A kind of preparation method of high purity atorvastatin calciumTechnical field
The present invention relates to technical field of organic synthesis, and in particular to a kind of preparation method of high purity atorvastatin calcium.
Background technology
Atorvastatin calcium Chinese chemical name is [R- (R*, R*)] -2- (4- fluorophenyls)-β, δ-dihydroxy -5- (1- methylEthyl) -3- phenyl -4- [(anilino-) carbonyl] -1H- pyrroles's -1- Calcium salt enanthates, English language Chemical name：[R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-prrole-1-heptanoic acid,calcium salt (2:1) trihydrate, CAS registration numberIt is third generation Statins regulating plasma lipid drug, for treating hypercholesterolemia and mixed type hyperlipemia for 344423-98-9The prevention of disease, coronary heart disease and headstroke.
Atorvastatin calcium was listed in 1997 in Britain and the U.S., and the market demand is huge always since listing.With completeBall population aging is on the rise, and hyperlipidemia, coronary heart disease and Patients with Stroke are more and more, therefore, develops AtorvastatinCalcium can not only bring good economic benefit that can also benefit senile hyperlipemia, coronary heart disease and Patients with Stroke, bring goodSocial benefit.
Such as application No. is 201110271664.8 patents to disclose a kind of preparation method of amorphous atorvastatin calcium,Including following four step：
The reaction temperature of 1st step is 80-100 DEG C, reaction time 20-40h, and catalyst is pivalic acid, compound I withThe molar ratio of compound II is 1:1-1:2, solvent is normal heptane and tetrahydrofuran, and normal heptane and tetrahydrochysene is recovered under reduced pressure in reaction productAfter furans, methanol is added and is recrystallized, compound III is dried to obtain in centrifugation；The 2-4 steps reaction uses three step one kettle ways：In the reaction of the 2nd step, compound III is dissolved in methanol and tetrahydrofuran, dilute hydrochloric acid is added and carries out acidolysis deprotection, reaction temperatureIt is 30-50 DEG C；In the reaction of 3rd step, liquid caustic soda is added and carries out macromolecule alkali for hydrolysis, 20-40 DEG C of temperature control is recovered under reduced pressure after completion of the reactionMethanol and tetrahydrofuran, after n-hexane extraction is added, water layer enters in next step；In the reaction of 4th step, second is added into the water layerThe mixture of acetic acid, ethyl acetate, one kind in propyl acetate or arbitrary proportion is added at calcium salt in sour calcium solution, heat preservation, pointLayer, concentration finish, and acetone, press filtration are added, then concentrate, direct baking material obtains amorphous atorvastatin calcium.
But this method has the following problems：
(1) purity can only achieve 99%, and total recovery can only ensure to be more than 75%, also have greater room for improvement；
(2) stability of the unformed Atorvastatin calcium obtained is bad and bioavailability is bad；
(3) it needs to extract in step 4 and concentrate, not only complex process influences yield, it is also necessary to expend a large amount of energy.
Invention content
The purpose of the present invention is to provide a kind of product purity height, the Atorvastatin calciums of safety and high yield easy to operatePreparation method.To achieve the goals above, the present invention provides the following technical solutions：
The present invention provides a kind of preparation method of high purity atorvastatin calcium, reaction stream formula is：
Wherein, in step (4), compound V（[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- methyl secondBase) -3- phenyl-[(anilino-)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salts, preferably aqueous solution）With calcium acetate in water and alcoholIt is reacted in mixed solvent system, 40-70 DEG C of reaction temperature, the molar ratio of calcium acetate and compound V is 0.4-0.8：1, insteadIt is 1 to answer the volume ratio of alcohol and water in system:2-8, compound V are 5-10% in the mass percent concentration of in the mixed solvent, insteadDecrease temperature crystalline, filtering etc. obtain Atorvastatin calcium crude product after the completion of answering.Wherein, alcohol is selected from methanol, ethyl alcohol, isopropanol and second twoIt is one or more in alcohol etc..
Atorvastatin calcium crude product is dissolved in recrystallization solvent A, Atorvastatin calcium crude product is in recrystallization solvent AMass percent concentration be 5-10%, under the conditions of 45-85 DEG C be added Ι type Atorvastatin calcium crystal seeds（Outsourcing or by this methodIt obtains）It carries out turning crystalline substance, decrease temperature crystalline after the completion of turning brilliant is filtered, washed and dried etc. and to obtain fine work.Wherein, recrystallization solvent A isAlcohol and water by volume 1：The mixed solvent of 2-5 compositions, one kind in methanol, ethyl alcohol, isopropanol and ethylene glycol etc. of alcohol orIt is a variety of.
Wherein, step (1) includes：Chemical compounds I（2- [2- (4- fluorophenyls) -2- oxo -1- phenylethyls] -4- methyl -3-Oxo-N-phenyl-pentanamide）And compound ii（(4R-cis) 6- aminoethyl -2,2- dimethyl -1,3- dioxane -4- acetic acidThe tert-butyl ester）Condensation reaction is carried out under pivalic acid effect in organic solvent A, reaction temperature is 60-120 DEG C, chemical compounds I, changeThe molar ratio for closing object II and pivalic acid is 1:1.1-1.3:0.6-1.5 obtains compound III after the completion of reaction（(4R-cis)-6-[2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2- twoPenta ring -4- tert-butyl acetates of methyl-1,3-dioxy）, organic solvent A be selected from toluene, benzene, n-hexane, normal heptane, tetrahydrofuran andIt is one or more in dioxane etc..After this patent with pivalic acid by compound ii by being made salt, then with chemical compounds I contractIt closes, yield is more much higher than compound ii and chemical compounds I direct polycondensation.
Further, step (1) further includes：The crude product for reacting cool down, wash, being concentrated to give after the completion compound III, changesClose crude product and the recrystallization solvent B of object III dissolved clarification under reflux conditions, decrease temperature crystalline, the essence for filtering, being dried to obtain compound IIIProduct.Wherein, recrystallization solvent B is selected from ethylene glycol, isopropanol, normal propyl alcohol or glycerine etc.；Preferably isopropanol.Change in the stepThe purity of the fine work of object III is closed up to 99.5% or more.
Wherein, step (2) includes：Compound III is dissolved in organic solvent B, it is molten that acid is added dropwise under the conditions of 5-25 DEG CLiquid is reacted after being added dropwise to complete under the conditions of 20-30 DEG C, and extraction after having reacted takes organic phase to be concentrated to give compounds Ⅳ（(4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases]Ethyl] -1,3- dihydroxy -4- tert-butyl acetates）.Wherein, organic solvent B is selected from tetrahydrofuran, dioxane, methanol and ethyl alcoholIt is one or more in, preferably methanol.Further, in step (2)：Acid solution is the hydrochloric acid of 8-18wt%, compoundIII with the mass ratio of hydrochloric acid is 1：0.3-0.8（The quality of equivalent hydrogen chloride）.
In this step, inventor improves the concentration of hydrochloric acid and reduces reaction temperature.Reason is：Sloughing acetonylideneIt is lactone, acid and methyl esters respectively there is also other three kinds of products in real reaction product during protecting group.Apply for human hairExisting, these four products, which are present in product in next step macromolecule alkali for hydrolysis, can be hydrolyzed to sodium atorvastatin, therefore itBetween component content to next step reaction have no significant effect.Therefore, we are reacted for this and mainly considers dropAdd the parameters such as temperature and the reaction temperature of dilute hydrochloric acid.And low acid concentration, it is unfavorable for sloughing acetonylidene protecting group completely, and it is higherReaction temperature, and be easy to generate the unfavorable impurity except four kinds of products.
Wherein, step (3) includes：Compounds Ⅳ is dissolved in organic solvent C, alkali soluble is added dropwise under the conditions of 0-15 DEG CLiquid is reacted after being added dropwise to complete under the conditions of 10-30 DEG C, and extraction after having reacted, water intaking mutually obtains the solution of compound V.ItsIn, organic solvent C is one or more in tetrahydrofuran, dioxane, methanol and ethyl alcohol etc., preferably methanol.Into oneStep ground, in step (3)：Aqueous slkali is the sodium hydroxide solution of 10-20wt%, mole of compounds Ⅳ and sodium hydroxide solutionThan being 1:1.3-2.0（The mol numbers of equivalent sodium hydroxide）.
Wherein, the extractant in step (2) and (3) is selected from benzene, toluene, ethyl acetate or dichloromethane etc., as neededWater can be added or be added without in order to preferably extract.Preferably, extractant is toluene.
Wherein, in step (4)：Add or be added without alcohol in the solution of compound V（The water of adjustment system and the ratio of alcoholExample）And it is warming up to 40-70 DEG C, the alcohol-water mixed solution for adding calcium acetate (is subject to and is easier to dissolving, such as the volume of alcohol and waterThan being 1:0.5-2.0).Preferably, alcohol is methanol in step (4).It is highly preferred that step (3) and (4) use methanol, noBut it is avoided that the introducing of impurity, moreover it is possible to product be made to crystallize out as possible.
Wherein, in step (4)：It is 24-48 hours to turn the brilliant time, and decrease temperature crystalline process is：It is naturally cold after the completion of turning brilliantBut it to 20-35 DEG C, stirs 0.5-2 hours, is cooled to 0-5 DEG C, stirring at low speed 1-4 hours is filtered, washed and dried to obtain essenceProduct.
Preferably, in step (4), recrystallization solvent A is the mixed solvent of isopropanol, first alcohol and water, isopropanol, methanolVolume ratio with water is 1:1-4:8-10.
Specifically, the preparation method of high purity atorvastatin calcium of the invention specifically includes：
(1) chemical compounds I and compound ii carry out condensation reaction, reaction temperature 60- in organic solvent A under pivalic acid effect120 DEG C, it is 1 to change the molar ratio for closing object I, compound ii and pivalic acid:1.1-1.3:0.6-1.5 is obtained after the completion of reactionCompound III.
(2) compound III is dissolved in organic solvent B, hydrochloric acid solution is added dropwise under the conditions of 5-25 DEG C, after being added dropwise to completeIt is reacted under the conditions of 20-30 DEG C, extraction after having reacted takes organic phase to be concentrated to give compounds Ⅳ.
(3) compounds Ⅳ is dissolved in organic solvent C, sodium hydroxide solution is added dropwise under the conditions of 0-15 DEG C, drippedIt is reacted under the conditions of 10-30 DEG C after, extraction after having reacted, water intaking mutually obtains the solution of compound V.
(4) in the solution of compound V plus or be added without alcohol or water and be warming up to 40-70 DEG C, be slow added into calcium acetateAlcohol-water mixed solution, the molar ratio of 40-70 DEG C of reaction temperature, calcium acetate and compound V is 0.4-0.8：1, reaction systemThe volume ratio of middle alcohol and water is 1:2-8, compound V is 5-10% in the mass percent concentration of mixed solvent, after the completion of reactionDecrease temperature crystalline, filtering etc. obtain Atorvastatin calcium crude product.Wherein, alcohol is in methanol, ethyl alcohol, isopropanol and ethylene glycol etc.It is one or more.
(5) Atorvastatin calcium crude product is dissolved in recrystallization solvent A, Atorvastatin calcium crude product is in recrystallization solventMass percent concentration in A is 5-10%, and Ι type Atorvastatin calcium crystal seeds are added under the conditions of 45-85 DEG C and carry out turning crystalline substance 24-48 hours, 20-35 DEG C is naturally cooled to after the completion of turning brilliant, is stirred 0.5-2 hours, is cooled to 0-5 DEG C, stirring at low speed 1-4 is smallWhen, it is filtered, washed and dried to obtain fine work.Wherein, recrystallization solvent A is the mixed solvent of isopropanol, first alcohol and water, isopropylAlcohol, first alcohol and water volume ratio be 1:1-4:8-10.
The present invention is reacted with calcium acetate in specific solvent by compound V, in the premise for ensureing that reaction fully carries outUnder, so that Atorvastatin calcium is precipitated out to the maximum extent；Again by specific recrystallization solvent to Atorvastatin calcium crude productRecrystallized, the product of specific crystal formation can be obtained and greatly improve the purity of product, make product purity reach 99.9% withOn, list is miscellaneous to be less than 0.03%, is far above 98.5% purity of USP requirement.In addition, the control of many condition and specific pureChange method makes total recovery be more than 84%.Therefore, Atorvastatin calcium preparation method provided by the invention has product purity height, behaviourThe advantages that making simple and safe and high income is suitble to large-scale industrial production, there is very high economic value added.
Specific implementation mode
To make the object, technical solutions and advantages of the present invention clearer, embodiment of the present invention is made below furtherIt is described in detail on ground.
Embodiment one：
（a）（4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrrolesCough up -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- tert-butyl acetates preparation
1kg (4R-cis) 6- aminoethyl -2,2- dimethyl -1,3- dioxane -4- is put into the reaction kettle of 10L dried and cleansTert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettleFluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）ExtremelyReaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30DEG C, the saturated sodium bicarbonate solution that 5L is added washed once, and organic phase purifies water washing 2 times with 2*5L again, then by organic phaseIt is transferred in Rotary Evaporators, is concentrated to dryness at 60 DEG C, obtains 4R-cis) [[(1- is different by -5- by 2- (4- fluorophenyls) by 2- by -6-Propyl) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- acetic acidTert-butyl ester.Crude product and 4L isopropanols are mixed and heated to reflux, after feed liquid dissolved clarification, it is small to keep the temperature half for cooled to room temperatureWhen, 0 DEG C -5 DEG C are then cooled to, insulated and stirred 1 hour filters, and elutes filter cake with 1L petroleum ethers, drying obtains 4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2-Dimethyl -1,3-dioxolane -4- tert-butyl acetate fine work 1.5kg, yield 94%, purity 99.5%.
（b）(4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H-Pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetates preparation
By step（a）Gained fine work is transferred to after being dissolved with 4.5L methanol in the reaction kettle of 20L dried and cleans, after 4.5L water is added,It cools to 0 DEG C -5 DEG C, the dilute hydrochloric acid of 6L10wt% is slowly added dropwise, control the entire process reaction liquid temperature that is added dropwise and be no more than 25℃.After completion of dropwise addition, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2 hours for insulated and stirred（TLC is detectedTracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dressEnter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropylsBase) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.35kg, are receivedRate is 96%, purity 98.9%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilineBase)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution preparation.
By step（b）Products obtained therefrom with 6L methanol dissolve after put into the reaction kettle of 20L dried and cleans, cool to0 DEG C -5 DEG C, the sodium hydroxide solution of 1L10wt% is slowly added dropwise, controls the entire process reaction liquid temperature that is added dropwise and is no more than 15 DEG C.DropAfter adding, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2.5 hours for insulated and stirred（TLC detection withTrack, solvent are ethyl acetate：Petroleum ether=1:1）.6L purified waters and 6L toluene are added into reaction solution, stirs 20 minutes, it is quietLayering is set, water phase is collected.Water phase washed once with 6L toluene again, and gained water phase is [R, (R*, R*)] -2- (4- fluorophenyls) -β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilino-)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution.
（d）The preparation of Atorvastatin calcium crude product
By step（c）Middle gained sodium salt solution is transferred in the reaction kettle of 10L clean drieds, then 3L methanol is added into kettle, heatingTo 60 DEG C -65 DEG C, calcium acetate solution is slowly added dropwise by constant pressure funnel（Calcium acetate solution be mono- acetate hydrate calcium of 150g with700ml purified waters and 700ml methanol mixed preparing and obtain）.After completion of dropwise addition, the insulated and stirred 2 hours at 60 DEG C -65 DEG C.StopIt only heats, is cooled to 5 DEG C -10 DEG C, insulated and stirred 1 hour.It filters, obtains white filter cake, as Atorvastatin calcium crude product.
（e）The preparation of Atorvastatin calcium fine work
By step（d）It is clean that middle gained Atorvastatin calcium crude product and 1L isopropanols, 2L methanol and 8L purified waters put into 20L dryingsIn net reaction kettle, temperature rising reflux is to 80 DEG C -85 DEG C and Ι type crystal seeds are added, and insulated and stirred 36h naturally cools to 25 DEG C -35DEG C, insulated and stirred 1 hour cools to 0 DEG C -5 DEG C, and heat preservation stirring at low speed 2 hours filters, and filter cake is pure with 0 DEG C -5 DEG C of 2LChange and be dried in vacuo at water washing 2 times, 60 DEG C, obtains the Atorvastatin calcium fine work 1.21kg of high-purity, total recovery 84%, purity99.92%, maximum single miscellaneous 0.019%.
Embodiment two：
（a）（4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrrolesCough up -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- tert-butyl acetates preparation
1kg (4R-cis) 6- aminoethyl -2,2- dimethyl -1,3- dioxane -4- is put into the reaction kettle of 10L dried and cleansTert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettleFluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）ExtremelyReaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30DEG C, the saturated sodium bicarbonate solution that 5L is added washed once, and organic phase purifies water washing 2 times with 2*5L again, then by organic phaseIt is transferred in Rotary Evaporators, is concentrated to dryness at 60 DEG C, obtains 4R-cis) [[(1- is different by -5- by 2- (4- fluorophenyls) by 2- by -6-Propyl) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- acetic acidTert-butyl ester.Crude product and 4L isopropanols are mixed and heated to reflux, after feed liquid dissolved clarification, it is small to keep the temperature half for cooled to room temperatureWhen, 0 DEG C -5 DEG C are then cooled to, insulated and stirred 1 hour filters, and elutes filter cake with 1L petroleum ethers, drying obtains 4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2-Dimethyl -1,3-dioxolane -4- tert-butyl acetate fine work 1.54kg, yield 96.5%, purity 99.3%.
（b）(4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H-Pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate solution preparation
By step（a）Gained fine work is transferred to after being dissolved with 4.7L methanol in the reaction kettle of 20L dried and cleans, after 4.7L water is added,It cools to 0 DEG C -5 DEG C, the dilute hydrochloric acid of 6L10wt% is slowly added dropwise, control the entire process reaction liquid temperature that is added dropwise and be no more than 25℃.After completion of dropwise addition, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2 hours for insulated and stirred（TLC is detectedTracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dressEnter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropylsBase) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.36kg, are receivedRate is 96.7%, purity 98.8%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilineBase)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution preparation.
By step（b）Products obtained therefrom is put into after being dissolved with 6.5L methanol in the reaction kettle of 20L dried and cleans, is cooledTo 0 DEG C -5 DEG C, the sodium hydroxide solution of 1L10wt% is slowly added dropwise, controls the entire process reaction liquid temperature that is added dropwise and is no more than 15 DEG C.After completion of dropwise addition, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2.5 hours for insulated and stirred（TLC detection withTrack, solvent are ethyl acetate：Petroleum ether=1:1）.6.5L purified waters and 6L toluene are added into reaction solution, stirs 20 minutes,Stratification collects water phase.Water phase washed once with 6L toluene again, and gained water phase is [R, (R*, R*)] -2- (4- fluorobenzeneBase)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilino-)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution.
（d）The preparation of Atorvastatin calcium crude product
By step（c）Middle gained sodium salt solution is transferred in the reaction kettle of 10L clean drieds, then 3.1L methanol is added into kettle, is risenCalcium acetate solution is slowly added dropwise to 60 DEG C -65 DEG C, by constant pressure funnel in temperature（Calcium acetate solution is mono- acetate hydrate calcium of 153gIt is obtained with 714ml purified waters and 714ml methanol mixed preparing）.After completion of dropwise addition, the insulated and stirred 2 hours at 60 DEG C -65 DEG C.Stop heating, is cooled to 5 DEG C -10 DEG C, insulated and stirred 1 hour.It filters, obtains white filter cake, as Atorvastatin calcium crude product.
（e）The preparation of Atorvastatin calcium fine work
By step（d）Middle gained Atorvastatin calcium crude product puts into 20L dryings with 1L isopropanols, 4L methanol and 10L purified watersIn clean reaction kettle, Ι type crystal seeds are added to 80 DEG C -85 DEG C in temperature rising reflux, and insulated and stirred 40h naturally cools to 25 DEG C -35DEG C, insulated and stirred 1 hour cools to 0 DEG C -5 DEG C, and heat preservation stirring at low speed 2 hours filters, and filter cake is purified with 2L0 DEG C -5 DEG CIt is dried in vacuo at water washing 2 times, 60 DEG C, obtains the Atorvastatin calcium fine work 1.22kg of high-purity, total recovery 85.4%, purity99.94%, maximum single miscellaneous 0.023%.
Embodiment three：
（a）（4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrrolesCough up -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- tert-butyl acetates preparation
1kg (4R-cis) 6- aminoethyl -2,2- dimethyl -1,3- dioxane -4- is put into the reaction kettle of 10L dried and cleansTert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettleFluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）ExtremelyReaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30DEG C, the saturated sodium bicarbonate solution that 5L is added washed once, and organic phase purifies water washing 2 times with 2*5L again, then by organic phaseIt is transferred in Rotary Evaporators, is concentrated to dryness at 60 DEG C, obtains 4R-cis) [[(1- is different by -5- by 2- (4- fluorophenyls) by 2- by -6-Propyl) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2- dimethyl -1,3- dioxolanes -4- acetic acidTert-butyl ester.Crude product and 4L isopropanols are mixed and heated to reflux, after feed liquid dissolved clarification, it is small to keep the temperature half for cooled to room temperatureWhen, 0 DEG C -5 DEG C are then cooled to, insulated and stirred 1 hour filters, and elutes filter cake with 1L petroleum ethers, drying obtains 4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -2,2-Dimethyl -1,3-dioxolane -4- tert-butyl acetate fine work 1.48kg, yield 93.2%, purity 99.4%.
（b）(4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H-Pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetates preparation
By step（a）Gained fine work is transferred to after being dissolved with 4.4L methanol in the reaction kettle of 20L dried and cleans, after 4.4L water is added,It cools to 0 DEG C -5 DEG C, the dilute hydrochloric acid of 6L10wt% is slowly added dropwise, control the entire process reaction liquid temperature that is added dropwise and be no more than 25℃.After completion of dropwise addition, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2 hours for insulated and stirred（TLC is detectedTracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dressEnter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropylsBase) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.33kg, are receivedRate is 94.5%, purity 99.3%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilineBase)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution preparation.
By step（c）Products obtained therefrom is put into after being dissolved with 5.8L methanol in the reaction kettle of 20L dried and cleans, is cooledTo 0 DEG C -5 DEG C, the sodium hydroxide solution of 1L10wt% is slowly added dropwise, controls the entire process reaction liquid temperature that is added dropwise and is no more than 15 DEG C.After completion of dropwise addition, cooling is closed, is warming up to 25 DEG C -30 DEG C, extremely the reaction was complete in -3 hours 2.5 hours for insulated and stirred（TLC detection withTrack, solvent are ethyl acetate：Petroleum ether=1:1）.5.8L purified waters and 6L toluene are added into reaction solution, stirs 20 minutes,Stratification collects water phase.Water phase washed once with 6L toluene again, and gained water phase is [R, (R*, R*)] -2- (4- fluorobenzeneBase)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(anilino-)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salt solution.
（d）The preparation of Atorvastatin calcium crude product
By step（c）Middle gained sodium salt solution is transferred in the reaction kettle of 10L clean drieds, then 2.9L methanol is added into kettle, is risenCalcium acetate solution is slowly added dropwise to 60 DEG C -65 DEG C, by constant pressure funnel in temperature（Calcium acetate solution is mono- acetate hydrate calcium of 148gIt is obtained with 690ml purified waters and 690ml methanol mixed preparing）.After completion of dropwise addition, the insulated and stirred 2 hours at 60 DEG C -65 DEG C.Stop heating, is cooled to 5 DEG C -10 DEG C, insulated and stirred 1 hour.It filters, obtains white filter cake, as Atorvastatin calcium crude product.
（e）The preparation of Atorvastatin calcium fine work
By step（d）Middle gained Atorvastatin calcium crude product puts into 20L dryings with 1L isopropanols, 1L methanol and 10L purified watersIn clean reaction kettle, Ι type crystal seeds are added to 80 DEG C -85 DEG C in temperature rising reflux, and insulated and stirred 40h naturally cools to 25 DEG C -35DEG C, insulated and stirred 1 hour cools to 0 DEG C -5 DEG C, and heat preservation stirring at low speed 2 hours filters, and filter cake is pure with 0 DEG C -5 DEG C of 2LChange and be dried in vacuo at water washing 2 times, 60 DEG C, obtains the Atorvastatin calcium fine work 1.22kg of high-purity, total recovery 85.4% is pureDegree 99.91%, maximum single miscellaneous 0.026%.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit andWithin principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.