CN102516404B - Preparation method of rosuvastatin-dextran ester - Google Patents
Preparation method of rosuvastatin-dextran ester Download PDFInfo
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- CN102516404B CN102516404B CN201110329343.9A CN201110329343A CN102516404B CN 102516404 B CN102516404 B CN 102516404B CN 201110329343 A CN201110329343 A CN 201110329343A CN 102516404 B CN102516404 B CN 102516404B
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Abstract
The invention discloses a preparation method of a rosuvastatin-dextran ester. The preparation method comprises the following steps that dextran and rosuvastatin calcium undergo a reaction in the presence of an organic solvent and an acylation agent at a reaction temperature of 20 to 80 DEG C; after the reaction, reaction products are precipitated from reaction product liquid by isopropanol; the reaction products are filtered; and the filter cake is washed by absolute ethanol and then is dried by an oven to form the rosuvastatin-dextran ester. The preparation method of the rosuvastatin-dextran ester has the advantage that rosuvastatin is grafted to a dextran molecule and thus the rosuvastatin-dextran ester as a derivative has high water solubility and high bioavailability.
Description
(1) technical field
The present invention relates to a kind of preparation method of Rosuvastatin-dextran ester.
(2) background technology
Rosuvastatine; English name is Rosuvastatin; its chemistry is by name: two-[E-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino]-pyrimidine-5-yl] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid] calcium salt (2:1).
Rosuvastatin is in the U.S., through Food and Drug Administration (FDA) approval, to go on the market in August, 2003, becomes the statins of the 7th listing.Be mainly to suppress the HMG-CoA reductase enzyme, reduce the biosynthesizing of cholesterol.The HMG-CoA reductase inhibitor can promote body to remove low density lipoprotein cholesterol (LDL-C).In addition, the HMG-CoA reductase inhibitor also, by suppressing the synthetic of cholesterol, disturbs the generation of lipoprotein, thereby has reduced the level of blood plasma LDL-C, level that can also high density lipoprotein increasing cholesterol (HDL-C).Therefore Rosuvastatin is blood lipid-lowering medicine of new generation, there is powerful reduction total cholesterol and low density lipoprotein cholesterol ability, and can fall well total triglyceride level, and high density lipoprotein increasing cholesterol preferably, and be conducive to the prevention of coronary heart disease.The formulation of this medicine has the formulations such as conventional tablet, capsule, but, in these formulations, Rosuvastatin is because of its poorly water-soluble, and oral rear absorption is slow, and bioavailability is lower, thereby onset is also comparatively slow.The preparation method who the purpose of this invention is to provide the Rosuvastatin-dextran ester of a kind of water-soluble increase, bioavailability raising.
(3) summary of the invention
The invention provides a kind of technology for preparing Rosuvastatin-dextran ester, the technical solution used in the present invention is:
A kind of preparation method of Rosuvastatin-dextran ester, described method is: the dextran as shown in formula II and the Rosuvastatine calcium shown in formula I, under organic solvent and acylating reagent existence, control temperature of reaction at 20～80 ℃, reaction finishes, reaction solution is separated out with Virahol, and filter cake absolute ethanol washing post-drying after filtering obtains dextran as shown in formula III-Rosuvastatine ester; Described organic solvent is methyl-sulphoxide or DMF; Described acylating reagent is carbonyl dimidazoles, 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide; The amount of substance of described Rosuvastatine calcium, acylating reagent and dextran is than being 1.0:1.0～2.5:0.5～2.5.
The present invention recommends the method for described Rosuvastatin-dextran ester to carry out as follows: take the dextran as shown in formula II; add organic solvent, stirring and dissolving, then add acylating reagent and the Rosuvastatine calcium as shown in formula I; control temperature of reaction at 20～80 ℃; stirring reaction, reaction finishes, and the gained reaction solution is separated out with Virahol; filter; absolute ethanol washing 2～3 times for filter cake, dry, and obtains dextran as shown in formula III-Rosuvastatine ester.
Further, the consumption of organic solvent of the present invention is 10-50mL/mmol Rosuvastatine calcium.
The preferred temperature of reaction of the present invention is 40～60 ℃.
The present invention is 4～36h in the preferred reaction times, is more preferably 10～24h.
Concrete, the preparation method of Rosuvastatin-dextran ester of the present invention, it is characterized in that described method carries out as follows: take the dextran as shown in formula II, add organic solvent, stirring and dissolving, add again acylating reagent N, N`-or and the Rosuvastatine calcium as shown in formula I, control temperature of reaction at 40～60 ℃, stirring reaction 10～24h, the gained reaction solution is separated out with Virahol, filter, filter cake absolute ethanol washing 2～3 times, dry, obtain dextran as shown in formula III-Rosuvastatine ester, described Rosuvastatine calcium, the amount of substance of acylating reagent and dextran is than being 1.0:1.0～2.5:0.5～2.5, the consumption of described organic solvent is 10～50mL/mmol Rosuvastatine calcium, described organic solvent is methyl-sulphoxide or N, dinethylformamide, described acylating reagent is N, the N`-carbonyl dimidazoles, 1, 3-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide.
Beneficial effect of the present invention is embodied in: by Rosuvastatin is grafted on dextran molecule, and the Rosuvastatin that provides a kind of water-soluble increase, bioavailability to improve-dextran ester derivative.
(4) accompanying drawing explanation
Fig. 1 is embodiment 1 dextran IR collection of illustrative plates.
Fig. 2 is the IR collection of illustrative plates of the Rosuvastatin that makes of embodiment 1.
Fig. 3 is the IR collection of illustrative plates of Rosuvastatin-dextran ester of making of embodiment 1.
Fig. 4 is Rosuvastatin-dextran ester that embodiment 1 makes
1h-NMR.
Fig. 5 is Rosuvastatin-dextran ester that embodiment 1 makes
13c-NMR.
(5) embodiment
Below with specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to this:
Take the 0.62mmol dextran and put into three-necked bottle, add 6mL methyl-sulphoxide (DMSO), after stirring and dissolving 24h, then add N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, temperature of reaction is controlled at 60 ℃, stirs 24h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and measures infrared, the nuclear-magnetism of this product, and products obtained therefrom is dextran-Rosuvastatine ester.
Take the 0.50mmol dextran and put into three-necked bottle, add 10mL methyl-sulphoxide (DMSO), after stirring and dissolving 4h, add again N, N`-carbonyl dimidazoles (CDI) 0.46mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 60 ℃, stirring reaction 10h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 3
Take the 0.77mmol dextran and put into three-necked bottle, add 30mL DMSO, after stirring and dissolving 4h, then add N, N`-carbonyl dimidazoles (CDI) 0.77mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 55 ℃, stirring reaction 12h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 4
Take the 0.62mmol dextran and put into three-necked bottle, add 15mL DMSO, after stirring and dissolving 4h, then add N, N`-carbonyl dimidazoles (CDI) 0.62mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 60 ℃, stirring reaction 15h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 5
Take the 0.31mmol dextran and put into three-necked bottle, add 5mL DMSO, after stirring and dissolving 4h, then add N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 45 ℃, stirring reaction 16h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Take the 0.62mmol dextran and put into three-necked bottle, add 25mL DMSO, after stirring and dissolving 4h, then add N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 60 ℃, stirring reaction 20h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 7
Take the 0.62mmol dextran and put into three-necked bottle, add 25mL DMSO, after stirring and dissolving 4h, then add 1,3-dicyclohexylcarbodiimide DCC0.46mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 40 ℃, stirring reaction 12h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Take the 0.62mmol dextran and put into three-necked bottle, add 15mL N, dinethylformamide (DMF), be heated to 85 ℃, after stirring and dissolving 4h, be cooled to room temperature, add again N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, temperature of reaction is controlled at 50 ℃, stirring reaction 14h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Take the 0.62mmol dextran and put into three-necked bottle, add 20mL DMF, be heated to 85 ℃, after stirring and dissolving 4h, be cooled to room temperature, then add 1,3-dicyclohexylcarbodiimide DCC0.46mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 50 ℃, stirring reaction 16h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Take the 0.62mmol dextran and put into three-necked bottle, add 20mL DMSO, after stirring and dissolving 4h, then add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide EDC0.31mmol and Rosuvastatine calcium 0.31mmol, the reflection temperature is controlled at 40 ℃, stirring reaction 10h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and products obtained therefrom is dextran-Rosuvastatine ester, and all collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 11
Take the 0.62mmol dextran and put into three-necked bottle, add 10mL methyl-sulphoxide (DMSO), after stirring and dissolving 24h, then add N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, temperature of reaction is controlled at 80 ℃, stirs 4h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and measures infrared, the nuclear-magnetism of this product, and products obtained therefrom is dextran-Rosuvastatine ester.All collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Embodiment 12
Take the 0.15mmol dextran and put into three-necked bottle, add 15mL methyl-sulphoxide (DMSO), after stirring and dissolving 24h, then add N, N`-carbonyl dimidazoles (CDI) 0.31mmol and Rosuvastatine calcium 0.31mmol, temperature of reaction is controlled at 20 ℃, stirs 36h.Products therefrom is separated out with Virahol, with absolute ethanol washing twice, collects post-drying, and measures infrared, the nuclear-magnetism of this product, and products obtained therefrom is dextran-Rosuvastatine ester.All collection of illustrative plates of IR, NMR and embodiment 1 are identical.
Claims (7)
1. auspicious relaxing cut down the preparation method of his spit of fland ?dextran ester, it is characterized in that described method is: the dextran as shown in formula II and the Rosuvastatine calcium shown in formula I, under organic solvent and acylating reagent existence, control temperature of reaction at 20～80 ℃, reaction finishes, reaction solution is separated out with Virahol, filter cake absolute ethanol washing post-drying after filtering, and sugared acid anhydride ?Rosuvastatine ester is revolved on the right side obtained as shown in formula III; Described organic solvent is methyl-sulphoxide or N, N ?dimethyl formamide; Described acylating reagent is N, N` ?carbonyl dimidazoles, 1,3 ?dicyclohexylcarbodiimide or 1 ?(3 ?dimethylamino-propyl) ?3 ?ethyl carbodiimide; The amount of substance of described Rosuvastatine calcium, acylating reagent and dextran is than being 1.0:1.0～2.5:0.5～2.5.
Auspicious easypro Fa Ta Ting as claimed in claim 1 ?the preparation method of dextran ester; it is characterized in that described method carries out as follows: take the dextran as shown in formula II; add organic solvent; stirring and dissolving; add again acylating reagent and the Rosuvastatine calcium as shown in formula I; control temperature of reaction at 20～80 ℃; stirring reaction; reaction finishes; the gained reaction solution is separated out with Virahol, filters filter cake absolute ethanol washing 2～3 times; dry, sugared acid anhydride ?Rosuvastatine ester is revolved on the right side obtained as shown in formula III.
3. preparation method as claimed in claim 1, the consumption that it is characterized in that described organic solvent is 10～50mL/mmol Rosuvastatine calcium.
4. preparation method as claimed in claim 1, is characterized in that described temperature of reaction is 40～60 ℃.
5. preparation method as claimed in claim 1, is characterized in that the described reaction times is 4～36h.
6. preparation method as claimed in claim 4, is characterized in that the described reaction times is 10～24h.
7. preparation method as claimed in claim 1, it is characterized in that described method carries out as follows: take the dextran as shown in formula II, add organic solvent, stirring and dissolving, add again acylating reagent and the Rosuvastatine calcium as shown in formula I, control temperature of reaction at 40～60 ℃, stirring reaction 10～24h, the gained reaction solution is separated out with Virahol, filter, filter cake absolute ethanol washing 2～3 times, dry, sugared acid anhydride ?Rosuvastatine ester is revolved on the right side obtained as shown in formula III, described Rosuvastatine calcium, the amount of substance of acylating reagent and dextran is than being 1.0:1.0～2.5:0.5～2.5, the consumption of described organic solvent is 10～50mL/mmol Rosuvastatine calcium, described organic solvent is methyl-sulphoxide or N, N ?dimethyl formamide, described acylating reagent is N, N` ?carbonyl dimidazoles, 1, 3 ?dicyclohexylcarbodiimide or 1 ?(3 ?dimethylamino-propyl) ?3 ?ethyl carbodiimide.
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