20180621 Address after: The north side of Jianzhong Avenue, 301 provincial road, Pingluo Industrial Park, Shizuishan, the Ningxia Hui Autonomous Region Applicant after: LIVZON GROUP NINGXIA FUXING PHARMACEUTICAL CO.,LTD. Address before: 753400 west side of head rock road, 301 provincial road south of Pingluo Industrial Zone, Shizuishan, the Ningxia Hui Autonomous Region Applicant before: LIVZON GROUP NINGXIA XINBEIJIANG PHARMACEUTICAL CO.,LTD. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |