CN103288702B - A kind of preparation method of atorvastatin amino acid salts - Google Patents
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Abstract
The present invention relates to a kind of preparation method of atorvastatin amino acid salts, atorvastatin acid is obtained by reacting this compounds with basic aminoacids, its preparation method: (1) take atorvastatin acid, is dissolved in the alcoholic solvent of C1-C6, water or in halogenated hydrocarbon solvent, dissolves and forms solution first; (2) take basic aminoacids, in the alcoholic solvent being dissolved in C1-C6 or water, dissolve and form solution second; (3) above-mentioned second solution is added first solution, mixing solutions starts clarification, and crystallize out from mother liquor, is the amino acid salts of atorvastatin.Atorvastatin amino acid salts prepared by the present invention not only has the effect for the treatment of hypercholesterolemia blood fat and combined hyperlipidemia familial; also add the function that amino acid has; such as arginine has the function of protection to liver, and therefore invented salt effectively makes up the defect to the side effect of hepar damnification such as known calcium salt, sylvite and sodium salt.
Description
This application is the divisional application of a kind of atorvastatin amino acid salts and preparation method thereof, November 14 2011 original application applying date, original applying number: 2011103588632, invention and created name: a kind of atorvastatin amino acid salts and preparation method thereof.
Technical field
The invention belongs to cardiovascular diseases field of medicaments, relate to atorvastatin salt, especially a kind of preparation method of atorvastatin amino acid salts.
Background technology
The cardiovascular disorder serious harm health of the mankind, have impact on the quality of the life of the mankind, Lipitor (Lipitor), has another name called atorvastatin (Atorvastatin), as Statins blood lipid regulation medicine, belong to HMG-CoA reductase inhibitor, the mainly atorvastatin calcium salt used at present.
The non-activity of atorvastatin calcium salt own, its main active ingredient is the hydrolysate after oral administration absorbs.It suppresses the rate-limiting enzyme HMG-CoA reductase in cholesterol biosynthesis process in vivo competitively, thus the synthesis of cholesterol is reduced, and also making low density lipoprotein receptor synthesize increases.Its Main Function position is at liver, result makes blood cholesterol and low-density lipoprotein cholesterol level reduce, moderate reduces serum triglyceride level and increases blood hdl level, thus to the control generation effect of atherosclerosis and coronary heart disease, often be used to treatment hypercholesterolemia and combined hyperlipidemia familial, the control of coronary heart disease and cerebral apoplexy, but, long-term taking it also can cause the problem of liver.The same with other lipid lowerers, it is abnormal relevant with the biochemistry of liver function, and when taking, blood ammonia based transferase may increase, and during long-term treatment, needs periodic detection liver function.
The activeconstituents of atorvastatin is organic acid, and it can react with alkali, generates salt, and atorvastatin has the effect for the treatment of hypercholesterolemia and combined hyperlipidemia familial simultaneously.
Arginine is one of necessary amino acid of human body; for basic aminoacids; salt can be generated with atorvastatin acid-respons; arginine can protect liver effectively; reduce blood ammonia levels, be often used to hepatic coma, cause poisoning to the ammonia that liver accumulates too much, there is removing toxic substances and the effect alleviating fat; other much useful physiological functions such as the formation of prevention liver cirrhosis, are therefore called as the loyal guard of liver organ.
Histidine can safeguard growth and digestion, and plays the function of immunity; Methionin can promote human development, strengthen immunologic function, improves the performance of medicine, and improve drug effect, also can be used as the ancillary drug of diuretic(s), it can improve the damage effect to renal function of the former medicine of Lipitor.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of good water solubility, can available protecting liver, improve immunizing power and improve high atorvastatin amino acid salts of medicine purity that renal function damages and preparation method thereof.
The technical scheme that the present invention realizes object is:
A kind of atorvastatin amino acid salts, is obtained by reacting with basic aminoacids by atorvastatin acid.
And its structural formula is as follows:
And described atorvastatin acid is by atorvastatin tert-butyl ester C
40h
47fN
2o
5prepare.
A preparation method for atorvastatin amino acid salts, step is as follows:
(1) take atorvastatin, be dissolved in the alcoholic solvent of C1-C6 or water or in halogenated hydrocarbon solvent, dissolve and form solution first;
(2) taking basic aminoacids, is 1-5:1 with the mol ratio of atorvastatin, in the alcoholic solvent being dissolved in C1-C6 or water, dissolves and forms solution second;
(3) above-mentioned second dropwise instilled or directly add first solution, mixing solutions starts clarification, room temperature or heating reflux reaction, be the amino acid salt solution of atorvastatin, salts solution is static to room temperature, white precipitate or clear crystal produce, and filter and obtain the amino acid salts that white solid or clear crystal are atorvastatin.
A kind of preparation method of atorvastatin amino acid salts, reactions steps is: atorvastatin tert-butyl ester C40H47FN2O5 to be dissolved in the alcoholic solvent of C1-C6 or halogenated hydrocarbon solvent or halogenated hydrocarbon solvent or water → to add in solution organic acid or mineral acid → add basic aminoacids → obtain atorvastatin amino acid salt solution → cooling, filter obtain atorvastatin amino acid salts or directly solvent evaporated obtain atorvastatin amino acid salts, the wherein atorvastatin tert-butyl ester: hydrochloric acid: the molar equivalent of basic aminoacids is than being 1:1:3.
And described reactions steps is:
(1) the atorvastatin tert-butyl ester is joined in dehydrated alcohol, stirring and dissolving;
(2) in above-mentioned solution, add hydrochloric acid soln, about 70-80 DEG C stirring, reflux, solution is clarified very soon, after about 1-2h, reacts completely;
(3) continue to add basic aminoacids, after reflux is about 25-35h, stopped reaction;
(4) revolve and steam except desolventizing, remove unnecessary alkaline ammonia propylhomoserin, obtain atorvastatin amino acid salts,
The wherein atorvastatin tert-butyl ester: hydrochloric acid: the molar equivalent of basic aminoacids is than being 1:1:3.
And described alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propylene glycol, glycerol solvent, and described mineral acid is hydrochloric acid, trifluoroacetic acid, Glacial acetic acid, sulfuric acid, phosphoric acid, and affiliated halogenated hydrocarbon solvent is: chloroform, methylene dichloride, ethylene dichloride.
A preparation method for atorvastatin amino acid salts, reactions steps is: atorvastatin tert-butyl ester C
40h
47fN
2o
5be dissolved in the alcoholic solvent of C1-C6 or in halogenated hydrocarbon solvent or water → in solution, add organic acid or mineral acid → add in solution organic bases or mineral alkali → add in solution organic acid or mineral acid → add again basic aminoacids → obtain crystallize out and atorvastatin amino acid salts in atorvastatin amino acid salt solution → solution
And reactions steps is as follows:
(1) add atropic in the reactor and cut down the fourth tert-butyl ester, methyl alcohol, stirring and dissolving;
(2) the hydrochloric acid soln added again, at room temperature 30-35 DEG C of stirring reaction, is white suspension liquid when reaction solution starts, becomes colorless transparent through after a period of time, complete through TLC detection reaction; Sodium hydroxide solution regulator solution to neutral or weakly alkaline, then add equimolar sodium hydroxide solution, TLC follows the tracks of reaction, and obtaining now solution is atorvastatin sodium salt solution;
(3) use hydrochloric acid soln regulator solution pH=3-4, now solution is atorvastatin acid solution; Regulator solution is to slightly acidic again, the basic aminoacids of 1-1.5 molar equivalent is added again in solution, reflux 6-7 hour at 70-80 DEG C, revolve and steam except desolventizing, vacuum-drying 1-3h, anhydrous methanol dissolves dried solid, cross and filter basic aminoacids, removing methyl alcohol, the residue dry 2h of vacuum oil pump, obtains atorvastatin amino acid salts;
Wherein said alkali is mineral alkali or organic bases, described mineral alkali is lithium bicarbonate, sodium bicarbonate, saleratus, Quilonum Retard, sodium carbonate, salt of wormwood, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, and described organic bases is ammoniacal liquor, ammonium hydroxide, methylamine, triethylamine, diethylamide, propyl group amine, butylamine.
Application in application in the medicine of the application of above-mentioned atorvastatin amino acid salts in cholesterol lowering drug thing or treatment hypercholesterolemia and combined hyperlipidemia familial or protection liver drug or as the application in renal function protecting medicine while of improving immunizing power medicine.
Advantage of the present invention and beneficial effect are:
1, the present invention is directed to the salt such as known atorvastatin calcium salt, sylvite and sodium salt to improve and invent, present invention employs atorvastatin acid and react the sour amino acid salts of the new atorvastatin of the Form generation that generates salt with amino acid.Well-known amino acid is except generation energy; also has multiple physiological function; as promoted protein synthesis, promote collage synthesis, growth promoting effects hormone secretion, liver function protecting, liver dysfunction that removing toxic substances, prevention alcohol cause and improve immunologic function, sleeping, skin makeup beauty treatment etc.; medicine after improvement not only has the effect for the treatment of hypercholesterolemia blood fat and combined hyperlipidemia familial; also add the function that amino acid has, effectively make up the defect of the hepar damnification in this medicine therapeutic process.
2, the water-soluble of atorvastatin amino acid salts that prepared by the present invention is greatly improved, more formulation can be made after dissolving, as injection liquid, oral liquid, tablet, electuary, capsule, dripping pill, syrup type etc., enrich the formulation of Stains medicine, the range of application of such medicine of raising.
4, the invention provides other two kinds and prepare atorvastatin amino acid salts method, the initiator of these two kinds of methods is the atorvastatin tert-butyl ester, the atorvastatin tert-butyl ester has more preferential price, and the carrying out reacted can be controlled in reaction process, the yield rate of effective control atorvastatin amino acid salts, improve reaction efficiency, increase the utilization ratio of original prod.
5, the atorvastatin amino acid salts prepared by the present invention also improves the physiological function of known atorvastatin calcium salt, sylvite and sodium salt etc.; Have employed atorvastatin acid and react with amino acid the salt generated, improve solubleness than known calcium salt medicine; Atorvastatin amino acid salts not only has the effect for the treatment of hypercholesterolemia blood fat and combined hyperlipidemia familial; also add the function that amino acid has; such as arginine has the function of protection to liver, and therefore invented salt effectively makes up the defect to the side effect of hepar damnification such as known calcium salt, sylvite and sodium salt.Again such as, Methionin can promote human development, strengthen immunologic function, improves the performance of medicine, improves drug effect, also can be used as the ancillary drug of diuretic(s), this improves the damage effect to renal function of the former medicine of Lipitor.
6, the atorvastatin amino acid salts that the present invention relates to, compared with the calcium salt of atorvastatin, improves water-soluble, is conducive to the absorption of human body.
Accompanying drawing explanation
Fig. 1 is the MS spectrogram of atorvastatin arginic acid salt of the present invention;
Fig. 2 is the 1HNMR figure of atorvastatin arginic acid salt of the present invention;
Fig. 3 is the crystallogram of atorvastatin arginic acid salt of the present invention;
Fig. 4 is atorvastatin arginic acid salt photo of the present invention;
Fig. 5 is different time points mice serum transaminase level after drug injection of the present invention;
Fig. 6 is 24 hours mouse liver pathologic conditions after drug injection of the present invention.
Embodiment
Below by specific embodiment, the invention will be further described, and following examples are descriptive, is not determinate, can not limit protection scope of the present invention with this.
The principle of the atorvastatin amino acid salts that the present invention relates to adopts atorvastatin acid to react with amino acid, and amino acid whose general structure is, wherein-R base comprises-NH
2or-NH-group
The amino acid of class, also comprises such amino acid whose partial derivatives, and the basic aminoacids related in the present embodiment is arginine, Methionin, Histidine.In the present invention, in atorvastatin amino acid salts, atorvastatin and amino acid bonding force comprise ionic linkage and Van der Waals force.
The atorvastatin amino acid salts that the present invention relates to, compared with the calcium salt of atorvastatin, improves water-soluble, is conducive to the absorption of human body.
Embodiment 1
A kind of atorvastatin arginic acid salt, the structural formula after its salify is as follows:
A preparation method for atorvastatin arginic acid salt, step is as follows:
(1) take 117mg atorvastatin, be dissolved in 1mL ethanol, be heated to about 75 DEG C, solution is homogeneous opaque shape, forms solution first;
(2) take 36mg arginine, be dissolved in 0.1mL H
2in O, and be heated to about 75 DEG C, solution is homogeneous clarification shape, forms solution second;
(3) above-mentioned solution second is dropwise instilled first solution, mixing solutions starts clarification, is heated to about about 75 DEG C backflows, and cooling crystallize out, by product separation out, by mensuration such as 1H NMR, MS, it is the arginic acid salt of atorvastatin.
The present embodiment adopts the acid of atorvastatin; there is the effect of reducing blood-fat; itself and arginine effect form the salt of good water solubility; arginine not only has and can produce the function of salt with atorvastatin acid-respons, improves cardiovascular system diseases, can also available protecting liver; cause poisoning to the ammonia that liver accumulates too much; have removing toxic substances and the effect alleviating fat, the formation of prevention liver cirrhosis benefits, and it is called as the loyal guard of liver organ.The new compound that both salifies obtain can have reducing blood-fat concurrently and protect the effect of liver, reduces the side effect of atorvastatin medication.
Embodiment 2
A kind of atorvastatin lysine salt, the structural formula after its salify is as follows:
A preparation method for atorvastatin lysine salt, step is as follows:
(1) take 117mg atorvastatin, be dissolved in 1mL ethanol, be heated to about 75 DEG C, solution is homogeneous opaque shape, forms solution first;
(2) take 30mg Methionin, be dissolved in 0.1mL H
2in O, and be heated to about 75 DEG C, solution is homogeneous clarification shape, forms solution second;
(3) above-mentioned solution second is dropwise instilled first solution, mixing solutions starts clarification, is heated to about about 75 DEG C, is heated to about about 75 DEG C backflows, and cooling crystallize out, by product separation out, by mensuration such as 1H NMR, MS, it is the lysine salt of atorvastatin.
Atorvastatin acid is reacted with Methionin by the present embodiment, generates its salt, just further promotes effect of former medicine atorvastatin.Methionin is one of essential amino acid, human development can be promoted, strengthen immunologic function, and be improved the effect of central nervous tissue function, because the lysine content in cereal foods is very low, and be easily destroyed in the course of processing and lack, therefore be called the first limiting amino acids; Also can improve the performance of some drugs at pharmaceutically Methionin, improve drug effect; Methionin pharmaceutically also can be used as the ancillary drug of diuretic(s), this improves the damage effect to renal function of the former medicine of Lipitor, and it can reduce the level of triglyceride level in blood simultaneously, the generation of prevention cardiovascular and cerebrovascular diseases.
Embodiment 3
A kind of atorvastatin Histidine salt, the structural formula after its salify is as follows:
A preparation method for atorvastatin Histidine salt, step is as follows:
(1) take 117mg atorvastatin, be dissolved in 1mL ethanol, and be heated to about 75 DEG C, solution is homogeneous opaque shape, forms solution first;
(2) take 32mg Histidine, be dissolved in 0.1mL H
2in O, and be heated to about 75 DEG C, solution is homogeneous clarification shape, forms solution second;
(3), by above-mentioned second dropwise instillation first solution, mixing solutions starts clarification, and be heated to about about 75 DEG C backflows, isolate product, it is the Histidine salt of atorvastatin.
Atorvastatin acid is formed salt with alkaline histidine reaction by the present embodiment, has the side effect improved in the medication of former medicine atorvastatin.Histidine (L-Histidine) can safeguard our growth and digestion, Histidine is to growing, organizing maintenance, ulcer, control hydrochloric acid in gastric juice, digestion and gastric juice etc. all to have important effect, it contributes to the diseases such as treatment allergy, rheumatic arthritis, anaemia, and manufacture red blood corpuscle, white cell all need Histidine; Histidine constitutes organizes ammonia, and it can be discharged into extracellular, can also play the function of immunity.
In the present invention, atorvastatin amino acid salts can by atorvastatin tert-butyl ester elder generation and acid-respons, then with basic amine group acid-respons, finally generate atorvastatin amino acid salts, embodiment is as follows:
Following examples 4,5,6 react to illustrate the preparation method of atorvastatin amino acid salts:
Embodiment 4
A preparation method for atorvastatin arginic acid salt, step is as follows:
(1) by 264mg(0.4mmol) the atorvastatin tert-butyl ester joins in 3mL dehydrated alcohol, stirring and dissolving;
(2) in above-mentioned solution, add 1mL hydrochloric acid soln (1mol/L), about 75 DEG C stirrings, reflux, solution is clarified very soon, after about 1.5h, reacts completely;
(3) continue to add 1g arginine, after continuation reflux is about 30h, stopped reaction;
(4) revolve and steam except desolventizing, oil pump is drained, and uses appropriate anhydrous alcohol solution, suction filtration, collects filtrate.Then revolve and boil off filtrate, drain, dissolve, the repetitive operations such as filtration several times, ensure that arginine removes completely, namely obtain purer atorvastatin arginic acid salt.
In the present embodiment, atorvastatin arginic acid salt productive rate is 86%.
The chemical reaction structural formula of embodiment 4 is as follows:
Embodiment 5
A preparation method for atorvastatin arginic acid salt, step is as follows:
(1) atorvastatin tert-butyl ester 10g, 70mL anhydrous methanol is in the there-necked flask of 250mL, stirs under normal temperature;
(2) dropwise add 5mL concentrated hydrochloric acid and make its pH≤1, stir under normal temperature, solution clear after several minutes, process TLC detects (chloroform: methyl alcohol=50:1), after one hour, reacts complete.
(3) reaction flask is placed in ice bath, with 5mol/L NaOH solution alkali tune pH=13-14, reacts complete after 3h, revolve the methyl alcohol steamed in removing reaction solution, residual residue is poured in 100mL water, this suspension liquid 100mL × 2 methyl tertiary butyl ether washings.Be separated removing methyl tertiary butyl ether, remain the HCl solution acid adjustment of the suspension liquid 1mol/L of water to pH=3-4, the extraction into ethyl acetate of this solution 80mL × 3, the saturated NaHCO of isolated organic phase
3solution is adjusted to pH=6-7, is separated the water that removing is a small amount of, and the saturated sodium chloride solution 40mL of organic phase washs once, and anhydrous sodium sulfate drying 2h, revolves and boil off except ethyl acetate, obtains atorvastatin acid 7.5g.
Will obtain 7.5g atorvastatin acid, with 30mL anhydrous methanol, the L-arginine of 4.7g, the water mixed dissolution of 5mL in there-necked flask, reflux 8h.
(5) revolve and steam except desolventizing, vacuum-drying 2h, 50mL anhydrous methanol dissolves dried solid, crosses and filters L-arginine, five times repeatedly, revolves and steams removing methyl alcohol, and the residue dry 2h of vacuum oil pump, obtains atorvastatin arginic acid salt 7.2g.
In the present embodiment, atorvastatin arginic acid salt productive rate is 72.9%.
Embodiment 6
A preparation method for atorvastatin arginic acid salt, step is as follows:
(1) add atorvastatin tert-butyl ester 0.369g (0.564mmol) in the reactor, methyl alcohol 5ml, stirring and dissolving;
(2) add the hydrochloric acid soln of the 1mol/L of 0.3ml again, at room temperature 30-35 DEG C of stirring reaction, be white suspension liquid, become colorless transparent through after a period of time when reaction solution starts, detect raw material through TLC and disappear, reaction completes; The extremely neutral or weakly alkaline with the sodium hydroxide solution regulator solution of 1mol/L, then add equimolar sodium hydroxide solution, TLC follows the tracks of reaction, and after question response terminates, now solution is atorvastatin sodium salt solution.
(3) use hydrochloric acid soln regulator solution pH=3-4, now solution is atorvastatin acid solution; Regulator solution is to slightly acidic again, the arginine of 1-1.5 molar equivalent is added again in solution, reflux 6-7 hour at 75 DEG C, revolves and steams except desolventizing, vacuum-drying 2h, 10mL anhydrous methanol dissolves dried solid, cross and filter L-arginine, five times repeatedly, revolve and steam removing methyl alcohol, the residue dry 2h of vacuum oil pump, obtains atorvastatin arginic acid salt.
The reaction principle of embodiment 5-6 is as follows:
Note: the atorvastatin tert-butyl ester (i.e. (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-sec.-propyl)-3-phenyl-4-[(aniline) hydroxyl]-1H-pyrroles-1-base] ethyl]-2,2-dimethyl-1,3-dioxolane-4-tert.-butyl acetate) structural formula, molecular formula: C
40h
47fN
2o
5, structural formula is as follows:
The structural formula of atorvastatin acid is:
In the present invention, the structural formula of atorvastatin amino acid salts is as follows:
1, atorvastatin acid+multiple arginine (namely n) structural formula:
2, atorvastatin acid+multiple Histidine (namely n) structural formula:
3, atorvastatin acid+multiple Methionin (namely n) structural formula:
4, atorvastatin acid+(arginine) m+ (Histidine) n+ (Methionin) m etc. or wherein two amino acid whose structural formulas:
Animal
Experiment
Arginic acid salt (its experiment code name is HL-002-001-01) the hepatotoxicity examining report of compound Lipitor
Experiment purpose
By the hepatotoxicity of mouse liver injured animal model checking compound H L-002-001-01, and with under same dosage concanavalin A (positive control), Lipitor compare.
Experimental technique
The mouse vena ophthalmica injection concanavalin A (positive control) of 10mg/kg, Lipitor and compound H L-002-001-01, transaminase level is surveyed at different time points reitman-frankel method, get hepatic tissue dehydration, embedding, paraffin section, HE dyeing after 24 hours, carry out pathological analysis.
Experimental result
Serum transaminase water bottle curve (Fig. 5) after mouse liver injury;
24 hours mouse liver pathologic conditions (Fig. 6) after drug injection.
As can be seen from experimental result, under the concentration of 10mg/kg, the hepatotoxicity of compound H L-002-001-01 is significantly lower than Lipitor and the concanavalin A of same dosage, as can be seen from the section of 24 hours hepatic pathologies also, the hepatic pathology degree of injury that compound H L-002-001-01 causes comparatively Lipitor and concanavalin A light.
Conclusion
Under 10mg/kg dosage, the hepatotoxicity of compound H L-002-001-01 is starkly lower than Lipitor and the positive control concanavalin A of same dosage.
Claims (1)
1. a preparation method for atorvastatin arginic acid salt, is characterized in that: step is as follows:
(1) add atorvastatin tert-butyl ester 0.369g in the reactor, methyl alcohol 5ml, stirring and dissolving;
(2) add the hydrochloric acid soln of the 1mol/L of 0.3ml again, at room temperature 30-35 DEG C of stirring reaction, be white suspension liquid, become colorless transparent through after a period of time when reaction solution starts, detect raw material through TLC and disappear, reaction completes; The extremely neutral or weakly alkaline with the sodium hydroxide solution regulator solution of 1mol/L, then add equimolar sodium hydroxide solution, TLC follows the tracks of reaction, and after question response terminates, now solution is atorvastatin sodium salt solution;
(3) use hydrochloric acid soln regulator solution pH=3-4, now solution is atorvastatin acid solution; Regulator solution is to slightly acidic again, the arginine of 1-1.5 molar equivalent is added again in solution, reflux 6-7 hour at 75 DEG C, revolves and steams except desolventizing, vacuum-drying 2h, 10mL anhydrous methanol dissolves dried solid, cross and filter L-arginine, five times repeatedly, revolve and steam removing methyl alcohol, the residue dry 2h of vacuum oil pump, obtains atorvastatin arginic acid salt.
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| CN1190957A (en) * | 1995-07-17 | 1998-08-19 | 沃尼尔·朗伯公司 | Form III crystalline (R-(R*,R*)-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methyl-ethyl)-3-phenyl-4-((phenylamino) carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
| WO2003082816A1 (en) * | 2002-03-28 | 2003-10-09 | Richter Gedeon Vegyészeti Gyár Rt. | New atorvastatin salts and pharmaceutical compositions containing them |
| WO2005105738A2 (en) * | 2004-05-05 | 2005-11-10 | Pfizer Products Inc. | Salt forms of atorvastatin |
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| GEP20001898B (en) * | 1995-11-02 | 2000-01-05 | Warner Lambert Co | Method and Pharmaceutical Composition for Regulating Lipid Concentration with Mam |
| HU226640B1 (en) * | 1999-10-18 | 2009-05-28 | Egis Gyogyszergyar Nyilvanosan | Process for producing amorphous atorvastatin calcium salt |
| HU227041B1 (en) * | 2003-03-24 | 2010-05-28 | Richter Gedeon Nyrt | Process for the synthesis of amorphous atorvastatin calcium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190957A (en) * | 1995-07-17 | 1998-08-19 | 沃尼尔·朗伯公司 | Form III crystalline (R-(R*,R*)-2-(4-fluorophenyl)-beta-delta-dihydroxy-5-(1-methyl-ethyl)-3-phenyl-4-((phenylamino) carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
| WO2003082816A1 (en) * | 2002-03-28 | 2003-10-09 | Richter Gedeon Vegyészeti Gyár Rt. | New atorvastatin salts and pharmaceutical compositions containing them |
| WO2005105738A2 (en) * | 2004-05-05 | 2005-11-10 | Pfizer Products Inc. | Salt forms of atorvastatin |
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| Publication number | Publication date |
|---|---|
| CN103288702A (en) | 2013-09-11 |
| CN103274985B (en) | 2016-03-09 |
| CN102424663B (en) | 2013-08-14 |
| CN102424663A (en) | 2012-04-25 |
| CN103274985A (en) | 2013-09-04 |
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