CN101434526A - Column chromatography preparation of high-content valone - Google Patents
Column chromatography preparation of high-content valone Download PDFInfo
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- CN101434526A CN101434526A CNA2008101634403A CN200810163440A CN101434526A CN 101434526 A CN101434526 A CN 101434526A CN A2008101634403 A CNA2008101634403 A CN A2008101634403A CN 200810163440 A CN200810163440 A CN 200810163440A CN 101434526 A CN101434526 A CN 101434526A
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Abstract
The invention discloses a preparation method of column chromatography of high-content valone. The rough industrial product of valone is adopted as a raw material for preparing the high-content valone. The content of the valone in the rough product ranges from 65.0 percent to 95.0 percent and after dissolution, column chromatography, condensation and drying, the valone with a content of over 99.0 percent is obtained. The method has simple technological process, low production costs and easy industrialization. Products prepared by the method have high purity and high yield.
Description
Technical field
The present invention relates to technical field of chemical engineering, relate in particular to a kind of column chromatography preparation method of high-load Valone.
Background technology
Valone (the 2-pivaloyl--1,3-indenes diketone, Valone, molecular formula: C
14H
14O
3Molecular weight: 230.26) be a kind of indandione class anticoagulation class mouse medicine of novelty, generally only contain Valone 65.0～95.0% by the thick product of the Valone that is synthesized into, separation need be further purified and the higher Valone of content could be obtained, because this is similar to the positional isomers chemical property for pindone and Valone in the raw material, difficult generally speaking the separation, only depend on recrystallization method to be difficult to produce highly purified Valone product, can't satisfy pharmacological research and quality control demand the high-content Valone.At present, domestic still do not have high-load Valone (purity〉99.0%) production.The chemical structural formula of Valone is:
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of column chromatography preparation method of high-load Valone is provided, and the present invention does not need raw material is carried out any processing by preferred adsorbent, directly carry out chromatographic separation, just can remove the various impurity that comprise positional isomers.
The technical solution adopted for the present invention to solve the technical problems is: a kind of column chromatography preparation method of high-load Valone may further comprise the steps:
1) with the industrial crude product of Valone, be the lower member ester and the dissolving of lower alcohol mixed solvent of 50:50～99:1 with volume ratio after, feed and be filled with in the chromatography column of sorbent material, temperature is 20～80 ℃, flow rate control 0.5～5 times of column volume/hour;
2) with the lower alcohol of 1～6 times of column volume, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
3) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 60:40～80:20, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
4) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 80:20～99:1, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation or the oven dry that obtains, high-load Valone.
Further, described lower member ester is ethyl acetate, propyl acetate or ethyl ester butyl ester; Described lower alcohol is methyl alcohol, ethanol or Virahol; Described sorbent material is a silica gel, and its order number is a kind of in 60～100 orders, 100～160 orders, 160～200 orders and 200～300 orders.
The useful effect that the present invention has is: the present invention does not need raw material is carried out any pre-treatment, directly carries out separation and purification with chromatographic separating process, products obtained therefrom content height (Valone content〉99.0%), the yield height, the purity height is easy to industrialization.
Description of drawings
Fig. 1 is the standardized solution liquid chromatogram of Valone and pindone; Moving phase be methyl alcohol/ammonium acetate-acetate buffer solution (5mmol/L, pH=5.5)=(70:30, v/v) HPLC figure; Among the figure, No. 1 peak is the chromatographic peak of pindone, and No. 2 peaks are the chromatographic peak of Valone, and the chromatographic peak of pindone is about 6.2min, and the chromatographic peak of Valone is about 7.0min.
Fig. 2 is the liquid chromatogram of the Valone product that obtained by embodiment 2; Moving phase be methyl alcohol/ammonium acetate-acetate buffer solution (5mmol/L, pH=5.5)=(70:30, v/v) HPLC figure; Among the figure, No. 1 peak is the chromatographic peak of Valone, and its retention time is about 7.0min.
The one-level mass spectrum that Fig. 3 obtains in the direct injection mode for the methanol solution (1.0mg/L) of the Valone product that obtained by embodiment 2.
Fig. 4 is that parent ion carries out cracked second order ms figure with m/z 229 for after the methanol solution (1.0mg/L) of the Valone product that obtained by embodiment 2 obtains quasi-molecular ion m/z229 in the direct injection mode then.
Embodiment
The present invention is the high-load Valone of feedstock production with the synthetic thick product of producing of Valone of industry, the content of Valone is 65.0～95.0% in the wherein thick product, carry out chromatographic separation by the adsorption column that is filled with 60～300 order silica gel, the employing volume ratio is that lower member ester and the lower alcohol mixed solvent of 60:40～99:1 carries out drip washing and wash-out, Fractional Collections, merge content greater than 98.0% collection liquid, after the drying, directly obtain content 99.0% high-content Valone;
The column chromatography preparation method of the high-load Valone of the present invention may further comprise the steps:
1) with the industrial crude product of Valone, be the lower member ester and the dissolving of lower alcohol mixed solvent of 50:50～99:1 with volume ratio after, feed and be filled with in the chromatography column of sorbent material, temperature is 20～80 ℃, flow rate control 0.5～5 times of column volume/hour;
2) with the lower alcohol of 1～6 times of column volume, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
3) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 60:40～80:20, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
4) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 80:20～99:1, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation or the oven dry that obtains, high-load Valone.
Described lower member ester is a kind of in ethyl acetate, propyl acetate and the ethyl ester butyl ester; Described lower alcohol is a kind of in methyl alcohol, ethanol and the Virahol; Described sorbent material is a silica gel, and its order number is a kind of in 60～100 orders, 100～160 orders, 160～200 orders and 200～300 orders.
Following examples are used for further understanding the present invention, but are not limited to the scope of this enforcement.
Chromatography column size Φ 28 * 500mm.The about 80g of interior dress 60-100 purpose silica gel.(its concentration is 10.0mg/mL to the Valone raw material for 60:40, v/v) dissolving, and last sample volume is 1000mL, and last sample and eluting temperature are 80 ℃ with propyl acetate/methyl alcohol.With the drip washing of 360mL methyl alcohol, use propyl acetate/methyl alcohol (80:20, v/v) the drip washing chromatography column of 1200mL more earlier; Use 800mL propyl acetate/methyl alcohol (95:5 at last, v/v) wash-out, flow velocity is 8.0mL/min, collects the chromatography column elutriant, Fractional Collections stream part, carry out the on-line ultraviolet monitoring, merging collection content is the elutriant more than 99%, gets Valone product 8.31g after the vacuum-drying, and the HPLC analytical results shows, Valone content 99.3% in the product, yield 83.1%.
Chromatography column size Φ 28 * 500mm.The about 60g of interior dress 160-200 purpose silica gel.(its material concentration is 10.0mg/mL to the Valone raw material for 60:40, v/v) dissolving, and last sample volume is 1000mL, and last sample and eluting temperature are 80 ℃ with propyl acetate/ethanol.With the drip washing of 350mL ethanol, use 1100mL ethyl acetate/ethanol (80:20, v/v) drip washing chromatography column more earlier; Use 800mL ethyl acetate/ethanol (95:5 at last, v/v) wash-out, flow velocity is 8.0mL/min, collects the chromatography column elutriant, Fractional Collections stream part, carry out the on-line ultraviolet monitoring, merging collection content is the elutriant more than 99%, gets Valone product 8.72g after the vacuum-drying, and the HPLC analytical results shows, Valone content 99.1% in the product, yield 87.2%.
Embodiment 3
Chromatography column size Φ 20 * 400mm.The about 40g of interior dress 160-200 purpose silica gel.(its material concentration is 10.0mg/mL to the Valone raw material for 60:40, v/v) dissolving, and last sample volume is 1000mL, and last sample and eluting temperature are 80 ℃ with butylacetate/Virahol.With the drip washing of 320mL Virahol, use 1000mL butylacetate/Virahol (80:20, v/v) drip washing chromatography column more earlier; Use 750mL butylacetate/Virahol (95: 5 at last, v/v) wash-out, flow velocity is 8.0mL/min, collects the chromatography column elutriant, Fractional Collections stream part, carry out the on-line ultraviolet monitoring, merging collection content is the elutriant more than 99%, gets Valone product 8.83g after the vacuum-drying, and the HPLC analytical results shows, Valone content 99.5% in the product, yield 88.3%.
Embodiment 4
Chromatography column size Φ 20 * 400mm.In adorn the about 40g of 200～300 purpose silica gel.(its material concentration is 10.0mg/mL to the Valone raw material for 60:40, v/v) dissolving, and last sample volume is 1000mL, and last sample and eluting temperature are 80 ℃ with butylacetate/methyl alcohol.With the drip washing of 350mL methyl alcohol, use 1100mL butylacetate/methyl alcohol (80:20, v/v) drip washing chromatography column more earlier; Use 800mL butylacetate/methyl alcohol (95:5 at last, v/v) wash-out, flow velocity is 8.0mL/min, collects the chromatography column elutriant, Fractional Collections stream part, carry out the on-line ultraviolet monitoring, merging collection content is the elutriant more than 99%, gets Valone product 8.76g after the vacuum-drying, and the HPLC analytical results shows, Valone content 99.5% in the product, yield 87.6%.
The foregoing description is used for the present invention that explains, rather than limits the invention, and in the protection domain of spirit of the present invention and claim, any modification and change to the present invention makes all fall into protection scope of the present invention.
Claims (4)
1. the column chromatography preparation method of a high-load Valone is characterized in that, may further comprise the steps:
1) with the industrial crude product of Valone, be the lower member ester and the dissolving of lower alcohol mixed solvent of 50:50～99:1 with volume ratio after, feed and be filled with in the chromatography column of sorbent material, temperature is 20～80 ℃, flow rate control 0.5～5 times of column volume/hour.
2) with the lower alcohol of 1～6 times of column volume, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity.
3) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 60:40～80:20, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity wash-out impurity.
4) volume ratio with 1～6 times of column volume is lower member ester and the lower alcohol mixing solutions of 80:20～99:1, in 20～80 ℃ of temperature ranges, with 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation or the oven dry that obtains, high-load Valone.
2. column chromatography preparation method according to claim 1 is characterized in that, described lower member ester is ethyl acetate, propyl acetate or ethyl ester butyl ester.
3. column chromatography preparation method according to claim 1 is characterized in that, described lower alcohol is methyl alcohol, ethanol or Virahol.
4. column chromatography preparation method according to claim 1 is characterized in that, described sorbent material is a silica gel, and its order number is a kind of in 60～100 orders, 100～160 orders, 160～200 orders and 200～300 orders.
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| CN2008101634403A CN101434526B (en) | 2008-12-22 | 2008-12-22 | Column chromatography preparation of high-content valone |
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| CN2008101634403A CN101434526B (en) | 2008-12-22 | 2008-12-22 | Column chromatography preparation of high-content valone |
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