Preparing method of high-purity atorvastatin calcium

A high-purity technology of atorvastatin calcium, applied in the field of preparation of high-purity atorvastatin calcium, can solve the problem of poor stability of amorphous atorvastatin calcium, poor bioavailability, high energy consumption, etc. problems, to achieve the effect of high product purity, improved purity, and high economic added value

Inactive Publication Date: 2018-09-21
HUBEI GUANGJI PHARMA
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Problems solved by technology

[0008] (1) The purity can only reach 99%, the total yield can only be guaranteed to be greater than 75%, and there is still a lot of room for improvement;
[0009] (2) The stability of the obtained amorphous atorvastatin calcium is not good and the bioavailability is not good;
[0010] (3) Extraction and concentration are required in step 4, which not only affects the yield due to complex process, but also consumes a large amount of energy

Method used

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  • Preparing method of high-purity atorvastatin calcium
  • Preparing method of high-purity atorvastatin calcium

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Experimental program
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Effect test

Embodiment 1

[0034] (a) (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)hydroxyl]-1H Preparation of -pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester

[0035] Put 1kg (4R-cis) 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate into a 10L dry and clean reactor, 6L toluene, 0.41kg Pivalic acid, stirred at room temperature for 1 hour; add 1.1kg of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3- Oxo-N-phenylpentanamide, heated to reflux (105°C-110°C) until the end of the reaction (TLC detection and tracking, developing solvent: ethyl acetate:petroleum ether=1:2). Stop heating, cool down to 25°C-30°C, add 5L of saturated sodium bicarbonate solution to wash once, and then wash the organic phase with 2*5L purified water twice, then transfer the organic phase to a rotary evaporator, at 60°C Concentrate to dryness under reduced pressure to give 4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline) Hydroxy]-1H-pyrr...

Embodiment 2

[0045] (a) (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)hydroxyl]-1H Preparation of -pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester

[0046] Put 1kg (4R-cis) 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate into a 10L dry and clean reactor, 6L toluene, 0.41kg Pivalic acid, stirred at room temperature for 1 hour; add 1.1kg of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3- Oxo-N-phenylpentanamide, heated to reflux (105°C-110°C) until the end of the reaction (TLC detection and tracking, developing solvent: ethyl acetate:petroleum ether=1:2). Stop heating, cool down to 25°C-30°C, add 5L of saturated sodium bicarbonate solution to wash once, and then wash the organic phase with 2*5L purified water twice, then transfer the organic phase to a rotary evaporator, at 60°C Concentrate to dryness under reduced pressure to give 4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline) Hydroxy]-1H-pyrr...

Embodiment 3

[0056] (a) (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)hydroxyl]-1H Preparation of -pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester

[0057] Put 1kg (4R-cis) 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate into a 10L dry and clean reactor, 6L toluene, 0.41kg Pivalic acid, stirred at room temperature for 1 hour; add 1.1kg of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3- Oxo-N-phenylpentanamide, heated to reflux (105°C-110°C) until the end of the reaction (TLC detection and tracking, developing solvent: ethyl acetate:petroleum ether=1:2). Stop heating, cool down to 25°C-30°C, add 5L of saturated sodium bicarbonate solution to wash once, and then wash the organic phase with 2*5L purified water twice, then transfer the organic phase to a rotary evaporator, at 60°C Concentrate to dryness under reduced pressure to give 4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline) Hydroxy]-1H-pyrr...

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Abstract

The invention discloses a preparing method of high-purity atorvastatin calcium, and belongs to the technical field of organic synthesis. The method includes the steps of making a compound V and calcium acetate react in a water and alcohol mixed solvent system, and conducting cooling crystallization and filtration after the reaction is completed to obtain an atorvastatin calcium crude product, wherein the reaction temperature is 40-70 DEG C, the volume ratio of alcohols to water in the reaction system is 1:(2-8), and the mass percentage concentration of the compound V in a mixed solvent is 5-10%; dissolving the atorvastatin calcium crude product in a recrystallization solvent A, adding I-type atorvastatin calcium crystals at 45-85 DEG C for crystal transformation, and conducting cooling crystallization, filtration, washing and drying after crystal transformation is completed to obtain a fine product, wherein the mass percentage concentration of the atorvastatin calcium crude product inthe recrystallization solvent A is 5-10%. The method has the advantages of being high in product purity, easy and safe to operate, high in yield and the like and is suitable for large-scale industrialproduction.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of high-purity atorvastatin calcium. Background technique [0002] The Chinese chemical name of atorvastatin calcium is [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3 -Phenyl-4-[(anilino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt, English 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 Registry No. 344423- 98-9 is the third-generation statin blood lipid regulating drug, which is used for the treatment of hypercholesterolemia and mixed hyperlipidemia, coronary heart disease and the prevention and treatment of cerebral apoplexy. [0003] Atorvastatin calcium was launched in the United Kingdom and the United States in 1997, and the market demand has been huge since its launch. With the aging of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34
CPCC07D207/34
Inventor 卢正东安靖郭韶智郑志长王柳黎艳华柯伯雄
Owner HUBEI GUANGJI PHARMA
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