CN109232355A - A method of effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product - Google Patents
A method of effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product Download PDFInfo
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- CN109232355A CN109232355A CN201811174359.5A CN201811174359A CN109232355A CN 109232355 A CN109232355 A CN 109232355A CN 201811174359 A CN201811174359 A CN 201811174359A CN 109232355 A CN109232355 A CN 109232355A
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- atorvastatin
- atorvastatin calcium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
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Abstract
The invention discloses a kind of methods for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product, Atorvastatin calcium crude product is dissolved in alcohol compound-ether compound in the mixed solvent, active carbon and heating stirring are added, it is spare to obtain filtrate for suction filtration while hot；In the water of filtrate added drop-wise to 25 ~ 75 DEG C, there will be a large amount of white solids to be precipitated after being added dropwise, cooling and standings, suction filtration obtains white solid, washs filter cake, and vacuum drying obtains high purity atorvastatin calcium.The Atorvastatin calcium that the present invention is prepared using this method can effectively remove impurity E, improve the purity of Atorvastatin calcium, the content of impurity E can be down to 0.03% or less, have many advantages, such as step it is easy, it is low in cost, economic and environment-friendly, be suitable for industrialization production, be it is a kind of with industrial production value remove Atorvastatin calcium crude product in impurity E method.
Description
Technical field
The invention belongs to a kind of minimizing technology of the impurity of medical compounds, in particular to one kind effectively removes atropic and cuts down him
The method of impurity Atorvastatin condensation product in the calcium crude product of spit of fland.
Background technique
Atorvastatin calcium (Atorvastatin Calcium) product name is Lipitor (Lipitor), chemical name
For [R, (R*, R*)] -2- (4- fluorophenyl)-β, alpha-dihydroxy -5- (1- Methylethyl) -3- phenyl-[(anilino-)-hydroxyl] -
1H- pyrroles's -1- enanthic acid calcium trihydrate, white or off-white color crystalline powder, odorless, bitter is readily soluble in methyl alcohol,
Slightly soluble in ethyl alcohol or acetone, atomic molten in water, almost insoluble or insoluble in chloroform, ether, molecular formula is
(C33H34FN2O5)2Ca·3H2O, molecular weight 1209.42, structural formula is as follows:
Its discrimination method is as follows: taking Atorvastatin calcium, methanol is added to be made in every 1mL containing 12g Atorvastatin calcium
Solution measures according to spectrophotometry (1995 editions two annex IVA of Chinese Pharmacopoeia), has absorption maximum at wavelength 246nm.
Atorvastatin calcium is a kind of auxiliary A (HMG- of 3- hydroxy-3-methyl glutaryl of the tissue selectivity of novel synthesis
GoA) reductase inhibitor can inhibit the synthesis of cholesterol in blood plasma.Since it and HMG-CoA have similar chemical structure,
Can be in conjunction with HMG-CoA reductase, and its affinity is strong, so it has stronger Reverse transcriptase to make HMG-COA reductase
With can block the metabolic pathway of intracellular hydroxyl first valeric acid by selective depression HMG-CoA reductase, it is intracellular to reach reduction
The purpose of cholesterol level, while it is also adjustable low-density lipoprotein cholesterol level, reduces the low-density lipoprotein in circulation
White cholesterol levels.Compared to other statins Atorvastatin calciums have it is rapid-action, effect for reducing fat is strong, action time
It is long, have the characteristics that efficient, safe, other than with regulating blood lipid action, also there is effect outside rouge of adjusting, including inhibition inflammation,
The effects of improving function of vascular endothelium, promoting angiogenesis, repair injured endothelium and stablize patch, be always treatment high cholesterol
One of best-selling drug of mass formed by blood stasis.Principal indication are as follows: 1, primary high cholesterol and combined hyperlipidemia；2, high cholesterol
Mass formed by blood stasis and the dangerous patient for having atherosclerosis.Its tablet usage and dosage: common initial dose be 10mg once a day or
It follows the doctor's advice.
Plurality of impurities is mixed into the preparation process of Atorvastatin calcium, and some impurity are difficult to separate, it is difficult to remove
It goes, these impurity include:
Impurity A: fluorine Atorvastatin calcium is removed；
Impurity B: Atorvastatin non-corresponding isomers；
Impurity C: difluoro Atorvastatin calcium；
Impurity D: Atorvastatin lactone；
Impurity E: Atorvastatin condensation product, title and structural formula are as follows: (4R-cis) -6- [2- [2-9 (4- fluorophenyl) -
5- (1- isopropyl) -3- phenyl -4- [(aniline) carbonyl] -1H- pyrroles -1- base] ethyl] -1,3 dioxane of -2,2- dimethyl -
4- tert-butyl acetate.
The method that Atorvastatin calcium is prepared in existing literature has very much, but in Atorvastatin calcium crude product to related
The minimizing technology of impurity is rarely reported and describes, also rare explanation, and in practice, in Atorvastatin calcium purifying crude process
In, the related very difficult removing of substance Atorvastatin condensation product (impurity E), the present invention is to atorvastatin calcium associated object thus
In the minimizing technology research of matter, by certain method effectively to remove the impurity E in Atorvastatin crude product.
Summary of the invention
Impurity atropic in Atorvastatin calcium crude product, which is effectively removed, the technical problem to be solved by the present invention is to provide one kind cuts down him
The method of spit of fland condensation product.
The present invention adopts the following technical scheme that one kind effectively removes Atorvastatin calcium crude product to solve above-mentioned technical problem
The method of middle impurity Atorvastatin condensation product, it is characterised in that specific steps are as follows:
Step S1: Atorvastatin calcium crude product is dissolved in alcohol compound-ether compound in the mixed solvent, adds work
Property charcoal and heating stirring, filter spare, the alcohol compound-ether compound in the mixed solvent alcohols that obtains filtrate while hot
Conjunction object be methanol, ethyl alcohol or isopropanol, ether compound ether, petroleum ether, dioxane or methyl tertiary butyl ether(MTBE),
Step S2: in the water of the filtrate added drop-wise that step S1 is obtained to 25~75 DEG C, there are a large amount of whites solid after being added dropwise
Body is precipitated, cooling and standings, and suction filtration obtains white solid, washs filter cake, and vacuum drying obtains high purity atorvastatin calcium, wherein
The content of impurity Atorvastatin condensation product is lower than 0.03%.
Preferably, alcohol compound described in step S1-ether compound in the mixed solvent alcohol compound and ethers
The volume ratio for closing object is 9~20:1~10.
Preferably, the mass ratio of active carbon described in step S1 and Atorvastatin calcium crude product is 5~20:100.
Preferably, the charge ratio of Atorvastatin calcium crude product described in step S1, alcohol compound and ether compound
For 1Kg:9~20L:1~10L.
Preferably, the temperature of water described in step S2 is preferably 60 DEG C.
Preferably, the charge ratio of the dosage of water described in step S2 and Atorvastatin calcium crude product is 10~50L:1Kg.
Compared with the prior art, the invention has the following beneficial effects: the Atorvastatin calcium purified using this method
Impurity E can be effectively removed, the purity of Atorvastatin calcium is improved, the content of impurity E is down to 0.03% hereinafter, having step
It is easy, low in cost, economic and environment-friendly, be suitable for the advantages that industrialization production, be it is a kind of with industrial production value removing Ah
The method of impurity E in atorvastatin calcium crude product.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
1Kg Atorvastatin calcium crude product (purity 98.87%, impurity E 0.58%) is weighed to be added to 9L methanol and 10L first
50g active carbon is added in reaction solution relaying after stirring 15min under the conditions of 30 DEG C of temperature in the in the mixed solvent of base tertbutyl ether
Continuous heating stirring 30min, then filters while hot, the filtrate being obtained by filtration is slowly added into 60 DEG C of 10L water, is added dropwise
After there are a large amount of white solids to be precipitated, cooling and standings, suction filtration obtains white solid, with 1L water washing filter cake, in a vacuum drying oven
Dry, yield 97.3% detects resulting Atorvastatin calcium by HPLC, and content reaches 99.87%, related impurities E
Content be 0.03%.
Embodiment 2
1Kg Atorvastatin calcium crude product (purity 98.87%, impurity E 0.58%) is weighed to be added to 20L methanol and 10L first
200g active carbon is added in reaction solution after stirring 15min under the conditions of 30 DEG C of temperature in the in the mixed solvent of base tertbutyl ether
Continue heating stirring 30min, then filters while hot, the filtrate being obtained by filtration is slowly added into 60 DEG C of 20L water, is dripped
The a large amount of white solids of Bi Houyou are precipitated, cooling and standings, and suction filtration obtains white solid, with 1L water washing filter cake, in vacuum oven
Middle drying, yield 98.2% detect gained Atorvastatin calcium by HPLC, and content reaches 99.94%, related impurities E
Content be 0.01%.
Embodiment 3
1Kg Atorvastatin calcium crude product (purity 98.87%, impurity E 0.58%) is weighed to be added to 16L methanol and 3L first
50g active carbon is added in reaction solution relaying after stirring 15min under the conditions of 30 DEG C of temperature in the in the mixed solvent of base tertbutyl ether
Continuous heating stirring 30min, then filters while hot, the filtrate being obtained by filtration is slowly added into 60 DEG C of 30L water, is added dropwise
After there are a large amount of white solids to be precipitated, cooling and standings, suction filtration obtains white solid, with 1L water washing filter cake, in a vacuum drying oven
Dry, yield 98.7% detects gained Atorvastatin calcium by HPLC, and content reaches 99.78%, related impurities E's
Content is 0.03%.
Embodiment 4
1Kg Atorvastatin calcium crude product (purity 98.87%, impurity E 0.58%) is weighed to be added to 9L methanol and 3L methyl
100g active carbon is added in reaction solution relaying after stirring 15min under the conditions of 30 DEG C of temperature in the in the mixed solvent of tertbutyl ether
Continuous heating stirring 30min, then filters while hot, the filtrate being obtained by filtration is slowly added into 60 DEG C of 30L water, is added dropwise
After there are a large amount of white solids to be precipitated, cooling and standings, suction filtration obtains white solid, with 1L water washing filter cake, in a vacuum drying oven
Dry, yield 98.9% detects gained Atorvastatin calcium by HPLC, and content reaches 99.82%, related impurities E's
Content is 0.03%.
Embodiment 5
1Kg Atorvastatin calcium crude product (purity 98.87%, impurity E 0.58%) is weighed to be added to 9L methanol and 1L methyl
100g active carbon is added in reaction solution relaying after stirring 15min under the conditions of 30 DEG C of temperature in the in the mixed solvent of tertbutyl ether
Continuous heating stirring 30min, then filters while hot, the filtrate being obtained by filtration is slowly added into 60 DEG C of 50L water, is added dropwise
After there are a large amount of white solids to be precipitated, cooling and standings, suction filtration obtains white solid, with 1L water washing filter cake, in a vacuum drying oven
Dry, yield 99.1% detects gained Atorvastatin calcium by HPLC, and content reaches 99.83%, related impurities E's
Content is 0.01%.
The above examples only illustrate the technical idea of the present invention, and this does not limit the scope of protection of the present invention, all
According to the technical idea provided by the invention, any changes made on the basis of the technical scheme each falls within the scope of the present invention
Within.
Claims (6)
1. a kind of method for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product, it is characterised in that specific
Step are as follows:
Step S1: Atorvastatin calcium crude product is dissolved in alcohol compound-ether compound in the mixed solvent, adds active carbon
And heating stirring, spare, the alcohol compound-ether compound in the mixed solvent alcohol compound that obtains filtrate is filtered while hot
For methanol, ethyl alcohol or isopropanol, ether compound ether, petroleum ether, dioxane or methyl tertiary butyl ether(MTBE),
Step S2: in the water of the filtrate added drop-wise that step S1 is obtained to 25 ~ 75 DEG C, a large amount of white solids analyse after being added dropwise
Out, cooling and standings, suction filtration obtain white solid, wash filter cake, and vacuum drying obtains high purity atorvastatin calcium, wherein impurity
The content of Atorvastatin condensation product is lower than 0.03%.
2. the side according to claim 1 for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product
Method, it is characterised in that: alcohol compound described in step S1-ether compound in the mixed solvent alcohol compound and ethers chemical combination
The volume ratio of object is 9 ~ 20:1 ~ 10.
3. the side according to claim 1 for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product
Method, it is characterised in that: the mass ratio of active carbon described in step S1 and Atorvastatin calcium crude product is 5 ~ 20:100.
4. the side according to claim 1 for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product
Method, it is characterised in that: the charge ratio of Atorvastatin calcium crude product, alcohol compound and ether compound described in step S1 is
1Kg:9~20L:1~10L。
5. the side according to claim 1 for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product
Method, it is characterised in that: the temperature of water described in step S2 is preferably 60 DEG C.
6. the side according to claim 1 for effectively removing impurity Atorvastatin condensation product in Atorvastatin calcium crude product
Method, it is characterised in that: the charge ratio of the dosage of water described in step S2 and Atorvastatin calcium crude product is 10 ~ 50L:1Kg.
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Citations (5)
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|---|---|---|---|---|
| EP1659110A1 (en) * | 2004-03-17 | 2006-05-24 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium un amorphous form |
| WO2007096751A1 (en) * | 2006-02-21 | 2007-08-30 | Cadila Healthcare Limited | Process for the preparation of atorvastatin calcium |
| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
| CN103108863A (en) * | 2010-04-19 | 2013-05-15 | 中化帝斯曼制药有限公司荷兰公司 | Production of atorvastatin low in ether impurities |
| CN104945300A (en) * | 2015-06-17 | 2015-09-30 | 北京嘉林药业股份有限公司 | Purification method for I-type atorvastatin calcium |
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2018
- 2018-10-09 CN CN201811174359.5A patent/CN109232355A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1659110A1 (en) * | 2004-03-17 | 2006-05-24 | Ranbaxy Laboratories Limited | Process for the production of atorvastatin calcium un amorphous form |
| CN1942439A (en) * | 2004-03-17 | 2007-04-04 | 兰贝克赛实验室有限公司 | Process for the production of atorvastatin calcium in amorphous form |
| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
| WO2007096751A1 (en) * | 2006-02-21 | 2007-08-30 | Cadila Healthcare Limited | Process for the preparation of atorvastatin calcium |
| CN103108863A (en) * | 2010-04-19 | 2013-05-15 | 中化帝斯曼制药有限公司荷兰公司 | Production of atorvastatin low in ether impurities |
| CN104945300A (en) * | 2015-06-17 | 2015-09-30 | 北京嘉林药业股份有限公司 | Purification method for I-type atorvastatin calcium |
Non-Patent Citations (1)
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| 张晓峰 等: "HPLC法测定阿托伐他汀钙有关物质", 《药物分析杂志》 * |
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Application publication date: 20190118 |