CN102796036B - Preparation method of atorvastatin calcium - Google Patents
Preparation method of atorvastatin calcium Download PDFInfo
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- CN102796036B CN102796036B CN201210335130.1A CN201210335130A CN102796036B CN 102796036 B CN102796036 B CN 102796036B CN 201210335130 A CN201210335130 A CN 201210335130A CN 102796036 B CN102796036 B CN 102796036B
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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, within 1997, go on the market at UK and USA, for third generation Statins blood lipid regulation medicine, be used for the treatment of the control of hypercholesterolemia and combined hyperlipidemia familial, coronary heart disease and cerebral apoplexy.
The conventional synthetic method of atorvastatincalcuim is as shown below
Atorvastatincalcuim is water-soluble very little, and has found that its crystallized form is than more indissoluble of amorphous form.Preparation method to atorvastatincalcuim in prior art is studied.
Application number is 200810104156.9, publication number is the preparation method that the Chinese patent literature of CN101560177A discloses a kind of atorvastatincalcuim, by (4R-CiS)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1-H pyrroles-1-yl]-2,2-methyl isophthalic acid, 3-dioxolane-4-tert.-butyl acetate is successively through organic acid hydrolysis, basic hydrolysis, and hydrolysate reacts and obtains atorvastatincalcuim with calcium salt.
Application number is 200480042834.3, publication number is the preparation method that the Chinese patent literature 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 is in process acid hydrolysis and basic hydrolysis, hydrolysate is through being immiscible in water or micro-mixed water-soluble solvent wash, prepare atorvastatincalcuim with calcium salt or calcium hydroxide again, the thick atorvastatincalcuim separating is dissolved in the mixture of tetrahydrofuran (THF) and methyl alcohol, water makes its precipitation, the pure atorvastatincalcuim that makes crystalline form is converted into amorphous form again.
Application number is 200580022538.1, publication number is the preparation method that the Chinese patent literature 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 bases) add after 1N hydrochloric acid hydrolysis in the solution of-tert.-butyl acetate in methyl alcohol and tetrahydrofuran (THF) (1:1), pass through again sodium hydroxide hydrolysis, except desolventizing, hydrolysate is dissolved in water, wash water layer with ether, neutralize with hydrochloric acid, by organic substance extraction in ethyl acetate, through concentrated, and column chromatography (silica gel 100-200 order), obtain atorvastatin, becoming calcium salt with lime acetate, through washing, dry atorvastatincalcuim.
Application number is 02803968.8, publication number is the preparation method that the Chinese patent literature of CN1487921A discloses noncrystalline atorvastatincalcuim, and method comprises a) provides a kind of solution that contains the midbody compound of formula (I) in non-hydroxyl solvent
wherein A represents dihydric common protecting group or separately protected base, and B represents carboxylic acid protecting group; B) complete dihydric deprotection; C) complete carboxylic acid protecting group's deprotection; Wherein step order b) and c) can be put upside down; D) solution is concentrated into the approximately half of initial volume or less; E) add the water exceeding through the volume of concentrated solution; F) add the volume of the water adding in e) with step approximately identical or more volume, one can be with water slight miscible or can not be with water miscible and atorvastatincalcuim insoluble or insoluble,practically solvent therein; G) optionally carry out married operation, and separate two-phase; H) in and water; I) atorvastatincalcuim is converted into pharmacologically acceptable salts form; And j) form the precipitation of atorvastatincalcuim that is converted into described pharmacologically acceptable salts form.
At present, prior art all adopts first acid hydrolysis basic hydrolysis again, and the method for salify again after purifying, but adopt first acid hydrolysis can generate two kinds of side reaction things, thereby affect the yield of whole reaction in the process of hydrolysis, and has increased and go deimpurity difficulty.Can put upside down although recorded the step of acid hydrolysis and basic hydrolysis in Chinese patent 02803968.8, not provide acid-hydrolyzed technical scheme after concrete first basic hydrolysis, also two schemes not compared.Root it is documented, prior art scheme is prepared the yield of atorvastatincalcuim between 64%-83%.
Summary of the invention
The present invention is directed to prior art deficiency, a kind of preparation method of atorvastatincalcuim is provided, adopt acid-hydrolyzed method after first basic hydrolysis, alkaline hydrolysis process does not generate other impurity and can directly generate the sodium salt that has the two hydroxyls of acetone protection that purity is higher; And with removing with acid the hydroxyl sodium salt that in the reaction of acetone protection hydroxyl, more easily the de-acetone of generation is protected again after alkali reaction.The technical program has increased the purification step to calcium salt after the step that generates atorvastatin calcium salt, adopts ethyl acetate and hexanaphthene and diatomite further remove residual impurity and product yield is not affected.。
Technical solution of the present invention is specific as follows:
A preparation method for atorvastatincalcuim, step comprises:
(1) by (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, in the tetrahydrofuran solution of 3-dioxane-4-tert.-butyl acetate (compound 1), add alkali, preferred concentration is 20%(percent weight in volume) NaOH solution, regulating reaction soln pH is alkalescence, preferably pH is 11, (TLC monitors reaction process to reacting completely to be warming up to 30-35 ℃ of back flow reaction, developping agent is methylene dichloride: ethyl 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, 2-dimethyl-1, 3-dioxane-4-sodium acetate,
(2) by the hydrolysate of step (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, in the tetrahydrofuran solution of 3-dioxane-4-sodium acetate, slowly add 10% aqueous hydrochloric acid, 30-35 ℃ of return stirring is to react completely (TLC monitors reaction process, and developping agent is methylene dichloride: methyl alcohol=3:1);
(3) hydrolyzed solution vacuum concentration step (2) being obtained, fling to organic solvent tetrahydrofuran, add water, divide and extract mixed solutions water intaking layer for three times with methyl tertiary butyl ether, add tetrahydrofuran (THF), drip again alkali, preferably 10% (percent weight in volume) NaOH solution, the pH that adjusts solution is alkalescence, preferably pH is 7.5-8, be added in ethyl 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 tetrahydrofuran (THF) and water, drip 10% calcium acetate reaction, after finishing, reaction is extracted with ethyl acetate, get ethyl acetate phase, with anhydrous sodium sulfate drying, suction filtration, vacuum concentration, with diatomite filtration, adds in hexanaphthene and stirs, filter, drain to obtain atorvastatincalcuim sterling;
(5) atorvastatincalcuim of purifying is added to the water to stirring at normal temperature, suction filtration is dried and obtains unbodied atorvastatincalcuim.
The product yield of technical solution of the present invention is high, and total recovery is more than 90%, and purity is high, is with a wide range of applications.
Accompanying drawing explanation
The syntheti c route figure of Fig. 1 technical solution of the present invention atorvastatincalcuim.
The nuclear magnetic resonance map of Fig. 2 technical solution of the present invention atorvastatincalcuim.
Embodiment
The term that used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skills understand conventionally.
Below in conjunction with specific embodiment 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 the scope of the 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% adjust pH be 11 and reaction process in pH remain unchanged, 35 ℃ of return stirrings 7 hours, have reacted (TLC monitors reaction process), stop heating nature and cool to room temperature.Above-mentioned solution slowly splashes in the water of 5 ℃ of 120ml, and temperature control is at 5 ℃, and adularescent solid is separated out, and within approximately 20 minutes, drips and finishes, and temperature control stirs 30 minutes at 5 ℃, suction filtration, and filter cake washes with water to neutrality.Dry 12 hours of 40 ℃ of solid convection oven white solid 2.79g, yield 97.9%.
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, return stirring 5 hours, has reacted (TLC monitors reaction process) at 35 ℃.35 ℃ of above-mentioned solution of vacuum concentration is till the remaining aqueous solution only will add 50ml water in the aqueous solution, divides extraction mixed solutions water intaking layer three times with about 150ml methyl tertiary butyl ether.In water layer solution, occur solid, add the THF of 10ml to make solution clarification, then dripping 10% NaOH, to adjust the pH of solution be 7.5-8.After above-mentioned solution is cooled to room temperature, join in 10 ℃ of 150ml ethyl acetate, temperature control has solid to separate out in 1 hour 10 ℃ of stirrings, static 30 minutes, filters filter cake ethyl acetate rinse.Dry 12 hours of 40 ℃ of solid convection oven pink solid 2.54g, yield 97.2%.
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 about 150ml ethyl acetate extraction of rear use (until ethyl acetate layer clarification), stirs 30min with anhydrous magnesium sulfate in ethyl acetate layer, filters, with 15ml ethyl acetate rinse filter cake.35 ℃ of vacuum concentration ethyl acetate layers are to surplus about 25ml, diatomite filtration, 5ml ethyl acetate rinse.Add in the 300ml hexanaphthene of 10 ℃-15 ℃ and stir 30min, filter, by 15ml hexanaphthene flush cake, drain to obtain atorvastatincalcuim.
To in above-mentioned pressed powder, add 30ml water stirring at normal temperature 12h, suction filtration, 40 ℃ of dry white solids obtain the amorphous atorvastatin calcium of 2.53g, and productive rate is 96.6%.Its hydrogen spectrum is consistent with atorvastatin standard diagram after testing, as shown in Figure 2.
Claims (3)
1. a preparation method for atorvastatincalcuim, step comprises:
(1) by (the 4R-cis)-6-[2-[2-shown in compound 1 (4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) carbonyl]-1H-pyrroles-1-yl] ethyl]-2, 2-dimethyl-1, in the tetrahydrofuran solution of 3-dioxane-4-tert.-butyl acetate, add alkali to regulate reaction soln pH for 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) by the hydrolysate of step (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, in the tetrahydrofuran solution of 3-dioxane-4-sodium acetate, slowly add 10% aqueous hydrochloric acid, 30-35 ℃ of return stirring is to reacting completely;
(3) hydrolyzed solution vacuum concentration step (2) being obtained, fling to organic solvent tetrahydrofuran, add water, divide and extract mixed solutions water intaking layer for three times with methyl tertiary butyl ether, add tetrahydrofuran (THF), dripping alkali adjusts the pH of solution for alkaline again, be added in ethyl 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 tetrahydrofuran (THF) and water, drip 10% calcium acetate reaction, after finishing, reaction is extracted with ethyl acetate, get ethyl acetate phase, with anhydrous sodium sulfate drying, suction filtration, vacuum concentration, with diatomite filtration, adds in hexanaphthene and stirs, filter, drain to obtain atorvastatincalcuim sterling;
(5) atorvastatincalcuim of purifying is added to the water to stirring at normal temperature, suction filtration is dried and obtains unbodied atorvastatincalcuim;
The described alkali of above-mentioned steps (1) and step (3) is NaOH.
2. preparation method as claimed in claim 1, is characterized in that the described reaction soln pH of described step (1) is 11.
3. preparation method as claimed in claim 1, is characterized in that the described pH value of solution of described step (3) is 7.5-8.
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| CN105111123A (en) * | 2013-11-25 | 2015-12-02 | 李兴惠 | Atorvastatin calcium and composition |
| CN105085362B (en) * | 2015-09-18 | 2018-01-05 | 浙江海森药业有限公司 | The preparation method of high-purity crystallized type Atorvastatin calcium |
| CN108218759B (en) * | 2018-01-12 | 2021-01-01 | 天方药业有限公司 | Preparation method of atorvastatin calcium |
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