CN1698925A - Chromatogram arrangement of supercritical fluid imitation moving bed with four subareas - Google Patents
Chromatogram arrangement of supercritical fluid imitation moving bed with four subareas Download PDFInfo
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Abstract
This invention discloses a quartering color spectrum device, which comprises 4~48 filling columns, wherein the exit end of the front column is connected with the entrance end of next rear column through the voltage regulator, and the exit end of the last column is connected with the entrance end of the first column; the entrance end of each column is connected with the mobile phase inlet orifice and the injection port, while the exit end of each column is connected with the extraction pipe, relict pipe and the mobile phase outlet orifice; the exit end of the extraction pipe, relict pipe and the mobile phase outlet orifice are connected with the cyclonic separator individually; the mobile phase is the supercritical fluid. The device can apply pressure gradient operator schema and the modifier gradient operator schema. Meanwhile, it uses the supercritical carbon dioxide fluid as the mobile phase, and uses the chirality fixed phase as the filler of the filling column.
Description
Technical field
The present invention relates to include the preparing chromatograph in industry separator of handling supercritical fluid with adsorbent, relate in particular to a kind of supercritical fluid simulated movable bed chromatography device that is used for four subregions of resolving chiral medicine racemic modification.
Background technology
Food and Drug Administration (FDA) has issued the chiral drug guideline in March, 1992, has proposed to develop the strategy of the littler single enantiomer medicine of toxic and side effect.Therefore, the racemic modification chiral drug is developed into the single enantiomer medicine of high added value, become the key subjects that global pharmaceutical industry can not be avoided and need to be resolved hurrily.
In recent years, along with the development and the suitable commercialization for preparing the chiral stationary phase of usefulness of preparative chromatography technology, preparative liquid chromatography is that new way has been opened up in the acquisition of single enantiomer medicine.The medicine scholar adopts preparative liquid chromatography to separate preparation chiral drug enantiomer on a small scale usually in the laboratory, to satisfy the needs that carry out biological activity test, toxicity research and clinical testing with pure enantiomer.But preparative liquid chromatography exist fixedly the phase utilization rate low, flow the phase consumption greatly, intermittently operated, separation costs height, shortcoming such as seriously polluted, hindered its further application in industrial production.
Preparation type supercritical fluid chromatography be owing to can remedy the preparative liquid chromatography problems such as the phase consumption is big, seriously polluted that flow effectively, emerged many compelling achievements at aspects such as the analysis of chiral drug and preparations.Supercritical fluid chromatography be adopt near or the high-pressure fluid that surpasses critical-temperature (TC) and critical pressure (PC) as mobile chromatographic separation technology mutually, be to put forward at first, but people begin more and more to pay attention to its application aspect the preparation separation now as a kind of novel chromatography means.Carbon dioxide because have that colourless, tasteless, nontoxic, nonflammable explosive, chemical property is stable, moderate (TC=31.06 ℃ PC=7.376MPa), environmental friendliness, cheap advantage such as be easy to get, is the most frequently used mobile phase of supercritical fluid chromatography to critical condition.Be non-polar fluid, be unfavorable for the deficiency of separating polar compound at carbon dioxide, by add have on a small quantity strong polarity and good with the carbon dioxide intersolubility, under operating condition stable modifier such as ethanol, just can significantly improve the solvability of the relative polarity sample that flows, enlarge the scope of application of carbon dioxide sample; Simultaneously, because can also reducing, modifier has the activity of the activated centre point of strong adsorption capacity in the chiral stationary phase, so even a spot of modifier also can obviously improve the eluting power of mobile phase.Supercritical fluid chromatography outlet flow mutually in not only contain supercritical carbon dioxide fluid but also contain separated material, as long as reduce pressure or rising temperature, both are separated fully, do not relate to operating processes such as the evaporation of a large amount of organic solvents and recovery, thereby significantly reduce to the pollution of environment with to operating personnel's murder by poisoning.But because preparation type supercritical fluid chromatography generally adopts andnon-continuous operation manner, the weakness that fixedly the phase utilization rate is on the low side, separation costs is higher still exists, and has hindered its application in industrial production.
Fixedly the phase utilization rate is low in order to solve preparative liquid chromatography, intermittently operated, shortcomings such as separation costs height, people will be at petrochemical industry and the field of food simulation moving-bed Design of device thought of large-scale liquid phase of successful Application, combine with the preparative liquid chromatography isolation technics, invented and possessed fixedly phase utilization rate height, continued operation, the liquid phase SMBC of advantages such as separation costs is low, and obtaining successful application aspect the extensive fractionation of chiral drug, as American UOP, Japan Daicel Chemical, companies such as Belgium UCB Pharma have built up the liquid phase SMBC commercial plant of tonne scale in succession and have produced the single enantiomer chiral drug, but for the needs that maintain the competitiveness, each big drugmaker is all holded in close confidence correlation technique and data.People such as the Japan Daicel Chemical Nagamatsu of company adopt research (the Joumal of Chromatography A of liquid phase SMBC separating chiral new drug intermediate DOLE, 832 (1-2): 55-65 (1999)), be pilot scale report the most full and accurate in the document of publishing up to now.Pilot experiment shows, the liquid phase SMBC is 20 times of preparative liquid chromatography based on the production capacity of unit mass chiral stationary phase, and the mobile phase consumption that obtains the unit mass product then has only the latter's 1/20.Although the liquid phase SMBC has shown the performance of excellence like this, but produce the per kilogram product and still need to consume the mobile phase of 439 liters of organic solvents, this means that producing the solvent cost that one ton of single enantiomer medicine consumed can also can bring the environmental problem that can not be ignored simultaneously up to nearly 1,000,000 yuans.
In addition, existing liquid phase SMBC is when carrying out the commercial scale amplification, owing to relate to the conveying of a large amount of organic solvent high-pressure fluids, and these organic solvents often have inflammable and explosive characteristic, therefore, to pump, valve, instrument, the type selecting of key equipment such as electric and the design of technology workshop integral body, very harsh security requirement all can be proposed, increased equipment investment and running cost.
In sum, although existing supercritical fluid chromatography, liquid phase SMBC have been obtained the achievement that attracts people's attention at the separation field of chiral drug, but how to develop that an analogy prior art is more efficient, more low consumption, more cleaning, safer preparing chromatograph in industry new technology, further reduce the production cost of chiral drug, be one of the target of preparative chromatography researcher unremitting pursue and focus of international pharmaceuticals industry concern always.
Summary of the invention
The object of the present invention is to provide a kind of supercritical fluid simulated movable bed chromatography device of four subregions, be that supercritical fluid chromatography device and liquid phase simulated movable bed chromatography device are integrated into the supercritical fluid simulated movable bed chromatography device, particularly with supercritical carbon dioxide fluid be flow phase, be the supercritical fluid simulated movable bed chromatography device of packed column filler with the chiral stationary phase, realize efficient, low consumption, cleaning, extensive resolving chiral medicine racemic modification safely.
The technical solution used in the present invention is:
It comprises 4 to 48 packed columns, is connected successively with the entrance point of a back packed column by the port of export of last packed column, and the entrance point of the port of export of last root packed column and first packed column is formed by connecting; Open-close type valve and mobile entrance pipe mutually, injection port pipeline that the entrance point of every packed column passes through respectively separately connect; The port of export of the every packed column open-close type valve by separately and output respectively is enriched with the mobile phase export pipeline that remaining mouthful pipeline, the output of the extract port pipeline of the fluid of strong retained fraction, fluid that output is enriched with weak retained fraction flows mutually and connects; On the pipeline of the entrance point of the port of export that connects last packed column and a back packed column, be connected to open-close type valve or check-valves; On the pipeline of the entrance point of the port of export that connects last root packed column and first packed column, be connected to open-close type valve or check-valves; On the pipeline of the entrance point of the port of export that connects last packed column and a back packed column, be connected to back pressure regulator or back pressure regulating valve or counterbalance valve; On the pipeline of the entrance point of the port of export that connects last root packed column and first packed column, be connected to back pressure regulator or back pressure regulating valve or counterbalance valve; The port of export of the port of export of the port of export of extract port pipeline, remaining mouthful pipeline, the phase export pipeline that flows is connected to cyclone separator respectively; The modifier pipeline inserts the phase entrance pipe that flows behind a constant flow pump; The sample introduction liquid pipeline inserts the injection port pipeline behind another constant flow pump.
Force fluid to flow to same direction in the inside of above-mentioned all packed columns according to the order that packed column connects successively, along fluid flow direction, on off state by by-pass valve control sets gradually the phase entry position of flowing, the extract port position, the injection port position, remaining mouthful position, mobile phase exit position, thereby all packed columns four subregions have been divided into, each subregion comprises a packed column at least, after having passed through a given time cycle, by changing the on off state of valve, make the phase entry position of flowing, the extract port position, the injection port position, remaining mouthful position, pass along the packed column that is directed downwards that fluid flows respectively mobile phase exit position, same four subregions are also passed to next root packed column thereupon, thereby form the effect mobile round about that flow, realize the continued operation of separation process with the packed column filler.
Above-mentioned four subregions are finished different functions respectively.Belong to subregion I at the packed column that flows between phase entry position and the extract port position, main effect is a complete wash-out of realizing strong retained fraction; Packed column between extract port position and injection port position belongs to subregion II, and main effect is with strong retained fraction absorption, displaces weak retained fraction and sends into subregion III; Packed column between injection port position and remaining mouthful position belongs to subregion III, and main effect is the weak retained fraction of wash-out; Be positioned at a remnants mouthful position and belong to subregion IV with the packed column of mobile exit position mutually, main effect is that weak retained fraction is adsorbed fully, and making flows to export does not mutually contain the component that will separate in the fluid, be convenient to recycling of mobile phase.
Above-mentioned flow adopts temperature, pressure to surpass the supercritical fluid of critical-temperature, critical pressure mutually, perhaps adopts temperature, the pressure subcritical fluids a little less than critical-temperature, critical pressure.
The useful effect that the present invention has is:
1. the continued operation mode of supercritical fluid simulated movable bed chromatography device can solve supercritical fluid chromatography because the low efficiency problem that the shortcoming of intermittently operated is brought;
2. the supercritical fluid simulated movable bed chromatography device adopts the supercritical fluid replace organic solvent as the phase that flows, and can solve the liquid phase SMBC owing to adopt organic solvent as the organic solvent high flow rate, the high pollution problem that flow and bring mutually;
3. the supercritical fluid simulated movable bed chromatography device can be implemented gradient operation mode easily, and especially barometric gradient operator scheme and modifier gradient operation mode significantly improve the separative efficiency of device;
4. product with flow compatible easily separated, extract port with remaining mouthful flow out flow mutually can by heat up, the effects of step-down, will be as the supercritical fluid moment gasification of the phase that flows, and pass through the cyclonic separation effect of cyclone separator, obtain product easily;
5. for supercritical carbon dioxide fluid as for the supercritical fluid simulated movable bed chromatography device of the phase that flows, also have following advantage especially: because carbon dioxide is colourless, tasteless, nontoxic, so be highly suitable for handling medical product; Because nonflammable explosive, the chemical property of carbon dioxide is stable, so production process is as safe as a house; Owing to the carbon dioxide environment close friend, cheaply be easy to get, so separation costs is low; Because carbon dioxide critical condition is moderate, so plant-scale device is easy to realize.
Description of drawings
Fig. 1 is a structural representation of the present invention;
Fig. 2 is the state conversion and recycling principle schematic of mobile phase among the present invention;
Fig. 3 (a) is the supercritical fluid simulated movable bed chromatography device that subregion I, II, III, IV comprise four subregions of 1,2,2,1 packed column respectively, in two adjacent valve switching cycles, the situation of movement schematic diagram of the phase entry position of flowing, extract port position, injection port position, remaining mouthful position, the phase exit position of flowing;
Fig. 3 (b) is the principle schematic that the supercritical fluid simulated movable bed chromatography device of subregion I, II, III, IV four subregions that comprise 1,2,2,1 packed column is respectively implemented barometric gradient operator scheme and modifier gradient operation mode;
Among the figure: 1, mobile phase wet tank, 2, the export pipeline of mobile phase wet tank, 3, constant pressure pump, 4, surge tank, 5, the heated constant temperature groove, 6, the phase entrance pipe flows, 7, the injection port pipeline, 8, the modifier jar, 9, constant flow pump, 10, the modifier pipeline, 11, the sample introduction flow container, 12, constant flow pump, 13, the sample introduction liquid pipeline, 14, the extract port pipeline, 15, remaining mouthful pipeline, 16, the phase export pipeline flows, 17, the heated constant temperature case, 18, the heated constant temperature groove, 19, the exit gas main pipe rail, 20, activated-charcoal column, 21, the phase steel cylinder flows, 22, the cyclinder gas pipeline, 23, low temperature thermostat bath, 24, computer control system.
The specific embodiment
The supercritical fluid simulated movable bed chromatography device of a kind of four subregions as shown in Figure 1, each subregion have all only disposed 1 packed column, are the simplest and the clearest forms of implementation of the present invention.It comprises four packed column Z1, Z2, Z3, Z4, by the port of export of first packed column Z1 successively through open-close type valve VF1, pressure sensor PZ1, back pressure regulator VPZ1 is connected with the entrance point of second packed column Z2, by the port of export of second packed column Z2 successively through open-close type valve VF2, pressure sensor PZ2, back pressure regulator VPZ2 is connected with the entrance point of the 3rd packed column Z3, by the port of export of the 3rd packed column Z3 successively through open-close type valve VF3, pressure sensor PZ3, back pressure regulator VPZ3 is connected with the entrance point of the 4th packed column Z4, by the port of export of the 4th packed column Z4 successively through open-close type valve VF4, pressure sensor PZ4, back pressure regulator VPZ4 is connected with the entrance point of first packed column Z1; The entrance point of every packed column Z1, Z2, Z3, Z4 open-close type valve VA1, the VA2 by separately, VA3, VA4 respectively is connected with injection port pipeline 7, mobile entrance pipe 6 mutually with open-close type valve VB1, VB2, VB3, the VB4 by separately respectively; The port of export of every packed column Z1, Z2, Z3, Z4 open-close type valve VC1, the VC2 by separately, VC3, VC4 respectively is connected with extract port pipeline 14, a remnants mouth pipeline 15 with open-close type valve VD1, VD2, VD3, the VD4 by separately respectively; The port of export of every packed column Z1, Z2, Z3, Z4 is open-close type valve VE1, VE2, VE3, the VE4 and mobile 16 connections of export pipeline mutually by separately respectively also; On extract port pipeline 14, be connected to mass flowmenter F2, flow control valve VR2, pressure sensor PE, back pressure regulator VPE, heated constant temperature groove 18 and cyclone separator S1 successively; On remaining mouthful pipeline 15, be connected to mass flowmenter F3, flow control valve VR3, pressure sensor PR, back pressure regulator VPR, heated constant temperature groove 18 and cyclone separator S2 successively; On mobile phase export pipeline 16, be connected to mass flowmenter F4, flow control valve VR4, pressure sensor PD, back pressure regulator VPD, heated constant temperature groove 18 and cyclone separator S3 successively; Open-close type valve VS1, VS2, VS3 that the outlet at bottom of cyclone separator S1, S2, S3 passes through separately respectively are connected with recycling can L1, L2, L3; Open-close type valve VL1, VL2, VL3 that the outlet at bottom of recycling can L1, L2, L3 passes through separately respectively connect non-pressure vessel; The top exit gas main pipe rail 19 of cyclone separator S1, S2, S3, behind pressure sensor PS, back pressure regulator VPS, activated-charcoal column 20, converge with the cyclinder gas pipeline 22 that is connected to pressure-reducing valve VG, pressure sensor PG, open-close type valve VH successively from mobile steel cylinder 21 mutually, behind low temperature thermostat bath 23, enter the phase wet tank 1 that flows; On the export pipeline 2 of mobile phase wet tank 1, after being connected to constant pressure pump 3, surge tank 4, heated constant temperature groove 5 successively, be divided into two-way, one the tunnel is the phase entrance pipe 6 that flows, converge with the modifier pipeline 10 that is connected to constant flow pump 9 from modifier jar 8, behind mixing chamber M1, be connected with packed column Z1, Z2, Z3, Z4 respectively by open-close type valve VB1, VB2, VB3, VB4; Another road is an injection port pipeline 7, behind pressure-reducing valve VJ, pressure sensor PJ, converge with the sample introduction liquid pipeline 13 that is connected to constant flow pump 12 from sample introduction flow container 11, behind mixing chamber M2, mass flowmenter F1, flow control valve VR1, be connected with packed column Z1, Z2, Z3, Z4 respectively by open-close type valve VA1, VA2, VA3, VA4.
In said apparatus, with the on off state of four packed column Z1, Z2, Z3, direct-connected all open-close type valves of Z4 4 kinds of combinations are arranged, with suitable switching cycle, switch and move in circles according to following order:
1. open valve VA3, VB1, VC1, VD3, VE4, VF1, VF2, VF3; Closing valve VA1, VA2, VA4, VB2, VB3, VB4, VC2, VC3, VC4, VD1, VD2, VD4, VE1, VE2, VE3, VF4; At this moment, the packed column that is in subregion I, II, III, IV is respectively packed column Z1, Z2, Z3, Z4.
2. open valve VA4, VB2, VC2, VD4, VE1, VF2, VF3, VF4; Closing valve VA1, VA2, VA3, VB1, VB3, VB4, VC1, VC3, VC4, VD1, VD2, VD3, VE2, VE3, VE4, VF1; At this moment, the packed column that is in subregion I, II, III, IV is respectively packed column Z2, Z3, Z4, Z1.
3. open valve VA1, VB3, VC3, VD1, VE2, VF1, VF3, VF4; Closing valve VA2, VA3, VA4, VB1, VB2, VB4, VC1, VC2, VC4, VD2, VD3, VD4, VE1, VE3, VE4, VF2; At this moment, the packed column that is in subregion I, II, III, IV is respectively packed column Z3, Z4, Z1, Z2.
4. open valve VA2, VB4, VC4, VD2, VE3, VF1, VF2, VF4; Closing valve VA1, VA3, VA4, VB1, VB2, VB3, VC1, VC2, VC3, VD1, VD3, VD4, VE1, VE2, VE4, VF3; At this moment, the packed column that is in subregion I, II, III, IV is respectively packed column Z4, Z1, Z2, Z3.
In above-mentioned and packed column Z1, Z2, direct-connected all open-close type valves of Z3, Z4, VF1, VF2, VF3, VF4 also can replace with check-valves respectively.Need by the situation of external world's control differently with the on off state of open-close type valve, the on off state of check-valves is controlled automatically by the pressure of fluid in the pipeline, and is consistent all the time with the on off state of VF1, VF2, VF3, VF4.In addition, these open-close type valves are not limited to two general formula valves, and they also can be the combinations of triple valve or multiple-way valve or rotary valve or above-mentioned valve.
Supercritical fluid simulated movable bed chromatography device of the present invention adopts constant temperature method, so all packed columns all place heated constant temperature case 17.
And the safety valve VK1, the VK2 that install at the device diverse location, VK3 can further guarantee the pressure security of whole system owing to be totally independent of computer control system 24.
The structural representation of Fig. 1 according to the present invention, mobile phase state conversion and recycling principle schematic in conjunction with Fig. 2, at with supercritical carbon dioxide fluid be flow phase, be the concrete application background of packed column filler separating chiral medicine with the chiral stationary phase, further that brief description of the process is as follows:
Temperature, pressure is (T1, liquid CO P1) in the mobile phase wet tank 1
2, enter surge tank 4 through constant pressure pump 3 pressurizations, becoming temperature, pressure is (T1, liquid CO P2)
2, becoming temperature, pressure through 5 intensifications of heated constant temperature groove again is (T2, supercritical CO P2)
2Behind the fluid, be divided into two-way: the first via is the phase entrance pipe 6 that flows, the supercritical CO of this pipeline
2A small amount of modifier of fluid and constant flow pump 9 constant currents input injects to packed column in mobile phase entry position after mixing chamber (can be the quartz particles post) M1 mixes; The second the tunnel is injection port pipeline 7, the supercritical CO of this pipeline
2Fluid reduces pressure through pressure-reducing valve VJ behind the pressure P J, mix through mixing chamber M2 with the sample introduction liquid (being dissolved in the solution that modifier disposes) of constant flow pump 12 constant currents input by chiral drug racemic modification sample, the flow measuring and controlling assembly that is made of mass flowmenter F1 and flow control valve VR1 injects to packed column in the injection port position after regulating flow; The temperature, pressure that extract port pipeline 14 flows out is (T2, PE) supercritical fluid, regulate flow by the flow measuring and controlling assembly that mass flowmenter F2 and flow control valve VR2 constitute, the step-down behind the back pressure regulator VPE of flowing through, and after heated constant temperature groove 18 heated up, entering temperature, pressure was (T3, cyclone separator S1 PS), since the acting in conjunction of intensification and step-down, supercritical CO
2The gasification of fluid moment, and since the boiling point of modifier and solute often than CO
2Boiling point much higher, therefore the modifier solution that is enriched with strong retained fraction will be separated out with the form of little drop (or crystallite), effect by cyclonic separation realizes that gas-liquid two-phase separates then, obtain the modifier solution of strong retained fraction in the bottom of cyclone separator S1, that flow out from the outlet of the top of cyclone separator S1 then is the CO that only carries micro-modifier secretly
2Gas; The temperature, pressure that remaining mouthful pipeline 15 flows out is that (T2, supercritical fluid PR) through similar step, realize being enriched with the modifier solution and the CO of weak retained fraction
2Separation; The temperature, pressure that the phase export pipeline 16 that flows flows out is that (T2, supercritical fluid PD) through similar step, are realized modifier and CO
2Separation.From the temperature, pressure that converges after the top of cyclone separator S1, S2, S3 exports out is (T3, CO PS)
2Gas, to become temperature, pressure be (T3, CO P1) in step-down behind the back pressure regulator VPS that flows through
2Gas, after activated-charcoal column 20 adsorption cleanings and low temperature thermostat bath 23 cooling liquefaction, becoming temperature, pressure is (T1, liquid CO P1)
2, it is recycling to enter the phase wet tank 1 that flows.The operating pressure PS of above-mentioned cyclone separator S1, S2, S3 unifies control by the back pressure regulator VPS in downstream.The outlet at bottom of cyclone separator S1, S2, S3 connects recycling can L1, L2, L3 respectively, and then connect non-pressure vessel respectively, by the alternation switch state of gauge tap formula valve VS1, VS2, VS3 and open-close type valve VL1, VL2, VL3, guarantee cyclone separator internal pressure stabilises in the discharge process of product and modifier.Because special operation conditions such as device driving, cyclone separator discharging, activated-charcoal column replacing cause the inner CO of device
2Quantity not sufficient the time, be used for CO from the phase steel cylinder 21 that flows
2Gas replenishes.
The present invention is not limited in the form of implementation that above-mentioned each subregion has all only disposed 1 packed column, the packed column that in fact each subregion is also configurable more than, number does not wait, and the annexation of device can be expanded.In theory, when all packed columns add together total length and remain unchanged, the sum that the length that shortens every packed column increases packed column simultaneously will be more favourable to separating effect, but the increase of packed column number also causes shortcomings such as equipment complexity, investment increase, reliability reduction, so the packed column sum that the supercritical fluid simulated movable bed chromatography device is disposed generally is no more than 48.With the number of the on off state of direct-connected all open-close type valves of packed column combination total identical with packed column in general.For instance, dispose the supercritical fluid simulated movable bed chromatography device of 1,2,2,1 packed column respectively at subregion I, II, III, IV, with the on off state of direct-connected all open-close type valves of packed column 6 kinds of combinations are just arranged, by suitable switching cycle, switch in regular turn make the phase entry position of flowing, extract port position, injection port position, remaining mouthful position, the phase exit position of flowing passes and moves in circles along the packed column that is directed downwards that fluid flows respectively.Fig. 3 is the supercritical fluid simulated movable bed chromatography device that above-mentioned subregion I, II, III, IV comprise four subregions of 1,2,2,1 packed column respectively, in two adjacent valve switching cycles, the situation of movement schematic diagram of the phase entry position of flowing, extract port position, injection port position, remaining mouthful position, the phase exit position of flowing; Fig. 3 (a) is the mobile inlet mutually of current period, extract port, injection port, remaining mouthful, the mobile desired location of outlet mutually; Fig. 3 (b) is flow in next cycle inlet, extract port, injection port, remaining mouthful, the mobile desired location of outlet mutually mutually.
In addition, the supercritical fluid simulated movable bed chromatography device of four subregions can also be implemented gradient operation mode easily, significantly improves separative efficiency.The basic thought of gradient operation mode is, in SMBC inside along the I district on the direction in IV district, the eluting power of the phase that form to flow by strong to weak gradient, or form the gradient that solute and fixing affinity mutually grow from weak to strong, control by the precision of operating parameter simultaneously, above-mentioned gradient is kept and all the time along with valve switches along the dynamically translation of flow direction of the phase that flows, flow out by complete wash-out and from extract port in the I district thereby help strong retained fraction, then do not adsorbed fully as yet in the IV district from the remaining mouthful of weak retained fractions that flow out.The gradient operation mode that the supercritical fluid simulated movable bed chromatography device can conveniently be implemented comprises barometric gradient operator scheme and modifier gradient operation mode.
The principle of barometric gradient operator scheme is: in the shooting flow body region, isopycnic is contracted near the critical point, therefore, at this near zone, when temperature constant, the minor variations of pressure will cause the density generation marked change of supercritical fluid, and the density of supercritical fluid almost can be comparable with liquid at this moment.The solubility of solute then has substantial connection with the density of supercritical fluid.In general, along with the rising of pressure, the density of supercritical fluid increases, and the solubility of solute increases, and the eluting power of the phase that flows strengthens.Therefore, the present invention proposes to utilize supercritical fluid to have the dull corresponding relation of pressure-density-solubility-eluting power when temperature constant, carry out independently pressure adjusting by back pressure regulator to installing each subregion, be controlled at subregion I, subregion II and form the high pressure high density district and form the low pressure low density area, thereby realize the barometric gradient operator scheme at subregion III, subregion IV.
The principle of modifier gradient operation mode is: the adding of modifier, both can significantly improve solubility, and the approach of activity intensity that again can be by reducing the adsorption activity central point directly strengthens eluting power.Therefore, the present invention proposes in the higher mobile phase of subregion I porch injection modifier concentration, and inject the lower sample introduction fluid of modifier concentration at subregion III, thereby realize that subregion I, subregion II have higher modifier concentration, subregion III, subregion IV have the modifier gradient operation mode of low modifier concentration.
The supercritical fluid simulated movable bed chromatography device barometric gradient operator scheme of four subregions and the specific implementation process of modifier gradient operation mode, with the supercritical fluid simulated movable bed chromatography device of subregion I, the II of Fig. 3, four subregions that III, IV comprise 1,2,2,1 packed column respectively as an example, principle schematic in conjunction with Fig. 4 is described as follows:
When implementing the barometric gradient operator scheme, the inner back pressure regulator standard-sized sheet between adjacent chromatographic column in each district, and four terminal back pressure regulators of each district are in adjustment state, make flow inlet, extract port, injection port, remaining mouthful, the stepped successively reduction of supercritical fluid pressure of outlet mutually of flowing mutually.In the barometric gradient operator scheme, in fact the formation of barometric gradient have two factors: one is back pressure regulator is regulated generation to each subregion pressure pressure drop; Another is the flow resistance pressure drop that flow resistance causes when the I district flows to the IV district of flowing, this means under the situation of all back pressure regulator standard-sized sheets, also there is barometric gradient in the supercritical fluid SMBC, but this barometric gradient is difficult to regulate, and effect neither highly significant.So the barometric gradient operator scheme mainly refers to the barometric gradient of each subregion pressure being regulated formation by back pressure regulator.
When implementing the modifier gradient operation mode, the modifier concentration in the supercritical fluid of phase entrance pipe 6 that flows is greater than the modifier concentration in the supercritical fluid of injection port pipeline 7.From the flow process of Fig. 1, can find, modifier does not inject to injection port pipeline 7 separately, but inject with the form of sample introduction liquid as the solvent of sample dissolution, therefore, to be mixed with concentration through the sample introduction liquid of constant flow pump 12 constant currents inputs a little less than saturated solution, both guarantee sample feeding amount as much as possible, reduced the amount of modifier again to greatest extent.
With supercritical carbon dioxide fluid be flow phase, be packed column filler, the four subregion supercritical fluid simulated movable bed chromatography devices that adopt barometric gradient operator scheme and modifier gradient operation mode with the chiral stationary phase, can be efficiently, low consumption, cleaning, resolving chiral medicine racemic modification on a large scale safely.
The packed column that relates among the present invention, the suitable structure that adopts the dynamic axial compression chromatography post is imitated the post of chromatography packed column and is kept stable, is convenient to also to solve when industry is amplified that the post effect directly increases with post and the problem that reduces.
The filler of the packed column that relates among the present invention is not limited in chiral stationary phase, also can be various separation solid fillers such as molecular sieve, resin.
The supercritical fluid that the present invention relates to is not limited in supercritical CO
2Fluid also can be supercritical propane fluid, supercritical water etc.In addition, flowing of the present invention relates to is not limited in the supercritical fluid that temperature, pressure surpass critical-temperature, critical pressure mutually, also can be temperature, the pressure subcritical fluids a little less than critical-temperature, critical pressure.
Claims (7)
1, a kind of supercritical fluid simulated movable bed chromatography device of four subregions, it comprises 4 to 48 packed columns, the port of export by last packed column is connected successively with the entrance point of a back packed column, and the entrance point of the port of export of last root packed column and first packed column is formed by connecting; Open-close type valve and mobile entrance pipe mutually, injection port pipeline that the entrance point of every packed column passes through respectively separately connect; The port of export of the every packed column open-close type valve by separately and output respectively is enriched with the mobile phase export pipeline that remaining mouthful pipeline, the output of the extract port pipeline of the fluid of strong retained fraction, fluid that output is enriched with weak retained fraction flows mutually and connects; It is characterized in that: on the pipeline of the entrance point of the port of export that connects last packed column and a back packed column, be connected to open-close type valve or check-valves; On the pipeline of the entrance point of the port of export that connects last root packed column and first packed column, be connected to open-close type valve or check-valves; On the pipeline of the entrance point of the port of export that connects last packed column and a back packed column, be connected to back pressure regulator or back pressure regulating valve or counterbalance valve; On the pipeline of the entrance point of the port of export that connects last root packed column and first packed column, be connected to back pressure regulator or back pressure regulating valve or counterbalance valve; The port of export of the port of export of the port of export of extract port pipeline, remaining mouthful pipeline, the phase export pipeline that flows is connected to cyclone separator respectively; The modifier pipeline inserts the phase entrance pipe that flows behind a constant flow pump; The sample introduction liquid pipeline inserts the injection port pipeline behind another constant flow pump.
2, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1, it is characterized in that: it comprises four packed column (Z1, Z2, Z3, Z4), by the port of export of first packed column (Z1) successively through open-close type valve (VF1), pressure sensor (PZ1), back pressure regulator (VPZ1) is connected with the entrance point of second packed column (Z2), by the port of export of second packed column (Z2) successively through open-close type valve (VF2), pressure sensor (PZ2), back pressure regulator (VPZ2) is connected with the entrance point of the 3rd packed column (Z3), by the port of export of the 3rd packed column (Z3) successively through open-close type valve (VF3), pressure sensor (PZ3), back pressure regulator (VPZ3) is connected with the entrance point of the 4th packed column (Z4), by the port of export of the 4th packed column (Z4) successively through open-close type valve (VF4), pressure sensor (PZ4), back pressure regulator (VPZ4) is connected with the entrance point of first packed column (Z1); The entrance point of every packed column (Z1, Z2, Z3, Z4) respectively the open-close type valve (VA1, VA2, VA3, VA4) by separately and respectively the open-close type valve (VB1, VB2, VB3, VB4) by separately be connected with injection port pipeline (7), mobile entrance pipe (6) mutually; The port of export of every packed column (Z1, Z2, Z3, Z4) respectively the open-close type valve (VC1, VC2, VC3, VC4) by separately and respectively the open-close type valve (VD1, VD2, VD3, VD4) by separately be connected with extract port pipeline (14), remnants mouth pipelines (15); The open-close type valve (VE1, VE2, VE3, VE4) that the port of export of every packed column (Z1, Z2, Z3, Z4) also passes through separately respectively connects with mobile export pipeline mutually (16); On extract port pipeline (14), be connected to mass flowmenter (F2), flow control valve (VR2), pressure sensor (PE), back pressure regulator (VPE), heated constant temperature groove (18) and cyclone separator (S1) successively; On remaining mouthful of pipeline (15), be connected to mass flowmenter (F3), flow control valve (VR3), pressure sensor (PR), back pressure regulator (VPR), heated constant temperature groove (18) and cyclone separator (S2) successively; On mobile phase export pipeline (16), be connected to mass flowmenter (F4), flow control valve (VR4), pressure sensor (PD), back pressure regulator (VPD), heated constant temperature groove (18) and cyclone separator (S3) successively; The open-close type valve (VS1, VS2, VS3) that the outlet at bottom of cyclone separator (S1, S2, S3) passes through separately respectively is connected with recycling can (L1, L2, L3); The open-close type valve (VL1, VL2, VL3) that the outlet at bottom of recycling can (L1, L2, L3) passes through respectively separately connects non-pressure vessel; The top exit gas main pipe rail (19) of cyclone separator (S1, S2, S3), behind pressure sensor (PS), back pressure regulator (VPS), activated-charcoal column (20), converge with the cyclinder gas pipeline (22) that is connected to pressure-reducing valve (VG), pressure sensor (PG), open-close type valve (VH) successively from mobile steel cylinder (21) mutually, behind low temperature thermostat bath (23), enter the phase wet tank (1) that flows; On the export pipeline (2) of mobile phase wet tank (1), after being connected to constant pressure pump (3), surge tank (4), heated constant temperature groove (5) successively, be divided into two-way, one the tunnel is the phase entrance pipe (6) that flows, converge with the modifier pipeline (10) that is connected to constant flow pump (9) from modifier jar (8), behind mixing chamber (M1), be connected with packed column (Z1, Z2, Z3, Z4) respectively by open-close type valve (VB1, VB2, VB3, VB4); Another road is injection port pipeline (7), behind pressure-reducing valve (VJ), pressure sensor (PJ), converge with the sample introduction liquid pipeline (13) that is connected to constant flow pump (12) from sample introduction flow container (11), behind mixing chamber (M2), mass flowmenter (F1), flow control valve (VR1), be connected with packed column (Z1, Z2, Z3, Z4) respectively by open-close type valve (VA1, VA2, VA3, VA4).
3, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1 and 2 is characterized in that: with the direct-connected open-close type valve of packed column be two general formula valves or triple valve or multiple-way valve or rotary valve.
4, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1 and 2 is characterized in that: described packed column is the dynamic axial compression chromatography post.
5, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1 and 2, it is characterized in that: flowing surpasses the supercritical fluid of critical-temperature, critical pressure mutually for temperature, pressure, perhaps is temperature, the pressure subcritical fluids a little less than critical-temperature, critical pressure.
6, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1 and 2 is characterized in that: flowing is supercritical carbon dioxide fluid mutually.
7, the supercritical fluid simulated movable bed chromatography device of a kind of four subregions according to claim 1 and 2 is characterized in that: the filler of packed column is a chiral stationary phase.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100358606C (en) * | 2005-12-26 | 2008-01-02 | 卢建刚 | Simulated moving bed chromatogram equipment employed dual-open loop structure to reduce operation pressure |
| CN100450575C (en) * | 2006-06-28 | 2009-01-14 | 华杰 | Preparing continuous feeding cross flow extracting and chromatographic separating system |
| CN104056467A (en) * | 2014-06-30 | 2014-09-24 | 许建中 | Five-zone series supercritical carbon dioxide fluid simulated moving bed chromatography device and operation method thereof |
| CN102216769B (en) * | 2008-11-12 | 2014-10-29 | 沃特世科技公司 | Collection system for purification flowstreams |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1099899C (en) * | 1997-12-31 | 2003-01-29 | 孙传经 | Commercial scale supercritical carbon dioxide prepn. chromatography and use thereof |
| CN1169595C (en) * | 2002-03-13 | 2004-10-06 | 浙江大学 | Analogue mobile bed chromatic reactor |
| CN2786626Y (en) * | 2005-03-28 | 2006-06-07 | 浙江大学 | Super critical four subarea simulating moving bed equipment |
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2005
- 2005-03-28 CN CNB200510049491XA patent/CN100348290C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100358606C (en) * | 2005-12-26 | 2008-01-02 | 卢建刚 | Simulated moving bed chromatogram equipment employed dual-open loop structure to reduce operation pressure |
| CN100450575C (en) * | 2006-06-28 | 2009-01-14 | 华杰 | Preparing continuous feeding cross flow extracting and chromatographic separating system |
| CN102216769B (en) * | 2008-11-12 | 2014-10-29 | 沃特世科技公司 | Collection system for purification flowstreams |
| CN104056467A (en) * | 2014-06-30 | 2014-09-24 | 许建中 | Five-zone series supercritical carbon dioxide fluid simulated moving bed chromatography device and operation method thereof |
| CN104056467B (en) * | 2014-06-30 | 2016-08-24 | 许建中 | Five district's series connection supercritical carbon dioxide fluid simulated movable bed chromatography device and operational approach thereof |
| CN106226427A (en) * | 2016-07-18 | 2016-12-14 | 江苏德源药业股份有限公司 | A kind of supercritical fluid chromatography quickly splits the method for aranidipine racemic modification |
| CN107163618A (en) * | 2017-06-02 | 2017-09-15 | 广州立达尔生物科技股份有限公司 | Supercritical fluid column chromatography prepares the method and device of high-purity capsochrome Capsaicin |
| CN110465114A (en) * | 2019-08-23 | 2019-11-19 | 内蒙古金达威药业有限公司 | A kind of Simulation moving bed continuous chromatography chromatographic system and its application and the method for purifying Co-Q10 |
| CN110465114B (en) * | 2019-08-23 | 2021-08-20 | 内蒙古金达威药业有限公司 | Simulated moving bed continuous chromatography chromatographic system, application thereof and method for purifying coenzyme Q10 |
| CN112782315A (en) * | 2020-12-31 | 2021-05-11 | 江苏汉邦科技有限公司 | Continuous separation type supercritical fluid chromatographic system |
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