CN108976190B - Method for recovering lovastatin from lovastatin crystallization mother liquor - Google Patents
Method for recovering lovastatin from lovastatin crystallization mother liquor Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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 relates to a method for recovering lovastatin from lovastatin crystallization mother liquor. The recovery method comprises the following steps: 1) adding an inorganic alkali solution into the lovastatin crystallization mother liquor to form a lovastatin salt solution; 2) adding water into the salt solution obtained in the step 1), standing for layering, and taking the lower layer solution for twice extraction, wherein the twice extraction comprises the following steps: adding organic salt of inorganic acid into the lower solution, extracting with organic solvent, separating to obtain organic solvent layer, adding neutralizing acid into the organic solvent layer, washing, and separating to obtain upper solution; 3) adding oxalic acid into the upper layer solution obtained in the step 2), carrying out cyclization reaction, washing, and taking an organic solution layer; 4) and 3) carrying out reduced pressure concentration on the organic solution layer obtained in the step 3), and cooling and crystallizing to obtain the organic solvent. The recovery method has the advantages of simple condition control, convenience and easy operation, easily obtained and nontoxic used reagents, low cost, high yield which can reach over 74 percent, high purity of the obtained product which can reach 99.3 percent and content of the product which exceeds 99.0 percent, and suitability for industrial production.
Description
Technical Field
The invention relates to the field of organic chemical medicines, in particular to a method for recovering lovastatin from lovastatin crystallization mother liquor.
Background
LOVASTATIN (LOVASTATIN), chemical name: (S) a 2-methylbutanoic acid-15, 35,75,85, saR-1, 2,3,7, S, sa-hexahydro-3, 7-dimethylyl-8- { 2-di (ZR,4R) -4-diyl-6-oxo-2-tetrahydropycnidinyl-ethyl } 1-cai acetate; the molecular formula is C24H36O5, and the molecular weight is 404.55.
In 1987, lovatatin (Mevacor), a hypolipidemic drug of merck corporation, immediately after approval by FDA for marketing, attracted attention from the medical community, and its success opened a new stage for hypolipidemic drugs. The drug reduces the synthesis of liver cholesterol, stimulates the production of Low Density Lipoprotein (LDL) receptors and enhances the clearance of low density lipoprotein in plasma by inhibiting the activity of the enzyme, and the very low density lipoprotein level is also reduced, thereby being the first HMG-CoA reductase inhibitor approved to be on the market all over the world.
Lovastatin is a secondary metabolite of fungi, the industrially major producers being aspergillus terreus (aspergillus terreus), Penicillium citrinum (Penicillium citrinum) and monascurrobus (Monascusruber). There are two main extraction routes for extracting lovastatin from lovastatin fermentation broth: one method comprises acidifying lovastatin fermentation broth, flocculating to retain lovastatin in mycelium, filtering, extracting the residue with organic solvent, concentrating the extractive solution, crystallizing, separating to obtain crude lovastatin product, and recrystallizing to obtain final product. And the other is that lovastatin fermentation liquor is subjected to alkaline hydrolysis treatment to destroy the hypha wall, the lovastatin is hydrolyzed into ring-opened lovastatin salt, the lovastatin salt enters a water phase, the filtration is carried out, the filtrate is collected and precipitated by adding acid, the precipitate is collected by filtration and extracted by using organic solvent, the extract is concentrated, crystallized and separated to obtain lovastatin crude product, and the lovastatin crude product is recrystallized to obtain lovastatin finished product.
The extraction processes of the two lovastatin products do not effectively purify the extract, a small amount of fat-soluble impurities enter the crude product to greatly influence the quality and yield of the crude product, a large amount of fat-soluble impurities are remained in the mother liquor in the crystallization process, and 4.5-5.5m can be generated in each production of 1 ton of lovastatin finished product3The mother liquor of crystallization contains a large amount of lovaStatins, unit is above 30000U/ml. And only a very small part of lovastatin can be recovered by carrying out simple secondary concentration crystallization on the crystallization mother liquor. Therefore, the current extraction process treats the crystallization mother liquor as production waste, and the aim of effective recovery cannot be achieved, so that the extraction yield is low.
In order to improve the extraction yield of lovastatin and reduce the production cost, the Chinese patent CN103012344A describes that lovastatin is recovered from lovastatin mother liquor, the technical key points are that under the alkaline condition, the lovastatin is subjected to ring opening, two precipitating agents are added to obtain precipitation, filter residue is obtained by filtration, after organic solution is extracted, acid washing is carried out, lactonization is carried out in oxalic acid solution, water washing, concentration and crystallization are carried out, a crude product is crystallized by ethanol, the recovery yield is 53.6 percent, the content reaches 99.2 percent, the process is complex, and the yield is lower.
Therefore, a recovery method with relatively simple process and quality and yield is needed.
Disclosure of Invention
The invention provides a method for recovering lovastatin from crystallization mother liquor, which has the advantages of high yield, simple operation, low cost and strong practicability.
The recovery method comprises the following steps:
1) adding an inorganic alkali solution into the lovastatin crystallization mother liquor to form a lovastatin salt solution;
2) adding water into the salt solution obtained in the step 1), standing for layering, and taking the lower layer solution for two-time extraction (adding organic salt of inorganic acid into the lower layer solution, extracting with an organic solvent, separating to obtain an organic solvent layer, adding neutralizing acid into the organic solvent layer, washing, and separating to obtain an upper layer solution);
3) adding oxalic acid into the upper layer solution obtained in the step 2), carrying out cyclization reaction, washing, and taking an organic solution layer;
4) and 3) carrying out reduced pressure concentration on the organic solution layer obtained in the step 3), and cooling and crystallizing to obtain the organic solvent.
The crude lovastatin product can be recovered by the method, and the yield of the lovastatin recovered from the mother liquor is up to 90 percent. Further purification operations can be carried out by those skilled in the art according to conventional procedures. The invention also provides a more preferable subsequent purification operation, which comprises the following steps (serial numbers):
5) dissolving the lovastatin crude product obtained in the step 4) with ethanol, adding activated carbon for decolorization, performing hot filtration, standing, cooling for crystallization, separating, and performing vacuum drying to obtain a secondary finished product;
6) and (3) thermally dissolving the secondary finished product obtained in the step 5) by using ethanol, standing, cooling, crystallizing, separating, and drying in vacuum to obtain a lovastatin product.
After subsequent purification operation, the yield of the lovastatin recovered from the mother liquor is 74%, the HPLC purity of the product is 99.3%, and the content is more than 99.0%.
In the recovery method, the lovastatin mother liquor in the step 1) is preferably mother liquor obtained by carrying out primary crystallization treatment on lovastatin fermentation liquor, and mother liquor obtained after secondary and tertiary crystallization or a mixed solution thereof. Such crystallization treatment may be a method generally employed in the art.
The inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium fluoride and sodium fluoride. The inorganic base is selected to have the function of leading the lovastatin to open the ring to form the lovastatin salt.
Preferably, the molar ratio of the inorganic base to lovastatin in the crystallization mother liquor is (1.0-1.6): 1.
in the recovery method of the present invention, preferably, step 1) further comprises adding a lower alcohol or ketone as a solvent during the reaction, wherein the lower alcohol or ketone is selected from one or more of methanol, ethanol, propanol, isopropanol and acetone; the alcohol or ketone has the advantages of good miscibility with water and organic solvent, low cost and less residue in the product. Ethanol is preferred.
More preferably, the volume ratio of the amount of the lower alcohol or ketone to the crystallization mother liquor is (0.1-0.7): 1, preferably (0.15-0.5): 1.
preferably, the conditions in the step 1) are controlled at 30-48 ℃; preferably 35-43 deg.C. In this temperature range, the reaction is mild and the amount of impurities produced is small.
In the recovery method of the present invention, preferably, in the step 2), the organic salt of the inorganic acid is one or more selected from methylamine sulfate, ethylamine sulfate, methylamine hydrochloride, ethylamine hydrochloride, methylamine nitrate, ethylamine nitrate, methylamine phosphate and ethylamine phosphate. The organic salt has the advantages that the lower weak base salt of strong acid and medium strong acid can react with sodium and potassium lovastatin carboxylate to generate lower ammonium salt of lovastatin carboxylate, the lower ammonium salt can be extracted by a water-insoluble organic solvent under alkaline condition, and other impurities and salts thereof are remained in a water phase.
More preferably, the mass ratio of the added mass of the organic salt of the inorganic acid to the mass of the lower layer solution obtained in step 2) is 1: (40-200), preferably 1: (50-130).
In step 2), preferably, the organic solvent is selected from one or more of ethyl acetate, ethyl formate, methyl acetate, propyl formate, methyl propionate, ethyl propionate, propyl propionate, butyl formate, butyl acetate, methyl butyrate, ethyl butyrate, toluene and benzene; butyl acetate is preferred. The organic solvent has the advantages of good extraction effect, moderate boiling point, less volatilization and less residue in the finished product.
In step 2), preferably, the acid for neutralization is selected from sulfuric acid, sulfurous acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sodium hydrogen sulfate, potassium dihydrogen phosphate, sodium dihydrogen phosphate and oxalic acid. Hydrochloric acid is preferred. The molar concentration of the acid for neutralization is 1-2 mol/L. The neutralization acid not only can achieve the purpose of neutralization, but also has the advantage of partial dehydration and lactonization of lovastatin ring-opening acid.
In the recovery method, the mass volume (g/ml) ratio of oxalic acid to the crystallization mother liquor in the step 3) is 1: (450- & lt1800), preferably 1: (500-1300).
Preferably, the cyclization reaction in the step 3) is performed at a temperature of 70-90 ℃ (more preferably 80 ℃) for 1.5-2.5 hours under reflux. The "cyclization reaction" in the present invention refers to a reaction in which ring-opened lovastatin is closed under acidic conditions. The oxalic acid and the temperature are controlled, so that the ring closing speed is high, the generated impurities are less, the oxalic acid is easy to remove, and the lovastatin product with higher purity can be obtained.
In the recovery method, the step 4) is gradually cooling crystallization, and the temperature is reduced to 3-13 ℃ according to the speed of 2.3 ℃/h.
In the step 5) of the method, the lovastatin crude product is crystallized, and the adding amount of ethanol is 2.4-8.5 ml per gram of lovastatin crude product; preferably 2.6-4.5 ml.
In the step 6) of the method, the addition amount of the ethanol used for crystallizing the secondary finished product is 2.3-5 ml per gram of lovastatin secondary finished product; preferably 2.5-4 ml.
The method comprises the steps of filtering, extracting, crystallizing and purifying lovastatin fermentation liquor to obtain crystallization mother liquor which contains a large amount of fat-soluble impurities, and reacting under mild alkaline conditions to make lovastatin and a dimer thereof into lovastatin salt; extracting twice in alkaline environment to remove most impurities, refluxing and lactonizing under acidic condition, concentrating under reduced pressure, cooling for crystallization, separating, and drying to obtain lovastatin crude product; recrystallizing the crude product with ethanol twice to obtain the lovastatin product. The yield of lovastatin in the mother liquor reaches 74 percent, the HPLC purity of the product reaches 99.3 percent, the content of the lovastatin in the mother liquor reaches more than 99.0 percent, and the lovastatin content accords with the 2010 version of Chinese pharmacopoeia.
The recovery method has the advantages of simple condition control, convenience and easy operation, easily obtained and nontoxic used reagents and low cost. The yield is high and can reach over 74 percent, the purity of the obtained product can reach 99.3 percent, the content exceeds 99.0 percent, and the method is suitable for industrial production.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the following examples, reagents are commercially available, for example, from Qingsheng chemical trade, Inc., Tianjin, unless otherwise specified.
The liquid chromatograph used in each of the following examples was available from Shimadzu corporation of Japan, model number LC-2010 AHT; the rotary evaporator can be purchased from Shanghai Yangrong Biochemical apparatus factories, and is of model RE 5220; the JJ-1 electric stirrer is available from Jiangsu Jintanronghua instruments manufacturing.
The lovastatin crystallization mother liquor used in the following examples can be prepared by the method of test example 1, but the present invention is not limited thereto.
The lovastatin crystallization mother liquor can be mother liquor obtained by carrying out primary crystallization treatment on lovastatin fermentation liquor, and mother liquor obtained by carrying out secondary crystallization and tertiary crystallization or mixed liquor thereof. Such crystallization treatment may be a method generally employed in the art.
For example, fermentation broth of lovastatin can be acidified and filtered to obtain residue containing lovastatin; extracting the fungus residue with organic solvent to obtain extractive solution, lactonizing, concentrating, and crystallizing to obtain lovastatin crude product, and separating to obtain crystallization mother liquor.
For example, the lovastatin fermentation broth can be subjected to alkaline hydrolysis treatment to break the hyphal wall and hydrolyze lovastatin to open the loop and form a salt; filtering, collecting filtrate, carrying out acidification precipitation treatment on the filtrate, filtering and collecting precipitate, extracting the precipitate with an organic solvent to obtain an extract, carrying out lactonization, concentration and crystallization on the extract to obtain a lovastatin crude product, wherein the liquid after the lovastatin crude product is separated is lovastatin crystallization mother liquor.
For example, the crude lovastatin product is dissolved by ethanol, added with active carbon for decolorization, filtered by heating, crystallized by cooling, and separated to obtain lovastatin crystallization mother liquor. Test example 1 provides a means for obtaining a lovastatin mother liquor.
The measurement method of the unit and content of lovastatin used in the following examples is as follows:
the unit and content determination method of lovastatin comprises the following steps:
1. preparation of working reference solution
Taking 10mg of lovastatin working reference substance in a 25ml volumetric flask, precisely weighing, dissolving with an appropriate amount of methanol, fixing the volume to scale, and shaking up to obtain the lovastatin-containing liquid.
2. Preparation of test solution
Taking 10ml of uniform lovastatin test solution or finished product (seed solution, fermentation solution, filter pressing waste liquid, crystallization mother liquor) or weighing proper amount of finished product, dissolving with proper amount of methanol, mixing well, and filtering to obtain the final product.
3. Measurement of
And starting the liquid chromatograph, taking 40% methanol water solution as a mobile phase, enabling the flow rate to be 1ml/min, accurately sucking 10 mu l of reference substance solution after the system is stabilized, injecting the reference substance solution into the chromatograph, and recording the chromatogram. And carrying out parallel sample injection for three times, and taking the average value of the peak areas of the three times as the peak area of the control solution. And injecting the test solution into a chromatograph, recording the chromatogram, and calculating the content of the lovastatin effective component in each test solution according to the following formula.
4. Computing
Lovastatin content (μ g/ml) ═ A1+ A2)/A × C × sample dilution multiple
In the formula: a1-peak area of lovastatin acid in test solution;
a2-the peak area of lovastatin in the test sample solution;
a is the peak area of the working control solution.
C-working control solution concentration (μ g/ml)
Test example 1
1. Lovastatin fermentation process
Inoculating 3-5L of Aspergillus terreus seed solution into a first-class seed tank, wherein 1000L of sterile first-class seed culture solution containing peptone, soybean meal, maltose, glucose and cottonseed cake powder with pH value of 6.6-7.0 is loaded; culturing at 25-28 deg.C for 80-150 hr, and transferring into secondary seed tank for culturing.
The secondary seed tank is loaded with 4000-; culturing at 25-28 deg.C for 40-120 hr, and transferring into fermenter for culturing.
The fermentation tank is loaded with 38000-; fermenting and culturing at 25-28 deg.C for 160-180 hr, and placing into a pot when the mycelium is at the final stage of metabolism.
2. Extraction process of lovastatin
And (3) filter pressing:
after fermentation liquid is inoculated, an acidification barrel is started to stir, and 5-6mol of × L is used-1Adjusting the pH value of the solution to 2.5-3.5 by HCl, introducing air, stirring for more than 0.5 hour, and extracting a filter cake after filter pressing.
And (3) extraction:
adding the fungus residue into an extraction barrel, adding 5-15L/Kg of butyl acetate into the extraction barrel, and stirring at 45-50 deg.C for 2-6 hr. Then pumping into an automatic lower discharging separator for solid-liquid separation, and concentrating the extract liquor.
Concentration:
feeding and concentrating under vacuum degree of less than or equal to-0.07 Mpa, concentrating under heating at steam pressure of less than or equal to 0.2Mpa and at temperature of less than or equal to 70 ℃. The material is concentrated in a concentration tank until crystallization is just separated out, and the material is immediately put into a crystallization tank for crystallization.
And (3) crystallization separation:
the concentrated material enters a crystallizing tank, is cooled to below 30 ℃ by low-temperature water, is stirred and crystallized, and lasts for 8-24 hours. And (3) separating the materials in a three-foot centrifuge to obtain a lovastatin crude product and a lovastatin crystallization mother liquor respectively.
Example 1
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of 95% ethanol into 1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 120ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 280ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.12mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, gradually cooling for crystallization, separating at 13 deg.C, and drying to obtain 38.06g lovastatin crude product; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 35.03g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 32.61g is obtained, the yield is 75.85%, the HPLC content is 99.51% and the lovastatin content is 99.15% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 2
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 300ml of 95% ethanol, adding 120ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 480ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.12mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 37.50 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 33.78g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 31.4g is obtained, the yield is 73.08%, the HPLC content is 99.44% and the lovastatin content is 99.19% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 3
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of 95% ethanol into 1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 110ml of 1mol/l sodium carbonate solution, stirring, heating to 43 ℃, keeping for 50min, adding 290ml of water, standing for layering, adding 700ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.11mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain 38.18g lovastatin crude product; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 34.14g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 32.05g is obtained, the yield is 74.61%, the HPLC content is 99.57% and the lovastatin content is 99.21% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 4
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of acetone into 1000ml of lovastatin crystallization mother liquor with the unit of 42617U/ml, adding 120ml of 1mol/l sodium carbonate solution, stirring, heating to 35 ℃, keeping for 50min, adding 280ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.12mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 36.53 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. Thus, 31.61g of a second product was obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 29.50g is obtained, the yield is 68.53%, the HPLC content is 98.86% and the lovastatin content is 99.01% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 5
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 300ml of 95% ethanol, adding 105ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 495ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.13mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 0.75g of oxalic acid into the upper layer, refluxing and cyclizing for 2.5 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 36.92 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 33.88g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 31.47g is obtained, the yield is 72.99%, the HPLC content is 98.45% and the lovastatin content is 98.85% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 6
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of 95% ethanol into 1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 110ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 280ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of ethylamine hydrochloride solution containing 0.12mol, standing for layering, adding 130ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 2.0g of oxalic acid into the upper layer, refluxing and cyclizing for 1.5 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 400ml of deionized water, stirring and washing, standing and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 34.05 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 30.47g of a secondary finished product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 28.02g is obtained, the yield is 64.18%, the HPLC content is 96.64% and the lovastatin content is 97.61% by inspection of 2010 version of Chinese pharmacopoeia.
Example 7
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 500ml of methanol into 1000ml of lovastatin crystallization mother liquor with the unit of 42617U/ml, adding 115ml of 1mol/l sodium hydroxide solution, stirring, heating to 38 ℃, keeping for 50min, adding 585ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.12mol, standing for layering, adding 180ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain crude lovastatin 36.21 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 33.42g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 30.12g is obtained, the yield is 69.34%, the HPLC content is 97.93% and the lovastatin content is 98.11% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 8
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml of lovastatin crystallization mother liquor, 42617U/ml in unit, adding 150ml of isopropanol, adding 130ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 270ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.14mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain crude lovastatin 35.46 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. Thus obtaining 31.68g of a secondary finished product.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 29.41g is obtained, the yield is 67.99%, the HPLC content is 98.26% and the lovastatin content is 98.52% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 9
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of 95% ethanol into 1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 120ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 280ml of water, standing for layering, adding 900ml of ethyl acetate into the lower layer, adding 50ml of methylamine sulfate solution containing 0.12mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain 38.02g lovastatin crude product; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 34.77g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 32.43g is obtained, the yield is 75.28%, the HPLC content is 99.48% and the lovastatin content is 98.92% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 10
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
adding 200ml of 95% ethanol into 1000ml of lovastatin crystallization mother liquor with unit of 42617U/ml, adding 60ml of 0.5mol/l sodium hydroxide solution, reacting for 20min, adding 60ml of 0.5mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 280ml of water, standing for layering, adding 800ml of butyl acetate into the lower layer, adding 50ml of methylamine hydrochloride solution containing 0.12mol, standing for layering, adding 150ml of 1mol/l hydrochloric acid solution into the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 200ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 37.94 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 34.69g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 32.34g is obtained, the yield is 75.30 percent, and the HPLC content is 99.45 percent and the lovastatin content is 99.23 percent by inspection of the 2010 version of Chinese pharmacopoeia.
Example 11
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml lovastatin crystallization mother liquor with unit of 42617U/ml, adding 200ml lovastatin mother liquor crystallized by ethanol and unit of 9873U/ml, adding 125ml sodium carbonate solution with 1mol/l, stirring, heating to 38 ℃, keeping for 50min, adding 280ml water, standing for layering, adding 800ml butyl acetate in the lower layer, adding 50ml methylamine hydrochloride solution containing 0.125mol, standing for layering, adding 150ml hydrochloric acid solution with 1mol/l in the upper layer, standing for layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 210ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain crude lovastatin 39.17 g; dissolving 120ml ethanol, adding 0.8g active carbon, filtering, diluting to a constant volume of 130ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 35.62g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 33.49g is obtained, the yield is 74.55%, the inspection of the 2010 version of Chinese pharmacopoeia shows that the HPLC content is 99.53%, and the lovastatin content is 99.24%.
Example 12
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml lovastatin crystallization mother liquor with unit of 42617U/ml, adding 300ml lovastatin mother liquor crystallized by ethanol and unit of 9873U/ml, adding 130ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 470ml water, standing for layering, adding 500ml butyl acetate and 500ml toluene in the lower layer, adding 50ml methylamine hydrochloride solution containing 0.13mol, standing for layering, adding 160ml hydrochloric acid solution containing 1mol/l in the upper layer, standing and layering; adding 1.6g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 300ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to 215ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain lovastatin crude product 40.10 g; dissolving 100ml ethanol, adding 0.8g active carbon, hot filtering, fixing volume to 110ml, standing for crystallization, gradually cooling to 20 deg.C, separating, and vacuum drying. 36.53g of a secondary product is obtained.
Dissolving 120ml ethanol with heat, diluting to 150ml volume, standing for crystallization, gradually cooling to 5 deg.C, separating, and vacuum drying. 33.56g is obtained, the yield is 72.86%, the HPLC content is 99.24% and the lovastatin content is 98.95% by inspection of the 2010 version of Chinese pharmacopoeia.
Example 13
This example provides a method for recovering lovastatin from a lovastatin crystallization mother liquor, comprising the steps of:
1000ml lovastatin crystallization mother liquor with unit of 42617U/ml, adding 400ml lovastatin mother liquor crystallized by ethanol and unit of 9873U/ml, adding 130ml of 1mol/l sodium carbonate solution, stirring, heating to 38 ℃, keeping for 50min, adding 670ml water, standing for layering, adding 850ml butyl acetate in the lower layer, adding 50ml methylamine hydrochloride solution containing 0.13mol, standing for layering, adding 160ml hydrochloric acid solution containing 1mol/l in the upper layer, standing for layering; adding 1.7g of oxalic acid into the upper layer, refluxing and cyclizing for 2 hours in a water bath at 80 ℃ under stirring, cooling to 30 ℃, adding 340ml of deionized water, stirring and washing, standing, and layering; concentrating the upper layer under reduced pressure to volume of 220ml, cooling for crystallization, separating at 13 deg.C, and drying to obtain crude lovastatin 40.82 g; dissolving 160ml of ethanol in heat, adding 0.8g of active carbon, filtering in heat, fixing the volume to 190ml, standing for crystallization, gradually cooling to 5 ℃, separating, and drying in vacuum. 36.32g of a secondary finished product is obtained.
Dissolving in 90ml ethanol, standing for crystallization, gradually cooling to 20 deg.C, separating, and vacuum drying. 34.47g is obtained, the yield is 73.18%, the HPLC content is 99.17% and the lovastatin content is 98.87% by inspection of the 2010 version of Chinese pharmacopoeia.
Comparative example 1
The comparative example provides a method for recovering lovastatin from lovastatin crystallization mother liquor, which comprises the following steps:
taking 1000ml of lovastatin crystallization mother liquor, wherein the unit of lovastatin is 42617U/ml, adding 430ml of 0.4mol/L sodium bicarbonate solution, stirring and washing for 30 minutes, standing after stirring and washing, and separating a water phase to obtain 975ml of an organic phase; 965ml of 1% oxalic acid aqueous solution was added thereto, and washing was carried out with stirring for 1 hour, followed by standing and separation of the aqueous phase to obtain 958ml of an organic phase. Adding 41ml acetic acid into the washed organic phase, performing cyclization treatment at 80 ℃ for 2 hours, properly concentrating at 75 ℃ and under the condition that the vacuum degree is less than or equal to minus 0.09Mpa, standing for crystallization for 8 hours, performing suction filtration to obtain 34.09g of crude lovastatin, performing thermal dissolution by using 120ml ethanol, adding 0.8g of activated carbon, performing thermal filtration, fixing the volume to 130ml, standing for crystallization, gradually cooling to 10 ℃, separating, and performing vacuum drying. 29.51g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 27.04g is obtained, the yield is 63.45%, the HPLC content is 89.84% and the lovastatin content is 91.63% by inspection of the 2010 version of Chinese pharmacopoeia.
Comparative example 2
The comparative example provides a method for recovering lovastatin from lovastatin crystallization mother liquor, which comprises the following steps:
taking 1000ml of lovastatin crystallization mother liquor, wherein the unit of lovastatin is 42617U/ml, adding 430ml of 0.4mol/L sodium bicarbonate solution, stirring and washing for 30 minutes, standing after stirring and washing, and separating a water phase to obtain 975ml of an organic phase; 965ml of 1% oxalic acid aqueous solution was added thereto, and washing was carried out with stirring for 1 hour, followed by standing and separation of the aqueous phase to obtain 956ml of an organic phase. Adding 5% oxalic acid ethanol solution (5g oxalic acid is dissolved in 100ml absolute ethyl alcohol) 100ml into the washed organic phase, performing cyclization treatment at 80 ℃ for 2 hours, properly concentrating at 73 ℃ and under the vacuum degree of less than or equal to-0.09 Mpa, standing for crystallization for 8 hours, performing suction filtration to obtain crude lovastatin 33.61g, performing thermal dissolution by using 120ml ethanol, adding 0.8g activated carbon, performing thermal filtration, fixing the volume to 130ml, standing for crystallization, gradually cooling to 10 ℃, separating, and performing vacuum drying. 29.22g of a secondary product is obtained.
Dissolving 100ml ethanol under heating, diluting to a constant volume of 110ml, standing for crystallization, gradually cooling to 10 deg.C, separating, and vacuum drying. 26.86g is obtained, the yield is 63.03 percent, the HPLC content is 91.02 percent and the lovastatin content is 92.95 percent according to the examination of the 2010 version of Chinese pharmacopoeia.
Comparative example 3
The comparative example provides a method for recovering lovastatin from lovastatin crystallization mother liquor, which comprises the following steps:
taking 1000ml of lovastatin crystallization mother liquor, wherein the unit of lovastatin is 49896U/ml, adding 500ml of 0.4mol/L sodium bicarbonate solution, stirring and washing for 30 minutes, standing after stirring and washing, and separating a water phase to obtain 970ml of an organic phase; 970ml of 1% oxalic acid aqueous solution was added thereto, and the mixture was washed with stirring for 1 hour, allowed to stand, and the aqueous phase was separated to obtain 950ml of an organic phase. Adding 5% oxalic acid ethanol solution (5g oxalic acid is dissolved in 100ml absolute ethyl alcohol) 114ml into the washed organic phase, performing cyclization treatment at 80 ℃ for 2 hours, properly concentrating at 73 ℃ and vacuum degree of less than or equal to-0.09 Mpa, standing for crystallization for 8 hours, and performing suction filtration to obtain 39.2g lovastatin crude product, wherein the content is 78.86%, and the yield is 78.56%.
Comparative example 4
The comparative example provides a method for recovering lovastatin from lovastatin crystallization mother liquor, which comprises the following steps:
taking 1000ml of lovastatin crystallization mother liquor, wherein the unit of lovastatin is 49896U/ml, adding 500ml of 0.4mol/L sodium bicarbonate solution, stirring and washing for 30 minutes, standing after stirring and washing, and separating a water phase to obtain 970ml of an organic phase; 970ml of 1% oxalic acid aqueous solution was added thereto, and the mixture was washed with stirring for 1 hour, allowed to stand, and the aqueous phase was separated to obtain 950ml of an organic phase. Adding 47.5ml acetic acid into the washed organic phase, performing cyclization treatment at 80 deg.C for 2 hr, concentrating at 75 deg.C under vacuum degree of-0.09 Mpa or less, standing for crystallization for 8 hr, and vacuum filtering to obtain lovastatin crude product 39.87g with content of 75.87% and yield of 79.9%.
The lovastatin product obtained by the recovery method provided by the invention can reach a yield of over 74 percent, an HPLC purity of 99.3 percent and a content of over 99.0 percent, and conforms to the 2010 version of Chinese pharmacopoeia; the yield of the lovastatin product obtained by the recovery method provided by the comparative example is 63.45%, the HPLC purity of the product is 91.02%, the content is 92.95%, and the product does not accord with the 2010 version of Chinese pharmacopoeia. Therefore, the method is greatly different from the prior art in yield and quality.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (17)
1. A method for recovering lovastatin from a lovastatin crystallization mother liquor is characterized by comprising the following steps of:
1) adding an inorganic alkali solution into the lovastatin crystallization mother liquor to form a lovastatin salt solution;
2) adding water into the salt solution obtained in the step 1), standing for layering, and taking the lower layer solution for twice extraction, wherein the twice extraction comprises the following steps:
adding organic salt of inorganic acid into the lower solution, extracting with organic solvent, separating to obtain organic solvent layer, adding neutralizing acid into the organic solvent layer, washing, and separating to obtain upper solution;
3) adding oxalic acid into the upper layer solution obtained in the step 2), carrying out cyclization reaction, washing, and taking an organic solution layer;
4) decompressing and concentrating the organic solution layer obtained in the step 3), and cooling and crystallizing;
5) dissolving the lovastatin crude product obtained in the step 4) with ethanol, adding activated carbon for decolorization, performing hot filtration, standing, cooling for crystallization, separating, and performing vacuum drying to obtain a secondary finished product;
6) thermally dissolving the secondary finished product obtained in the step 5) with ethanol, standing, cooling, crystallizing, separating, and drying in vacuum to obtain a lovastatin product;
the step 1) also comprises adding lower alcohol or ketone as a reaction solvent, wherein the lower alcohol or ketone is selected from one or more of methanol, ethanol, propanol, isopropanol and acetone; step 1) is carried out at the temperature of 30-48 ℃; the acid for neutralization is selected from hydrochloric acid or oxalic acid; the molar concentration of the acid for neutralization is 1-2 mol/L; the organic salt of the inorganic acid is selected from one or more of methylamine sulfate, methylamine hydrochloride and ethylamine hydrochloride; the inorganic base in the step 1) is selected from sodium hydroxide or sodium carbonate; the organic solvent is selected from one or more of ethyl acetate, butyl acetate and toluene.
2. A recovery process according to claim 1, characterized in that the inorganic base in step 1) is sodium carbonate.
3. The recovery process of claim 2, wherein the molar ratio of the inorganic base to lovastatin in the lovastatin crystallization mother liquor is (1.0-1.6): 1.
4. the recovery process of claim 1, wherein the lower alcohol or ketone is ethanol.
5. The recovery process according to claim 4, wherein the volume ratio of the lower alcohol or ketone to the mother liquor of the lovastatin crystallization is (0.1-0.7): 1.
6. the recovery process according to claim 5, wherein the volume ratio of the lower alcohol or ketone to the mother liquor of the lovastatin crystallization is (0.15-0.5): 1.
7. the recovery method according to claim 1, wherein the step 1) is performed at 35 to 43 ℃.
8. The recovery process according to any one of claims 1 to 7, wherein the organic salt of an inorganic acid is ethylamine hydrochloride.
9. The recovery method according to claim 8, wherein the mass-to-volume ratio of the organic salt of the inorganic acid to the lower layer solution obtained in step 2) is 1: (40-200).
10. The recovery method according to claim 9, wherein the mass-to-volume ratio of the organic salt of the inorganic acid to the lower layer solution obtained in step 2) is 1: (50-130).
11. The recovery process of claim 1, wherein the organic solvent is butyl acetate.
12. The recovery method according to any one of claims 1 to 7, wherein the mass-volume usage ratio of oxalic acid to the crystallization mother liquor in step 3) is 1: (450-1800).
13. The recovery method according to claim 12, wherein the mass-volume usage ratio of oxalic acid to the crystallization mother liquor in step 3) is 1: (500-1300).
14. The recovery process according to any one of claims 1 to 7, wherein the cyclization reaction in the step 3) is a reflux cyclization at a temperature of 70 to 90 ℃ for 1.5 to 2.5 hours.
15. The recovery method according to any one of claims 1 to 7, wherein the temperature-reduced crystallization in the step 6) is a gradual temperature-reduced crystallization, and the temperature is reduced to 3-13 ℃ at a speed of 2.3 ℃/h.
16. The recovery method according to any one of claims 1 to 7, wherein in the step 5), the crude lovastatin is crystallized, and the amount of ethanol added is 2.4 to 8.5 ml per gram of the crude lovastatin;
and/or the presence of a gas in the gas,
in the step 6), the addition amount of the ethanol used by the secondary finished product is 2.3-5 ml per gram of lovastatin secondary finished product.
17. The recovery method according to any one of claims 1 to 7, wherein in the step 5), the crude lovastatin is crystallized, and the amount of ethanol added is 2.6 to 4.5 ml per gram of the crude lovastatin;
and/or the presence of a gas in the gas,
in the step 6), the addition amount of the ethanol used by the secondary finished product is 2.5-4 ml per gram of lovastatin secondary finished product.
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