CN108558726A - A kind of preparation method of high purity atorvastatin calcium - Google Patents
A kind of preparation method of high purity atorvastatin calcium Download PDFInfo
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- CN108558726A CN108558726A CN201810208441.9A CN201810208441A CN108558726A CN 108558726 A CN108558726 A CN 108558726A CN 201810208441 A CN201810208441 A CN 201810208441A CN 108558726 A CN108558726 A CN 108558726A
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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
Abstract
The invention discloses a kind of preparation methods of high purity atorvastatin calcium, belong to technical field of organic synthesis.This method includes：Compound V is reacted with calcium acetate in the mixed solvent system of water and alcohol, 40 70 DEG C of reaction temperature, and the volume ratio of alcohol and water is 1 in reaction system:28, compound V is 5 10% in the mass percent concentration of in the mixed solvent, and Atorvastatin calcium crude product is obtained by filtration in decrease temperature crystalline after the completion of reaction；Atorvastatin calcium crude product is dissolved in recrystallization solvent A, mass percent concentration of the Atorvastatin calcium crude product in recrystallization solvent A is 5 10%, be added under the conditions of 45 85 DEG C Ι type Atorvastatin calcium crystal seeds carry out turn crystalline substance, decrease temperature crystalline after the completion of turning brilliant is filtered, washed and dried to obtain fine work.Atorvastatin calcium preparation method provided by the invention has many advantages, such as product purity height, safety and high income easy to operate, is suitble to large-scale industrial production.
Description
Technical 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- methyl
Ethyl) -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 number
It is third generation Statins regulating plasma lipid drug, for treating hypercholesterolemia and mixed type hyperlipemia for 344423-98-9
The 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 complete
Ball population aging is on the rise, and hyperlipidemia, coronary heart disease and Patients with Stroke are more and more, therefore, develops Atorvastatin
Calcium can not only bring good economic benefit that can also benefit senile hyperlipemia, coronary heart disease and Patients with Stroke, bring good
Social 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 with
The 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 product
After 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 temperature
It 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 reaction
Methanol 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 layer
The 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, point
Layer, 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 operate
Preparation 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 second
Base) -3- phenyl-[(anilino-)-hydroxyl] -1H- pyrroles's -1- heptanoic acid sodium salts, preferably aqueous solution）With calcium acetate in water and alcohol
It 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, instead
It 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, instead
Decrease 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 two
It 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 A
Mass 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 method
It 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 is
Alcohol 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 or
It 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 acid
The 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, change
The 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- two
Penta ring -4- tert-butyl acetates of methyl-1,3-dioxy）, organic solvent A be selected from toluene, benzene, n-hexane, normal heptane, tetrahydrofuran and
It 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 contract
It 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, changes
Close 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 III
Product.Wherein, recrystallization solvent B is selected from ethylene glycol, isopropanol, normal propyl alcohol or glycerine etc.；Preferably isopropanol.Change in the step
The 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 C
Liquid 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 alcohol
It is one or more in, preferably methanol.Further, in step (2)：Acid solution is the hydrochloric acid of 8-18wt%, compound
III 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 acetonylidene
It 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 hair
Existing, these four products, which are present in product in next step macromolecule alkali for hydrolysis, can be hydrolyzed to sodium atorvastatin, therefore it
Between component content to next step reaction have no significant effect.Therefore, we are reacted for this and mainly considers drop
Add 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 higher
Reaction 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 C
Liquid 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.Its
In, organic solvent C is one or more in tetrahydrofuran, dioxane, methanol and ethyl alcohol etc., preferably methanol.Into one
Step ground, in step (3)：Aqueous slkali is the sodium hydroxide solution of 10-20wt%, mole of compounds Ⅳ and sodium hydroxide solution
Than 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 needed
Water 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 alcohol
Example）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 water
Than being 1:0.5-2.0).Preferably, alcohol is methanol in step (4).It is highly preferred that step (3) and (4) use methanol, no
But 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 brilliant
But 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 essence
Product.
Preferably, in step (4), recrystallization solvent A is the mixed solvent of isopropanol, first alcohol and water, isopropanol, methanol
Volume 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 effect
120 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 reaction
Compound 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 complete
It 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, dripped
It 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 acetate
Alcohol-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 system
The 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 reaction
Decrease 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 solvent
Mass 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 small
When, it is filtered, washed and dried to obtain fine work.Wherein, recrystallization solvent A is the mixed solvent of isopropanol, first alcohol and water, isopropyl
Alcohol, 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 out
Under, so that Atorvastatin calcium is precipitated out to the maximum extent；Again by specific recrystallization solvent to Atorvastatin calcium crude product
Recrystallized, the product of specific crystal formation can be obtained and greatly improve the purity of product, make product purity reach 99.9% with
On, 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 pure
Change method makes total recovery be more than 84%.Therefore, Atorvastatin calcium preparation method provided by the invention has product purity height, behaviour
The 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 further
It 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- pyrroles
Cough 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 cleans
Tert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettle
Fluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）Extremely
Reaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30
DEG 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 phase
It 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 acid
Tert-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 temperature
When, 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 detected
Tracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dress
Enter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls
Base) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.35kg, are received
Rate is 96%, purity 98.9%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(aniline
Base)-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 to
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.Drop
After 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 with
Track, solvent are ethyl acetate：Petroleum ether=1:1）.6L purified waters and 6L toluene are added into reaction solution, stirs 20 minutes, it is quiet
Layering 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, heating
To 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 with
700ml 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.Stop
It 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 dryings
In 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 -35
DEG 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 2L
Change 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%, purity
99.92%, maximum single miscellaneous 0.019%.
Embodiment two：
（a）（4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles
Cough 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 cleans
Tert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettle
Fluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）Extremely
Reaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30
DEG 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 phase
It 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 acid
Tert-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 temperature
When, 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 detected
Tracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dress
Enter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls
Base) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.36kg, are received
Rate is 96.7%, purity 98.8%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(aniline
Base)-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 cooled
To 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 with
Track, 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- fluorobenzene
Base)-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 risen
Calcium 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 153g
It 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 waters
In 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 -35
DEG 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 C
It 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%, purity
99.94%, maximum single miscellaneous 0.023%.
Embodiment three：
（a）（4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles
Cough 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 cleans
Tert-butyl acetate, 6L toluene, 0.41kg pivalic acids are stirred at room temperature 1 hour;1.1kg2- [2- (4- are added into reaction kettle
Fluorophenyl) -2- oxo -1- phenylethyls] -4- methyl-3-oxo-N-phenyl-pentanamides, temperature rising reflux（105℃-110℃）Extremely
Reaction terminates（TLC detecting and trackings, solvent are ethyl acetate：Petroleum ether=1:2）.Stop heating, cools to 25 DEG C -30
DEG 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 phase
It 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 acid
Tert-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 temperature
When, 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 detected
Tracking, solvent is ethyl acetate：Petroleum ether=1:2）Reaction solution is extracted 2 times with 2*9L toluene, abandons water phase, merges organic phase, dress
Enter Rotary Evaporators, be concentrated to dryness at 60 DEG C, obtains (4R-cis) -6- [2- [2- (4- fluorophenyls) -5- (1- isopropyls
Base) -3- phenyl -4- [(aniline) hydroxyl] -1H- pyrroles -1- bases] ethyl] -1,3- dihydroxy -4- tert-butyl acetate 1.33kg, are received
Rate is 94.5%, purity 99.3%.
（c）[R, (R*, R*)] -2- (4- fluorophenyls)-β, alpha-dihydroxy -5- (1- Methylethyls) -3- phenyl-[(aniline
Base)-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 cooled
To 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 with
Track, 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- fluorobenzene
Base)-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 risen
Calcium 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 148g
It 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 waters
In 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 -35
DEG 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 2L
Change 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 pure
Degree 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 and
Within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of high purity atorvastatin calcium, reaction stream formula are：
It is characterized in that,
In step (4), compound V is reacted with calcium acetate in the mixed solvent system of water and alcohol, reaction temperature 40-
70 DEG C, the molar ratio of the calcium acetate and compound V is 0.4-0.8：1, the volume ratio of alcohol and water is 1 in reaction system:2-8,
The compound V is 5-10% in the mass percent concentration of in the mixed solvent, decrease temperature crystalline after the completion of reaction, be obtained by filtration Ah
Atorvastatin calcium crude product, the alcohol are one or more in methanol, ethyl alcohol, isopropanol and ethylene glycol；
Atorvastatin calcium crude product is dissolved in recrystallization solvent A, the Atorvastatin calcium crude product is in recrystallization solvent A
Mass percent concentration be 5-10%, Ι type Atorvastatin calcium crystal seeds are added under the conditions of 45-85 DEG C and carry out turning crystalline substance, turn brilliant complete
At rear decrease temperature crystalline, it is filtered, washed and dried to obtain fine work, the recrystallization solvent A is alcohol and water by volume 1：2-5 is formed
Mixed solvent, the alcohol is one or more in methanol, ethyl alcohol, isopropanol and ethylene glycol.
2. the preparation method of Atorvastatin calcium according to claim 1, which is characterized in that step (1) includes：
Chemical compounds I and compound ii carry out condensation reaction, reaction temperature 60-120 in organic solvent A under pivalic acid effect
DEG C, the molar ratio of the chemical compounds I, compound ii and pivalic acid is 1:1.1-1.3:0.6-1.5 obtains chemical combination after the completion of reaction
Object III, the organic solvent A are one or more in toluene, benzene, n-hexane, normal heptane, tetrahydrofuran and dioxane.
3. the preparation method of Atorvastatin calcium according to claim 2, which is characterized in that step (1) further includes：
The crude product of compound III is washed, is concentrated to give after the completion of reaction, and the crude product and recrystallization solvent B of compound III are in reflux condition
Dissolved clarification under part, decrease temperature crystalline, the fine work for filtering, being dried to obtain compound III；The recrystallization solvent B is selected from ethylene glycol, isopropyl
Alcohol, normal propyl alcohol or glycerine.
4. the preparation method of Atorvastatin calcium according to claim 3, which is characterized in that step (2) includes：
Compound III is dissolved in organic solvent B, acid solution is added dropwise under the conditions of 5-25 DEG C, in 20-30 DEG C after being added dropwise to complete
Under the conditions of reacted, extraction after having reacted takes organic phase to be concentrated to give compounds Ⅳ, and the organic solvent B is selected from tetrahydrochysene furan
It mutters, is in dioxane, methanol and ethyl alcohol one or more.
5. the preparation method of Atorvastatin calcium according to claim 4, which is characterized in that in step (2)：
The acid solution is the hydrochloric acid of 8-18wt%.
6. the preparation method of Atorvastatin calcium according to claim 4, which is characterized in that step (3) includes：By chemical combination
Object IV is dissolved in organic solvent C, and aqueous slkali is added dropwise under the conditions of 0-15 DEG C, is carried out under the conditions of 10-30 DEG C after being added dropwise to complete
Reaction, extraction after having reacted, water intaking mutually obtain the solution of compound V, and the organic solvent C is selected from tetrahydrofuran, dioxy six
It is one or more in ring, methanol and ethyl alcohol.
7. the preparation method of Atorvastatin calcium according to claim 6, which is characterized in that in step (4)：When turning brilliant
Between be 24-48 hours, decrease temperature crystalline process is：20-35 DEG C is naturally cooled to after the completion of turning brilliant, is stirred 0.5-2 hours, then cool down
To 0-5 DEG C, stirring at low speed 1-4 hours is filtered, washed and dried to obtain fine work.
8. the preparation method of Atorvastatin calcium according to claim 1, which is characterized in that in step (4)：It is described heavy
Recrystallisation solvent A be isopropanol, first alcohol and water mixed solvent, the isopropanol, first alcohol and water volume ratio be 1:1-4:8-10.
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Cited By (7)
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| CN109180633A (en) * | 2018-10-09 | 2019-01-11 | 河南师范大学 | A kind of purification process of Atorvastatin calcium intermediate A TS-9 |
| CN109280024A (en) * | 2018-10-09 | 2019-01-29 | 河南师范大学 | A kind of preparation method of the high purity atorvastatin tert-butyl ester |
| CN109293548A (en) * | 2018-10-09 | 2019-02-01 | 河南师范大学 | A kind of preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium |
| CN110563628A (en) * | 2019-08-26 | 2019-12-13 | 北京嘉林药业股份有限公司 | Crystallization method for preparing high-purity and monodisperse I crystal form atorvastatin calcium by double kettles |
| CN110776451A (en) * | 2020-01-02 | 2020-02-11 | 湖南迪诺制药股份有限公司 | Preparation method of I-type atorvastatin calcium |
| CN113321607A (en) * | 2020-02-28 | 2021-08-31 | 北京福元医药股份有限公司沧州分公司 | Purification method of atorvastatin calcium intermediate |
| CN114213308A (en) * | 2021-12-17 | 2022-03-22 | 江苏阿尔法药业股份有限公司 | Method for synthesizing atorvastatin ester by using continuous flow tubular reactor |
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Application publication date: 20180921 |