CN104151286A - Atorvastatin calcium intermediate preparation method - Google Patents
Atorvastatin calcium intermediate preparation method Download PDFInfo
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- CN104151286A CN104151286A CN201410404184.8A CN201410404184A CN104151286A CN 104151286 A CN104151286 A CN 104151286A CN 201410404184 A CN201410404184 A CN 201410404184A CN 104151286 A CN104151286 A CN 104151286A
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- SRQQHSSSMVFFRY-UHFFFAOYSA-N CC(C)C(CC(Nc1ccccc1)O)=O Chemical compound CC(C)C(CC(Nc1ccccc1)O)=O SRQQHSSSMVFFRY-UHFFFAOYSA-N 0.000 description 1
- YFYKGCQUWKAFLW-UHFFFAOYSA-N O=C(Cc1ccccc1)c(cc1)ccc1F Chemical compound O=C(Cc1ccccc1)c(cc1)ccc1F YFYKGCQUWKAFLW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
An Atorvastatin calcium intermediate preparation method comprises the following steps: selecting 1-p-fluorophenyl-2-phenyl-ethyl ketone, 1-anilino-4-methyl-(1,3-pentanedione) and (4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate under the protection of nitrogen; and placing the above three raw materials in a synthesis kettle, adding formic acid as a catalyst, adding benzene as a solvent, gradually heating to 100-110DEG C, refluxing for 10h, cooling, adding an aqueous solution of HCl to wash the obtained organic layer to neutrality, evaporating the solvent by reducing the pressure to a pressure p of below -0.090Mpa at below 50DEG C, adding ethanol and cyclohexane, crystallizing at 0-5DEG C for 24h, carrying out pumping filtration, and carrying out reduced pressure drying on the obtained filter cake to prepare (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl]-1H-pyrryl-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate. The preparation method adopting a one step process has the advantages of less synthesis steps, low price of the above used reagents, abundant sources of raw materials, safe operation, and suitableness for large scale industrial production.
Description
Technical field
The present invention relates to chemical industry or pharmacy field, especially prepare the synthetic method of the intermediate adopting in the technique of atorvastatincalcuim.
background technology
Atorvastatincalcuim, oneself knows chemistry [R-(R* by name, R*)]-2-(4-fluorophenyl)-b, d-dihydroxyl-5-(1-methyl-ethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-adjoins cough up-1-Semi-Heptanoic Acid Calcium Salt, it is HMG-CoA reductase inhibitor, and as antihypercholesterolemic.Method and key intermediate for the preparation of atorvastatin are disclosed in United States Patent (USP): 5,003,080. 5,097,045,5,103,024. 5,124,482,5,149,837,5,155,251,5,216,174,5,245,047,5,248,793,5,280,126,5, in 342,952 and 5,397,792; The manufacture craft relative complex that above-mentioned patent adopts, production cost is high, and yield is on the low side, thereby is necessary to be improved further on this basis.
First US Patent No. 4681893 has reported the synthetic of racemize atorvastatin lactone, in this route, taking the bromo-para-fluorophenylacetic acid ethyl ester of 2-as starting raw material, through aminolysis, acidylate and hydrolysis reaction obtain 2-[N-isobutyryl-N-2-(1, 3-dioxolane-2-) ethyl] amino-para-fluorophenylacetic acid, then with the cyclization of N-3-diphenylprop alkynyl amide, then hydrolysis obtains key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical)]-1H-pyrroles's propionic aldehyde, then this intermediate and methyl acetoacetate condensation under alkaline condition, with sodium borohydride and tri butyl boron reduction, obtain atorvastatin lactone through hydrolysis and esterification.
First US Patent No. 5273995 has reported the preparation method of optical purity atorvastatincalcuim; use chiral acetate and intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde issues green hand's property aldol reaction in diisopropylamine lithium effect, obtains chiral hydroxyl group pyrroles valerate.After transesterify, then with tert.-butyl acetate condensation, then obtain product through asymmetric reduction, hydrolysis, salify.Above two patents all adopt 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles's propionic aldehyde is key intermediate, then passes through aldol reaction, then reduce, hydrolysis, salify obtain product.Adopt above-mentioned two kinds of methods to synthesize atorvastatincalcuim, complete pyrrole ring synthetic after, obtain in dihydroxy heptyl ester side chain process through aldol reaction, use costliness and the dangerous reagent such as normal-butyl Lithium, sodium hydride, lithium diisopropyl amido, and under low temperature (78 DEG C), anhydrous and oxygen-free condition, complete, reaction conditions is very harsh, very inconvenient in industrial production, and US5273995 wants use aldol reaction twice in synthetic side chain process.
Chinese invention patent application CN101892276 discloses a kind of synthetic method of atorvastatincalcuim: 2-(2-amine ethyl)-1, 3-dioxolane and 1, 4-dicarbonyl compound is hydrolyzed and obtains key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group again after Paal-Knorr reaction generates pyrrole ring]-1H-pyrroles's propionic aldehyde, then react under the catalysis of chiral catalyst DRI-5-phosphoric acid zymohexase with acetaldehyde, the product generating obtains atorvastatin lactone through bromine oxidation again, and then hydrolysis and react with calcium acetate generation atorvastatincalcuim.The method need to adopt expensive chiral catalyst and large usage quantity, improves and synthetic cost, and adopts bromine to make oxygenant, poisons larger to environment.
US5003080, US5097045, US5103024; US5124482; US5245047, US5280126, US5298627; WO0068221 and US5155251 disclose the another kind of synthetic method of atorvastatincalcuim: first prepare 3 of chirality; 5-dihydroxyl heptyl ester fragment, then reacts the atorvastatin obtaining with protecting group through Paal-Knorr with Isosorbide-5-Nitrae-dicarbonyl compound; then deprotection, salify obtains atorvastatincalcuim.
The chemical structure of atorvastatincalcuim can be divided into two portions, one be the pyrrole ring structure (main ring) that replaces its two for chirality 3, the two hydroxyl enanthic acid structures (side chain) of 5-cis, up to the present, had many documents and patent report synthesizing of atorvastatincalcuim, these synthesize roughly can be divided into two kinds of strategies.
One (linear synthetic), first synthesizes the pyrrole ring of replacement, then on ring, introduces 3 of chirality, the two sourer structures of hydroxyl of 5-cis.Its two (can aggregate into), first prepares 3 of chirality, the two hydroxyl enanthic acid fragments of 5-cis, and then with the cyclization of Isosorbide-5-Nitrae dicarbonyl compound be substituted azole, obtain target product.
Conventional linear synthetic method has two kinds, phenylethylamine Split Method and chirality Adoal condensation
1. phenylethylamine Split Method:
The people such as Luo Si (Roth) and Butler (Butler) of Warner-Lambert AG Safnern (Warner-Lambert) of the U.S. has done a lot of research to atorvastatincalcuim synthetic.Taking the bromo-para-fluorophenylacetic acid ethyl ester of 2-as raw material; by aminated; amidation and saponification reaction; make 2-[N-isobutyryl-N-2-(1; 3-dioxolane-2-) ethyl]-para-fluorophenylacetic acid, then with N, 3-diphenylprop alkynyl amide closes ring; hydrolysis, obtains crucial intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles-propionic aldehyde.This compound and the condensation under alkaline condition of etheric acid formic acid.Then under tri butyl boron exists, reduce carbon back with NaBH4, obtain trans atorvastatin lactone through overweight knot product.Utilizing (R)-2-methyl-benzylamine is resolving agent, has obtained and has had optically active atorvastatincalcuim through chiral separation.
2. chirality Adoal condensation:
First prepare key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles-propionic aldehyde; and then with the chirality Adoal condensation under highly basic diisopropylamine lithium (LDA) effect of chirality acetic ester; obtain chiral hydroxyl group pyrroles valerate; this compound is converted into after methyl esters, under LDA effect with tert-butyl acetate condensation.Then under triethyl-boron effect, carbonyl is carried out to chiral reduction with sodium borohydride, after hydrolysis salifying, obtain target product atorvastatincalcuim.
Conventional convergence synthetic method [(3R, 5R)-7-amino-3,5-dihydroxyl is the synthetic 2 kinds of methods of acid ester derivant main ring more]
Main ring synthetic method 1: by isobutyryl Acetanilide and benzaldehyde, obtain alpha, beta-unsaturated ketone derivative, then under alkaline condition, utilize thiazole derivative for catalyzer, with p-Fluorobenzenecarboxaldehyde, Stetter occurs and react, make Isosorbide-5-Nitrae-dicarbonyl compound.
Main ring synthetic method 2: taking toluylic acid as raw material, through carboxylic acid halides, through Fu-Ke reaction, through bromination, finally make main ring by substitution reaction with (AlCl3 and Br2) with (AlCl3 and fluorobenzene) with SOCl2.
Linear synthesis strategy is first to synthesize to replace to adjoin to cough up ring and extend carbochain again and form side chain.Mainly contain two kinds of methods.The one, phenylethylamine Split Method, the 2nd, the Adol condensation of chirality.These two kinds of methods polysubstitutedly adjoin that to cough up ring time be identical forming.The linear synthetic subject matter of adjoining while coughing up ring is at the different acyl group-N-2-(1 of 2-[N-; 3-dioxolane-2-) ethyl] amino-para-fluorophenylacetic acid and N; 3-diphenylprop alkynyl amide can form isomer while closing ring, and similar being difficult to of this two isomer character separated by recrystallization.The route that phenylethylamine splits is to separate after two trans-isomer(ide)s in interior cruel four isomer of atorvastatin with toluene-acetic acid ethyl ester recrystallization, then uses (R)-2-methyl-benzylamine to split.The method of bibliographical information is column chromatography, separates these two isomer operations comparatively loaded down with trivial details, is not suitable for large suitability for industrialized production.
Main ring in convergence strategy synthetic mainly contains two kinds of methods, the one, from propanedioic acid, first obtain Mai Erdemu acid with acetone protection, then with isobutyryl chloride acidylate after, obtain isobutyryl Acetanilide with aniline reaction, after phenyl aldehyde Knovengal occurs reacts.There is Stetter with p-Fluorobenzenecarboxaldehyde again and react generation main ring, amount to five steps reactions.Difficult point is mainly the Stetter reaction of final step, and yield is not high.The 2nd, from toluylic acid, through chloride, then under the effect of aluminum chloride, there is Fu-Ke acylations with fluorobenzene, through bromo, at the lower main ring that generates of alkali (sodium ethylate or sodium carbonate), amount to seven steps with isobutyryl Acetanilide.
Contrast is linear synthesizes and can aggregate into, and linear synthesizing is not suitable for large industrial production, and in two kinds of methods that can aggregate into, Article 2 route has Chinese patent, and has isomer in the time there is Fu-Ke acylations, and many bromos also can occur when bromo.Separate these two isomer operations comparatively loaded down with trivial details, and the impurity of many bromos is extremely many, recrystallization DeGrain, yield is extremely low, therefore most of synthetic synthetic main ring of Article 1 route that is.
Isosorbide-5-Nitrae-dicarbonyl compound (4-fluoro-alpha-[2-methyl isophthalic acid-oxygen propyl group]-γ-oxo-N, β-bis-phenoxy group fenbutyramidum) side chain synthesizes 9 kinds of methods
Side chain synthetic method 1: from (R)-4-cyano-3-hydroxy butyric ester, through hydroxyl protection, saponification reaction,, react with propanedioic acid list tert-butyl ester magnesium salts, remove, after hydroxyl protecting group, to make (R)-6-cyano group-5-hydroxyl-3-oxo hecanoic acid t-butyl ester.By the chiral reduction of ketone group and the reduction amination of cyano group, obtain required chirality fragment again.
Side chain synthetic method 2: from (R)-4-cyano-3-hydroxy butyric ester, under the effect of di-isopropyl lithium, with tert-butyl acetate condensation, make (R)-6-cyano group-5-oxy-hecanoic acid t-butyl ester, by the chiral reduction of ketone group and the reduction amination of cyano group, obtain required chirality fragment again.
, there is cyano group substitution reaction with NaCN in side chain synthetic method 3: with (3R, 5R)-3,5,6-trihydroxy caproic acid tert-butyl ester derivative is raw material, then cyano reduction amination is obtained to chirality heptoic acid derivative fragment after sulfonylation.
Side chain synthetic method 4: with (3R, 5R)-3,5; 6-trihydroxy caproic acid tert-butyl ester derivative is raw material, is aldehyde radical by 6 hydroxyl oxidizes, is that Henry reaction occurs Nitromethane 99Min.; aceticanhydride acetylize hydroxyl, sodium borohydride reduction, last catalytic hydrogenation reduction nitro obtains side chain.
Side chain synthetic method 5: with the 3-alanine of amido protection be raw material; under the effect of CDI; react with propanedioic acid list tert-butyl ester magnesium salts and obtain under 9-amino-3-oxopentanoic acid ester derivative and then chirality rhodium catalyst existence condition, to carbonyl catalytic hydrogenation, obtaining (R)-5-amino-3-hydroxypentanoic acid ester derivative.Follow under diisopropylamine lithium effect, with tert-butyl acetate condensation, and then a chiral catalysis hydrogenation, obtain chirality enanthic acid fragment.
Side chain synthetic method 6: with biocatalysis reducing carbonyl generation chiral alcohol, replace halogen with ammonia or phthalic diamide and produce amino.
Side chain synthetic method 7: iodolactonization method, trouble.
Side chain synthetic method 8: producing along dihydroxyl method by methoxyl group diethyl boron/sodium borohydride system is more common and general method during atorvastatincalcuim synthesizes, but because the methoxyl group diethyl borine that this reduction reaction is required will be prepared in addition, and this reagent chemical property is active, unstable, inflammable and explosive, when reduction, require very low temperature also to make this method in industrial production, bring a lot of inconvenience.Produce the method for second chiral centre of side chain with reductase enzyme, do not need the very low temperature of chemosynthesis.Reductase enzyme is mainly from Pseudomonas is next below: Candida pelliculose (Candida), Neurosporacrassa (the mould genus of chain robe), preferably uses Hansenula anamola (Hansenula anomala bacterium).
Side chain synthetic method 9: the method for the synthetic side chain of biology is with a kind of zymohexase (DEAR), taking acetaldehyde as monomer one-step synthesis side chain.
The synthetic of side chain is the synthetic key of atorvastatincalcuim.
Method 1; the 2nd, under foretelling, carbonyl base diimidazole (CDI) effect extends two carbon atoms with propanedioic acid list tert-butyl ester magnesium salts; although this step reaction does not need low-temp reaction; but the hydroxyl in (S)-4-cyano-3-hydroxy butyric ester to be protected by TERT-BUTYL DIMETHYL CHLORO SILANE; after two carbon atoms of extension, tetrabutyl ammonium fluoride carries out deprotection again, more loaded down with trivial details.
Method 3 is directly raw material with Kaneka alcohol, and this alcohol is by the production of Japanese Kaneka company, and price is extremely expensive, is not suitable for industrialization.
Method 4 is to report recently, is the variation route growing up compared with difficult generation cyano group replacement after Kaneka alcohol semi-annular jade pendant acidylate in order to solve route 3.Its reason is to carry out cyanogen generation after superincumbent methylsulfonyl, and reaction is difficult for carrying out, and this method is very loaded down with trivial details.
The 3-alanine of method 5 use amido protections is raw material; under carbonyl dimidazoles effect, extend the fragment of two carbon with propanedioic acid list tert-butyl ester magnesium salts; then be chiral alcohol at chirality rhodium catalyst catalytic reduction ketone; produce first chiral centre; with two carbon atoms of diisopropylamine lithium method extension; be that chiral alcohol produces second chiral alcohol with chirality rhodium catalyst reduction ketone group again, this method is a kind of up-and-coming method with chirality rhodium catalyst, and this is also a brand-new research method.
Method 6,8,9 use biological method, be not too applicable to the production of most of enterprise.
9 kinds of routes that contrast is above, route is all very loaded down with trivial details, and all has corresponding patent protection, to this, comprehensively compares, and above synthetic route or route are long, or isomer is not easily separated, and based on this kind of situation, we have found a kind of more optimal synthetic route.
Summary of the invention
The object of this invention is to provide a kind of synthesis step few, agents useful for same cheapness, operational safety, the preparation method of the atorvastatincalcuim intermediate of applicable large-scale commercial production.
Technical scheme of the present invention is achieved in that
The preparation method that a kind of atorvastatincalcuim intermediate is provided, is characterized in that: under nitrogen protection effect, select 1-to fluorophenyl-2-phenyl-ethyl ketone, i.e. raw material (1), 1-anilino-4-methyl-(1,3-diacetylmethane), i.e. raw material (2), (4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate, i.e. raw material (3), insert in synthesis reactor, add first acid as catalyst, add benzene to make solvent, be warmed up to gradually 100-110 DEG C and the 10h that refluxes, then cooling adds the HCl aqueous solution that organic layer is washed as neutrality, then being decompressed to be less than-0.090Mpa of p at 50 DEG C steams solvent, add again ethanol and hexanaphthene in 0-5 DEG C of crystallization 24h, suction filtration, gained filter cake drying under reduced pressure and make (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(anilino) carbonyl]-1H-adjoins cough up-1-yl] ethyl]-2, 2-dimethyl-1, 3-dioxane-4-tert.-butyl acetate, be indication atorvastatincalcuim intermediate of the present invention, its composite structure formula is:
The preparation method of atorvastatincalcuim intermediate as above, is characterized in that: described catalyzer formic acid can be selected acetic acid, propionic acid, any replacement of butyric acid and PIVALIC ACID CRUDE (25).
The preparation method of atorvastatincalcuim intermediate as above, is characterized in that: described solvent can be selected toluene, dimethylbenzene, tetrahydrofuran (THF), any replacement in any of normal heptane or its combination.
The present invention adopts one-step synthesis process, and synthesis step is few, agents useful for same cheapness, and raw material sources are abundant, and operational safety is applicable to large-scale commercial production.
Embodiment
Embodiments of the invention are provided below, but should not be limited to following examples:
Embodiment 1:
Under the condition of nitrogen protection, in the four-hole boiling flask of 500ml, drop into successively 4.5g raw material (1), 4.5g raw material (2) and 5.46g raw material (3), add toluene 400ml, add PIVALIC ACID CRUDE (25) 0.1g, begin to warm to 100-110 DEG C of backflow 10h, cooling adds the HCl aqueous solution that organic layer is washed as neutrality, then the 50 DEG C of be less than-0.090Mpa of p that reduce pressure steam solvent, add 50ml ethanol and 50ml hexanaphthene in 0-5 DEG C of crystallization 24h, suction filtration, gained filter cake drying under reduced pressure, obtain dry product 10.12g, mole turnover ratio is 77.39%, taking raw material (3) calculated mass yield as 185%.
Embodiment 2:
Under the condition of nitrogen protection, in the four-hole boiling flask of 5000ml, drop into successively 22.0g raw material (1), 22.0g raw material (2) and 27.3g raw material (3), add 2700ml solvent, wherein dimethylbenzene 1000ml, heptane 1000ml, tetrahydrofuran (THF) 700ml, add again PIVALIC ACID CRUDE (25) 0.5g, begin to warm to 90-100 DEG C of backflow 10h, cooling adds the HCl aqueous solution that organic layer is washed as neutrality, then (50 DEG C of decompressions, be less than-0.090Mpa of p) solvent is steamed, add 450ml ethanol and 450ml hexanaphthene in 0-5 DEG C of crystallization 24h, suction filtration, gained filter cake drying under reduced pressure, obtain dry product 55.25g, mole turnover ratio is 84.51%, taking raw material (3) calculated mass yield as 202%.
Although disclosed detailed embodiment of the present invention above, those skilled in the art, under the prerequisite without prejudice to essence of the present invention, can carry out part modifications and changes to the technical characterictic of its synthesis technique; Description is above only as illustrative case; it is not limitation of the present invention; have by synthesis step of the present invention and make (4R; 6R)-6-aminoethyl-2; 2-dimethyl-1; 3-dioxane-4-tert.-butyl acetate is the method for gained of the present invention, all falls into this patent protection domain.
Claims (4)
1. a preparation method for atorvastatincalcuim intermediate, is characterized in that: under nitrogen protection effect, select 1-to fluorophenyl-2-phenyl-ethyl ketone, i.e. raw material (1), 1-anilino-4-methyl-(1,3-diacetylmethane), i.e. raw material (2), (4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate, i.e. raw material (3), insert in synthesis reactor, add first acid as catalyst, add benzene to make solvent, be warmed up to gradually 100-110 DEG C and the 10h that refluxes, then cooling adds the HCl aqueous solution that organic layer is washed as neutrality, then being decompressed to be less than-0.090Mpa of p at 50 DEG C steams solvent, add again ethanol and hexanaphthene in 0-5 DEG C of crystallization 24h, suction filtration, gained filter cake drying under reduced pressure and make (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(anilino) carbonyl]-1H-adjoins cough up-1-yl] ethyl]-2, 2-dimethyl-1, 3-dioxane-4-tert.-butyl acetate, be indication atorvastatincalcuim intermediate of the present invention, its composite structure formula is:
。
2. the preparation method of atorvastatincalcuim intermediate as claimed in claim 1, is characterized in that: described catalyzer formic acid can be selected acetic acid, propionic acid, any replacement of butyric acid and PIVALIC ACID CRUDE (25).
3. atorvastatincalcuim intermediate preparation method as claimed in claim 1, is characterized in that: described solvent can be selected toluene, dimethylbenzene, tetrahydrofuran (THF), any replacement in any of normal heptane or its combination.
4. atorvastatincalcuim intermediate preparation method as claimed in claim 1, is characterized in that: described reaction conditions is that temperature of reaction is 80-120 DEG C, and peak optimization reaction temperature is 100-110 DEG C, and the reaction times is 8-24h, and the peak optimization reaction time is 10-12h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440509A (en) * | 2018-04-23 | 2018-08-24 | 山西大同大学 | A kind of method prepared by Atorvastatin calcium intermediate |
| CN108658950A (en) * | 2018-04-23 | 2018-10-16 | 山西大同大学 | A kind of method prepared by Atorvastatin intermediate |
| CN109336319A (en) * | 2018-09-20 | 2019-02-15 | 河南慧锦药业有限公司 | A kind of comprehensive pretreatment method of the high concentration containing aniline waste water and the waste water containing benzaldehyde |
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|---|---|---|---|---|
| ES2289945A1 (en) * | 2006-07-21 | 2008-02-01 | Ercros Industrial, S.A | Method for obtaining two intermediates for obtaining amorphous calcium atorvastatin, includes reaction of two chemical compounds at low pressure in presence of strong base |
| WO2009084827A2 (en) * | 2007-12-27 | 2009-07-09 | Dong-A Pharm.Co., Ltd. | Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2289945A1 (en) * | 2006-07-21 | 2008-02-01 | Ercros Industrial, S.A | Method for obtaining two intermediates for obtaining amorphous calcium atorvastatin, includes reaction of two chemical compounds at low pressure in presence of strong base |
| WO2009084827A2 (en) * | 2007-12-27 | 2009-07-09 | Dong-A Pharm.Co., Ltd. | Synthetic intermediates, process for preparing pyrrolylheptanoic acid derivatives therefrom |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440509A (en) * | 2018-04-23 | 2018-08-24 | 山西大同大学 | A kind of method prepared by Atorvastatin calcium intermediate |
| CN108658950A (en) * | 2018-04-23 | 2018-10-16 | 山西大同大学 | A kind of method prepared by Atorvastatin intermediate |
| CN108440509B (en) * | 2018-04-23 | 2021-03-02 | 山西大同大学 | Method for preparing atorvastatin calcium intermediate |
| CN108658950B (en) * | 2018-04-23 | 2021-03-23 | 山西大同大学 | Method for preparing atorvastatin intermediate |
| CN109336319A (en) * | 2018-09-20 | 2019-02-15 | 河南慧锦药业有限公司 | A kind of comprehensive pretreatment method of the high concentration containing aniline waste water and the waste water containing benzaldehyde |
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