A kind of preparation method of Atorvastatin calcium intermediateTechnical field
The present invention relates to a kind of preparation method of Atorvastatin calcium intermediate, in particular to a kind of post-processing step is simpleHigh purity atorvastatin calcium intermediate preparation method.
Background technique
Atorvastatin calcium, English name: Atorvastatin Calcium, chemical name: [R- (R, R)] -2- (4- fluorinePhenyl)-β, beta-dihydroxy -5- (1- Methylethyl) -3- phenyl -4- [(aniline) carbonyl] -1- hydrogen-three water of pyrroles's -1- enanthic acid calciumObject is closed, is Gao Hecheng, High Purity, the highly selective drug for inhibiting HMG-CoA reductase, is developed by Pfizer, be theThree generations's statins.It is mainly used for treating the prevention and treatment of hypercholesterolemia, hyperlipidemia and coronary heart disease and headstroke.
The synthetic route of Atorvastatin calcium is using amine ester and diketone as starting material synthetic intermediate condensation product, so at presentAtorvastatin calcium is further synthesized by raw material of intermediate condensate again afterwards, in which: amine ester described in the present patent application fileMolecular formula following reaction formula shown in, be ((4R-cis) -2,2- dimethyl -6- (2- aminoethyl) -1,3- dioxane -4-Tert-butyl acetate) abbreviation；It is ((±)-α-different shown in the molecular formula following reaction formula of diketone described in this paper application documentsBytyry-γ-oxo-N, β-diphenyl -4- fluorobenzene butyramide) abbreviation；Intermediate condensate described in this paper application documentsMolecular formula following reaction formula shown in, be ((4R-cis) -6- [2- [2- (4- fluorophenyl) -5- (1- isopropyl) -3- phenyl -4- [(aniline) carbonyl] -1H- pyrroles -1- base] ethyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetate) and letterClaim, in the prior art composition principle following reaction formula:
The synthetic route of Atorvastatin calcium intermediate condensate is using amine ester and diketone as starting material in the prior artReaction, after reaction, the process steps of intermediate condensate are cumbersome, complicated for operation, the production cycle is long, organic solvent amountConsume that larger, higher cost, yield are low, there are problems that production security.Such as: adding toluene to extract, then through alkali cleaning, pickling, saltWash, then plus active carbon decoloring, then filter activity charcoal, solvent distillation, add ethyl alcohol and n-hexane crystallization, after centrifugal dryingAtorvastatin calcium intermediate condensate, weight yield 110%.
Summary of the invention
To overcome the shortcomings of existing technologies, the present invention provides a kind of preparation methods of Atorvastatin calcium intermediate.It shouldPreparation method is while improving Atorvastatin calcium intermediate yield, the post-processing approach letter of Atorvastatin calcium intermediateRisk when list, operating process simplification, production cycle shortening, organic solvent consumption reduction, production cost reduction, production operationIt reduces.
A kind of preparation method of Atorvastatin calcium intermediate, comprising the following steps:
It 1, is that 1:1-1.5 amine ester and diketone are anti-in in the mixed solvent according to following formulas as starting material using mass ratioIt answers, the mixed solvent is the normal heptane and tetrahydrofuran of volume ratio 1:1-3, every that 5-8ml mixed solvent is added using 1g amine ester；
2,1 gained reaction solution of concentration step removes mixed solvent, obtains Atorvastatin calcium crude intermediate；
3, after the dissolution clarification of 1 ethyl alcohol of recrystallisation solvent being added in step 2 products therefrom, 2 purified water of recrystallisation solvent is added, is droppedTemperature is crystallized to 40-75 DEG C, and preferably 50 DEG C, centrifugal drying is wherein every using just using 3- in 1g amine ester step 3 in step 17ml ethyl alcohol and 1-4ml purified water, preferably 4ml ethyl alcohol and 3ml purified water.
A kind of preparation method of Atorvastatin calcium intermediate, wherein the mass ratio of the amine ester and diketone is 1:1-1.25。
A kind of preparation method of Atorvastatin calcium intermediate, wherein the mixed solvent be volume ratio 1:2-2.5 justHeptane and tetrahydrofuran.
A kind of preparation method of Atorvastatin calcium intermediate, it is wherein every mixed using 1g amine ester addition 6-7.5ml in step 1Bonding solvent.
A kind of preparation method of Atorvastatin calcium intermediate, wherein the condition of reaction described in step 1 is to be heated to refluxReact 30-50h, preferably 36-40h.
Compared with prior art, the invention has the following beneficial effects:
1, no longer extraction, alkali cleaning, pickling and salt are washed in step, simplify production procedure, shorten the production cycle, are reducedThe consumption and sewage discharge of organic solvent, realize clean manufacturing, and risk when production operation reduces；
2, pass through amine ester and diketone special ratios, mixed solvent specific composition, recrystallisation solvent specific composition, crystallization temperature etc.The selection of condition makes 125% or more the weight yield of product Atorvastatin calcium intermediate condensate, the HPLC purity of productIt is 99.0%, the weight yield of product improves 15% or more, and cost is greatly lowered.
Detailed description of the invention
Fig. 1 is the flow chart of the preparation method of Atorvastatin calcium intermediate of the present invention.
Specific embodiment
With reference to the accompanying drawing, specific embodiments of the present invention will be described in detail, it is to be understood that guarantor of the inventionShield range is not limited by the specific implementation.
Embodiment 1
Amine ester 16g and diketone 20g is added in 250ml reaction flask and is dissolved in 34ml normal heptane and 68ml tetrahydrofuran groupAt in the mixed solvent, temperature rising reflux react 40 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain atropic and cut downStatin calcium crude intermediate is added purified water 64ml, is cooled to 50 DEG C after adding 110ml ethyl alcohol to make crude intermediate dissolution clarificationMaterial is precipitated, centrifugal filtration obtains intermediate 25.1g, and the weight yield relative to diketone is that 125.5%, HPLC purity is99.0%.
Embodiment 2
Amine ester 16g and diketone 20g is added in 250ml reaction flask and is dissolved in 34ml normal heptane and 85ml tetrahydrofuran groupAt in the mixed solvent, temperature rising reflux react 36 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain atropic and cut downAfter adding 64ml ethyl alcohol to make crude intermediate dissolution clarification purified water 48ml is added, being cooled to 75 DEG C makes in statin calcium crude intermediateMaterial is precipitated, and centrifugal filtration obtains intermediate condensate 25.3g, and relative to the weight yield 126.5% of diketone, HPLC purity is99.0%.
Embodiment 3
Amine ester 16g and diketone 24g is added in 250ml reaction flask and is dissolved in 34ml normal heptane and 85ml tetrahydrofuran groupAt in the mixed solvent, temperature rising reflux react 50 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain atropic and cut downAfter adding 80ml ethyl alcohol to make crude intermediate dissolution clarification purified water 32ml is added, being cooled to 70 DEG C makes in statin calcium crude intermediateMaterial is precipitated, and centrifugal filtration obtains intermediate condensate 25.2g, and relative to the weight yield 126.0% of diketone, HPLC purity is99.0%.
Embodiment 4
Amine ester 16g and diketone 20g is added in 250ml reaction flask and is dissolved in 38ml normal heptane and 76ml tetrahydrofuran groupAt in the mixed solvent, temperature rising reflux react 40 hours, after completion of the reaction concentration of reaction solution remove mixed solvent, obtain atropic and cut downAfter adding 64ml ethyl alcohol to make crude intermediate dissolution clarification purified water 48ml is added, being cooled to 50 DEG C makes in statin calcium crude intermediateMaterial is precipitated, and centrifugal filtration obtains intermediate condensate 26.6g, and relative to the weight yield 133.0% of diketone, HPLC purity is99.0%.
Disclosed above is only specific embodiments of the present invention, and still, the present invention is not limited to this, any this fieldWhat technical staff can think variation should all fall into protection scope of the present invention.