CN1683368A - Simulated moving bed chromatography separating method of omeprazole antimer - Google Patents
Simulated moving bed chromatography separating method of omeprazole antimer Download PDFInfo
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- CN1683368A CN1683368A CN 200510049387 CN200510049387A CN1683368A CN 1683368 A CN1683368 A CN 1683368A CN 200510049387 CN200510049387 CN 200510049387 CN 200510049387 A CN200510049387 A CN 200510049387A CN 1683368 A CN1683368 A CN 1683368A
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Abstract
The present invention discloses the chromatographic separation process of omeprazole antimer in simulated mobile bed. In a simulated mobile bed chromatographic system with chiral fixed phase of cellulose triphenyl carbomate and flow phase of the mixture of ethanol, n-hexane and diethylamine, mixture of R-(+)-omeprazole and S-(-)-omeprazole is separated to obtain high purity S-(-)-omeprazole. Said separation process is a continuous process, so that the present invention has high automation, high production efficiency, low solvent consumption and no toxic solvent.
Description
Technical field
The present invention relates to the disassemble technique of chiral drug, especially, relate to a kind of simulated moving bed chromatographic separation process of omeprazole enantiomer.
Background technology
Omeprazole (omeprazole); it is 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline; English chemistry 5-methoxy-2-[[(4-methoxy-3 by name; 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, molecular structural formula is:
Be synthetic by Sweden Haessel company, a kind of novel proton pump inhibitor (the Propton pump inhibitors that Sweden Astra company produces, PPIs) class anti-ulcerative drug, be used for the treatment of duodenal ulcer, stomach ulcer and anti-popular esophagitis, and can eliminate the intractable ulcer phenomenon, also very effective to Zhuo-Emhorn syndromes, and untoward reaction is few.Become the situation of selling well medicine of the whole world single medicine annual sales amount maximum at present.
Omeprazole antiulcer agent mechanism is different from histamine H
2-receptor antagonist class medicine, as western miaow for sting with the thunder Buddhist nun for stining.It is a kind of monoalkoxy pyridine compounds, with H
+/ K
+-adenosine triphosphatase (H
+/ K
+-ATPase) two combining sites being arranged, alternative, noncompetitive ground suppresses the H in the parietal cell film
+/ K
+-ATPase and produce antiulcer action, it is strong that it presses down the acid effect, the specificity height, the time length is permanent.The omeprazole molecule connects pyridine ring by benzoglyoxaline by sulfoxide group and forms, and includes chiral sulfur atom, has enantiomerism, and the administration curative effect of S-(-)-omeprazole is better than the raceme form administration.Astra company has released S-(-)-type omeprazole optical purity enantiomorph (medication name Preprazole, Perprazole).
At present, the synthetic method of racemic omeprazole is very ripe, and has dropped into large-scale commercial production.But difficulty is still compared in the preparation of optically pure omeprazole, and people have developed multiple preparation and method for splitting.For example, patent WO9617077 adopts the micro-reduction method, optionally R-(+)-omeprazole is reduced to omeprazole prochirality compound, obtains the ee value and reaches S-(-)-omeprazole of 99%.Because microbially stable is poor, can only near the neutral dilute aqueous soln, carry out, the purification of products difficulty that this method obtains, aftertreatment is loaded down with trivial details, and throughput is low.Patent DE403455 and WO9427988 with the omeprazole raceme through nitrogen for derivative reaction, make a pair of diastereomer, hydrolysis obtains optically pure omeprazole again after separating.This method need be passed through two-step reaction, and split process is quite loaded down with trivial details.Patent WO9602535 adopts improved Sharpless asymmetric oxidation method, with the chiral oxidization agent under alkaline condition in organic solvent asymmetric oxidation omeprazole prochirality compound, can make omeprazole with certain ee value.But the yield and the purity of product are on the low side, and yield has only 40%, ee value only 87%.The crude product of existing certain ee value that WO9702261 will obtain from asymmetric oxidation style is dissolved in acetonitrile, sec-butyl alcohol, the acetone equal solvent, and recrystallization can obtain S-(-)-omeprazole of ee value very high (＞95).This method requires the existing certain optical purity of raw material, as with the coupling of asymmetric oxidation method, no doubt can improve product purity, but will make whole process more complicated, running cost improves, productive rate is further reduction then.CN1223262 adopts the inclusion Split Method, with chipal compounds such as binaphthol compounds, di-phenanthrol or tartaric acid derivatives as the inclusion main body, be dissolved in the mixed solvent (as toluene/normal hexane) with racemic omeprazole, inclusion main selectivity ground and S-(-)-omeprazole (or R-(+)-omeprazole) form the inclusion complex compound, and separate out with crystallized form, another kind of enantiomorph is then stayed in the solvent, after the filtration inclusion main body is separated with S-(-)-omeprazole (or R-(+)-omeprazole), can make two kinds of enantiomorphs of omeprazole.S-(-)-omeprazole total recovery can reach 88%, and ee is 100%.This method is the same with patent DE403455 reported method, also needs the operation of two steps, and requires chiral reagent, needs to use a large amount of noxious solvents.The WO0351867 play-by-play adopt simulated moving bed chromatography to separate the novel process of omeprazole enantiomer.This technology is made chiral stationary phase with amylose starch-[three (S)-methyl phenyl carbamates], makes moving phase with ethanol, obtains S-(-)-omeprazole with simulated moving bed chromatography from the mixture separation of omeprazole two enantiomorphs.The preparation raw material of the chiral stationary phase (amylose starch-[three (S)-methyl phenyl carbamates]) that this method is used is not easy to obtain, and the commodity stationary phase costs an arm and a leg, and makes production cost higher.
Summary of the invention
The objective of the invention is to provides at the deficiencies in the prior art-simulated moving bed chromatographic separation process of kind of omeprazole enantiomer.
The technical scheme that the present invention adopts for achieving the above object is as follows: a kind of simulated moving bed chromatographic separation process of omeprazole enantiomer, it is characterized in that, with the chiral stationary phase that contains the cellulose iii phenylcarbamate phase that fixes, mixture with ethanol, normal hexane, diethylamine is made moving phase, isolates S-(-)-omeprazole with simulated moving bed chromatography system from the mixture of R-(+)-omeprazole and S-(-)-omeprazole.
Further, may further comprise the steps:
(1) mixture of R-(+)-omeprazole and S-(-)-omeprazole is dissolved in moving phase, and concentration is 1mg/mL～100mg/mL:
(2) from simulated moving bed chromatography system, isolate S-(-)-omeprazole solution;
(3) concentrate, recrystallization, filtration, drying obtain high-purity S-(-)-omeprazole crystal.
The present invention has following technique effect: the present invention's simulated moving bed chromatography makes optically pure S-(-)-omeprazole from the mixture separation of R-(+)-omeprazole and S-(-)-omeprazole.Technology is simple, produces continuously constant product quality.The technology greenization, whole production technology does not relate to toxic chemical substance, and solvent adopts ethanol, and recyclable applying mechanically is pollution-free, has really realized cleaner production.
Description of drawings
Fig. 1 is a simulated moving bed chromatography system structure iron of the present invention.
Embodiment
Describe the present invention below in detail.
1. adopt simulated moving bed chromatography (being called for short SMBC) system, this system comprises sampling pump, wash-out liquid pump, extraction pump, raffinate pump and recycle pump, rotary valve and chromatographic column.As shown in Figure 1, Arabic numerals are the chromatographic column numbering, sample solution and elutriant inject chromatographic system from sample liquid inlet and elutriant inlet respectively, and two enantiomorphs of omeprazole are then respectively from raffinate and two outlets of extraction liquid outflow system (as Fig. 1 solid arrow indication position).At regular intervals, sample liquid and elutriant inlet, extraction liquid and raffinate outlet switch to next root chromatogram column outlet (as Fig. 1 dotted arrow indication position) along the moving phase flow direction simultaneously.Service temperature is 20～60 ℃, and optimum temperature range is 20～30 ℃.
2. chromatographic column filler and moving phase are selected
Filler is a cellulose iii phenylcarbamate coating-type chiral stationary phase, adopts known method (Okamoto Y, Kawashima M, Hatada K J.Chromatogr.1986,363:173～186) preparation.Packing material size 1～150 μ m, particle diameter is more little, and size distribution is narrow more, helps more separating; But particle diameter reduces the increase post is pressed, and simulated moving bed system is had relatively high expectations.Optimum particle size range is 20～40 μ m.The chemical structure of cellulose iii phenylcarbamate is as follows:
The weight ratio 0.1～1: 0.1～1 of cellulose iii phenylcarbamate and aminopropyl silica gel wherein, optimum weight ratio is 1: 4.Moving phase (solvent) is the mixture of ethanol, normal hexane, diethylamine, volume ratio: 0～100: 0～100: 0～100, and optimum volume ratio is 100: 0: 0.5.
3. separating step
The mixture of R-(+)-omeprazole and S-(-)-omeprazole is dissolved in moving phase, and concentration is 1mg/mL～100mg/mL.The increase of sample introduction concentration helps improving productive rate, but its concentration is subjected to the solubility limit of omeprazole.Chromatographic system is made up of 4～24 chirality preparative columns, and the pillar number is many more, and separating effect is good more, but the complexity of system also improves, and only pillar number is 8～16.Sample solution and elutriant inject chromatographic system from injection port and elutriant inlet successively.Separate through simulated moving bed chromatography, can obtain high-purity R-(-)-omeprazole solution, then obtain high-purity S-(-)-omeprazole solution from the raffinate outlet from the extraction liquid outlet.The S-(-) that obtains-omeprazole solution obtains high-purity S-(-)-omeprazole through concentrated, recrystallization, filtration, drying; The then row separation again after racemization reaction obtains the omeprazole raceme of the R-(+) that obtains-omeprazole solution.
4. inspection after construction
Moving phase: ethanol
Flow velocity: 0.8ml/min
Pump: Knauer K501 pump
Chromatographic column: 4.6 * 250mm, 10 μ m, Chiralpak AD filler
Detector: Knauer K2501 UV-detector
Detect wavelength: 254nm
Further specify the present invention below in conjunction with embodiment.
1. tie up the preparation of plain triphenyl carbamate coating-type chiral stationary phase
Prepare according to literature method (Okamoto Y, Kawashima M, Hatada K J.Chromatogr.1986,363:173～186).Silica gel Mierocrystalline cellulose and different hydracid phenyl ester react 24h down at 100 ℃ in pyridine solution.The methyl alcohol insolubles that reaction obtains is the cellulose iii phenylcarbamate.The cellulose iii phenylcarbamate is dissolved in tetrahydrofuran (THF), and aminopropyl silica gel is dispersed in the solution, obtains cellulose iii phenylcarbamate coating-type chiral stationary phase after removing out tetrahydrofuran (THF) under reduced pressure.Wherein the weight ratio of cellulose iii phenylcarbamate and aminopropyl silica gel is 1: 4.Two kinds of aminopropyl silica gel have been used: aminopropyl silica gel A particle diameter 10 μ m, aperture 100nm, aminopropyl silica gel B particle diameter 20～40 μ m, aperture 80nm.Homogenate method dress post fills in based on the chiral stationary phase of aminopropyl silica gel A and to analyze chromatographic column and (in 4.6 * 200mm), fill in the preparative chromatography post based on the chiral stationary phase of aminopropyl silica gel B.
2. the selection of moving phase
In the moving phase, content influence omeprazole two Separation of Enantiomers of ethanol, normal hexane and diethylamine, and then influence the separation costs of simulated moving bed chromatography.At first (4.6 * 200mm) select moving phase with analyzing chromatographic column.As table 1, the retention time of omeprazole two enantiomorphs reduces with the increase of ethanol and diethylamine content, but separation factor changes not quite.It is better to select for use straight alcohol to make the moving phase effect.At first, the solute retention time is short, and solvent that simulation moving-bed sepn process consumes also will decrease; The second, the solubleness of omeprazole increases with ethanol content, uses straight alcohol to help the raising of sample introduction concentration; The 3rd, there is not the dissolvent residual problem in the straight alcohol safety non-toxic.Fine because of omeprazole stability under alkaline condition, thereby a small amount of diethylamine of interpolation will help improving the stability of omeprazole in the moving phase.
The selection of table 1 moving phase
| Moving phase (ethanol/normal hexane/diethylamine, V/V/V) | Retention time | Separation factor (α) | |
| ??t S?????????t R | |||
| ??20/80/0 | ??27.83 | ??40.56 | ????1.49 |
| ??40/60/0 | ??12.32 | ??17.48 | ????1.51 |
| ??60/40/0 | ??7.79 | ??10.69 | ????1.51 |
| ??80/20/0 | ??5.75 | ??7.48 | ????1.49 |
| ??100/0/0 | ??4.89 | ??6.05 | ????1.44 |
| ??80/20/0.1 | ??5.00 | ??6.36 | ????1.47 |
| ??80/20/0.2 | ??4.73 | ??6.03 | ????1.50 |
| ??80/20/0.3 | ??4.33 | ??5.35 | ????1.46 |
| ??80/20/0.4 | ??3.98 | ??4.91 | ????1.50 |
3.SMBC separate
Below list two separate instance.
A, operational condition
Moving phase: straight alcohol
Sample introduction concentration: racemic omeprazole concentration 20mg/ml
Sample introduction flow velocity: U
F=5ml/min
Eluent flow rate: U
E=23.5ml/min
Raffinate flow velocity: U
R=10ml/min
Extraction liquid flow velocity: U
X=18.5ml/min
Switching time: t
S=0.89min
B, check analysis
Analyze raffinate and extraction liquid composition with the ChiralpakAD post.S-(-) in the raffinate-omeprazole purity is 99.48, and R-(+) in the extraction liquid-omeprazole purity is 98.65%.The per kilogram stationary phase can be produced S-(-)-omeprazole and each 1.3kg of R-(+)-omeprazole every day, and moving phase consumption is 0.578m
3/ Kg, the rate of recovery of S-(-)-omeprazole is 98.64%.
A, operational condition
Moving phase: straight alcohol/diethylamine (100/1)
Sample introduction concentration: racemic omeprazole concentration 40mg/ml
Sample introduction flow velocity: U
F=4ml/min
Eluent flow rate: U
E=11.2ml/min
Raffinate flow velocity: U
R=5.4ml/min
Extraction liquid flow velocity: U
X=9.8ml/min
Switching time: t
s=1.04min
B, check analysis
Analyze raffinate and extraction liquid composition with the ChiralpakAD post.S-(-) in the raffinate-omeprazole purity is 98.84, and R-(+) in the extraction liquid-omeprazole purity is 99.45%.The per kilogram stationary phase can be produced S-(-)-omeprazole 2.1kg every day, and moving phase consumption is 0.25m
3/ Kg, the rate of recovery of S-(-)-omeprazole is 99.45%.
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 (5)
1. the simulated moving bed chromatographic separation process of an omeprazole enantiomer, it is characterized in that, with the chiral stationary phase that contains the cellulose iii phenylcarbamate phase that fixes, mixture with ethanol, normal hexane, diethylamine is made moving phase, isolates S-(-)-omeprazole with simulated moving bed chromatography system from the mixture of R-(+)-omeprazole and S-(-)-omeprazole.
2. according to the simulated moving bed chromatographic separation process of claim 1 described omeprazole enantiomer, it is characterized in that, may further comprise the steps:
(1) mixture with R-(+)-omeprazole and S-(-)-omeprazole is dissolved in moving phase, and concentration is 1mg/mL～100mg/mL.
(2) from simulated moving bed chromatography system, isolate S-(-)-omeprazole solution.
(3) concentrate, recrystallization, filtration, drying obtain high-purity S-(-)-omeprazole crystal.
3. according to the simulated moving bed chromatographic separation process of claim 1 described omeprazole enantiomer, it is characterized in that the volume ratio of ethanol, normal hexane, diethylamine is 0～100: 0～100 in the described moving phase: 0～100.
4. according to the simulated moving bed chromatographic separation process of claim 1 described omeprazole enantiomer, it is characterized in that the service temperature of described simulated moving bed chromatography system is 20～60 ℃.
5. according to the simulated moving bed chromatographic separation process of claim 4 described omeprazole enantiomers, it is characterized in that the optimum service temperature of the service temperature of described simulated moving bed chromatography system is 20～30 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801549A (en) * | 2016-05-13 | 2016-07-27 | 温州大学 | Simulated moving bed chromatography separation method of naringenin antipode |
| CN106390519A (en) * | 2016-09-12 | 2017-02-15 | 华东理工大学 | Method for continuously separating aminoglutethimide racemate through multi-column simulated moving bed chromatography technology |
| CN106928190A (en) * | 2015-12-29 | 2017-07-07 | 中美华世通生物医药科技（武汉）有限公司 | The method that Lansoprazole is prepared using SMBC separation |
| CN112666304A (en) * | 2019-10-15 | 2021-04-16 | 扬子江药业集团有限公司 | Method for detecting enantiomer in esomeprazole sodium medicine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0104295D0 (en) * | 2001-12-18 | 2001-12-18 | Astrazeneca Ab | New process |
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2005
- 2005-03-17 CN CNB2005100493870A patent/CN100348595C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928190A (en) * | 2015-12-29 | 2017-07-07 | 中美华世通生物医药科技（武汉）有限公司 | The method that Lansoprazole is prepared using SMBC separation |
| CN105801549A (en) * | 2016-05-13 | 2016-07-27 | 温州大学 | Simulated moving bed chromatography separation method of naringenin antipode |
| CN106390519A (en) * | 2016-09-12 | 2017-02-15 | 华东理工大学 | Method for continuously separating aminoglutethimide racemate through multi-column simulated moving bed chromatography technology |
| CN112666304A (en) * | 2019-10-15 | 2021-04-16 | 扬子江药业集团有限公司 | Method for detecting enantiomer in esomeprazole sodium medicine |
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