CN1258003A - Liquid-phase chromatographic method for separating antimer of trimebutine - Google Patents
Liquid-phase chromatographic method for separating antimer of trimebutine Download PDFInfo
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- CN1258003A CN1258003A CN 99126584 CN99126584A CN1258003A CN 1258003 A CN1258003 A CN 1258003A CN 99126584 CN99126584 CN 99126584 CN 99126584 A CN99126584 A CN 99126584A CN 1258003 A CN1258003 A CN 1258003A
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- trimebutine
- enantiomorph
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- normal hexane
- silica gel
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Abstract
A liquid-phase chromatographic separation method for the antimer of trimebutine includes applying cellulose tri(4-methylbenzoate (15 mass%) on the supporter of macroporous silica gel, preparing chiral filler, filling liquid-phase chromatographic column by wet method and direct separation. Its eluent is n-hexane/isopropanol (V/V). Its advantages are low cost of supporter and high effect.
Description
The present invention is a kind of liquid chromatography drug enantiomer separation method.Specifically, the present invention has narrated a kind of method for separating liquid phase chromatography of trimebutine enantiomorph.
Trimebutine has another name called trimebutine, is to eliminate the twin medicine of convulsion, is used by people in the mode of raceme at present.Structural formula is as shown below.This medicine has a significant curative effect to stomach, intestines, colon convulsion are twin.From the structural formula of Trimebutine as can be known, contain a unsymmetrical carbon, thereby Trimebutine has a pair of enantiomorph, but physiologically active, toxicity, the pharmacological kinetics of enantiomorph yet there are no report about pure (R) with (S).
Foreign patent has been applied for the method for separating liquid phase chromatography (JP05 of trimebutine enantiomorph at present, 215,736), chiral column is coating three (4-methyl benzoic acid) cellulose esters chiral column (250 * 4.6mmI.D), the carrier of column packing is particle mean size 10 μ m, specific surface area 20m
2The macropore silica bead of/g; Eluent is the HClO of 0.1M
4-NaClO
4And CH
3CN (80/20, V/V).
The method for separating liquid phase chromatography that the objective of the invention is to overcome the deficiencies in the prior art and a kind of trimebutine enantiomorph is provided.
Purpose of the present invention realizes by following measure:
The used chirality padding carrier of the present invention is a macro porous silica gel, particle mean size 6 μ m, average pore size 15nm, specific surface area 67.2m
2/ g, through the silanization pre-service, results of elemental analyses: C1.56%-2.30%, H0.28%-0.42%, N0.21%-0.39%.Chirality padding is a coating-type, and the chiral reagent of coating is three (4-methyl benzoic acid) cellulose esters, and coating amount is 15% (quality), and the solvent that adopts during coating is HCCl
3, in wet chirality padding, adding normal hexane then, bath temperature slowly steams down and removes normal hexane, can make three (4-methyl benzoic acid) cellulose esters even in silica gel carrier surface distributed like this, has chromatogram Chiral Separation ability.Wet method dress post adopts phenixin-dioxane (v/v) to make suspending liquid, and normal hexane is made displacement fluid.
Liquid chromatography of the present invention is separated on the HP1090 high performance liquid chromatograph carries out, and used eluent is normal hexane/isopropyl alcohol (v/v), and flow velocity is 1.0mL/min, each 20 μ L sample sizes.The volume ratio of normal hexane/isopropyl alcohol (v/v) is 98: 2～90: 10.
The preparation and the chromatographic resolution of chiral column of the present invention are achieved in that
The macro porous silica gel that the present invention is used, particle mean size 6 μ m, average pore size 15nm, specific surface area 67.2m
2/ g, through the silanization pre-service, results of elemental analyses: C1.56%-2.30%, H0.28%-0.42%, N0.21%-0.39%.
Chiral column of the present invention is a coating-type, and the chiral reagent of coating is three (4-methyl benzoic acid) cellulose esters, and coating process divided for three steps carried out.Add methenyl choloride in silanized silica gel, electromagnetic agitation is steamed on Rotary Evaporators and is removed methenyl choloride.Three (4-methyl benzoic acid) cellulose esters is dissolved in the methenyl choloride standing over night.Get this solution and add in the above-mentioned silanized silica gel, electromagnetic agitation is steamed on Rotary Evaporators and is removed methenyl choloride.Repeat said process once.Three (4-methyl benzoic acid) cellulose ester solution with remainder is added in the silanized silica gel that applies secondary electromagnetic agitation at last.This silanized silica gel is added in the normal hexane, electromagnetic agitation, bath temperature slowly steams down and removes normal hexane, and suction filtration washs successively with normal hexane and isopropyl alcohol, drains, the stationary phase vacuum drying that makes.Wet method dress post adopts phenixin/dioxane (v/v) to make suspending liquid, and normal hexane is made displacement fluid.
Liquid chromatography of the present invention is separated on the HP1090 high performance liquid chromatograph carries out, and is furnished with transistor secondary array detector and data processing work station, and all-wave is long to be detected.
The characteristics of the method for separating liquid phase chromatography of trimebutine enantiomorph of the present invention are as follows: use coating three (4-methyl benzoic acid) cellulose esters chiral column 1..The chromatogram carrier is a macro porous silica gel, particle mean size 6 μ m, average pore size 15nm, specific surface area 67.2m
2/ g.Results of elemental analyses after the aminopropyltriethoxywerene werene pre-service: C1.56%-2.30%, H0.28%-0.42%, N0.21%-0.39%, specific surface area 41-56m
2The coating amount 15% (wt) of/g. three (4-methyl benzoic acid) cellulose esters.2. eluent is normal hexane/isopropyl alcohol (v/v).Isopropanol content has bigger influence at chromatographic resolution enantiomorph aspect of performance in the eluent, and isopropanol content increases, and degree of separation reduces gradually.Column temperature is bigger to the degree of separation influence of chromatogram enantiomer separation.Along with the rising gradually of temperature, the retention time and the degree of separation of enantiomorph reduce gradually.
The preparation of embodiment 1. high performance liquid chromatography chiral columns: add the 20mL methenyl choloride in the 5g silanized silica gel, electromagnetic agitation 15min steams on Rotary Evaporators and removes methenyl choloride.0.882g three (4-methyl benzoic acid) cellulose esters is dissolved in the 23mL methenyl choloride standing over night.Get this solution 8mL and add in the above-mentioned silanized silica gel, electromagnetic agitation 15min steams on Rotary Evaporators and removes methenyl choloride repetition said process once.At last 7mL solution is added in the silanized silica gel that applies secondary electromagnetic agitation 15min.This silanized silica gel is added in the 50mL normal hexane, and electromagnetic agitation 20min, bath temperature slowly steam down and remove normal hexane, and suction filtration washs successively with normal hexane and isopropyl alcohol, drains, and the stationary phase that makes is at 70 ℃, P
2O
5There is vacuum drying 10h down.Wet method dress post (250mm * 4.6mmI.D.), adopt 1: 2 phenixin/dioxane (v/v) make suspending liquid, normal hexane is made displacement fluid.
Sample Trimebutine enantiomorph is dissolved in 90: 10 normal hexane/isopropyl alcohol (v/v), and eluent flow rate is 1.0mL/min, each 20 μ L sample sizes.With 90: 10 normal hexane/isopropyl alcohols (v/v) of eluent balance chromatographic column 30min.1.3.5-tri-butyl benzene is used to measure the dead time.
Column temperature is 24.9,30.0, and the chromatographic resolution result of Trimebutine enantiomorph is as shown in table 1 in the time of 35.0,40.0 and 45 ℃.As seen from Table 1, along with column temperature is elevated to 45.0 ℃ from 24.9 ℃, the capacity factor measure and the separation factor of enantiomorph reduce gradually; Degree of separation changes in 24.9 ℃～30.0 ℃ scopes not quite; In 30.0 ℃～45.0 ℃ scopes, reduce; When 24.9 ℃ of column temperatures, degree of separation Rs=1.02.Therefore, the rising column temperature is unfavorable for Separation of Enantiomers.
When table 1 column temperature changes, the capacity factor measure of Trimebutine enantiomorph, separation factor, degree of separation column temperature (℃) 24.9 30.0 35.0 40.0 45.0
k
1′ 3.31 2.98 2.38 1.99 1.63
k
2′ 4.52 4.00 3.11 2.55 2.06
α 1.37 1.35 1.31 1.28 1.26
Rs 1.02 1.01 1.02 0.99 0.91
In the table: k
1', the capacity factor measure of first wash-out enantiomorph; k
2', the capacity factor measure of back wash-out enantiomorph;
α, separation factor; Rs, degree of separation.
The preparation of embodiment 2 high performance liquid chromatography chiral columns and the mensuration in dead time such as embodiment 1.Sample Trimebutine enantiomorph is dissolved in eluent 90: 10 normal hexane/isopropyl alcohol (v/v), and eluent flow rate is 1.0mL/min, each 20 μ L sample sizes.With 90: 10 normal hexane/isopropyl alcohols (v/v) of eluent balance chromatographic column 30min.Temperature is a room temperature.
Change isopropanol content in eluent normal hexane/isopropyl alcohol (v/v), the result such as the table 2 of the capacity factor measure of chromatographic resolution Trimebutine enantiomorph, separation factor, degree of separation.As seen from Table 2, along with isopropanol content in the eluent is increased to 12% from 4%, the capacity factor measure of Trimebutine enantiomorph reduces gradually, and separation factor changes little, and degree of separation reduces gradually.Therefore, isopropanol content was at 4% o'clock in the eluent, and Separation of Enantiomers degree maximum is respectively Rs=1.14 and α=1.41.In table 2 eluent isopropanol content difference constantly, the capacity factor measure of Trimebutine enantiomorph, separation factor,
Degree of separation isopropyl alcohol (%) (v/v) 468 10 12
k
1′ 4.35 3.31 2.76 2.42 2.15
k
2′ 6.10 4.52 3.74 3.25 2.88
α 1.41 1.37 1.35 1.35 1.34
Rs 1.14 1.02 0.89 0.86 0.80
In the table: k
1', k
2', α, Rs is referring to table 1.
Claims (2)
1. the method for separating liquid phase chromatography of a trimebutine enantiomorph, it is characterized in that applying 15% (quality) three (4-methyl benzoic acid) cellulose esters on the macro porous silica gel carrier, the preparation chirality padding, wet method filling liquid-phase chromatographic column directly separates the Trimebutine enantiomorph; Eluent is normal hexane/isopropyl alcohol (v/v); Macro porous silica gel particle mean size 6 μ m wherein, average pore size 15nm, specific surface area 67.2m
2/ g, ultimate analysis after the aminopropyltriethoxywerene werene pre-service: C1.56%-2.30%, H0.28%-0.42%, N0.21%-0.39%.
2. chromatogram drug enantiomer separation method as claimed in claim 1 is characterized in that eluent is that the volume ratio of normal hexane/isopropyl alcohol is 98: 2～90: 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99126584 CN1258003A (en) | 1999-12-18 | 1999-12-18 | Liquid-phase chromatographic method for separating antimer of trimebutine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99126584 CN1258003A (en) | 1999-12-18 | 1999-12-18 | Liquid-phase chromatographic method for separating antimer of trimebutine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100339707C (en) * | 2005-02-01 | 2007-09-26 | 南京圣和药业有限公司 | Method of detecting ornidazole optical antipode by high efficient liquid chromatography |
| US7540184B2 (en) | 2004-12-15 | 2009-06-02 | Seiko Epson Corporation | Analyzing method for coloring material composition |
-
1999
- 1999-12-18 CN CN 99126584 patent/CN1258003A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7540184B2 (en) | 2004-12-15 | 2009-06-02 | Seiko Epson Corporation | Analyzing method for coloring material composition |
| CN100339707C (en) * | 2005-02-01 | 2007-09-26 | 南京圣和药业有限公司 | Method of detecting ornidazole optical antipode by high efficient liquid chromatography |
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