CN103232398B - A kind of Rosuvastatin amino acid salts and its preparation method and application - Google Patents
A kind of Rosuvastatin amino acid salts and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of Rosuvastatin amino acid salts and preparation method thereof, Rosuvastatin acid is obtained by reacting this compounds with basic aminoacids, its preparation method: (1) take Rosuvastatin 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) second solution is added first solution, stirring is spent the night, and reaction solution is cooled to room temperature, and steaming desolventizes; (4) add methyl alcohol, separate out the basic aminoacids that also filtering is excessive; (5) concentrated, backflow, cooling, filter, dry, obtain the amino acid salts of Rosuvastatin.Rosuvastatin 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, therefore invented salt effectively makes up the defect to the side effect of hepar damnification such as known calcium salt, sylvite and sodium salt.<!--1-->
Description
Technical field
The invention belongs to cardiovascular diseases field of medicaments, relate to Rosuvastatin salt, especially a kind of Rosuvastatin amino acid salts and its preparation method and application.
Background technology
The cardiovascular disorder serious harm health of the mankind, have impact on the quality of the life of the mankind, can determine (Crestor), have another name called Rosuvastatin (Rosuvastatin), as Statins blood lipid regulation medicine, belong to HMG-CoA reductase inhibitor, the mainly Rosuvastatin calcium salt used at present.
The non-activity of Rosuvastatin 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.Be applicable to hypercalcinuria and hypercholesterolemia, for not being in the mood for popular name for clinical manifestation but the patient of potential risk of cardiovascular diseases, to reduce myocardial infarction, apoplexy and to carry out the risk of coronary revascularization.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 Rosuvastatin is organic acid, and it can react with alkali, generates salt, and Rosuvastatin 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 Rosuvastatin 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, a kind of good water solubility, energy available protecting liver are provided, improve immunizing power and improve that renal function damages, that medicine purity is high Rosuvastatin amino acid salts and its preparation method and application.
The technical scheme that the present invention realizes object is:
A kind of Rosuvastatin amino acid salts, is obtained by reacting with basic aminoacids by Rosuvastatin acid.
And the structural formula of described Rosuvastatin amino acid salts is as follows:
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
And described Rosuvastatin acid is by Rosuvastatin tert-butyl ester C
29h
40fN
3o
6s prepares.
And, the preparation method of described Rosuvastatin amino acid salts, step is as follows:
(1) take Rosuvastatin, 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 Rosuvastatin, 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, room temperature or heating reflux reaction 2-35h; Reaction solution is cooled to room temperature, and steaming desolventizes;
(4) add methyl alcohol, separate out the basic aminoacids that also filtering is excessive;
(5) enrichment step (4) organic phase in solution, adds methyl tertiary butyl ether, refluxes and be cooled to room temperature after 0.5 hour, and white precipitate or clear crystal produce, and filters and drying obtains white solid or clear crystal, is the amino acid salts of Rosuvastatin.
And the preparation method of described Rosuvastatin amino acid salts, reactions steps is: Rosuvastatin tert-butyl ester C
29h
40fN
3o
6s to be dissolved in the alcoholic solvent of C1-C6 or halogenated hydrocarbon solvent or water → to add in solution organic acid or mineral acid → add basic aminoacids → obtain Rosuvastatin amino acid salt solution → except desolventizing, add methyl alcohol removal of impurities → concentrated organic phase and with methyl tertiary butyl ether reflux crystallization → cooling, filter obtain Rosuvastatin amino acid salts or directly solvent evaporated obtain Rosuvastatin amino acid salts, the wherein Rosuvastatin tert-butyl ester: hydrochloric acid: the molar equivalent of basic aminoacids is than being 1:1:3.
And, the preparation method of described Rosuvastatin amino acid salts, described reactions steps is:
(1) auspicious relaxing is cut down the fourth tert-butyl ester and joined in the alcohol of C1-C6 or water or in tetrahydrofuran (THF) or halogenated hydrocarbon solvent in solvent, stirring and dissolving;
(2) the organic acid added in step (1) solution or inorganic acid solution, stirring reaction at 30-35 DEG C is white suspension liquid when reaction solution starts, through become colorless after a period of time transparent after, complete through TLC detection reaction;
(3) continue to add basic aminoacids, backflow is spent the night, and is cooled to room temperature, and steaming desolventizes; Adding methyl alcohol wherein makes excess of ammonia base acid out go out removing;
(4) enrichment step (3) organic phase in solution, adds methyl tertiary butyl ether, reflux 0.5 hour; Be cooled to room temperature, crystallize out, filtration, drying obtain white solid, are Rosuvastatin amino acid salts.
And, the preparation method of described Rosuvastatin amino acid salts, described C1-C6 alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propylene glycol, glycerol solvent; Described mineral acid is hydrochloric acid, trifluoroacetic acid, Glacial acetic acid, sulfuric acid, nitric acid, phosphoric acid; Affiliated halogenated hydrocarbon solvent is: chloroform, methylene dichloride, ethylene dichloride.
And the preparation method of described Rosuvastatin amino acid salts, reactions steps is: Rosuvastatin tert-butyl ester C
29h
40fN
3o
6s is dissolved in the alcoholic solvent of C1-C6 or in tetrahydrofuran (THF) or 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 the neutral acidity on the weak side of mineral acid furnishing → add again basic aminoacids → obtain crystallize out and Rosuvastatin amino acid salts in Rosuvastatin amino acid salt solution → solution.
And, the preparation method of described Rosuvastatin amino acid salts, reactions steps is as follows:
(1) the Rosuvastatin tert-butyl ester is joined in C1-C6 alcoholic solvent or halogenated hydrocarbon solvent or water, stirring and dissolving;
(2) in above-mentioned solution, add organic acid or inorganic acid solution, at 30-35 DEG C of stirring reaction, reflux, solution is clarified very soon, after 1-5h, reacts completely;
(3) in above-mentioned reaction solution, add sodium hydroxide solution, stirred at ambient temperature, after 1 hour, by the mixed solution evaporate to dryness obtained, adds water wherein, and removes impurity with methyl tertiary butyl ether extraction.
(4) the hydrochloric acid of aqueous phase 2mol/L is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrates and obtains white solid, be Rosuvastatin acid;
(5) above-mentioned solid adds dissolve with methanol, and adds basic amine group aqueous acid, and after reflux 2-35h, stopped reaction, is cooled to room temperature, and revolves steaming except desolventizing;
(6) add methyl alcohol, remove unnecessary basic aminoacids;
(7) concentrated organic phase, adds methyl tertiary butyl ether, refluxes 0.5 hour, be cooled to room temperature, obtain crystal, filter, be drying to obtain the amino acid salts of Rosuvastatin;
Wherein, the Rosuvastatin tert-butyl ester: hydrochloric acid: the molar equivalent of basic aminoacids is than being 1:1:3;
Wherein, described acid is mineral acid or organic acid.Described mineral acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc.; Described organic acid is formic acid, acetic acid, propionic acid, trifluoroacetic acid;
Wherein, described 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;
Wherein, described organic bases is ammoniacal liquor, ammonium hydroxide, methylamine, triethylamine, diethylamide, propyl group amine, butylamine.
The above-mentioned application of Rosuvastatin amino acid salts in cholesterol lowering drug thing; or the application in the medicine for the treatment of hypercholesterolemia and combined hyperlipidemia familial; or the application in protection liver drug; or as treatment hypercholesterolemia liver-protective medicine simultaneously, or as the application in raising immunizing power medicine simultaneously renal function protecting medicine.
Advantage of the present invention and beneficial effect are:
1, the present invention is directed to the salt such as known Rosuvastatin calcium salt, sylvite and sodium salt to improve and invent, present invention employs Rosuvastatin acid and react the sour amino acid salts of the new Rosuvastatin of the Form generation that generates salt with amino acid.As everyone knows; 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 Rosuvastatin 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 Rosuvastatin class medicine, improve the range of application of such medicine.
4, the invention provides three kinds and prepare Rosuvastatin amino acid salts method, the initiator of these three kinds of methods is the Rosuvastatin tert-butyl ester, the Rosuvastatin tert-butyl ester has more preferential price, and the carrying out reacted can be controlled in reaction process, the yield rate of effective control Rosuvastatin amino acid salts, improve reaction efficiency, increase the utilization ratio of original prod.
5, the Rosuvastatin amino acid salts prepared by the present invention also improves the physiological function of known Rosuvastatin calcium salt, sylvite and sodium salt etc.; Have employed Rosuvastatin acid and react with amino acid the salt generated, improve solubleness than known calcium salt medicine; Rosuvastatin 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 can determining former medicine.
6, the Rosuvastatin amino acid salts that the present invention relates to, compared with the calcium salt of Rosuvastatin, improves water-soluble, is conducive to the absorption of human body.
Accompanying drawing explanation
Fig. 1 is the 1HNMR figure of Rosuvastatin arginic acid salt of the present invention;
Fig. 2 is the HPLC figure of Rosuvastatin arginic acid salt of the present invention; Compound purity 99.60%;
Fig. 3 is the crystallogram of Rosuvastatin arginic acid salt of the present invention;
Fig. 4 is Rosuvastatin arginic acid salt photo of the present invention;
Fig. 5 is the serum transaminase water bottle curve after mouse liver injury 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 Rosuvastatin amino acid salts that the present invention relates to adopts Rosuvastatin acid to react with amino acid, and amino acid whose general structure is
, wherein-R base comprises-NH
2or the amino acid of-NH-group class, also comprise such amino acid whose partial derivatives, the basic aminoacids related in the present embodiment is arginine, Methionin, Histidine.In the present invention, in Rosuvastatin amino acid salts, Rosuvastatin and amino acid bonding force comprise ionic linkage and Van der Waals force.
The Rosuvastatin amino acid salts that the present invention relates to, compared with the calcium salt of Rosuvastatin, improves water-soluble, is conducive to the absorption of human body.
Embodiment 1
A kind of Rosuvastatin arginic acid salt, the structural formula after its salify is as follows:
Or
Or
A preparation method for Rosuvastatin arginic acid salt, step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester (3.46mmol), be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid (4mmol) of 4ml1mol/L, stir 2h at 30-35 DEG C, TLC detection reaction completes;
(3) in step (2) solution, add the sodium hydroxide (4.2mmol) of 1.4ml3mol/L again, after stirred at ambient temperature reaction 1h, by reaction solution solvent evaporate to dryness; Add water wherein, and remove impurity with methyl tertiary butyl ether extraction;
(4) the hydrochloric acid of aqueous phase 2mol/L in step (3) solution is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, uses anhydrous sodium sulfate drying, concentrate and obtain white solid, be Rosuvastatin acid;
By step (4) in 1.8g Rosuvastatin acid (3.74mmol) be dissolved in 20ml methyl alcohol and form settled solution, take 976mgL-arginine (5.107mmol) and be dissolved in 10ml water, and instill in above-mentioned solution, reflux at 80 DEG C, stir and spend the night; Solvent evaporated;
(6) add methyl alcohol, separate out the L-arginine that also filtering is unnecessary;
(7) concentrated organic phase, and add methyl tertiary butyl ether backflow 0.5h, be cooled to room temperature, obtain clear crystal, and filtration drying, obtain the amino acid salts of Rosuvastatin.
The present embodiment adopts the acid of Rosuvastatin; 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 Rosuvastatin 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 Rosuvastatin medication.
Embodiment 2
A kind of Rosuvastatin lysine salt, the structural formula after its salify is as follows:
Or
Or
A preparation method for Rosuvastatin lysine salt, step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester (3.46mmol), be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid (4mmol) of 4ml1mol/L, 30-35 DEG C is stirred 2h, TLC detection reaction and completes;
(3) in step (2) solution, add the sodium hydroxide (4.2mmol) of 1.4ml3mol/L again, after stirred at ambient temperature reaction 1h, by reaction solution solvent evaporate to dryness; Add water wherein, and remove impurity with methyl tertiary butyl ether extraction;
(4) the hydrochloric acid of aqueous phase 2mol/L in step (3) solution is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, concentrated, anhydrous sodium sulfate drying, obtains white solid, is Rosuvastatin acid;
By step (4) in 1.8g Rosuvastatin acid (3.74mmol) be dissolved in 20ml methyl alcohol and form settled solution, taking 747mgL-Methionin (5.107mmol) is dissolved in 10ml water, and instill in above-mentioned solution, at 80 DEG C, reflux, stirring are spent the night, solvent evaporated;
(6) add methyl alcohol, separate out the 1B that also filtering is unnecessary;
(7) concentrated organic phase, and add methyl tertiary butyl ether backflow 0.5h, be cooled to room temperature, obtain clear crystal, and filtration drying, obtain the lysine salt of Rosuvastatin.
Rosuvastatin acid is reacted with Methionin by the present embodiment, generates its salt, just further promotes effect of former medicine Rosuvastatin.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 can determining former medicine, 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 Rosuvastatin Histidine salt, the structural formula after its salify is as follows:
Or
Or
A preparation method for Rosuvastatin Histidine salt, step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester (3.46mmol), be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid (4mmol) of 4ml1mol/L, stir 2h at 30-35 DEG C, TLC detection reaction completes;
(3) in step (2) solution, add the sodium hydroxide (4.2mmol) of 1.4ml3mol/L again, after stirred at ambient temperature reaction 1h, by reaction solution solvent evaporate to dryness; Add water wherein, and remove impurity with methyl tertiary butyl ether extraction;
(4) the hydrochloric acid of aqueous phase 2mol/L in step (3) solution is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrates to obtain white solid, obtain Rosuvastatin acid;
By step (4) in 1.8g Rosuvastatin acid (3.74mmol) be dissolved in 20ml methyl alcohol and form settled solution, taking 792mgL-Histidine (5.107mmol) is dissolved in 10ml water, and instill in above-mentioned solution, at 80 DEG C, reflux, stirring are spent the night, solvent evaporated;
(6) add methyl alcohol, separate out the L-Histidine that also filtering is unnecessary;
(7) concentrated organic phase, and add methyl tertiary butyl ether backflow 0.5h, be cooled to room temperature, obtain crystal, and filtration drying, obtain Rosuvastatin amino acid salts.
Rosuvastatin acid is formed salt with alkaline histidine reaction by the present embodiment, has the side effect improved in the medication of former medicine Rosuvastatin.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, Rosuvastatin amino acid salts can by Rosuvastatin tert-butyl ester elder generation and acid-respons, then with basic amine group acid-respons, finally generate Rosuvastatin amino acid salts, embodiment is as follows:
Following examples 4,5,6 react to illustrate the preparation method of Rosuvastatin amino acid salts:
Embodiment 4
A preparation method for Rosuvastatin arginic acid salt, step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester (3.46mmol), be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid (4mmol) of 4ml1mol/L, stir 2h at 30-35 DEG C, be white suspension liquid when reaction solution starts, become colorless transparent through after a period of time, TLC detection reaction completes;
(3) in step (2) solution, add 1.952gL-arginine (10.214mmol) be again dissolved in 10ml water, and instill in above-mentioned solution, at 80 DEG C, reflux, stirring are spent the night, solvent evaporated; Add methyl alcohol wherein, separate out the L-arginine that also filtering is unnecessary;
(4) enrichment step (3) organic phase in solution, and add methyl tertiary butyl ether, reflux 0.5h, be cooled to room temperature, crystallize out, and filtration drying, obtain white solid, be the amino acid salts of Rosuvastatin.
In the present embodiment, Rosuvastatin arginic acid salt productive rate is 86%.
The chemical reaction structural formula of embodiment 4 is as follows:
Embodiment 5
A preparation method for Rosuvastatin arginic acid salt, step is as follows:
(1) take the 10g Rosuvastatin tert-butyl ester, be dissolved in 70mL anhydrous methanol in the there-necked flask of 250mL, stirring and dissolving under normal temperature;
(2) in step (1) solution, dropwise add 5mL concentrated hydrochloric acid, make pH value of solution≤1, stir, solution clear after several minutes at 30-35 DEG C, process TLC detects, and after one hour, reacts complete;
(3) reaction flask is placed in ice bath, reacts complete after adjusting pH=13-14,3h with 5mol/LNaOH solution, revolve the methyl alcohol steamed in removing reaction solution, residual residue is poured in 100mL water, this suspension liquid 100mL × 2(2 washing) methyl tertiary butyl ether washing;
(4) be separated removing step (3) middle 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 Rosuvastatin acid 8.3g;
Will obtain 8.3g Rosuvastatin acid, with 30mL anhydrous methanol, the L-arginine of 4.7g, the water mixed dissolution of 5mL in there-necked flask, reflux 8h;
(6) revolve and steam except desolventizing, vacuum-drying 2h, and then use 50mL anhydrous methanol to dissolve dried solid, cross filtering L-arginine, five times repeatedly, revolve and steam removing methyl alcohol, the residue dry 2h of vacuum oil pump, obtains Rosuvastatin arginic acid salt 8.3g.
In the present embodiment, Rosuvastatin arginic acid salt productive rate is 73%.
Embodiment 6
A preparation method for Rosuvastatin arginic acid salt, step is as follows:
(1) add the 0.326g Rosuvastatin tert-butyl ester (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 30-35 DEG C of stirring reaction, be white suspension liquid when reaction solution starts, become colorless transparent through after a period of time, complete through TLC detection reaction, reaction completes; The extremely neutral or weakly alkaline with the sodium hydroxide solution regulator solution of 1mol/L, then add the sodium hydroxide solution of equimolar amount, TLC follows the tracks of reaction, and after question response terminates, now solution is Rosuvastatin sodium salt solution;
(3) pH value of solution=3-4 in using hydrochloric acid soln regulating step (2), now solution is Rosuvastatin 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, re-use 10mL anhydrous methanol and dissolve 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 Rosuvastatin arginic acid salt.
The reaction principle of embodiment 5-6 is as follows:
Note: 1) the Rosuvastatin tert-butyl ester (i.e. 6-[1E-2]-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino]-5-pyrimidine] vinyl]-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate)
Molecular formula: C
29h
40fN
3o
6s
Structural formula is as follows:
2) Rosuvastatin acid (two-(E)-7-[the fluorine-based phenyl of 4-(4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-pyrimidine-5-base] (3R, 5S)-3,5-hydroxyl-6-in heptan olefin(e) acid)
Molecular formula: C
22h
28fN
3o
6s
Structural formula is:
In the present invention, the structural formula of Rosuvastatin amino acid salts is as follows:
1, Rosuvastatin acid+multiple arginine (namely n) structural formula:
2, Rosuvastatin acid+multiple Histidine (namely n) structural formula:
3, Rosuvastatin acid+multiple Methionin (namely n) structural formula:
4, Rosuvastatin acid+(arginine) m+ (Histidine) n+ (Methionin) p etc. or wherein two amino acid whose structural formulas:
Or
Or
Experimentation on animals part
Rosuvastatin amino acid salts hepatotoxicity is tested
By the hepatotoxicity of mouse liver injured animal model checking Rosuvastatin amino acid salts, and compare with the concanavalin A (positive control) under same dosage, Rosuvastatin calcium salt.
Experimental technique: the mouse vena ophthalmica injection concanavalin A (positive control) of 10mg/kg, Rosuvastatin calcium salt and Rosuvastatin amino acid salts, surveys transaminase level at different time points reitman-frankel method.Experimental result: the serum transaminase water bottle curve (Fig. 5) after mouse liver injury
As can be seen from experimental result, under the concentration of 10mg/kg, the hepatotoxicity of Rosuvastatin amino acid salts is significantly lower than Rosuvastatin calcium salt and the concanavalin A of same dosage.Therefore can reach a conclusion: under 10mg/kg dosage, the hepatotoxicity of Rosuvastatin amino acid salts is starkly lower than Rosuvastatin calcium salt and the positive control concanavalin A of same dosage.
Claims (4)
1. a preparation method for Rosuvastatin amino acid salts, is characterized in that: described reactions steps is:
(1) auspicious relaxing is cut down the fourth tert-butyl ester and joined in the alcohol of C1-C6 or water or in tetrahydrofuran (THF) or halogenated hydrocarbon solvent in solvent, stirring and dissolving;
(2) the organic acid added in step (1) solution or inorganic acid solution, stirring reaction at 30-35 DEG C is white suspension liquid when reaction solution starts, through become colorless after a period of time transparent after, complete through TLC detection reaction;
(3) continue to add basic aminoacids, backflow is spent the night, and is cooled to room temperature, and steaming desolventizes; Adding methyl alcohol wherein makes excess of ammonia base acid out go out removing;
(4) enrichment step (3) organic phase in solution, adds methyl tertiary butyl ether, reflux 0.5 hour; Be cooled to room temperature, crystallize out, filtration, drying obtain white solid, are Rosuvastatin amino acid salts;
Described C1-C6 alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propylene glycol, glycerol solvent; Described mineral acid is hydrochloric acid, trifluoroacetic acid, Glacial acetic acid, sulfuric acid, nitric acid, phosphoric acid; Described halogenated hydrocarbon solvent is: chloroform, methylene dichloride, ethylene dichloride;
Describedly auspiciously relax that to cut down the structural formula of the fourth tert-butyl ester as follows:
2. a preparation method for Rosuvastatin amino acid salts, is characterized in that: reactions steps is as follows:
(1) the Rosuvastatin tert-butyl ester is joined in halogenated hydrocarbon solvent, stirring and dissolving;
(2) in above-mentioned solution, add organic acid or inorganic acid solution, at 30-35 DEG C of stirring reaction, reflux, solution is clarified very soon, after 1-5h, reacts completely;
(3) in above-mentioned reaction solution, add sodium hydroxide solution, stirred at ambient temperature, after 1 hour, by the mixed solution evaporate to dryness obtained, adds water wherein, and removes impurity with methyl tertiary butyl ether extraction;
(4) the hydrochloric acid of aqueous phase 2mol/L is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrates and obtains white solid, be Rosuvastatin acid;
(5) above-mentioned solid adds dissolve with methanol, and adds basic amine group aqueous acid, and after reflux 2-35h, stopped reaction, is cooled to room temperature, and revolves steaming except desolventizing;
(6) add methyl alcohol, remove unnecessary basic aminoacids;
(7) concentrated organic phase, adds methyl tertiary butyl ether, refluxes 0.5 hour, be cooled to room temperature, obtain crystal, filter, be drying to obtain the amino acid salts of Rosuvastatin;
Wherein, the Rosuvastatin tert-butyl ester of the two hydroxyl protection of band: hydrochloric acid: the molar equivalent of basic aminoacids is than being 1:1:3;
Wherein, described acid is mineral acid or organic acid, and described mineral acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc.; Described organic acid is formic acid, acetic acid, propionic acid, trifluoroacetic acid;
Describedly auspiciously relax that to cut down the structural formula of the fourth tert-butyl ester as follows:
3. a preparation method for Rosuvastatin arginic acid salt, is characterized in that: step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester, be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid of 4ml1mol/L, stir 2h at 30-35 DEG C, be white suspension liquid when reaction solution starts, become colorless transparent through after a period of time, TLC detection reaction completes;
(3) in step (2) solution, add 1.952gL-arginine to be again dissolved in 10ml water, and instill in above-mentioned solution, at 80 DEG C, reflux, stirring are spent the night, solvent evaporated; Add methyl alcohol wherein, separate out the L-arginine that also filtering is unnecessary;
(4) enrichment step (3) organic phase in solution, and add methyl tertiary butyl ether, reflux 0.5h, be cooled to room temperature, crystallize out, and filtration drying, obtain white solid, be the amino acid salts of Rosuvastatin;
Describedly auspiciously relax that to cut down the structural formula of the fourth tert-butyl ester as follows:
4. a preparation method for Rosuvastatin Histidine salt, is characterized in that: step is as follows:
(1) take the 2g Rosuvastatin tert-butyl ester, be dissolved in the solvent of 20ml methyl alcohol and 5ml tetrahydrofuran (THF), stirring and dissolving;
(2) in step (1) solution, add the hydrochloric acid of 4ml1mol/L, stir 2h at 30-35 DEG C, TLC detection reaction completes;
(3) in step (2) solution, add the sodium hydroxide of 1.4ml3mol/L again, after stirred at ambient temperature reaction 1h, by reaction solution solvent evaporate to dryness; Add water wherein, and remove impurity with methyl tertiary butyl ether extraction;
(4) the hydrochloric acid of aqueous phase 2mol/L in step (3) solution is adjusted to neutral or acidity on the weak side, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrates to obtain white solid, obtain Rosuvastatin acid;
By step (4) in 1.8g Rosuvastatin is acid-soluble in 20ml methyl alcohol, form settled solution, take 792mgL-Histidine and be dissolved in 10ml water, and instill in above-mentioned solution, reflux at 80 DEG C, stir and spend the night, solvent evaporated;
(6) add methyl alcohol, separate out the L-Histidine that also filtering is unnecessary;
(7) concentrated organic phase, and add methyl tertiary butyl ether backflow 0.5h, be cooled to room temperature, obtain crystal, and filtration drying, obtain Rosuvastatin amino acid salts;
Describedly auspiciously relax that to cut down the structural formula of the fourth tert-butyl ester as follows:
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| JP2018027987A (en) * | 2017-11-24 | 2018-02-22 | 共和薬品工業株式会社 | Pharmaceutical composition |
| CN111100075B (en) * | 2019-12-20 | 2022-04-12 | 南通常佑药业科技有限公司 | Method for preparing rosuvastatin and pitavastatin 2, 6-diene heptanoate compound |
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