CN102796036A - Preparation method of atorvastatin calcium - Google Patents
Preparation method of atorvastatin calcium Download PDFInfo
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- CN102796036A CN102796036A CN2012103351301A CN201210335130A CN102796036A CN 102796036 A CN102796036 A CN 102796036A CN 2012103351301 A CN2012103351301 A CN 2012103351301A CN 201210335130 A CN201210335130 A CN 201210335130A CN 102796036 A CN102796036 A CN 102796036A
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Abstract
The invention belongs to the field of medicine chemical industry, and provides a preparation method of atorvastatin calcium, which comprises the following steps: purifying to obtain a calcium salt by basic hydrolysis and acid hydrolysis, and repurifying to obtain an amorphous calcium salt. The technical scheme provided by the invention has the advantages of high product yield (the total yield is higher than 90%), high product purity and wide application value.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of atorvastatincalcuim.
Background technology
Atorvastatin is complete synthesis; Highly selective suppresses the medicine of HMG-CoA reductase enzyme; Be third generation Statins blood lipid regulation medicine in Britain and U.S.'s listing, and be used to treat the control of hypercholesterolemia and combined hyperlipidemia familial, coronary heart disease and Stroke in 1997.
The conventional compound method of atorvastatincalcuim is shown in the following figure
Atorvastatincalcuim is water-soluble very little, and has found that its crystallized form is than amorphous form indissoluble more.Preparing method to atorvastatincalcuim in the prior art studies.
Application number is 200810104156.9; Publication number is the preparation method that the Chinese patent document of CN101560177A discloses a kind of atorvastatincalcuim; With (4R-CiS)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1-H pyrroles-1-yl]-2; The 2-methyl isophthalic acid, 3-dioxolane-4-tert.-butyl acetate passes through organic acid hydrolysis, basic hydrolysis successively, and hydrolysate and calcium salt reaction obtain atorvastatincalcuim.
Application number is 200480042834.3; Publication number is the preparation method that the Chinese patent document of CN1942439A discloses a kind of atorvastatincalcuim: (4R-is suitable)-1; 1-dimethyl ethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrroles-1-yl] ethyl }-2; 2-dimethyl--1,3-diox-4-acetic ester are in process acid hydrolysis and basic hydrolysis, and hydrolysate is through being immiscible in water or little mixed water-soluble solvent wash; Prepare atorvastatincalcuim with calcium salt or calcium hydroxide again; Isolating thick atorvastatincalcuim is dissolved in THF and the methanol mixture, and water makes its deposition, and the pure atorvastatincalcuim that makes crystalline form is converted into amorphous form again.
Application number is 200580022538.1, and publication number is the preparation method that the Chinese patent document of CN1980890A also discloses a kind of similar a kind of atorvastatincalcuim: (6-{2-2 [2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-phenyl amino formyl radical-pyrroles-1-yl]-ethyl }-2,2-dimethyl--[1; 3]-diox-4 base)-add the 1N hydrochloric acid hydrolysis in the solution of tert.-butyl acetate in methyl alcohol and THF (1:1) after, pass through sodium hydroxide hydrolysis again, remove and desolvate; Hydrolysate is dissolved in the water, washs water layer, neutralize with hydrochloric acid with ether; In ETHYLE ACETATE, warp concentrates, and column chromatography (silica gel 100-200 order) with organic substance extraction; Obtain atorvastatin; Becoming calcium salt with lime acetate, through washing, exsiccant atorvastatincalcuim.
Application number is 02803968.8; Publication number is the preparation method that the Chinese patent document of CN1487921A discloses noncrystalline atorvastatincalcuim; Method comprise a) provide a kind of solution
that in non-hydroxyl solvent, contains the midbody compound of formula (I) wherein A represent dihydric common protection base or separately protected base, and B representes the carboxylic acid protecting group; B) accomplish dihydric deprotection; C) completion carboxylic acid protecting group's deprotection; Wherein step b) and c) order can put upside down; D) pact of solution concentration to initial volume is half the or littler; E) add the water that surpasses through the volume of spissated solution; F) add with step e) in the volume of the water that adds approximately identical or more volume, a kind of can be with water slightly miscible or can not be with water miscible and the insoluble therein or insoluble,practically solvent of atorvastatincalcuim; G) randomly carry out married operation, and separate two phases; H) in and water; I) atorvastatincalcuim is converted into the pharmacologically acceptable salts form; And j) formation is converted into the deposition of the atorvastatincalcuim of said pharmacologically acceptable salts form.
At present, prior art all adopts first acid hydrolysis basic hydrolysis again, salifiable again method behind the purifying, but adopt first acid hydrolysis, in the process of hydrolysis, can generate two kinds of side reaction things, thereby influence the yield of entire reaction, and increase the difficulty of removing impurity.Can put upside down though put down in writing the step of acid hydrolysis and basic hydrolysis in the Chinese patent 02803968.8, not provide acid-hydrolyzed technical scheme after the concrete first basic hydrolysis, also two kinds of schemes not compared.According to the document record, the prior art scheme prepares the yield of atorvastatincalcuim between 64%-83%.
Summary of the invention
The present invention is directed to the prior art deficiency, a kind of preparation method of atorvastatincalcuim is provided, adopt acid-hydrolyzed method after the first basic hydrolysis, alkaline hydrolysis process does not generate other impurity and can directly generate the higher sodium salt that the two hydroxyls of acetone protection are arranged of purity; And more be prone to generate the hydroxyl sodium salt that takes off the acetone protection in the reaction of hydroxyl with going acetone to protect with acid again behind the alkali reaction.The present technique scheme has increased the purification step to calcium salt after the step that generates the atorvastatin calcium salt, employing ETHYLE ACETATE and hexanaphthene and zeyssatite are further removed remaining impurities and product yield is not influenced.。
Technical scheme of the present invention is specific as follows:
A kind of preparation method of atorvastatincalcuim, step comprises:
(1) with (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; Add alkali in the tetrahydrofuran solution of 3-dioxane-4-tert.-butyl acetate (compound 1), preferred concentration is the NaOH solution of 20% (percent weight in volume), and the conditioned reaction pH value of solution is an alkalescence; Preferred pH is 11; (TLC monitors reaction process, and developping agent is a methylene dichloride: ETHYLE ACETATE=17:3), obtain (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2 to reacting completely to be warming up to 30-35 ℃ of back flow reaction; 2-dimethyl--1,3-dioxane-4-sodium acetate;
(2) with hydrolysate (the 4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2 of step (1); 2-dimethyl--1; In the tetrahydrofuran solution of 3-dioxane-4-sodium acetate; Slowly add 10% aqueous hydrochloric acid, (TLC monitors reaction process, and developping agent is a methylene dichloride: methyl alcohol=3:1) to reacting completely for 30-35 ℃ of refluxing and stirring;
(3) the hydrolyzed solution vacuum concentration that step (2) is obtained is flung to organic solvent tetrahydrofuran, adds entry; Divide extraction mixed solution water intaking layer three times with MTBE, add THF, drip alkali again; Preferred 10% (percent weight in volume) NaOH solution, the pH that transfers solution are alkalescence, and preferred pH is 7.5-8; Be added in the ETHYLE ACETATE, filter, obtain (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1,3-dihydroxyl-4-sodium acetate;
(4) to (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1,3-dihydroxyl-4-sodium acetate is dissolved in the mixing solutions of THF and water; Drip the reaction of 10% calcium acetate, reaction finishes the back and uses ethyl acetate extraction, gets the ETHYLE ACETATE phase; Use anhydrous sodium sulfate drying, suction filtration, vacuum concentration; Use diatomite filtration; Add in the hexanaphthene and stir, filter, drain the pure article of atorvastatincalcuim;
(5) atorvastatincalcuim with purifying adds stirring at normal temperature in the entry, and the suction filtration drying obtains unbodied atorvastatincalcuim.
The product yield of technical scheme of the present invention is high, and total recovery is more than 90%, and purity is high, is with a wide range of applications.
Description of drawings
The preparation route map of Fig. 1 technical scheme atorvastatincalcuim of the present invention.
The nuclear magnetic resonance map of Fig. 2 technical scheme atorvastatincalcuim of the present invention.
Embodiment
Employed in the present invention term except as otherwise noted, generally has the implication of those of ordinary skills' common sense.
Below in conjunction with specific embodiment and comparable data the present invention is described in further detail.Should be understood that these embodiment just in order to demonstrate the invention, but not limit scope of the present invention by any way.
In following examples, various processes and the method do not described in detail are ordinary methods as known in the art.
Embodiment 1 (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1, the preparation of 3-dioxane-4-sodium acetate
In reaction flask, add (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; 3-dioxane-4-tert.-butyl acetate 3.0g (4.6mmol), THF 30ml, 35 ℃ of stirred solutions become clarification; The NaOH that slowly drips (joining day is greater than 10min) 20% transfer pH be 11 and reaction process in pH remain unchanged, 35 ℃ of refluxing and stirring 7 hours, (TLC monitors reaction process) accomplished in reaction, stops to heat nature and cools to room temperature.Above-mentioned solution slowly splashes in the water of 5 ℃ of 120ml, and temperature control is at 5 ℃, and the adularescent solid is separated out, and finishes for about 20 minutes, and temperature control stirred 30 minutes at 5 ℃, suction filtration, and the filter cake water is washed till neutrality.40 ℃ of dryings of solid convection oven got white solid 2.79g, yield 97.9% in 12 hours.
Embodiment 2 (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1, the preparation of 3-dihydroxyl-4-sodium acetate
In reaction flask, add 2.79g (4.5mmol) (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; 3-dioxane-4-sodium acetate, 30mlTHF, 35 ℃ of stirred solutions become clarification; Slowly drip 10% HCl (joining day is greater than 10min) 14ml (46mmol) in above-mentioned solution, 35 ℃ of refluxed stirred 5 hours, and (TLC monitors reaction process) accomplished in reaction.35 ℃ of above-mentioned solution of vacuum concentration with adding 50ml water in the aqueous solution, divides three extraction mixed solutions to fetch water layer with about 150ml MTBE till the remaining aqueous solution only.Solid occurs in the water layer solution, the THF that adds 10ml makes the solution clarification, and the pH that drips 10% NaOH accent solution again is 7.5-8.Join in 10 ℃ of 150ml ETHYLE ACETATE after above-mentioned solution cooled to room temperature, temperature control stirs at 10 ℃ had solid to separate out in 1 hour, static 30 minutes, filtered filter cake and used rinsed.40 ℃ of dryings of solid convection oven got pink solid 2.54g, yield 97.2% in 12 hours.
Embodiment 3 [R, (R ﹡, R ﹡)]-2-(4-fluorophenyl)-α, the preparation of beta-dihydroxyl-5-(1-methylethyl)-3-phenyl-[(anilino)-hydroxyl]-1H-pyrroles-1-Calcium salt enanthate (atorvastatincalcuim)
In reaction flask, add 2.54g (4.38mmol) (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; 3-dihydroxyl-4-sodium acetate, 15mlTHF and 15ml water, 35 ℃ of stirred solutions become clarification; Solution is warmed up to 40 ℃, in solution, drips the 5.3ml aqueous solution of 10% calcium acetate (3mmol), stirring reaction 1.5 hours; Reaction finishes the back with about 150ml ethyl acetate extraction (till the ethyl acetate layer clarification), in ethyl acetate layer, stirs 30min with anhydrous magnesium sulfate, filters, with 15ml rinsed filter cake.35 ℃ of vacuum concentration ethyl acetate layers are to surplus about 25ml, diatomite filtration, 5ml rinsed.Add in 10 ℃-15 ℃ the 300ml hexanaphthene and stir 30min, filter, with 15ml hexanaphthene flush cake, drain atorvastatincalcuim.
With adding 30ml water stirring at normal temperature 12h in the above-mentioned pressed powder, suction filtration, 40 ℃ of dry white solids get the amorphous atorvastatin calcium of 2.53g, and productive rate is 96.6%.Consistent through detecting its hydrogen spectrum with the atorvastatin standard diagram, shown in accompanying drawing 2.
Claims (4)
1. the preparation method of an atorvastatincalcuim, step comprises:
(1) with (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; Adding alkali conditioned reaction pH value of solution in the tetrahydrofuran solution of 3-dioxane-4-tert.-butyl acetate (compound 1) is alkalescence; Be warming up to 30-35 ℃ of back flow reaction to reacting completely; Obtain (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1,3-dioxane-4-sodium acetate;
(2) with hydrolysate (the 4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2 of step (1); 2-dimethyl--1; In the tetrahydrofuran solution of 3-dioxane-4-sodium acetate; The aqueous hydrochloric acid of slow adding 10%, 30-35 ℃ of refluxing and stirring is to reacting completely;
(3) the hydrolyzed solution vacuum concentration that step (2) is obtained is flung to organic solvent tetrahydrofuran, adds entry; Divide extraction mixed solution water intaking layer three times with MTBE, add THF, drip alkali again and transfer the pH of solution to be alkalescence; Be added in the ETHYLE ACETATE, filter, obtain (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1,3-dihydroxyl-4-sodium acetate;
(4) to (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1,3-dihydroxyl-4-sodium acetate is dissolved in the mixing solutions of THF and water, drips the reaction of 10% calcium acetate; Reaction finishes the back and uses ethyl acetate extraction, gets the ETHYLE ACETATE phase, uses anhydrous sodium sulfate drying; Suction filtration, vacuum concentration is used diatomite filtration; Add in the hexanaphthene and stir, filter, drain the pure article of atorvastatincalcuim;
(5) atorvastatincalcuim with purifying adds stirring at normal temperature in the entry, and the suction filtration drying obtains unbodied atorvastatincalcuim.
2. preparation method as claimed in claim 1 is characterized in that said step (1) and the described alkali of step (3) are NaOH.
3. preparation method as claimed in claim 1 is characterized in that the said pH value of solution of said step (1) is 11.
4. preparation method as claimed in claim 1 is characterized in that the said pH value of solution of said step (3) is 7.5-8.
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Cited By (3)
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|---|---|---|---|---|
| CN103641764A (en) * | 2013-11-25 | 2014-03-19 | 李兴惠 | Pharmaceutical composition for regulating blood lipid |
| CN105085362A (en) * | 2015-09-18 | 2015-11-25 | 浙江海森药业有限公司 | Preparing method for high-purity crystal type atorvastatin calcium |
| CN108218759A (en) * | 2018-01-12 | 2018-06-29 | 天方药业有限公司 | A kind of Atorvastatin calcium preparation method |
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|---|---|---|---|---|
| CN103641764A (en) * | 2013-11-25 | 2014-03-19 | 李兴惠 | Pharmaceutical composition for regulating blood lipid |
| CN103641764B (en) * | 2013-11-25 | 2015-12-02 | 北京三泉医药技术有限公司 | The pharmaceutical composition of adjusting blood lipid |
| CN105085362A (en) * | 2015-09-18 | 2015-11-25 | 浙江海森药业有限公司 | Preparing method for high-purity crystal type atorvastatin calcium |
| CN108218759A (en) * | 2018-01-12 | 2018-06-29 | 天方药业有限公司 | A kind of Atorvastatin calcium preparation method |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.9 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |