CN109293548A - A kind of preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium - Google Patents
A kind of preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium Download PDFInfo
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- CN109293548A CN109293548A CN201811173254.8A CN201811173254A CN109293548A CN 109293548 A CN109293548 A CN 109293548A CN 201811173254 A CN201811173254 A CN 201811173254A CN 109293548 A CN109293548 A CN 109293548A
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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-quality HMG-CoA reductase inhibitor Atorvastatin calcium, belong to treatment cardiovascular medicament field.Compound shown in formula (I) is dissolved in organic solvent, then alkaline solution is added dropwise, heating stirring；Distilled water is added after having reacted, heat temperature raising, at the uniform velocity dropwise addition calcium salt soln are added dropwise insulated and stirred, are cooled to room temperature, stand and filter, washing, drying obtains Atorvastatin calcium crude product；Atorvastatin calcium crude product is dissolved with organic solvent, active carbon and solid base, heating stirring is added, Atorvastatin calcium solution is obtained by filtration, it is added dropwise in warm water, insulated and stirred drops to room temperature, it stands, is washed with solvent, drying obtains high purity atorvastatin calcium.The present invention uses the Atorvastatin tert-butyl ester of purification for raw material, obtains high purity atorvastatin calcium by hydrolysis, clarification, reaches the quality requirement of high-quality Atorvastatin calcium.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of high-quality HMG-CoA reductase inhibitor atropic cuts down him
The preparation method of spit of fland calcium.
Background technique
Cardiovascular and cerebrovascular disease is referred to as always the number one killer for threatening human health.Currently, China's cardiovascular and cerebrovascular disease is suffered from
Person alreadys exceed 2.7 hundred million people, and the people for dying of cardiovascular and cerebrovascular disease every year has 3,000,000 or so, accounts for our states total Death causes every year
51%, and the patient to survive has 75% different degrees of disability, wherein 40% weight is residual.
Atherosclerosis is the pathologic basis of ischemic angiocardiopathy and cerebrovascular disease, its main feature is that involvement arterial disease is opened from inner membrance
Begin, generally first has lipid and the accumulation of compound carbohydrate, bleeding and thrombosis, proliferation of fibrous tissue and calcinosis, and have artery
The gradually transformation and calcification in middle layer, lesion often involve elastic and big medium muscular artery, are enough to block lumen of artery once developing to,
The tissue or organ that then the artery is supplied are by ischemic or necrosis.
The drug of antiatherosclerosis is more: having and adjusts blood pharmacy, antioxidant, protection arterial endothelium medicine etc..Wherein
HMG-CoA reductase depressant is the one kind for adjusting blood pharmacy, the statins such as mevastatin, Lovastatin, Fluvastatin, Atorvastatin
Class drug is at present for drop plasma cholesterol, primary high-cholesterol disease, the high lipid proteinosis of type III and diabetic keratopathy and kidney
The choice drug of property hyperlipemia, therefore have a vast market application prospect.
All it has been reported that preparing Atorvastatin calcium salt, Patent No. WO02/083637A1 is introduced many patents now
The synthetic method of Atorvastatin calcium be using the structure formula (I) compound represented Atorvastatin tert-butyl ester as raw material, wherein Ah
The atorvastatin tert-butyl ester is made by structure (II) L1 for raw material, and the Atorvastatin tert-butyl ester is in organic solvent through acid removing third
Then ketone protecting group becomes sodium atorvastatin after the saponification removing tert. butyl protection group of in the mixed solvent of acid and water
Then solution calcium acetate solution is added into solution and becomes calcium salt, using filter, washs, is dried to obtain Atorvastatin
Calcium finished product.This is also the usual synthetic route of Atorvastatin calcium, but the purity of Atorvastatin calcium prepared by the technique is not
It is high, it is difficult to reach the quality requirement of high-quality Atorvastatin calcium.Patent No. CN00814458.3 is also to introduce amorphism
The preparation of Atorvastatin calcium, be related to it is a kind of prepared from organic solvent by the recrystallization of crude product Atorvastatin it is noncrystalline
The method of shape Atorvastatin calcium, this method describe in a heated condition, the low-level chain triacontanol comprising 2-4 carbon or this
In the mixture of sample alkanol, thick amorphous atorvastatin calcium is dissolved, the crystalline substance atropic of the former precipitating of separation is cut down after cooling
Statin calcium.This method is simple, but the purity of amorphous atorvastatin calcium obtained is lower, and drug toxicity is larger, and patient takes
Adverse reaction is more.Patent No. CN02803968.8 describes the preparation of amorphism Atorvastatin calcium, be related to it is a kind of by Ah
The intermediate or Atorvastatin Lactose conversion of the synthesis of atorvastatin calcium are the new method of noncrystalline Atorvastatin calcium, this method
The midbody solution of synthesis is concentrated into the 15%~50% of initial volume, adds and is concentrated 1~5 times of water volume of solvent such as
Above-mentioned acquired solution is vigorously mixed by vibrating, is then separated by n-hexane, normal heptane, hexamethylene, ether, diisopropyl ether etc.
Organic phase, is added inorganic acid and neutralizes, be heated to 30~40 DEG C, forms Atorvastatin calcium salt using suitable calcium salt.It is above-mentioned anti-
The drug biology that should be known that operation is cumbersome, and cause the injury of human body with solvent volatilization, while be prepared by this method
Availability is lower, and the effect of the atherosclerosis such as treatment hyperlipidemia is poor.
Summary of the invention
The present invention is not high for Atorvastatin calcium purity is prepared present in above-mentioned preparation process, it is difficult to reach high-quality
The quality requirement of Atorvastatin calcium, and provide a kind of simple process and the suppression of low-cost high-quality HMG-CoA reductase
The preparation method of preparation Atorvastatin calcium reaches high-quality atropic so that the impurity content that obtained atropic cuts down his calcium is effectively reduced
Cut down the quality requirement of statin calcium.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, and a kind of high-quality HMG-CoA reductase inhibits
The preparation method of agent Atorvastatin calcium, it is characterised in that specific steps are as follows:
Step S1: the 99.9% Atorvastatin tert-butyl ester as shown in formula (I) is higher than as raw material using purity, uses organic solvent
Dissolution, then it is 9~12 that alkaline solution, which is added dropwise, to adjust the pH value of reaction system, is stirred to react in 45~60 DEG C, wherein alkaline solution
For in sodium hydroxide solution, sodium bicarbonate solution, sodium carbonate liquor, potassium hydroxide solution, solution of potassium carbonate or ammonia spirit
It is one or more；
Step S2: step S1, which has reacted rear, is added distilled water, and calcium salt soln is at the uniform velocity added dropwise in 45~60 DEG C, guarantor is added dropwise
Temperature stirring, is cooled to room temperature standing, filters, and washing, drying obtains Atorvastatin calcium crude product, and wherein calcium salt soln is calcium nitrate
One of solution, calcium chloride solution or calcium acetate solution are a variety of；
Step S3: the Atorvastatin calcium crude product that step S2 is obtained is dissolved with organic solvent, is added active carbon and is consolidated
The pH value that body alkali adjusts reaction system is 7~9, stirs in 25~35 DEG C, Atorvastatin calcium solution is obtained by filtration, wherein solid
Alkali is one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide or potassium carbonate or a variety of；
Step S4: the Atorvastatin calcium solution that step S3 is obtained is added drop-wise in 45~60 DEG C of warm water, in 45~60
DEG C insulated and stirred, is cooled to room temperature standing, is washed with solvent, and drying obtains high purity atorvastatin calcium.
Preferably, organic solvent described in step S1 is acetonitrile, tetrahydrofuran, methanol, ethyl alcohol or Isosorbide-5-Nitrae-dioxane, institute
The mass concentration for stating alkaline solution is 3%~10%.
Preferably, the specific synthesis process of the Atorvastatin tert-butyl ester described in step S1 are as follows:
Step A: the preparation of Atorvastatin tert-butyl ester dissolves compound L 1 with organic solvent, then molten with acidity
The pH value that liquid adjusts reaction system is 2~3, and the pH value of reaction system is adjusted to 7 after having reacted, is rotated and is largely consolidated until having
Body precipitation is filtered, and drying obtains Atorvastatin tert-butyl ester, and wherein organic solvent is methanol, and acid solution is quality
The hydrochloric acid solution of concentration 5%~27%；
Step B: the preparation of the high purity atorvastatin tert-butyl ester, the Atorvastatin tert-butyl ester that step A is obtained
It is recrystallized with suitable solvent, filtered and is washed with frost solvent, filter cake air blast dries to obtain the Ah that purity is higher than 99.9%
The atorvastatin tert-butyl ester, wherein suitable solvent is methanol, ethyl alcohol, tetrahydrofuran, acetonitrile or isopropanol；
The structural formula of the compound L 1 are as follows:
Preferably, the mass concentration of calcium salt soln described in step S2 be 1%~5%, at the uniform velocity dropwise addition calcium salt soln when
Between be 2.5~4h, 1~2h of insulated and stirred is added dropwise, is cooled to room temperature 6~10h of standing.
Preferably, washing process described in step S2 is specially to use methanol and water washing, then washed with methyl tertiary butyl ether(MTBE),
Finally it is washed with water.
Preferably, organic solvent described in step S3 is acetonitrile, methanol, ethyl alcohol or Isosorbide-5-Nitrae-dioxane.
Preferably, the time for adding of Atorvastatin calcium solution described in step S4 is 3~6h, is stirred in 45~60 DEG C of heat preservations
1~2h is mixed, 4~7h of standing is cooled to room temperature.
Preferably, washing process described in step S4 is specially to use methanol and water washing, is washed with water and washs.
Compared with the prior art, the present invention has the following advantages: in having been reported, the purity of Atorvastatin calcium reaches
The content of 98% synthetic method, single contaminant is greater than 1%, and the requirement of high-quality Atorvastatin calcium, institute of the present invention is not achieved
High-quality Atorvastatin calcium obtained reaches 99.9% or more through HPLC detection level, and the content of single contaminant is less than
0.05%, it can reach the quality requirement of high-quality Atorvastatin calcium.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
1, the preparation of the Atorvastatin tert-butyl ester
The purity of raw materials used compound L 1 is 98.0%.
Embodiment 1
Methanol 90mL, 1 10g of compound L are put into 250mL there-necked flask first, it is 5% that mass concentration, which is slowly added dropwise,
Hydrochloric acid solution 15mL monitors end of reaction in 35 DEG C of reactions 2h, TLC, saturation NaHCO is added3The pH of solution adjusting reaction system
Value is 7；It filters, and distills water washing filter cake with 25mL × 2, dried in 60 DEG C of air blast；The Atorvastatin tert-butyl ester that will be obtained
Crude product and 30mL tetrahydrofuran are added to 50mL single port bottle reflux 30min, freeze crystallization, filter, the tetrahydrofuran freezed with 5mL
Washing, in 60 DEG C of forced air dryings, is weighed as 9.33g, yield 93.3%, purity 99.9%.
Embodiment 2
Methanol 82mL, 1 10g of compound L are put into 250mL there-necked flask first, it is 27% that mass concentration, which is slowly added dropwise,
Hydrochloric acid solution 12mL monitors end of reaction in 35 DEG C of reactions 2h, TLC, saturation NaHCO is added3The pH of solution adjusting reaction system
Value is 7；It filters, and distills water washing filter cake with 25mL × 2, dried in 60 DEG C of air blast；The Atorvastatin tert-butyl ester that will be obtained
Crude product and 30mL methanol are added to 50mL single port bottle reflux 30min, freeze crystallization, filter, are washed with the methanol that 5mL is freezed, in
60 DEG C of forced air dryings are weighed as 9.26g, yield 92.6%, purity 99.95%.
Embodiment 3
Methanol 90mL, 1 10g of compound L are put into 250mL there-necked flask first, it is 15% that mass concentration, which is slowly added dropwise,
Hydrochloric acid solution 12mL monitors end of reaction in 35 DEG C of reactions 2h, TLC, saturation NaHCO is added3The pH of solution adjusting reaction system
Value is 7；It filters, and distills water washing filter cake with 25mL × 2, dried in 60 DEG C of air blast；The Atorvastatin tert-butyl ester that will be obtained
Crude product and 30mL ethyl alcohol are added to 50mL single port bottle reflux 30min, freeze crystallization, filter, the ethanol washing freezed with 5mL, in
60 DEG C of forced air dryings are weighed as 9.35g, yield 93.5%, purity 99.9%.
Embodiment 4
Methanol 90mL, 1 10g of compound L are put into 250mL there-necked flask first, it is 5% that mass concentration, which is slowly added dropwise,
Hydrochloric acid solution 12mL monitors end of reaction in 35 DEG C of reactions 2h, TLC, saturation NaHCO is added3The pH of solution adjusting reaction system
Value is 7；It filters, and distills water washing filter cake with 25mL × 2, dried in 60 DEG C of air blast；The Atorvastatin tert-butyl ester that will be obtained
Crude product and 30mL acetonitrile are added to 50mL single port bottle reflux 30min, freeze crystallization, filter, are washed with the acetonitrile that 5mL is freezed, in
60 DEG C of forced air dryings are weighed as 9.48g, yield 94.8%, purity 99.9%.
Embodiment 5
Methanol 90mL, 1 10g of compound L are put into 250mL there-necked flask first, it is 5% that mass concentration, which is slowly added dropwise,
Hydrochloric acid solution 12mL monitors end of reaction in 35 DEG C of reactions 2h, TLC, saturation NaHCO is added3The pH of solution adjusting reaction system
Value is 7；It filters, and distills water washing filter cake with 25mL × 2, dried in 60 DEG C of air blast；The Atorvastatin tert-butyl ester that will be obtained
Crude product and 30mL isopropanol are added to 50mL single port bottle reflux 30min, freeze crystallization, filter, are washed with the isopropanol that 5mL is freezed
It washs, in 60 DEG C of forced air dryings, is weighed as 9.53g, yield 95.3%, purity 99.97%.2, Atorvastatin calcium crude product
Preparation
Embodiment 6
Methanol 360mL, Atorvastatin tert-butyl ester 50g are put into 2L there-necked flask first, temperature is controlled at 45~60 DEG C
The sodium hydroxide solution 150mL that mass concentration is 6% is slowly added dropwise, drips stirring 3h, TLC monitors end of reaction；1L is steamed
Distilled water is added in reaction solution, is warming up to 45~60 DEG C, and at the uniform velocity dropwise addition mass concentration is 3.5% calcium acetate solution 290mL, is dripped
It is 3h between added-time, drips insulated and stirred 1.5h, be cooled to room temperature and stand 8h, filters and use methanol and water washing, then use methyl- tert
Butyl ether washing, is finally washed with water drying and obtains Atorvastatin calcium crude product；Atorvastatin calcium crude product is dry in 60 DEG C of air blast
It is dry, it is weighed as 49.3g, yield 98.60%, purity 99.82%.
Embodiment 7
Ethyl alcohol 360mL, Atorvastatin tert-butyl ester 50g are put into 2L there-necked flask first, temperature is controlled at 45~60 DEG C
The sodium hydroxide solution 150mL that mass concentration is 6% is slowly added dropwise, drips stirring 3h, TLC monitors end of reaction；1L is steamed
Distilled water is added in reaction solution, is warming up to 45~60 DEG C, and at the uniform velocity dropwise addition mass concentration is 3.5% calcium chloride solution 290mL, is dripped
It is 3h between added-time, drips insulated and stirred 1.5h, be cooled to room temperature and stand 8h, filters and use methanol and water washing, then use methyl- tert
Butyl ether washing, is finally washed with water drying and obtains Atorvastatin calcium crude product；Atorvastatin calcium crude product is dry in 60 DEG C of air blast
It is dry, it is weighed as 49.73g, yield 99.46%, purity 99.85%.
Embodiment 8
Acetonitrile 360mL, Atorvastatin tert-butyl ester 50g are put into 2L there-necked flask first, temperature is controlled at 45~60 DEG C
The sodium hydroxide solution 150mL that mass concentration is 6% is slowly added dropwise, drips stirring 3h, TLC monitors end of reaction；1L is steamed
Distilled water is added in reaction solution, is warming up to 45~60 DEG C, and at the uniform velocity dropwise addition mass concentration is 3.5% calcium nitrate solution 290mL, is dripped
It is 3h between added-time, drips insulated and stirred 1.5h, be cooled to room temperature and stand 8h, filters and use methanol and water washing, then use methyl- tert
Butyl ether washing, is finally washed with water drying and obtains Atorvastatin calcium crude product；Atorvastatin calcium crude product is dry in 60 DEG C of air blast
It is dry, it is weighed as 49.81g, yield 99.62%, purity 99.87%.
Embodiment 9
Isosorbide-5-Nitrae-dioxane 360mL, Atorvastatin tert-butyl ester 50g are put into 2L there-necked flask first, temperature control exists
45~60 DEG C are slowly added dropwise the sodium hydroxide solution 150mL that mass concentration is 6%, drip stirring 3h, TLC monitoring and have reacted
Finish；1L distilled water is added in reaction solution, is warming up to 45~60 DEG C, at the uniform velocity dropwise addition mass concentration is molten for 3.5% calcium acetate
Liquid 290mL, time for adding 3h drip insulated and stirred 1.5h, are cooled to room temperature and stand 8h, filter and use methanol and water washing,
It is washed again with methyl tertiary butyl ether(MTBE), drying is finally washed with water and obtains Atorvastatin calcium crude product；Atorvastatin calcium crude product in
60 DEG C of forced air dryings are weighed as 48.96g, yield 97.92%, purity 99.85%.
3, the preparation of Atorvastatin calcium fine work
Embodiment 10
Ethyl alcohol 320mL, Atorvastatin calcium crude product 40g, sodium hydroxide 0.8g, active carbon 2g are put into 2L there-necked flask first
In, 25~35 DEG C of dissolved clarifications are warming up to, suction filtration obtains Atorvastatin calcium solution, Atorvastatin calcium solution is added drop-wise to 45~60
DEG C warm water in, time for adding 5h is dripped and is continued to keep the temperature 1.5h, and cooling stands 6h, filter, with methanol and water washing, then
Drying obtains Atorvastatin calcium fine work after being washed with water, and in 60 DEG C of forced air dryings, is weighed as 37.36g, yield 93.40%,
Purity is 99.93%.
Embodiment 11
Methanol 320mL, Atorvastatin calcium crude product 40g, sodium carbonate 0.8g, active carbon 2g are put into 2L there-necked flask first
In, 25~35 DEG C of dissolved clarifications are warming up to, suction filtration obtains Atorvastatin calcium solution, Atorvastatin calcium solution is added drop-wise to 45~60
DEG C warm water in, time for adding 5h is dripped and is continued to keep the temperature 1.5h, and cooling stands 6h, filter, with methanol and water washing, then
Drying obtains Atorvastatin calcium fine work after being washed with water, and in 60 DEG C of forced air dryings, is weighed as 38.02g, yield 95.05%,
Purity is 99.92%.
Embodiment 12
Acetonitrile 320mL, Atorvastatin calcium crude product 40g, potassium hydroxide 0.8g, active carbon 2g are put into 2L there-necked flask first
In, 25~35 DEG C of dissolved clarifications are warming up to, suction filtration obtains Atorvastatin calcium solution, Atorvastatin calcium solution is added drop-wise to 45~60
DEG C warm water in, time for adding 5h is dripped and is continued to keep the temperature 1.5h, and cooling stands 6h, filter, with methanol and water washing, then
Drying obtains Atorvastatin calcium fine work after being washed with water, and in 60 DEG C of forced air dryings, is weighed as 37.78g, yield 94.45%,
Purity is 99.96%.
Embodiment 13
1,4- dioxane 320mL, Atorvastatin calcium crude product 40g, sodium hydroxide 0.8g, active carbon 2g are put into first
In 2L there-necked flask, 25~35 DEG C of dissolved clarifications are warming up to, suction filtration obtains Atorvastatin calcium solution, Atorvastatin calcium solution is added dropwise
Into 45~60 DEG C of warm water, time for adding 5h is dripped and is continued to keep the temperature 1.5h, and cooling stands 6h, is filtered, with first alcohol and water
Washing is washed with water drying after washing and obtains Atorvastatin calcium fine work, in 60 DEG C of forced air dryings, is weighed as 36.99g, yield is
92.48%, purity 99.95%.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (8)
1. a kind of preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium, it is characterised in that specific steps
Are as follows:
Step S1: using purity be higher than the 99.9% Atorvastatin tert-butyl ester as shown in formula (I) as raw material, it is molten with organic solvent
Solution, then it is 9~12 that alkaline solution, which is added dropwise, to adjust the pH value of reaction system, is stirred to react in 45~60 DEG C, wherein alkaline solution is
One in sodium hydroxide solution, sodium bicarbonate solution, sodium carbonate liquor, potassium hydroxide solution, solution of potassium carbonate or ammonia spirit
Kind is a variety of；
Step S2: step S1, which has reacted rear, is added distilled water, and calcium salt soln is at the uniform velocity added dropwise in 45~60 DEG C, heat preservation is added dropwise and stirs
It mixes, is cooled to room temperature standing, filter, washing, drying obtains Atorvastatin calcium crude product, and wherein calcium salt soln is that calcium nitrate is molten
One of liquid, calcium chloride solution or calcium acetate solution are a variety of；
Step S3: the Atorvastatin calcium crude product that step S2 is obtained is dissolved with organic solvent, adds active carbon and solid base
The pH value for adjusting reaction system is 7~9, stirs in 25~35 DEG C, Atorvastatin calcium solution is obtained by filtration, wherein solid base is
One of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide or potassium carbonate are a variety of；
Step S4: the Atorvastatin calcium solution that step S3 is obtained is added drop-wise in 45~60 DEG C of warm water, is protected in 45~60 DEG C
Temperature stirring, is cooled to room temperature standing, is washed with solvent, and drying obtains high purity atorvastatin calcium.
2. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: organic solvent described in step S1 is acetonitrile, tetrahydrofuran, methanol, ethyl alcohol or Isosorbide-5-Nitrae-dioxane, and the alkalinity is molten
The mass concentration of liquid is 3%~10%.
3. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: the specific synthesis process of the Atorvastatin tert-butyl ester described in step S1 are as follows:
Step A: the preparation of Atorvastatin tert-butyl ester dissolves compound L 1 with organic solvent, then with acid solution tune
The pH value for saving reaction system is 2~3, and the pH value of reaction system is adjusted to 7 after react, is rotated until there is the analysis of a large amount of solids
It is filtered out, drying obtains Atorvastatin tert-butyl ester, and wherein organic solvent is methanol, and acid solution is mass concentration
5%~27% hydrochloric acid solution；
Step B: the preparation of the high purity atorvastatin tert-butyl ester, the Atorvastatin tert-butyl ester that step A is obtained close
Suitable solvent is recrystallized, and is filtered and wash with frost solvent, and filter cake air blast, which dries to obtain purity and is higher than 99.9% atropic, to be cut down
The statin tert-butyl ester, wherein suitable solvent is methanol, ethyl alcohol, tetrahydrofuran, acetonitrile or isopropanol；
The structural formula of the compound L 1 are as follows:
4. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: the mass concentration of calcium salt soln described in step S2 be 1%~5%, at the uniform velocity dropwise addition calcium salt soln time be 2.5~
1~2h of insulated and stirred is added dropwise in 4h, is cooled to room temperature 6~10h of standing.
5. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: washing process described in step S2 is specially to use methanol and water washing, then washed with methyl tertiary butyl ether(MTBE), finally uses water
Washing.
6. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: organic solvent described in step S3 is acetonitrile, methanol, ethyl alcohol or 1,4- dioxane.
7. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: the time for adding of Atorvastatin calcium solution described in step S4 is 3~6h, in 45~60 DEG C of 1~2h of insulated and stirred,
It is cooled to room temperature 4~7h of standing.
8. the preparation method of high-quality HMG-CoA reductase inhibitor Atorvastatin calcium according to claim 1, special
Sign is: washing process described in step S4 is specially to use methanol and water washing, is washed with water and washs.
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Cited By (2)
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| 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 |
| CN115043769A (en) * | 2022-06-28 | 2022-09-13 | 江苏阿尔法药业股份有限公司 | Preparation method of atorvastatin calcium |
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| 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 |
| CN115043769A (en) * | 2022-06-28 | 2022-09-13 | 江苏阿尔法药业股份有限公司 | Preparation method of atorvastatin calcium |
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