CN1296708C - Double column switching chromatograph preparing device for chira medicine saparation - Google Patents
Double column switching chromatograph preparing device for chira medicine saparation Download PDFInfo
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- CN1296708C CN1296708C CNB011140771A CN01114077A CN1296708C CN 1296708 C CN1296708 C CN 1296708C CN B011140771 A CNB011140771 A CN B011140771A CN 01114077 A CN01114077 A CN 01114077A CN 1296708 C CN1296708 C CN 1296708C
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Abstract
The present invention relates to a chiral medicine separation technology, particularly to a double column switching chromatographic preparation device for chira medicine separation. The device is controlled by a computer and is mainly composed of four chromatographic columns, three electromagnetic valves and a preparation pump, wherein a raw material container to be separated is connected with a pre-column through the preparation pump and a sample introduction electromagnetic valve, a solvent container is connected to the sample introduction electromagnetic valve, the pre-column is connected in series with first and second chiral preparative columns through a switching electromagnetic valve and then connected with a balancing column, and the output end of the balancing column is respectively connected to product collection containers A and B and a solvent recovery container through a UV-detector and a collection electromagnetic valve. The present invention has the advantages of high utilization rate of stationary phase, high separation efficiency, low cost and simple operation.
Description
The present invention relates to the chiral drug isolation technics, specifically a kind of double column switching chromatograph preparing device for chira medicine saparation.
The most frequently used in the world chiral drug enantiomorph method for splitting is that chemical method, enzyme process split and chromatography.Split with chemical method and enzyme process and to compare, chromatography is owing to have recovery height, good reproducibility, advantage such as selectivity is good, simple to operate, cost is low and the development time is short and extremely people's favor.In order to save chipal compounds liquid chromatography preparation cost, the most attractive preparative chromatography technology is a simulated moving bed chromatography, it is together in series 8～12 joint chromatographic columns, with an ebullator separated sample constantly being circulated in post reaches required separation, then it is flowed out with the post position at the fixed time.Compare with general preparative chromatography, can separate difficult separate object, also can save a large amount of moving phase and expensive chiral stationary phase with short chromatographic column.Document 1:J.Strube, S.Haumreisser, H.S.Traub, M.Schulte, R.Ditz, Org.Proc.Res.Dev., 1998,2,305; Document 2:C.B.Ching, B.G.Lim, J.Chromatogr., 1992,634,215; Document 3:M.Schulte, R.Ditz, R.M.Devant, J.N.Kinkel, F.Charton, J.Chromatogr., 1997,769,93; Document 4:E.R.Francotte, P.Richert, J.Chromatogr., 1997,769,101; Document 5:L.S.Pais, J.M.Loureiro, A.E.Rodigues, Chem.Eng.Sci., 1997,52,245; Document 6:D.W.Guest, J.Chromatogr., 1997,760,159, owing to adopt different filler and pillar scale, the amount of the simulated moving bed chromatography separating chiral medicine of reporting in the document is generally several the gram between one or two hectograms every day.When the separating chiral medicine, in order to improve productive rate, sample size is very big usually, and at this moment chromatographic peak can take place serious overlapping.If sample introduction again after this part sample collection concentrated, this needs extra-pay, and lap also has separation to a certain degree simultaneously, and sample introduction can slattern this part and separates again, that is to say can the certain stationary phase of waste utilization factor.The another kind of more preparative chromatography technology of using in chiral drug separates is the recycle chromatogram, and the recycle chromatogram can address this problem, and it enters the sample of lap in the chromatographic column together with new sample introduction separates.Simulated moving bed chromatography and recycle chromatographic resolution sample introduction and extraction point be very similar, and the equipment investment of recycle chromatogram will be far below simulated moving bed chromatography with respect to the position of CONCENTRATION DISTRIBUTION.But, the intermittently operated of recycle chromatogram, the treatment capacity of its separation efficiency, sample and all will be lower than simulated moving bed chromatography to the saving of solvent.
The purpose of this invention is to provide a kind of stationary phase utilization factor height, double column switching chromatograph preparing device for chira medicine saparation that separation efficiency is high.
Technical scheme of the present invention is: computerized control, mainly form by four root chromatogram columns, three solenoid valves, preparation pumps, wherein: material container to be split is connected with pre-column through preparation pump, solenoid valve for sampling, solvent container is received solenoid valve for sampling, pre-column links to each other with balance columns by switching solenoid valve and the first～two chirality preparative column series connection back, the balance columns output terminal through UV-detector, collection solenoid valve respectively to product collection container A, B and solvent recovery container;
Described switching solenoid valve is six three-way electromagnetic valves, and its concrete connected mode is: the pre-column outlet of 1 termination, 2,5 termination chirality preparative column two ends, 3,6 termination chirality preparative column two ends, 4 termination balance columns inlet; Described solenoid valve for sampling and pump and pre-column link, and collect solenoid valve and detecting device and three collection containers and link; Described preparation pump, three solenoid valves and UV-detector are electrically connected with computing machine.
Separation principle of the present invention is:
Large-scale separation is equipped with chiral drug, requires all to want a large amount of sample introductions at every turn, and a large amount of sample introductions can pass through low concentration large volume sample injection and high concentration sample introduction, and are more desirable for the consideration high concentration sample introduction of Optimizing operation.Under this high concentration sample introduction situation, the absorption of sample on stationary phase presents strong non-linear, and chromatographic peak just will overlap simultaneously, and lap can not get separating fully.The lap both sides can obtain separating better, purer component, and the present invention overlaps the part both sides with the sample extraction at chromatographic peak exactly, and at overlap of peaks place sample introduction.Similar in the sample concentration distribution that in column system, produces like this and simulated moving bed chromatography and the cyclical chromatography, and by the sample introduction of twin columns switching device shifter of the present invention and the position of extraction in CONCENTRATION DISTRIBUTION also to simulated moving bed chromatography and cyclical chromatography in also very similar, all be that the part sample introduction at overlap of peaks separates part extraction preferably at two ends.The present invention adopts the twin columns switching construction, and its detachment process is exactly the twin columns handoff procedures, promptly finishes by switching solenoid valve and two chirality preparative columns.Shown in Fig. 2 a, 2b, sample enters a chirality preparative column through switching solenoid valve and separates therein, and when the little component of retention distributed this pillar, switching solenoid valve switched the part that front end will be collected and cuts out system; When front end to collect the part cut out system basically after, switching solenoid valve switches once more, does not just have complete separated portions to switch in another root chirality preparative column cyclic part; After cyclic part entered described another root chirality preparative column fully, switching solenoid valve switches wanted the collection unit branch to cut out system the rear end, and so circulation reaches the stable of operation; Under the smaller situation of sample size, adopt the round-robin way to make it that circulation is equivalent to make column length to increase several times repeatedly to improve degree of separation like this in system and device under the situation that does not improve pressure for the sample of difficult branch; Under the bigger situation of sample size, adopt the method for peak cutting to make not obtain separated portions and in system and device, circulate, can improve the utilization factor of chiral stationary phase like this and improve productive rate.
The present invention has following advantage:
1. stationary phase utilization factor height, the separation efficiency height.Adopt the present invention under the smaller situation of sample size, adopt the round-robin way to make it that circulation is equivalent to make column length to increase several times repeatedly to improve degree of separation like this in system and device under the situation that does not improve pressure for the sample of difficult branch; Under the bigger situation of sample size, adopt the method for peak cutting to make not obtain separated portions and in system and device, circulate, can improve the utilization factor of chiral stationary phase like this and improve productive rate.
2. cost is low, and is simple to operate.The present invention compares with the multicolumn simulated moving bed chromatography, utilize the design of switching solenoid valve and chirality preparative column, realized that twin columns switch separation, its equipment cost has only the latter's about 1/10th, simultaneously because the present invention has considered the problem of solvent recovery, therefore saving relatively simulation moving-bed near multicolumn of the present invention aspect the solvent, also be better than common preparative chromatography.Further, sample only between two posts circulation do not pass through pump once more, its extra column effect is far below the recycle chromatogram, in addition by computer control, the automaticity height such as has and operator scheme is flexible simple to operate at advantage.
Fig. 1 is a structural representation of the present invention.
Fig. 2 a switches one of electric solenoid valves to switch the embodiment connection diagram among Fig. 1.
Fig. 2 b switches another switching of electric solenoid valves embodiment connection diagram among Fig. 1.
Fig. 3 a is twin columns separation principle figure of the present invention (state 1).
Fig. 3 b is twin columns separation principle figure of the present invention (state 2).
Fig. 3 c is twin columns separation principle figure of the present invention (state 3).
Fig. 3 d is twin columns separation principle figure of the present invention (state 4).
Fig. 4 a is Fig. 3 c detachment process concentration profile (beginning).
Fig. 4 b is Fig. 3 c detachment process concentration profile (end).
Fig. 5 a separates neodicoumarin purity analysis figure in the embodiment of the invention, wherein molecule space is configured as S-neodicoumarin (S-Warfarin) enantiomorph.
Fig. 5 b separates neodicoumarin purity analysis figure in the embodiment of the invention, wherein molecule space is configured as R-neodicoumarin (R-Warfarin) enantiomorph.
Below in conjunction with drawings and Examples in detail the present invention is described in detail.
As shown in Figure 1, with computing machine 15 controls, mainly form by four root chromatogram columns, three solenoid valves, preparation pumps, wherein: material container 10 to be split is connected with pre-column 1 through preparation pump 7, solenoid valve for sampling 2, solvent container 9 is received solenoid valve for sampling 2, pre-column 1 links to each other with balance columns 5 with the first～two chirality preparative column, 41,42 series connection backs respectively by switching solenoid valve 3, balance columns 5 output terminals through UV-detector 6, collection solenoid valve 8 respectively to product collection container A11, B12 and solvent recovery container 13; Described switching solenoid valve 3 is six three-way electromagnetic valves; Described solenoid valve for sampling 2 and collection solenoid valve 8 are eight three-way electromagnetic valves; Described preparation pump 7, three solenoid valves and UV-detector 6 are electrically connected with computing machine.
Being used for the chiral drug neodicoumarin separates:
Solvent and sample are got in the system by preparation pump 7, sample at first enters chirality preparative column 41,42 again by pre-column 1, by the circulation in two chirality preparative columns 41,42 that switches in of switching solenoid valve 3, the sample of separator well is collected by collection container A11, B12 through balance columns 5, collection solenoid valve 8.
Through neodicoumarin having been carried out continuous highly purified separation preparation, separate the back enantiomeric purity and can reach more than 97%, the purity analysis of product is seen accompanying drawing 5a, 5b.Compare with common preparative chromatography and can save solvent more than 50%, and can save a large amount of spent energy of sample of handling once more.
Adopt switching solenoid valve 3 to realize that two chirality preparative columns 41,42 switch method of attachment shown in Fig. 2 a, 2b, the six-way valve that on behalf of the present invention, two with one heart circles adopt, its connected mode is: 1 outlet of 1 termination pre-column, 2,5 termination chirality preparative columns, 41 two ends, 3,6 termination chirality preparative columns, 42 two ends, 4 termination balance columns, 5 inlets; With switching solenoid valve 3 two chirality preparative columns are together in series, change the separation sequencing of described two root chromatogram columns by the switching of switching solenoid valve 3; Switching solenoid valve 3 has two positions, and when valve was in as Fig. 2 a position 1, chirality preparative column 41 was preceding, when valve was in as Fig. 2 b position 2, chirality preparative column 42 was preceding, by this switching, the part that can collect cuts out system, will not have divided portion to switch in another root pillar.
Component in the situation of separating in the system shown in Fig. 3 a, 3b, 3c, 3d, wherein: sample enters the first chirality preparative column 41 through six logical switching solenoid valves 3 and is separating in the pillar shown in Fig. 3 a, is state 1; When the little component of retention flowed out this pillar, switching solenoid valve 3 switched, and the part that front end will be collected cuts out system, shown in Fig. 3 b, was state 2; When front end to collect the part cut out system basically after, switching solenoid valve 3 switches once more, with cyclic part, does not just have complete separated portions to switch in the second chirality preparative column 42, shown in Fig. 3 c, is state 3; After cyclic part entered the second chirality preparative column 42 fully, switching solenoid valve 3 switched, and the collection unit branch to cut out system the rear end, shown in Fig. 3 d, is state 4.Wherein: the present invention is sample introduction on two times, i.e. sample introduction in the beginning of state 3 and when finishing respectively.These two kinds of sample introduction positions on CONCENTRATION DISTRIBUTION are shown in Fig. 4 a, 4b, and sample introduction lays respectively at the cyclic part rear and front end of separating part sample not just.
Preparation pump of the present invention 7, three solenoid valves and UV-detector 6 are electrically connected with computing machine 15 through control interface (RS-232 serial port protocol) 14 by pump control plate, control circuit board and data acquisition board respectively, its circuit and programmed control partly are prior art, and UV-detector adopts commercial UV200 ultraviolet variable-wavelenght detector.
Claims (1)
1. double column switching chromatograph preparing device for chira medicine saparation, it is characterized in that: with computing machine (15) control, mainly by four root chromatogram columns, three solenoid valves, the preparation pump is formed, wherein: material container to be split (10) is through preparation pump (7), solenoid valve for sampling (2) is connected with pre-column (1), solvent container (9) is received solenoid valve for sampling (2), pre-column (1) is by the switching solenoid valve (3) and the first～two chirality preparative column (41,42) the series connection back links to each other with balance columns (5), and balance columns (5) output terminal is through UV-detector (6), collect solenoid valve (8) respectively to product collection container A, B (11,12) and solvent recovery container (13);
Described switching solenoid valve (3) is six three-way electromagnetic valves, and its concrete connected mode is: the outlet of 1 termination pre-column (1), 2,5 terminations, first chirality preparative column (41) two ends, 3,6 terminations, second chirality preparative column (42) two ends, 4 termination balance columns (5) inlet; Preparation pump (7), three solenoid valves and UV-detector (6) are electrically connected with computing machine (15).
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| Application Number | Priority Date | Filing Date | Title |
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| CNB011140771A CN1296708C (en) | 2001-06-15 | 2001-06-15 | Double column switching chromatograph preparing device for chira medicine saparation |
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| CNB011140771A CN1296708C (en) | 2001-06-15 | 2001-06-15 | Double column switching chromatograph preparing device for chira medicine saparation |
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| CN1296708C true CN1296708C (en) | 2007-01-24 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101271094B (en) * | 2008-05-15 | 2011-06-01 | 宁波科宁达工业有限公司 | Zwitterion analysis system of ion chromatographic instrument |
| CN102441294A (en) * | 2010-09-30 | 2012-05-09 | 中国科学院昆明植物研究所 | Separation and preparation chromatograph containing series static axial compression (SAC) preparative chromatographic columns |
| JP6331485B2 (en) * | 2014-03-04 | 2018-05-30 | 株式会社島津製作所 | Liquid chromatograph and liquid chromatographic analysis method |
| WO2019186469A1 (en) * | 2018-03-29 | 2019-10-03 | Waters Technologies Corporation | Automated two-column recycling chromatography method for unlocking challenging separation problems |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1227210A (en) * | 1998-02-24 | 1999-09-01 | 财团法人生物技术开发中心 | Liquid phase chromatography device and method for separating optical isomeric compound |
| US6004518A (en) * | 1997-12-12 | 1999-12-21 | Uop Llc | High-purity simulated moving bed adsorptive separation apparatus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6004518A (en) * | 1997-12-12 | 1999-12-21 | Uop Llc | High-purity simulated moving bed adsorptive separation apparatus |
| CN1227210A (en) * | 1998-02-24 | 1999-09-01 | 财团法人生物技术开发中心 | Liquid phase chromatography device and method for separating optical isomeric compound |
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