CN104788387A - Preparation method for high-purity rosuvastatin calcium - Google Patents
Preparation method for high-purity rosuvastatin calcium Download PDFInfo
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- CN104788387A CN104788387A CN201510183930.XA CN201510183930A CN104788387A CN 104788387 A CN104788387 A CN 104788387A CN 201510183930 A CN201510183930 A CN 201510183930A CN 104788387 A CN104788387 A CN 104788387A
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- solution
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- high purity
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- 0 CC(C)C(C1)=C(C=CC2OC(C)(C)OC(C*)C2)C(c(cc2)ccc2F)=N[C@]1C=CS Chemical compound CC(C)C(C1)=C(C=CC2OC(C)(C)OC(C*)C2)C(c(cc2)ccc2F)=N[C@]1C=CS 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to preparation methods for compounds, in particular to a preparation method for high-purity rosuvastatin calcium. The preparation method comprises the following steps: in a N2 protection and light-shading environment, removing an acetonylidene protecting group in an acidic condition from an ester compound, hydrolyzing an ester bond in an alkali condition, regulating the pH (potential of hydrogen) value, adding active carbon for decoloration, performing extraction for removing impurities, dropwise adding a water soluble calcium salt solution, filtering and drying to obtain high-purity rosuvastatin calcium. The method adopts an alcohol solvent and the ester compound for synthesizing rosuvastatin calcium; an intermediate body is not separated in the process; rosuvastatin calcium is obtained with a one-pot procedure and is high in purity and high in yield; the process is simple, convenient and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, be specially the preparation method of high purity rosuvastain calcium.
Technical background
Rosuvastain calcium; chemical name: two-[E-7-[4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-pyrimidine-5-base] (3R; 5S)-3; 5-dihydroxy heptyl-6-olefin(e) acid] calcium salt (2: 1); Japanese Shionogi Seiyaku Kabushiki Kaisha last century late nineteen eighties screen the aminopyridine derivative obtained; after transfer Astrazeneca AB of Britain, be developed to blood lipid-lowering medicine of new generation by Astrazeneca AB.Belong to HMG-CoA reductase inhibitor, low density lipoprotein cholesterol, total cholesterol and triglyceride level can be reduced, simultaneously the concentration of increasing high density cholesterol.There is excellent lipid-lowering effect, be called " superstatin " by industry.
US20050124639 discloses the synthetic method of rosuvastain calcium; ester compound (I) is removed acetonylidene protecting group by acid hydrolysis; basic hydrolysis ester group obtains Rosuvastatin sodium salt; Rosuvastatin sodium salt and amine are obtained by reacting Rosuvastatin ammonium salt; be obtained by reacting Rosuvastatin calcium salt with the calcium salt such as sodium hydroxide and calcium chloride successively again, the method obtains intermediate Rosuvastatin ammonium salt by separation and carries out purifying, then is converted into calcium salt; synthesis step is many, and yield is low.
WO2009157014 discloses the synthetic method of rosuvastain calcium, ester compound is changed into separable intermediate ammonium salt, obtain Rosuvastatin calcium salt further again, the large second cyanogen of toxicity used by the solvent in technique, toluene, macromolecule alkali for hydrolysis is for up to 6-8h, react the solvent species related to many, toxicity is large, long reaction time, complex steps yield is low, is unsuitable for suitability for industrialized production.
Chinese patent CN200810146732 discloses a kind of synthetic method of rosuvastain calcium; ester compound is adopted to remove acetonylidene protecting group by acid hydrolysis; basic hydrolysis ester group obtains Rosuvastatin sodium salt; change into new ester compound with halohydrocarbons reaction again, further basic hydrolysis, finally becomes calcium salt; the method is converted into rosuvastain calcium again by forming new ester intermediate; operation steps is long, and yield is lower, and purity needs to be improved further.
Summary of the invention
For above-mentioned technical problem, the invention provides the preparation method of the rosuvastain calcium that a kind of technique is simple, yield is high.
Concrete technical scheme is:
The preparation method of high purity rosuvastain calcium, comprises the following steps:
(1) N
2protection and light protected environment under, Compound I in organic solvent acidic conditions sloughs acetonylidene protecting group, temperature of reaction 0-70 DEG C, preferred 40-55 DEG C;
Then, under same environment, hydrolyse ester bond in the basic conditions, obtains Rosuvastatin sodium salt solution, temperature of reaction 0-70 DEG C, preferred 40-55 DEG C;
The structural formula of Compound I is:
r is C
1-C
10alkyl.
Wherein, organic solvent is one or more mixtures in ethanol, 95% ethanol, methyl alcohol, ethanol and carbinol mixture, 95% ethanol and carbinol mixture, Virahol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, acetone, ether, methyl tertiary butyl ether, toluene, water, dioxane.
Acidic conditions sloughs acetonylidene protecting group, and the acid adopted is a kind of in hydrochloric acid soln, salpeter solution, sulphuric acid soln, acetum, H
+ionic concn is 0.5-6mol/L, preferred H
+ionic concn is 1-2mol/L hydrochloric acid soln.
Hydrolyzed under basic conditions ester bond, the alkali adopted is a kind of in sodium hydroxide solution, potassium hydroxide solution, aqua calcis, HO
-ionic concn is 0.5-6mol/L, preferred HO
-ionic concn is 1-2mol/L sodium hydroxide solution.
(2) pure water is added, the PH regulating Rosuvastatin sodium salt solution is 7-10, preferred PH is 7.5-8.5, Rosuvastatin sodium salt solution and pure water volume ratio are 1-8: 1, be preferably 5: 1, add activated carbon decolorizing again, gac and Compound I mass ratio are 1: 5-50, stir 30min, then filter under lucifuge condition and concentrate, be concentrated in temperature 30-70 DEG C, preferably carry out under 40-60 DEG C of condition, except desolventizing, then obtain Rosuvastatin sodium-salt aqueous solution with organic solvent extraction removing impurity.
Wherein, the organic solvent of extraction is tetrahydrofuran (THF), normal hexane, one or more in sherwood oil, ethyl acetate, methylene dichloride, acetone, ether, methyl tertiary butyl ether, toluene, water, dioxane, methyl alcohol, ethanol, organic solvent and Rosuvastatin sodium salt solution volume ratio are 1: 1-30, preferably 1: 1-15.
(3) under lucifuge condition, be added dropwise to water-soluble calcium salts solution in Rosuvastatin sodium-salt aqueous solution, temperature of reaction is 0-70 DEG C, preferred 0-20 DEG C, refilters, drying obtains high purity rosuvastain calcium.
Wherein, water-soluble calcium salts solution is calcium chloride solution, calcium acetate solution, ca nitrate soln or aqua calcis, preferred calcium acetate solution, and water-soluble Ca salt concentration of polymer solution is 2%-40%, preferred 3%-20%.
The preparation method of high purity rosuvastain calcium provided by the invention, adopts the synthesis of alcoholic solvent, ester compound to relax and cuts down statin calcium, not separation of intermediates in process, one kettle way just obtains relaxing and cuts down statin calcium, and purity is high, yield is high, simple process, is suitable for suitability for industrialized production.
Specific implementation method
Below in conjunction with specific embodiment, the present invention is further described, but do not limit invention.
Embodiment 1
N
2protection, under lucifuge condition, Compound I 5.0g (8.66mmol) is added in 250ml round-bottomed flask, 95% ethanol 90ml, the HCl solution that 10ml concentration is 1N is added dropwise under 55 DEG C of conditions, stirring reaction 30min, TLC detection reaction is complete, slowly be added dropwise to the sodium hydroxide solution that 20ml concentration is 1N, stirring reaction 1h, TLC detection reaction is complete, be cooled to room temperature, add 10ml pure water, the HCl dripping 2N regulates PH to 8.3-8.5, add 0.5g activated carbon decolorizing again and stir 30min, filter under lucifuge condition, 55 DEG C concentrated except desolventizing, water layer 15ml extraction into ethyl acetate twice, water layer is concentrated removing organic solvent at 50 DEG C, under 5 DEG C of conditions, slow dropping 5ml concentration is 20% calcium acetate solution, stirring reaction 30min, filter, 3 times are washed with 5 DEG C of cold water 10ml, vacuum-drying obtains high purity Rosuvastatin calcium salt 3.62g.
Yield 83.7%, measuring rosuvastain calcium chromatographic purity through high performance liquid phase is 99.91%.
Embodiment 2
N
2protection, under lucifuge condition, Compound I 5.0g (8.66mmol) is added in 250ml round-bottomed flask, 95% ethanol 90ml, the HCl solution that 10ml concentration is 1N is dripped under 55 DEG C of conditions, stirring reaction 30min, TLC detection reaction is complete, under same temperature, slow dropping 20ml concentration is the sodium hydroxide solution stirring reaction 1h of 1N, TLC detection reaction is complete, be cooled to room temperature, add 10ml pure water, drip the HCl adjustment PH to 8.3-8.5 that concentration is 2N, add 0.5g activated carbon decolorizing again and stir 30min, filter under lucifuge condition, concentrated except desolventizing under 55 DEG C of conditions, water layer 15ml extraction into ethyl acetate twice, water layer is concentrated removing organic solvent at 50 DEG C, filtrate is under 5 DEG C of conditions, slow dropping concentration is 20% calcium acetate solution 5ml, stirring reaction 30min, filter, 3 times are washed with 5 DEG C of cold water 10ml, vacuum-drying obtains high purity Rosuvastatin calcium salt 3.5g.
Yield 80.8%, measuring rosuvastain calcium chromatographic purity through high performance liquid phase is 99.91%.
Embodiment 3
N
2protection, under lucifuge condition, Compound I 5.0g (8.66mmol) is added in 250ml round-bottomed flask, tetrahydrofuran (THF) 90ml, under 55 DEG C of conditions, drip the HCl stirring reaction 30min that 10ml concentration is 1N, TLC detection reaction is complete, under same temperature, slow dropping 20ml concentration is the sodium hydroxide solution stirring reaction 1h of 1N, TLC detection reaction is complete, be cooled to room temperature, add 10ml pure water, drip the HCl adjustment PH to 8.3-8.5 that concentration is 2N, add 0.5g activated carbon decolorizing again and stir 30min, filter under lucifuge condition, 55 DEG C concentrated except desolventizing, water layer 15ml n-hexane extraction twice, water layer is concentrated removing organic solvent at 50 DEG C, under 5 DEG C of conditions, slow dropping concentration is 20% calcium chloride solution 5ml, stirring reaction 30min, filter, 3 times are washed with 5 DEG C of cold water 10ml, vacuum-drying obtains high purity Rosuvastatin calcium salt 3.55g.
Yield 82.0%, measuring rosuvastain calcium chromatographic purity through high performance liquid phase is 99.94%.
Claims (7)
1. the preparation method of high purity rosuvastain calcium, is characterized in that, comprises the following steps:
(1) N
2protection and light protected environment under, in organic solvent, first acidic conditions sloughs acetonylidene protecting group to Compound I; Then hydrolyse ester bond in the basic conditions, obtains Rosuvastatin sodium salt solution;
The structural formula of Compound I is:
r is C
1-C
10alkyl;
(2) pure water is added, the PH regulating Rosuvastatin sodium salt solution is 7-10, Rosuvastatin sodium salt solution and pure water volume ratio are 1-8: 1, add activated carbon decolorizing again and stir 30min, then filter under lucifuge condition and concentrate, carry out under being concentrated in temperature 30-70 DEG C of condition, except desolventizing, then obtain Rosuvastatin sodium-salt aqueous solution with organic solvent extraction removing impurity;
(3) under lucifuge condition, be added dropwise to water-soluble calcium salts solution in Rosuvastatin sodium-salt aqueous solution, refilter, drying obtains high purity rosuvastain calcium.
2. the preparation method of high purity rosuvastain calcium according to claim 1, it is characterized in that, the organic solvent described in step (1) is one or more mixtures in ethanol, 95% ethanol, methyl alcohol, ethanol and carbinol mixture, 95% ethanol and carbinol mixture, Virahol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, acetone, ether, methyl tertiary butyl ether, toluene, water, dioxane.
3. the preparation method of high purity rosuvastain calcium according to claim 1; it is characterized in that; acidic conditions described in step (1) sloughs acetonylidene protecting group, and the acid adopted is a kind of in hydrochloric acid soln, salpeter solution, sulphuric acid soln, acetum, H
+ionic concn is 0.5-6mol/L.
4. the preparation method of high purity rosuvastain calcium according to claim 1, it is characterized in that, hydrolyzed under basic conditions ester bond described in step (1), the alkali adopted is a kind of in sodium hydroxide solution, potassium hydroxide solution, aqua calcis, HO
-ionic concn is 0.5-6mol/L.
5. the preparation method of high purity rosuvastain calcium according to claim 1, it is characterized in that, pure water is added described in step (2), the PH regulating Rosuvastatin sodium salt solution is 7.5-8.5, and Rosuvastatin sodium salt solution and pure water volume ratio are 5: 1, then add activated carbon decolorizing, gac and Compound I mass ratio are 1: 5-50, stir 30min, then filter under lucifuge condition and concentrate, carrying out under being concentrated in temperature 40-60 DEG C of condition.
6. the preparation method of high purity rosuvastain calcium according to claim 1, it is characterized in that, the organic solvent of the extraction described in step (2) is tetrahydrofuran (THF), normal hexane, one or more in sherwood oil, ethyl acetate, methylene dichloride, acetone, ether, methyl tertiary butyl ether, toluene, water, dioxane, methyl alcohol, ethanol, organic solvent and Rosuvastatin sodium salt solution volume ratio are 1: 1-30.
7. the preparation method of high purity rosuvastain calcium according to claim 1, it is characterized in that, water-soluble calcium salts solution described in step (3) is calcium chloride solution, calcium acetate solution, ca nitrate soln or aqua calcis, preferred calcium acetate solution, water-soluble Ca salt concentration of polymer solution is 2%-40%.
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| CN201510183930.XA CN104788387A (en) | 2015-04-17 | 2015-04-17 | Preparation method for high-purity rosuvastatin calcium |
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| CN201510183930.XA CN104788387A (en) | 2015-04-17 | 2015-04-17 | Preparation method for high-purity rosuvastatin calcium |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153040A (en) * | 2015-10-15 | 2015-12-16 | 江苏师范大学 | New rosuvastatin calcium crystal form and preparation method thereof |
| CN111170950A (en) * | 2020-01-16 | 2020-05-19 | 河南豫辰药业股份有限公司 | Method for preparing rosuvastatin calcium salt |
| CN115417824A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | High-purity preparation method of rosuvastatin intermediate |
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| CN1340052A (en) * | 1999-02-17 | 2002-03-13 | 阿斯特拉曾尼卡有限公司 | Process for the production of tert-butyl (E)-(6[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin 5-yl] (4R,6S)-2,2-dimethyl [1,3] dioxan-4-yl) acetate |
| WO2005023778A2 (en) * | 2003-08-28 | 2005-03-17 | Teva Pharmaceutical Industries Ltd. | Process for preparation of rosuvastatin calcium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153040A (en) * | 2015-10-15 | 2015-12-16 | 江苏师范大学 | New rosuvastatin calcium crystal form and preparation method thereof |
| CN105153040B (en) * | 2015-10-15 | 2018-04-13 | 江苏师范大学 | Rosuvastain calcium novel crystal forms and preparation method thereof |
| CN111170950A (en) * | 2020-01-16 | 2020-05-19 | 河南豫辰药业股份有限公司 | Method for preparing rosuvastatin calcium salt |
| CN115417824A (en) * | 2022-09-21 | 2022-12-02 | 安徽美诺华药物化学有限公司 | High-purity preparation method of rosuvastatin intermediate |
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