CN101434526B - Column chromatography preparation of high-content valone - Google Patents
Column chromatography preparation of high-content valone Download PDFInfo
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- CN101434526B CN101434526B CN2008101634403A CN200810163440A CN101434526B CN 101434526 B CN101434526 B CN 101434526B CN 2008101634403 A CN2008101634403 A CN 2008101634403A CN 200810163440 A CN200810163440 A CN 200810163440A CN 101434526 B CN101434526 B CN 101434526B
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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; Need be further purified separation and could obtain the higher Valone of content and since in the raw material Valone and Valone this is similar to the positional isomers chemical property, difficult generally speaking 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%) and produce.The chemical structural formula of Valone is:
Summary of the invention
The objective of the invention is to deficiency to prior art; A kind of column chromatography preparation method of high-load Valone is provided, and the present invention need not carry out any processing to raw material through 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, using volume ratio is that feeding is filled with in the chromatography column of sorbent material after 50: 50～99: 1 lower member ester and the dissolving of lower alcohol mixed solvent, and 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 TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
3) using the volume ratio of 1～6 times of column volume is 60: 40～80: 20 lower member ester and lower alcohol mixing solutions, in 20～80 ℃ of TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
4) volume ratio of 1～6 times of column volume of use is 80: 20～99: 1 lower member ester and a lower alcohol mixing solutions; In 20～80 ℃ of TRs; With 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation that obtains or oven dry, high-load Valone.
Further, said lower member ester is ETHYLE ACETATE, propyl acetate or ethyl ester butyl ester; Said lower alcohol is methyl alcohol, ethanol or Virahol; Said 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 high (Valone content＞99.0%), and yield is high, and purity is high, is easy to industrialization.
Description of drawings
Fig. 1 is the standardized solution liquid chromatogram of Valone and Valone; 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 No. 2 peaks are the chromatographic peak of Valone, and the chromatographic peak of Valone 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 RT is about 7.0min.
The one-level mass spectrum that Fig. 3 obtains with 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/z 229 with 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, carries out chromatographic separation through the adsorption column that is filled with 60～300 order silica gel, and the employing volume ratio is that 60: 40～99: 1 lower member ester and lower alcohol mixed solvent carries out drip washing and wash-out; Fractional Collections; Merge content greater than 98.0% collection liquid, after the drying, directly obtain the high-content Valone of content＞99.0%;
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, using volume ratio is that feeding is filled with in the chromatography column of sorbent material after 50: 50～99: 1 lower member ester and the dissolving of lower alcohol mixed solvent, and 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 TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
3) using the volume ratio of 1～6 times of column volume is 60: 40～80: 20 lower member ester and lower alcohol mixing solutions, in 20～80 ℃ of TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
4) volume ratio of 1～6 times of column volume of use is 80: 20～99: 1 lower member ester and a lower alcohol mixing solutions; In 20～80 ℃ of TRs; With 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation that obtains or oven dry, high-load Valone.
Described lower member ester is a kind of in ETHYLE 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.The Valone raw material with propyl acetate/methyl alcohol (60: 40, v/v) dissolving, its concentration is 10.0mg/mL, last appearance volume is 1000mL, last kind and eluting temperature are 80 ℃.Earlier with the drip washing of 360mL methyl alcohol, use again 1200mL propyl acetate/methyl alcohol (80: 20, v/v) drip washing chromatography column; Use at last 800mL propyl acetate/methyl alcohol (95: 5, v/v) wash-out, flow velocity are 8.0mL/min; Collect the chromatography column elutriant, Fractional Collections stream part is carried 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.The Valone raw material with propyl acetate/ethanol (60: 40, v/v) dissolving, its material concentration is 10.0mg/mL, last appearance volume is 1000mL, last kind and eluting temperature are 80 ℃.Earlier with the drip washing of 350mL ethanol, use again 1100mL ETHYLE ACETATE/ethanol (80: 20, v/v) drip washing chromatography column; Use at last 800mL ETHYLE ACETATE/ethanol (95: 5, v/v) wash-out, flow velocity are 8.0mL/min; Collect the chromatography column elutriant, Fractional Collections stream part is carried 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.The Valone raw material with butylacetate/Virahol (60: 40, v/v) dissolving, its material concentration is 10.0mg/mL, last appearance volume is 1000mL, last kind and eluting temperature are 80 ℃.Earlier with the drip washing of 320mL Virahol, use again 1000mL butylacetate/Virahol (80: 20, v/v) drip washing chromatography column; Use at last 750mL butylacetate/Virahol (95: 5, v/v) wash-out, flow velocity are 8.0mL/min; Collect the chromatography column elutriant, Fractional Collections stream part is carried 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%.
Chromatography column size φ 20 * 400mm.In adorn the about 40g of 200～300 purpose silica gel.The Valone raw material with butylacetate/methyl alcohol (60: 40, v/v) dissolving, its material concentration is 10.0mg/mL, last appearance volume is 1000mL, last kind and eluting temperature are 80 ℃.Earlier with the drip washing of 350mL methyl alcohol, use again 1100mL butylacetate/methyl alcohol (80: 20, v/v) drip washing chromatography column; Use at last 800mL butylacetate/methyl alcohol (95: 5, v/v) wash-out, flow velocity are 8.0mL/min; Collect the chromatography column elutriant, Fractional Collections stream part is carried 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 (2)
1. the column chromatography preparation method of a Valone is characterized in that, may further comprise the steps:
1) with the industrial crude product of Valone, using volume ratio is that feeding is filled with in the chromatography column of sorbent material after 50: 50～99: 1 lower member ester and the dissolving of lower alcohol mixed solvent, and 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 TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
3) using the volume ratio of 1～6 times of column volume is 60: 40～80: 20 lower member ester and lower alcohol mixing solutions, in 20～80 ℃ of TRs, with 0.5～5 times of column volume/hour flow velocity wash-out impurity;
4) volume ratio of 1～6 times of column volume of use is 80: 20～99: 1 lower member ester and a lower alcohol mixing solutions; In 20～80 ℃ of TRs; With 0.5～5 times of column volume/hour flow velocity flushing adsorption column, with elutriant rotary evaporation that obtains or oven dry, Valone;
Wherein, said lower member ester is ETHYLE ACETATE, propyl acetate or ethyl ester butyl ester;
Said lower alcohol is methyl alcohol, ethanol or Virahol.
2. column chromatography preparation method according to claim 1 is characterized in that, said 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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| Application Number | Priority Date | Filing Date | Title |
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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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| CN101434526A CN101434526A (en) | 2009-05-20 |
| CN101434526B true CN101434526B (en) | 2012-05-30 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2983743A (en) * | 1958-11-28 | 1961-05-09 | Galat Alexander | New and improved rodenticides |
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- 2008-12-22 CN CN2008101634403A patent/CN101434526B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2983743A (en) * | 1958-11-28 | 1961-05-09 | Galat Alexander | New and improved rodenticides |
Non-Patent Citations (1)
| Title |
|---|
| Joel E. Houglum et al..High-performance liquid chromatographic separation of indandione rodenticides.《Journal of Chromatography》.1989,第481卷458-460. * |
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