CN102746262B - Method for purifying Compactin - Google Patents
Method for purifying Compactin Download PDFInfo
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- CN102746262B CN102746262B CN201110101291.XA CN201110101291A CN102746262B CN 102746262 B CN102746262 B CN 102746262B CN 201110101291 A CN201110101291 A CN 201110101291A CN 102746262 B CN102746262 B CN 102746262B
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Abstract
The invention discloses a method for purifying Compactin, which comprises the following steps; A, using a burden water for heating the Compactin crude product and dissolving to obtain a solvent, filtering the solvent to obtain a filtrate; B, performing pressure reduction concentration on the filtrate from the step A, and crystallizing the concentrate to obtain a crystallization liquid under the low temperature; C, performing a solid-liquid separation on the crystallization liquid from the step B to obtain a primary crystallization product; D, using the burden water for dissolving the primary crystallization product from the step C and then crystallizing at low temperature to obtain the crystallization liquid; E, performing the solid-liquid separation on the crystallization liquid from the step D to obtain the secondary crystallization product; and F, performing pressure reduction and drying the crystallization product from the step E to obtain the finished product. The purifying method has the advantages of simple operation, short production period, low cost and high yield, the content of the obtained finished product is more than 99%, and the content of the impurity dihydro Compactin is lower than 0.01%.
Description
Technical field
The invention belongs to medicine industry technical field, relate in particular to the precursor of blood lipid regulation medicine Pravastatin---the purification process of ML236B.
Background technology
ML236B (Compactin) has another name called mevastatin (Mevastatin), CAS registration number 73573-88-3, chemical name (S)-2-Methyl Butyric Acid-(1S, 7S, 8S, 8aR)-1, 2, 3, 7, 8, 8a-six hydrogen-7-methyl-8-{2-[(2R, 4R)-4-hydroxyl-6-oxo-2H-THP trtrahydropyranyl]-ethyl }-1-naphthalene ester, it is the secondary metabolite of a kind of fungi, within 1976, from Penicillium citrinum nutrient solution, found by Endo etc. the earliest, belong to HMG-CoA reductase inhibitor, can effectively suppress the activity of HMG-CoA reductase enzyme, suppress the synthetic of body inner cholesterol.After develop the microbial transformation product derivative Pravastatin (Pravastatin) of ML236B by Japanese SanKyo company, reduce have aspect cholesterol stronger
Effect, be new and effective blood lipid regulation medicine, therefore the many parent materials of producing as Pravastatin of ML236B.Pravastatin is a kind of wetting ability HMG-CoA reductase inhibitor certain specific carbon back hydroxylation of ML236B being obtained by microorganism, it is synthetic by suppressing cholesterol in human body, can effectively reduce serum total cholesterol, low-density lipoprotein and triglyceride level, and high density lipoprotein increasing, be used for the treatment of at first hyperlipidemia and familial hypercholesterolemia, indication constantly expanded afterwards, can slow down atherosclerotic development, reduce the generation of coronary atherosclerosis and clinical cardiovascular events; Long-term taking Pravastatin, no matter whether patient suffers from coronary heart disease, can lower the mortality ratio due to a variety of causes, become in current statins only can be used for cholesterol levels higher or medicine that the patient of coronary heart disease carries out heart trouble, the defence of apoplexy firsts and seconds.Also studies show that, Pravastatin can also reduce the incidence of diabetes and alzheimer's disease (senile dementia); Can suppress the propagation of liver cancer cell; Can effectively treat ulcerative colitis, few side effects, half a year, recurrence rate was low; Aspect chronic heart failure, diastolic heart failure side, can improve heart function, improve Ventricular Remodeling.
(Dihydro-Compactin is called for short DHCPT, molecular formula C to two hydrogen ML236Bs
23h
36o
5, molecular weight 392.5) and be one of main impurity producing in ML236B production process, in the process of the production Pravastatin take ML236B as Precurosor fermentation, two hydrogen ML236Bs are two hydrogen Pravastatins by microbial transformation by following manner simultaneously.
The two hydrogen Pravastatins of the two hydrogen ML236B sodium of two hydrogen ML236Bs
The Pravastatin downstream extraction purifying process of existing patent and documents and materials, there are no report or the explanation that can effectively remove two hydrogen Pravastatins.Therefore, the existence of two hydrogen ML236B impurity in ML236B product, will directly cause two hydrogen Pravastatin impurity to occur in Pravastatin finished product, thereby has influence on the quality of Pravastatin sodium finished product.
The disclosed technology of preparing ML236B of extracting from microbial fermentation solution of existing patent or documents and materials comprises: 1. macroporous resin adsorption column chromatography; 2. organic solvent extraction mycelium, acid rinsing, activated carbon decolorizing, concentrating under reduced pressure closed loop, low temperature crystallization; 3. fermented liquid after filtration, lytic enzyme processing, vacuum concentration, hydrophobic organic solvent extraction, concentrated, hydrophilic organic solvent and ammonium salt or ammoniacal liquor mixes, and makes ML236B be converted to ammonium salts crystallization.
In above-mentioned technique, or there is the problems such as complex operation, extraction cost is high, the production cycle is long, yield is low; Exist to add to use the kind of raw and auxiliary material many, be unfavorable for the problem of subsequent product quality control; The most important thing is, although adopt ML236B purity after recrystallization prepared by above-mentioned technique can reach 98% or more than, all detection of not mentioned pair of hydrogen ML236B and control methods, thus may directly affect the impurity situation of Pravastatin.
Summary of the invention
For above-mentioned technological deficiency, the technical problem to be solved in the present invention is to utilize a kind of method of physics by ML236B raw product purifying.
The technical problem to be solved in the present invention is achieved through the following technical solutions: a kind of ML236B purification process, and step is: A, first ML236B raw product is obtained to lysate by ingredient water heating for dissolving, lysate is filtered, obtain filtered liquid; B, by the filtered liquid concentrating under reduced pressure of steps A, under concentrated solution low temperature, crystallization obtains crystal solution; C, the crystal solution of step B is carried out obtaining primary crystallization product after solid-liquid separation; D, by the primary crystallization product of step C first with ingredient water dissolve after more at low temperatures crystallization obtain crystal solution; E, by step D crystal solution carry out solid-liquid separation obtain secondary crystal product F, by the crystallization product drying under reduced pressure of step e, get product.
Further: in above-mentioned ML236B purification process, described steps A also comprises the step of first lysate being decoloured with gac.The crystallization product of described step F have also comprised repeatedly the crystallization product that D and E step obtain.Described ML236B raw product purity is more than or equal to 60%.The ingredient water of described steps A, D step is the mixture of organic molten Ji and water, and the volume ratio of described organic solvent and water is: described in 4: 1～49: 1, organic solvent is one or more mixtures in methyl alcohol, ethanol, propyl alcohol, butanols, acetone, butanone.Described ingredient water is (7-12) with the volume weight L/kg ratio of ML236B raw product: 1, and in described D step, ingredient water is (2-5) with the volume weight L/kg ratio of primary crystallization product: 1.The low temperature of described step B, D refers to that temperature is less than or equal to 20 ℃.
Compared with prior art, above-mentioned ML236B purification process, in the ML236B product obtaining, hardly containing (content≤0.01%) two hydrogen ML236B impurity, and more than can making ML236B purity to 99%.Its purification process is simple, with short production cycle, cost is low, yield is high, and the finished product content obtaining reaches more than 99%, and the two hydrogen ML236B content of impurity is below 0.01%.
Accompanying drawing explanation
Accompanying drawing 1 is the representative color atlas that in ML236B raw product, two hydrogen ML236Bs detect; Accompanying drawing 2 is the representative color atlass according to two hydrogen ML236Bs detect in the inventive method gained ML236B finished product.
Embodiment:
Purport of the present invention is by physical method purifying ML236B from ML236B raw product, and the method has mild condition, feature and the ML236B finished product purity that simple to operate, the cycle is short, cost is low, yield is high are significantly improved.Below in conjunction with embodiment, content of the present invention is described in further detail, in embodiment, mentioned content is not limitation of the invention, and wherein the selection of each starting material of method, pressure, temperature can be suited measures to local conditions and result be there is no to substantial effect.
Two hydrogen ML236B HPLC detection techniques of indication are as follows:
A. chromatographic condition: chromatographic column: Waters Symmetry Shield RP8 post, granularity 5.0 μ m, specification 4.6 × 250mm; Detector: UV-vis detector, detects wavelength 260nm; 30 ℃ of column temperatures, sampling volume 5 μ l, flow velocity 1.5ml/min, working time 35min.
B. sample preparation: precision takes ML236B 40mg, adds methylene dichloride to 10ml, shakes up; Extracting sample solution 1.5ml adds 4-nitrobenzoyl chloride solution 200 μ l, then adds DMAP solution 200 μ l, and shaking by swirling gently, makes to mix; Under sample liquid room temperature after reinforced, react 5～10min, get bottom organic phase sample introduction and measure.
C. sample determination: injected sample solution 1 pin, in HPLC system, records color atlas.
Embodiment 1
(1). compounding methanol-water (ratio 98/2) solution 12L, add ML236B raw product 1.32kg (purity 81%, two hydrogen ML236B content 8.2%), add 1.1kg gac, be warming up to more than 30 ℃ and dissolve;
(2). lysate filters through diatomite layer, and filtrate is evaporated to 3.2L above at 28 ℃;
(3). concentrated solution is incubated crystallization 2 hours at 10 ℃, and filtering for crystallizing liquid obtains primary crystallization product 1.23kg;
(4). primary crystallization product are with 5.3L methanol-water, ratio 98/2, solution is warming up to more than 30 ℃ and dissolves;
(5). lysate is incubated crystallization 2 hours at 10 ℃, and filtering for crystallizing liquid obtains secondary crystal product 1.12kg;
(6). secondary crystal product are with 2.8L methanol-water, ratio 98/2, solution is warming up to more than 30 ℃ and dissolves;
(7). lysate is incubated crystallization 2 hours at 10 ℃, and filtering for crystallizing liquid obtains crystallization product 0.98kg three times;
(8). three crystallization product drying under reduced pressure, obtain finished product 0.86kg;
Sampling HPLC records ML236B content 99.6%, two hydrogen ML236B content 0.002%.
Embodiment 2
(1). preparation butanone-water (ratio 90/10) solution 13.5L, add ML236B raw product 1.55kg (purity 87%, two hydrogen ML236B content 7.3%), drop into 1.1kg gac, be warming up to more than 50 ℃ and dissolve;
(2). lysate filters through diatomite layer, and filtrate is evaporated to 5.2L above at 45 ℃;
(3). concentrated solution is incubated crystallization 2 hours at 12 ℃, and filtering for crystallizing liquid obtains primary crystallization product 1.54kg;
(4). primary crystallization product are warming up to more than 40 ℃ and dissolve with 5.0L butanone-water (ratio 95/5) solution;
(5). lysate is incubated crystallization 2 hours at 12 ℃, and filtering for crystallizing liquid obtains secondary crystal product 1.37kg;
(6). secondary crystal product drying under reduced pressure, obtains finished product 1.14kg;
Sampling HPLC records ML236B content 99.7%, two hydrogen ML236B content 0.001%.
Embodiment 3
(1). preparation butanone-water (ratio 90/10) solution 8.5L, add ML236B raw product 2.50kg (purity 95%, two hydrogen ML236B content 3.3%), be warming up to more than 50 ℃ and dissolve;
(2). lysate is incubated crystallization 2 hours at 12 ℃, and filtering for crystallizing liquid obtains primary crystallization product 2.78kg;
(3). primary crystallization product are warming up to more than 50 ℃ and dissolve with 8.0L butanone-water (ratio 95/5) solution;
(4). lysate is incubated crystallization 2 hours at 8 ℃, and filtering for crystallizing liquid obtains secondary crystal product 2.52kg;
(5). secondary crystal product drying under reduced pressure, obtains finished product 2.14kg;
Sampling HPLC records ML236B content 99.6%, two hydrogen ML236B content 0.001%.
Embodiment 4-9
According to the technical process of embodiment 2, to study as starting material take the ML236B raw product of different purity and two hydrogen ML236B content, testing data sees the following form:
The more than just several preferred embodiments of the inventive method, but protection scope of the present invention is not limited to this.
Claims (3)
1. a ML236B purification process, step is:
A, first ML236B raw product is obtained to lysate by ingredient water heating for dissolving, lysate is decoloured with gac, then lysate is filtered, obtain filtered liquid; Wherein, ingredient water is the mixture of organic solvent and water, the volume ratio of described organic solvent and water is: 4:1～49:1, organic solvent is one or more mixtures in methyl alcohol, ethanol, propyl alcohol, butanols, acetone, butanone, and described ingredient water is (7-12) with the volume weight L/kg ratio of ML236B raw product: 1;
B, by the filtered liquid concentrating under reduced pressure of steps A, under concentrated solution low temperature, crystallization obtains crystal solution, described low temperature is that temperature is less than or equal to 20 ℃;
C, the crystal solution of step B is carried out obtaining primary crystallization product after solid-liquid separation;
D, by the primary crystallization product of step C first with ingredient water dissolve after more at low temperatures crystallization obtain crystal solution, described ingredient water is (2-5) with the volume weight L/kg ratio of primary crystallization product: 1, described low temperature is that temperature is less than or equal to 20 ℃;
E, step D crystal solution is carried out to solid-liquid separation obtain secondary crystal product;
F, by the crystallization product drying under reduced pressure of step e, get product.
2. ML236B purification process according to claim 1, is characterized in that: the crystallization product of described step F have also comprised repeatedly the crystallization product that D and E step obtain.
3. ML236B purification process according to claim 2, is characterized in that: described ML236B raw product purity is more than or equal to 60%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1504454A (en) * | 2002-12-05 | 2004-06-16 | 上海天伟生物制药有限公司 | Method for purifying mevastatin (forebody of pravastatin) from microorganism fermentation liquor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1504454A (en) * | 2002-12-05 | 2004-06-16 | 上海天伟生物制药有限公司 | Method for purifying mevastatin (forebody of pravastatin) from microorganism fermentation liquor |
Non-Patent Citations (8)
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| 孙华.洛伐他汀结晶过程研究.《天津大学硕士学位论文》.2007,第26-31页. |
| 李敏.美伐他汀提取工艺研究.《天津大学硕士学位论文》.2009,第38-41页. |
| 李敏等.溶剂重结晶法降低美伐他汀杂质D的选择性研究.《河北化工》.2007,第30卷(第1期),第52-53页. |
| 洛伐他汀结晶过程研究;孙华;《天津大学硕士学位论文》;20070131;第26-31页 * |
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| 美伐他汀提取工艺研究;李敏;《天津大学硕士学位论文》;20090430;第38-41页 * |
| 美伐他汀母液回收的研究;石磊等;《中国抗生素杂质》;20051030;第30卷(第10期);第633-635页 * |
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