CN1749248A - Process for preparing high purity atorvastatin calcium - Google Patents
Process for preparing high purity atorvastatin calcium Download PDFInfo
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- CN1749248A CN1749248A CN 200510060396 CN200510060396A CN1749248A CN 1749248 A CN1749248 A CN 1749248A CN 200510060396 CN200510060396 CN 200510060396 CN 200510060396 A CN200510060396 A CN 200510060396A CN 1749248 A CN1749248 A CN 1749248A
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- atorvastatin
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Abstract
The present invention provides the preparation of high purity atorvastatin calcium as medicine for treating cardiac and cerebral vascular diseases. The preparation process includes the following steps: 1. dissolving crystalline atorvastatin sodium in pure water to compound atorvastatin sodium solution; 2. dissolving calcium salt in pure water to compound calcium salt solution; and 3. adding the atorvastatin sodium solution into calcium acetate solution heated to 40-70 deg c while stirring, maintaining at the temperature for 2 hr, cooling to 10-35 deg c, filtering and drying to prepare the high content atorvastatin calcium product. Thus prepared atorvastatin calcium product has atorvastatin calcium content over 99.2 % and single impurity content lower than 0.1 %, and has high quality.
Description
Technical field
The present invention relates to a kind of preparation method of HMG-CoA HMG-CoA Reductase Inhibitor HMG-CoA, specifically, it relates to the preparation method of a kind of high purity atorvastatin calcium in the HMG-CoA HMG-CoA Reductase Inhibitor HMG-CoA; Belong to the field for the treatment of cardiovascular and cerebrovascular medicine.
Background technology
Cardiovascular and cerebrovascular diseases is known as the No.1 killer who threatens human health always, show that according to relevant report of survey the people that China dies from cardiovascular and cerebrovascular disease every year has more than 300 ten thousand, account for 50% of the annual total death toll of China, and the ill people who survives 75% disability in various degree, 4% is heavy residual.More alarmingly be, the grownup 80% of China more than 30 years old all more or less or light or important place suffer from cardiovascular and cerebrovascular diseases such as hyperlipidemia, hypertension, coronary heart disease, cerebral apoplexy.
Atherosclerosis is the pathologic basis of ischemic angiocardiopathy and cerebrovascular disease, the coronary heart disease that causes by it, cerebral apoplexy cardiovascular and cerebrovascular disease incidence and mortality obviously rises in recent years, so the research of antiatherosclerotic and application also come into one's own day by day, wherein atherosclerosis is meant that endarterium has the deposition of blood ingredients such as lipid, smooth muscle cell proliferation and collegen filament increase, cause the rotten sample of congee to contain the formation of fat focus and the sclerosis of arterial wall, pathology is mainly involved large-scale elastic artery (aorta and I level branch thereof) and middle isomyaria artery (cerebral arteries, heart coronary artery, the Renal artery and artery of extremity are given birth to and are propped up).Lesion nature is now thought the excessive reparation reaction after impaired of the endotheliocyte of arterial wall and smooth muscle cell.Pathology is sent out well in the easily impaired branch's peristome of tunica intima, being the patch shape distributes, make the blood vessel hardening, the official jargon stenosis or occlusion, cause the ischemic type of tissue and internal organs to change, what body was had the greatest impact is to cause myocardial infarction and cerebral infarction, causes that the atherosclerotic cause of disease sets forth as yet fully, mainly contains that relevant factor (title Hazard Factor) takes place is many and complicated with disease.Physical factor (comprising age, sex and familial inherited genetic factors etc.) and acquired Hazard Factor (comprising hyperlipidemia, hypertension, excessive smoking, diabetes, obesity etc.) two big classes are arranged generally.These factors cause atherosclerotic generation and development by multifactorial comprehensive action.
Antiatherogenic medicine is more: lipid regulating agent, antioxidant, many rare fatty acid medicines, protection arterial endothelium medicine are arranged.Wherein the HMG-CoA HMG-CoA Reductase Inhibitor HMG-CoA is a kind of in the lipid regulating agent, mainly form, have mevastatin, lovastatin, Simvastatin, fluvastatin, Zarator to constitute the statins of at present good general's plasma cholesterol by statins, to primary high-cholesterol disease, heterozygote familial hypercholesterolemia, the high lipid proteinosis of III type, and diabetic and renal hyperlipoidemia be choice drug, so market outlook are wide.At present, the scientific and technical personnel of research this respect medicine are a lot, also proposed various technical schemes; Obtain the method for HMG-CO A reductase inhibitors of high purify as Chinese patent application (99811076.0), this patent application relates to uses so-called " displacement chromatography " to separate a kind of new commercial run of HMG-CoA reductase inhibitor.Though use the method for this patent application can access highly purified HMG-CoA reductase inhibitor, and use this method yield than higher, production cost is lower, be fit to the eubiosis, but because nominally displacement chromatography is adopted in this patent application, in fact in summary of the invention, still used chromatographic column, the principle that adopts remains traditional chromatography principle, it is longer to use this method chromatography time, need the research work personnel operation, and carry out relatively difficulty of mass automatic production, can only be used for laboratory a spot of medicine of just purifying now and do experiment and use.Simultaneously, chromatographic column regeneration is cumbersome, progressively has been eliminated when being applied to purify Zarator; Zarator or to claim atorvastatin, holder to cut down his spit of fland (atovastatin) be statins antilipemic medicine of new generation wherein, be applicable to common hypercholesterolemia or be equipped with fat disease so that the mixed type of blood cholesterol levels rising is high, be particularly useful for refractory to the unresponsive hypercholesterolemia of medicine.
Some statins need just can reach result of treatment with other hypolipidemic coupling, and Zarator is but as long as single therapy can prove effective.Therefore, since the Zarator listing, its sale increases rapidly, becomes the maximum kind of statins.Zarator mainly is used for the treatment of atherosclerosis such as hyperlipidemia in the existing market with calcium salt forms; atorvastatin calcium synthetic method commonly used is to be raw material with the compound shown in the structural formula (III) (being called for short L1); in organic solvent; remove the acetone protecting group through acid, become the solution of atorvastatin sodium after in acid and the mixed solvent of water, removing tertiary butyl protecting group then with alkali soapization.In this solution, add the calcium acetate aqueous solution and make it become calcium salt, more after filtration, wash, be drying to obtain atorvastatin calcium finished product such as world patent: (WO02/083637A1).But the prepared atorvastatin calcium purity of this technology is not high, is difficult to reach the specification of quality of higher-grade atorvastatin calcium;
The and for example preparation of the noncrystalline atorvastatincalcuim of Chinese patent application (02803968.8); This patent application relates to a kind of novel method that intermediate in synthetic or atorvastatin lactose are converted into noncrystalline atorvastatincalcuim with atorvastatin.This patent application is concentrated into 15～50% of initial volume with the synthetic midbody solution, what add 1～5 times of being concentrated volume of water comprises ethane, heptane, hexanaphthene, ether, diisopropyl ether equal solvent, acutely mix by stirring, stirring or vibration solution, separate phase then above-mentioned gained; Add the mineral acid neutralization, be heated to 30～40 ℃, use suitable calcium salt to form the atorvastatin calcium salt.Though see that from above-mentioned reaction process this patent application has obtained the atorvastatin calcium salt, but because reaction process is more loaded down with trivial details, and the organism that uses is by stirring, stir or the vibration highly volatile, not only cause the waste of material, and the evaporable organism can cause the injury of human body; Simultaneously, the drug bioavailability of preparation is lower, and atherosclerotic effects such as treatment hyperlipidemia are relatively poor.The preparation method that Chinese patent application (00814458.3) amorphous atorvastatin calcium is arranged again in addition; This patent application relates to a kind of method for preparing amorphous atorvastatin calcium from organic solvent by the recrystallization of thick atorvastatin.This method is included under the heating condition, in the mixture of the low-level chain triacontanol that comprises 2-4 carbon atom or such alkanol, dissolves thick amorphous atorvastatin calcium and is cooling off the amorphous atorvastatin calcium of precipitation separation afterwards; Though this patent application provides even amorphous product in simple and repeatably mode, but because thick amorphous atorvastatin calcium is dissolved in the organic solvent, wash-out gets up cumbersome, and the amorphous atorvastatin calcium purity that makes is lower, the toxicity of medicine is bigger, and it is more that patient takes untoward reaction.
Summary of the invention
The atorvastatin calcium purity that the present invention is directed to existing preparation among the above-mentioned preparation technology is not high, is difficult to reach the specification of quality of higher-grade atorvastatin calcium; Technical problem; Provide a kind of production technique simple, it is higher to produce this low prepared atorvastatin calcium purity, can reach the preparation method of high purity atorvastatin calcium of the specification of quality of higher-grade atorvastatin calcium.
Above-mentioned technical problem of the present invention solves by the following technical programs: a kind of preparation method of high purity atorvastatin calcium may further comprise the steps:
(1), the preparation of the solution of atorvastatin sodium: with the crystal atorvastatin sodium shown in the structural formula (II) is raw material, described crystal atorvastatin sodium is dissolved in the solution that is made into atorvastatin sodium in the pure water;
(2), the preparation of calcium salt soln: calcium salt is dissolved in is made into calcium salt soln in the pure water;
(3), the preparation of high purity atorvastatin calcium finished product: under agitation in 0.5～3 hour, be added in the calcium acetate solution that is preheated to 40～70 ℃ above-mentioned atorvastatin sodium, be incubated 2 hours, be cooled to 10～35 ℃, filter, drying promptly can be made into high-load atorvastatin calcium finished product, and wherein molecular structural formula is shown in (I);
It below is molecular structural formula of the present invention
In the preparation method of above-mentioned high purity atorvastatin calcium, the mass ratio of described pure water amount and crystal atorvastatin sodium is 20～200: 1.
In the preparation method of above-mentioned high purity atorvastatin calcium, described crystal atorvastatin sodium is A type or Type B crystal atorvastatin sodium.
In the preparation method of above-mentioned high purity atorvastatin calcium, described calcium salt is a calcium acetate, and the mass ratio of described calcium acetate and crystal atorvastatin sodium is 0.12～0.20: 1.
In the preparation method of above-mentioned high purity atorvastatin calcium, the pure water amount of described dissolving calcium acetate and crystal atorvastatin sodium mass ratio are 10～30: 1.
Therefore the present invention compared with prior art has the following advantages:
The prepared Zarator calcium contents of the present invention can reach more than 99.2% (HPLC), and single impurity can reach the specification of quality of higher-grade atorvastatin calcium less than 0.1%.
Description of drawings
Accompanying drawing 2 is for making the X ray crystallogram of Type B crystal atorvastatin sodium of the present invention
Embodiment
By the following examples and in conjunction with the accompanying drawings beneficial effect of the present invention is further elaborated, but the present invention is not limited to these embodiment.
The A type atorvastatin sodium (HPLC content 99.6%) that 10g is had X ray diffracting characteristic shown in Figure 1 is dissolved in the 200g pure water, is made into the Zarator sodium solution; Add calcium acetate 1.2g in the 1000ml there-necked flask, pure water 100g is heated to 70 ℃ and makes sour calcium dissolving; Stir down, in about 0.5 hour, drip above-mentioned Zarator sodium solution, dripped off insulation reaction 2 hours, be cooled to 35 ℃, filter, filtration cakes torrefaction to water content reaches requirement, get atorvastatin calcium finished product 9.9g, content (HPLC) 99.6%, single impurity＜0.1%.
The Type B atorvastatin sodium (HPLC content 99.4%) that 10g is had X ray diffracting characteristic shown in Figure 2 is dissolved in the 2000g pure water, makes the Zarator sodium solution; Add the 2g calcium acetate in the 3000ml there-necked flask, the 300g pure water is heated to 40 ℃ and makes the calcium acetate dissolving; Stir down, drip above-mentioned Zarator sodium solution in about 3 hours, dripped off insulation reaction 2 hours, be cooled to 10 ℃, filter, filtration cakes torrefaction to water content reaches requirement, gets atorvastatin calcium finished product 9.2g, content (HPLC) 99.5%, single impurity＜0.1%.
The A type atorvastatin sodium (HPLC content 99.5%) that 10g is had X ray diffracting characteristic shown in Figure 1 is dissolved in the 500g pure water, makes the Zarator sodium solution; Add the 1.5g calcium acetate in the 1000ml there-necked flask, the 200g pure water is heated to 60 ℃ and makes the calcium acetate dissolving; Stir down, drip above-mentioned Zarator sodium solution in about 1 hour, dripped off insulation reaction 2 hours, be cooled to 25 ℃, filter, filtration cakes torrefaction to water content reaches requirement, gets atorvastatin calcium finished product 9.7g, content (HPLC) 99.5%, single impurity＜0.1%.
Specific embodiment described in the present invention only is that the present invention's spirit is illustrated.The technician of the technical field of the invention can make various modifications or replenishes or adopt similar mode to substitute described specific embodiment, but can't depart from spirit of the present invention or surmount the defined scope of appended claims.
Although the present invention has been made detailed explanation and has quoted some specific exampless as proof, to those skilled in the art, only otherwise leave that the spirit and scope of the present invention can be done various variations or correction is obvious.
Claims (5)
1, a kind of preparation method of high purity atorvastatin calcium may further comprise the steps:
(1), the preparation of the solution of atorvastatin sodium: with the crystal atorvastatin sodium shown in the structural formula (II) is raw material, described crystal atorvastatin sodium is dissolved in the solution that is made into atorvastatin sodium in the pure water;
(2), the preparation of calcium salt soln: calcium salt is dissolved in is made into calcium salt soln in the pure water;
(3), the preparation of high purity atorvastatin calcium finished product: under agitation in 0.5～3 hour, be added in the calcium acetate solution that is preheated to 40～70 ℃ above-mentioned atorvastatin sodium, be incubated 2 hours, be cooled to 10～35 ℃, filter, drying promptly can be made into high-load atorvastatin calcium finished product, and wherein molecular structural formula is shown in (I).
2, the preparation method of high purity atorvastatin calcium according to claim 1 is characterized in that, the mass ratio of described pure water amount and crystal atorvastatin sodium is 20～200: 1.
3, the preparation method of high purity atorvastatin calcium according to claim 1 and 2 is characterized in that, described crystal atorvastatin sodium is A type or Type B crystal atorvastatin sodium.
4, the preparation method of high purity atorvastatin calcium according to claim 1 is characterized in that, described calcium salt is a calcium acetate, and the mass ratio of described calcium acetate and crystal atorvastatin sodium is 0.12～0.20: 1.
5, the preparation method of high purity atorvastatin calcium according to claim 4 is characterized in that, the pure water amount of described dissolving calcium acetate and crystal atorvastatin sodium mass ratio are 10～30: 1.
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| CNB200510060396XA CN100484920C (en) | 2005-08-15 | 2005-08-15 | Process for preparing high purity atorvastatin calcium |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007020421A1 (en) * | 2005-08-15 | 2007-02-22 | Arrow International Limited | Crystalline and amorphous sodium atorvastatin |
| WO2007020413A1 (en) * | 2005-08-15 | 2007-02-22 | Arrow International Limited | Crystalline and amorphous sodium atorvastatin |
| WO2007118873A3 (en) * | 2006-04-14 | 2007-12-06 | Krka Tovarna Zdravil D D Novo | Polymorphs of atorvastatin sodium and magnesium salts |
| CN102311376A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Preparation process of atorvastatin calcium |
| CN104983702A (en) * | 2015-07-23 | 2015-10-21 | 青岛蓝盛洋医药生物科技有限责任公司 | Atorvastatin calcium composition tablet for treating hypercholesterolemia |
| CN105085362A (en) * | 2015-09-18 | 2015-11-25 | 浙江海森药业有限公司 | Preparing method for high-purity crystal type atorvastatin calcium |
| CN108675931A (en) * | 2018-05-18 | 2018-10-19 | 合肥合源药业有限公司 | A kind of low barium statin calcium and preparation method thereof |
| CN113321607A (en) * | 2020-02-28 | 2021-08-31 | 北京福元医药股份有限公司沧州分公司 | Purification method of atorvastatin calcium intermediate |
-
2005
- 2005-08-15 CN CNB200510060396XA patent/CN100484920C/en active Active
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8329922B2 (en) | 2005-08-15 | 2012-12-11 | Arrow International Limited | Crystalline sodium atorvastatin |
| WO2007020413A1 (en) * | 2005-08-15 | 2007-02-22 | Arrow International Limited | Crystalline and amorphous sodium atorvastatin |
| US8017647B2 (en) | 2005-08-15 | 2011-09-13 | Arrow International Limited | Crystalline sodium atorvastatin |
| US8097734B2 (en) | 2005-08-15 | 2012-01-17 | Arrow International Limited | Crystalline sodium atorvastatin |
| WO2007020421A1 (en) * | 2005-08-15 | 2007-02-22 | Arrow International Limited | Crystalline and amorphous sodium atorvastatin |
| US8440712B2 (en) | 2005-08-15 | 2013-05-14 | Arrow International Limited | Crystalline sodium atorvastatin |
| WO2007118873A3 (en) * | 2006-04-14 | 2007-12-06 | Krka Tovarna Zdravil D D Novo | Polymorphs of atorvastatin sodium and magnesium salts |
| CN102311376A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Preparation process of atorvastatin calcium |
| CN102311376B (en) * | 2010-06-29 | 2013-01-02 | 山东新华制药股份有限公司 | Preparation process of atorvastatin calcium |
| CN104983702A (en) * | 2015-07-23 | 2015-10-21 | 青岛蓝盛洋医药生物科技有限责任公司 | Atorvastatin calcium composition tablet for treating hypercholesterolemia |
| CN105085362A (en) * | 2015-09-18 | 2015-11-25 | 浙江海森药业有限公司 | Preparing method for high-purity crystal type atorvastatin calcium |
| CN108675931A (en) * | 2018-05-18 | 2018-10-19 | 合肥合源药业有限公司 | A kind of low barium statin calcium and preparation method thereof |
| CN113321607A (en) * | 2020-02-28 | 2021-08-31 | 北京福元医药股份有限公司沧州分公司 | Purification method of atorvastatin calcium intermediate |
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|---|---|
| CN100484920C (en) | 2009-05-06 |
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Address after: 318000 29 Binhai Road, Jiaojiang District, Taizhou, Zhejiang Patentee after: Zhejiang Le Pu pharmaceutical Limited by Share Ltd Address before: 318000 Jiefang Road, Jiaojiang District, Taizhou, Zhejiang Province, No. 83 Patentee before: Xindonggang Pharmaceutical Co., Ltd., Zhejiang |