CN101205209B - Method for refining atorvastatin intermediate - Google Patents
- ️Wed Jun 02 2010
CN101205209B - Method for refining atorvastatin intermediate - Google Patents
Method for refining atorvastatin intermediate Download PDFInfo
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- CN101205209B CN101205209B CN2007103068152A CN200710306815A CN101205209B CN 101205209 B CN101205209 B CN 101205209B CN 2007103068152 A CN2007103068152 A CN 2007103068152A CN 200710306815 A CN200710306815 A CN 200710306815A CN 101205209 B CN101205209 B CN 101205209B Authority
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- zarator Prior art date
- 2007-12-25 Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 42
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title abstract description 11
- 229960005370 atorvastatin Drugs 0.000 title abstract description 11
- 238000007670 refining Methods 0.000 title abstract description 6
- 239000012043 crude product Substances 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 16
- 230000004224 protection Effects 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001953 recrystallisation Methods 0.000 claims abstract description 11
- 230000000630 rising effect Effects 0.000 claims abstract description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000000746 purification Methods 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- 238000009413 insulation Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 10
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000004061 bleaching Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 37
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 150000002576 ketones Chemical class 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 239000003223 protective agent Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract 2
- 150000001875 compounds Chemical class 0.000 description 10
- 239000003814 drug Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 239000012327 Ruthenium complex Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 101150102415 Apob gene Proteins 0.000 description 1
- 101710095342 Apolipoprotein B Proteins 0.000 description 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a refining method for atorvastatin intermediate, which solves the problems that the existing atorvastatin intermediates have low purity and negatively high stereoselectivity, etc. The refining method of the invention for atorvastatin intermediate comprises the following steps: A. double-hydroxyl protection reaction: 1 parts by weight of the crude products of the atorvastatin intermediates I are added into 1 to 3 parts by weight of ketone organic solvents, and then the mixture is stirred; after the crude products of the atorvastatin intermediates are completely dissolved, the double hydroxyls of the crude products I are subject to the double-hydroxyl protection reaction under the effect of 0.2 to 0.5 parts by weight of alkyl ether hydroxyl protective agents so as togenerate the crude products III; B. recrystallization: the crude products III obtained through the double-hydroxyl protection reaction are added in 2 to 3 parts by weight of alcohol organic solutionand then the mixture is stirred with a rising temperature; after the crude products III are completely dissolved, the crude products III are cooled down to the room temperature and are crystallized bykeeping the temperature constant for 2 to 3 hours; then the crude products III are filtered, the cakes are washed with water and are dried before the refined products III are obtained; C. acid hydrolysis reaction: the refining method of the invention requires low cost and has strong operatability and the purity of the refined products of the atorvastatin intermediates is high.
Description
Technical field
The present invention relates to a kind of process for purification of pharmaceutical intermediate, relate in particular to a kind of process for purification of chemicals Zarator intermediate; Belong to medicine and chemical field.
Background technology
Zarator is a kind of blood lipid-lowering medicine, it be by its pharmaceutical intermediate (3R, 5R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-carbaniloyl,phenylcarbamoyl-pyrroles-1-yl]-3, the 5-dihydroxyl-enanthic acid tert-butyl ester, its chemical structure is made shown in I; Usually as drug use, its chemical structural formula is shown in II with the form of calcium salt for Zarator.
Zarator is as one of the most effective cholesterol-lowering agent, and its advantage one is that it not only can reduce TC, LDL-C, apoB (apolipoprotein B), but triglyceride reducing (TG) level also is also effective to heterozygosis subtype family hyperlipidemia; Its second advantage is to be used with other fat-reducing medicaments, reduces the TC and the LDL-C of the subtype family hyperlipemia that isozygotys.
Report about existing a lot of patents of the synthetic method of Zarator and document,, mainly can be divided into two big classes according to two morning and evenings that chiral hydroxyl group forms in the molecular structure:
Disclosed method in first kind method such as the U.S. Patent application (US5155251), it is to be raw material with the primary amine that contains two chiral hydroxyl groups, with 1, the reaction of 4-dicarbonyl compound generates pyrrole ring, generates Zarator through further reaction again.The shortcoming of these class methods is to need to use the expensive primary amine that contains two chiral hydroxyl groups to be raw material.
Second class methods are synthetic earlier intermediates that contain pyrrole ring, then introduce chiral hydroxyl group, thereby obtain the purpose product, as european patent application (EP409281) and Chinese patent application (CN1675200) disclosed method.
Wherein european patent application (EP409281) disclosed method is to be intermediate with chipal compounds IV, under the katalysis of LDA, carries out condensation reaction with tert.-butyl acetate and generates compound V, then uses NaBH under the inducing of borine 4Carry out chiral reduction and obtain intermediate compound I, after hydrolysis obtains Zarator.The shortcoming of this method is can produce a lot of impurity in the process of condensation and chiral reduction, and the purity of the intermediate compound I that obtains is lower, can not satisfy to be used for high purity atorvastatin synthetic needs, and these impurity is difficult to use
Common process for purification (as extraction, recrystallization etc.) is removed.
Chinese patent application (CN1675200) disclosed method is to be intermediate with non-chiral compound VI, under the katalysis of ruthenium complex two carbonyls is carried out chiral reduction and obtains intermediate compound I.The shortcoming one of this method is that catalyzer costs an arm and a leg, the 2nd, and stereoselectivity is not high, and the purity of intermediate compound I can not satisfy and is used for high purity atorvastatin synthetic needs in addition, and is difficult to make with extra care with common method (as extraction, recrystallization etc.).
Summary of the invention
The present invention is directed to low, the not high existing defective of stereoselectivity of Zarator intermediate purity of existing preparation, a kind of process for purification of Zarator intermediate is provided, Zarator intermediate by this method preparation enough satisfies the needs that are used to prepare high purity atorvastatin, stereoselectivity height.
Above-mentioned technical problem of the present invention is the process for purification of a kind of Zarator intermediate of being implemented by the following technical programs, and this method may further comprise the steps:
A, the reaction of two hydroxyl protection: the Zarator intermediate crude product I that gets 1 weight part, it is joined in 1～3 weight part organic solvent of ketone stir, after treating to dissolve fully, the two hydroxyl protections with crude product I under the effect of the alkyl oxide hydroxy-protecting agent of 0.2～0.5 weight part generate crude product III;
B, recrystallization: the crude product III with above-mentioned pair of hydroxyl protection reaction obtains, join in the alcohols organic solution of 2～3 weight parts, stir and heat up, after treating that crude product III dissolves fully, be cooled to room temperature, insulation crystallization 2～3 hours, filter, the filter cake washing, drain elaboration III;
C, acid hydrolytic reaction:, join in 7～10 weight part nitrile organic solvents, behind activated carbon decolorizing with the elaboration III that above-mentioned recrystallization obtains, filter, the water that adds 10～15 weight parts in filtrate behind acid hydrolytic reaction, is transferred pH value to 6.5～7.5 with alkali; Add water filtration, get elaboration I after filter cake washing, the drying.
Because Zarator intermediate compound I and the difference of its isomer on physical propertiess such as solubleness are very little; thereby be difficult to common process for purification (as extraction; recrystallization etc.) separate; the present invention has then produced bigger difference at other isomer that physical properties (especially solubleness) goes up with the Zarator intermediate compound I by the compound III that obtains after two hydroxyls of Zarator intermediate compound I are protected on physical propertiess such as solubleness, thereby the enough common method recrystallizations of energy are made with extra care and made elaboration I.
In the process for purification of above-mentioned Zarator intermediate, organic solvent of ketone is an acetone in the steps A; Described alkyl oxide hydroxy-protecting agent is 2, the 2-Propanal dimethyl acetal.
As preferably; the detailed process of two hydroxyl protections generation crude product III of crude product I is in the steps A: the Zarator intermediate crude product I that gets 1 weight part drops in the reaction unit; the acetone that adds 1～3 weight part; stirring and dissolving; add 2 of 0.2～0.5 weight part again; the 2-Propanal dimethyl acetal; transfer pH to 2～3 with methylsulfonic acid; insulation reaction adds aqueous solution accent pH to 6.5～7.5 of alkali to terminal under the room temperature, adds the water of 7.0～10.0 weight parts; stirred 0.5～1.0 hour; filter, the filter cake washing, drain crude product III.
In the process for purification of above-mentioned Zarator intermediate, the alcohols organic solution described in the step B is ethanol.
In the process for purification of above-mentioned Zarator intermediate, the nitrile organic solvent described in the step C is an acetonitrile, and described acid is methylsulfonic acid.
In the process for purification of above-mentioned Zarator intermediate, the gac that adds among the step C is 0.05～0.15 weight part, and bleaching time is 0.5～1.0 hour; The pH value of solution is 1～2 during described methylsulfonic acid hydrolysis reaction.
As preferably, the detailed process of acid hydrolytic reaction is among the step C: the elaboration III that above-mentioned recrystallization is obtained drops in the reaction unit, the acetonitrile that adds 7～10 weight parts, rising temperature for dissolving, the gac that adds 0.05～0.15 weight part, insulation decolouring 0.5～1.0 hour is filtered, the water that in filtrate, adds 10～15 weight parts, stir down and transfer pH to 1～2, be stirred to reaction end under the room temperature, transfer pH to 6.5～7.5 with the aqueous solution of alkali with methylsulfonic acid, the water that adds 8～12 weight parts stirred 0.5～1.0 hour, filter, the filter cake washing is drained, oven dry gets elaboration I.
In sum, the present invention has the following advantages:
1, process for purification of the present invention is by the two hydroxyl protections with Zarator intermediate crude product, and stereoselectivity can high can adopt common method to make with extra care, the refining Zarator intermediate elaboration purity height that forms; Can satisfy the demand of preparation high purity atorvastatin;
2, process for purification of the present invention need not to adopt expensive ruthenium complex as catalyzer, and is with low cost; Two hydroxyl protections and common process for purification are workable in the step; The refining Zarator intermediate elaboration yield height that forms.
Embodiment
The invention will be further described by the following examples, but the present invention is not limited to these embodiment.
Embodiment 1
Add 30g Zarator intermediate crude product I (purity is 94.1%) in the flask of 500ml, with 45g acetone stirring and dissolving, add 2 of 7.5g again, the 2-Propanal dimethyl acetal is transferred pH to 2～3 with methylsulfonic acid, and insulation reaction is used NaHCO to terminal under the room temperature 3The aqueous solution is transferred pH to 6.5～7.5, adds the water of 210g, stirs 1 hour.Filter, the filter cake washing, drain crude product III.
Above-mentioned crude product III is dropped in the 500ml flask, adds the ethanol of 90g, stir and be warming up to backflow, treat material dissolution after, be cooled to room temperature, insulation crystallization 2 hours is filtered, the filter cake washing, drain elaboration III.
Above-mentioned elaboration III is dropped in the 500ml flask again, add the acetonitrile of 210g, rising temperature for dissolving, the gac of adding 4.5g, insulation decolouring 1 hour is filtered, and adds the water of 300g in filtrate, stir down and transfer pH to 1～2, be stirred to reaction end under the room temperature, use NaHCO with methylsulfonic acid 3The aqueous solution is transferred pH to 6.5～7.5, and the water of adding 360g stirred 1 hour, filters, and the filter cake washing is drained, and oven dry gets 25.6g Zarator intermediate elaboration I (purity is 99.5%), yield 90.2%.
Embodiment 2
Add 30g Zarator intermediate crude product I (purity is 95.3%) in the flask of 500ml, with 60g acetone stirring and dissolving, add 2 of 9.0g again, the 2-Propanal dimethyl acetal is transferred pH to 2～3 with methylsulfonic acid, and insulation reaction is used KHCO to terminal under the room temperature 3The aqueous solution is transferred pH to 6.5～7.5, adds the water of 250g, stirs 1 hour.Filter, the filter cake washing, drain crude product III.
Above-mentioned crude product III is dropped in the 500ml flask, adds the ethanol of 75g, stir and be warming up to backflow, treat material dissolution after, be cooled to room temperature, insulation crystallization 3 hours is filtered, the filter cake washing, drain elaboration III.
Above-mentioned elaboration III is dropped in the 500ml flask again, add the acetonitrile of 250g, rising temperature for dissolving, the gac of adding 3.0g, insulation decolouring 0.5 hour is filtered, and adds the water of 360g in filtrate, stir down and transfer pH to 1～2, be stirred to reaction end under the room temperature, use KHCO with methylsulfonic acid 3The aqueous solution is transferred pH to 6.5～7.5, and the water of adding 300g stirred 1 hour, filters, and the filter cake washing is drained, and oven dry gets 26.3g Zarator intermediate elaboration I (purity is 99.6%), yield 91.6%.
Embodiment 3
Add 30g Zarator intermediate crude product I (purity is 96.8%) in the flask of 500ml, with 75g acetone stirring and dissolving, add 2 of 12.0g again, the 2-Propanal dimethyl acetal is transferred pH to 2～3 with methylsulfonic acid, and insulation reaction is used NaHCO to terminal under the room temperature 3The aqueous solution is transferred pH to 6.5～7.5, adds the water of 300g, stirs 0.5 hour.Filter, the filter cake washing, drain crude product III.
Above-mentioned crude product III is dropped in the 500ml flask, adds the ethanol of 60g, stir and be warming up to backflow, treat material dissolution after, be cooled to room temperature, insulation crystallization 2 hours is filtered, the filter cake washing, drain elaboration III.
Above-mentioned elaboration III is dropped in the 500ml flask again, add the acetonitrile of 300g, rising temperature for dissolving, the gac of adding 1.5g, insulation decolouring 0.5 hour is filtered, and adds the water of 450g in filtrate, stir down and transfer pH to 1～2, be stirred to reaction end under the room temperature, use NaHCO with methylsulfonic acid 3The aqueous solution is transferred pH to 6.5～7.5, and the water of adding 240g stirred 0.5 hour, filters, and the filter cake washing is drained, and oven dry gets 26.9g Zarator intermediate elaboration I (purity is 99.6%), yield 92.3%.
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 embodiments 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 (4)
1. the process for purification of a Zarator intermediate, this method may further comprise the steps:
A, the reaction of two hydroxyl protection: the Zarator intermediate crude product I that gets 1 weight part, it is joined in 1～3 weight part acetone stir, after treating to dissolve fully, at 2 of 0.2～0.5 weight part, the two hydroxyl protections with crude product I under the effect of 2-Propanal dimethyl acetal generate crude product III;
B, recrystallization: the crude product III with the reaction of the above-mentioned pair of hydroxyl protection obtains, join in the ethanol of 2～3 weight parts, stir and heat up, treat that crude product III dissolves fully after, be cooled to room temperature, insulation crystallization 2～3 hours is filtered, the filter cake washing, drain elaboration III; C, acid hydrolytic reaction: with the elaboration III that above-mentioned recrystallization obtains, join in 7～10 weight part acetonitriles, behind activated carbon decolorizing, filter, in filtrate, add the water of 10～15 weight parts, behind the methylsulfonic acid hydrolysis reaction, with adjusting PH with base value to 6.5～7.5; Add water filtration, get elaboration I after filter cake washing, the drying.
2. the process for purification of Zarator intermediate according to claim 1; it is characterized in that: the detailed process of two hydroxyl protections generation crude product III of crude product I is in the steps A: the Zarator intermediate crude product I that gets 1 weight part drops in the reaction unit; the acetone that adds 1～3 weight part; stirring and dissolving; add 2 of 0.2～0.5 weight part again; the 2-Propanal dimethyl acetal; transfer pH to 2～3 with methylsulfonic acid; insulation reaction adds aqueous solution accent pH to 6.5～7.5 of alkali to terminal under the room temperature, adds the water of 7.0～10.0 weight parts; stirred 0.5～1.0 hour; filter, the filter cake washing, drain crude product III.
3. the process for purification of Zarator intermediate according to claim 1 is characterized in that: the gac that adds among the step C is 0.05～0.15 weight part, and bleaching time is 0.5～1.0 hour; The pH value of solution is 1～2 during described methylsulfonic acid hydrolysis reaction.
4. the process for purification of Zarator intermediate according to claim 3, it is characterized in that: the detailed process of acid hydrolytic reaction is among the step C: the elaboration III that above-mentioned recrystallization is obtained drops in the reaction unit, the acetonitrile that adds 7～10 weight parts, rising temperature for dissolving, the gac that adds 0.05～0.15 weight part, insulation decolouring 0.5～1.0 hour is filtered, the water that in filtrate, adds 10～15 weight parts, stir down and transfer pH to 1～2, be stirred to reaction end under the room temperature, transfer pH to 6.5～7.5 with the aqueous solution of alkali with methylsulfonic acid, the water that adds 8～12 weight parts stirred 0.5～1.0 hour, filter, the filter cake washing is drained, oven dry gets elaboration I.
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| CN2007103068152A CN101205209B (en) | 2007-12-25 | 2007-12-25 | Method for refining atorvastatin intermediate |
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| CN2007103068152A CN101205209B (en) | 2007-12-25 | 2007-12-25 | Method for refining atorvastatin intermediate |
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| CN109180633B (en) * | 2018-10-09 | 2020-09-22 | 河南师范大学 | Purification method of atorvastatin calcium intermediate ATS-9 |
Citations (3)
* Cited by examiner, † Cited by third party| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN1675200A (en) * | 2002-08-06 | 2005-09-28 | 沃尼尔·朗伯有限责任公司 | Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy -6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide |
| 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 |
-
2007
- 2007-12-25 CN CN2007103068152A patent/CN101205209B/en active Active
Patent Citations (3)
* Cited by examiner, † Cited by third party| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN1675200A (en) * | 2002-08-06 | 2005-09-28 | 沃尼尔·朗伯有限责任公司 | Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy -6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide |
| 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 |
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Application publication date: 20080625 Assignee: Zhejiang Hongyuan Pharmaceutical Co., Ltd. Assignor: Xindonggang Pharmaceutical Co., Ltd., Zhejiang Contract record no.: 2012330000581 Denomination of invention: Method for refining atorvastatin intermediate Granted publication date: 20100602 License type: Exclusive License Record date: 20121225 |
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Assignee: Zhejiang Hongyuan Pharmaceutical Co., Ltd. Assignor: Xindonggang Pharmaceutical Co., Ltd., Zhejiang Contract record no.: 2012330000581 Date of cancellation: 20180108 |
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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 |