CN1673736A - Supercritical fluid analog moving bed chromatograph of ternary area - Google Patents
Supercritical fluid analog moving bed chromatograph of ternary area Download PDFInfo
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- CN1673736A CN1673736A CN 200510049524 CN200510049524A CN1673736A CN 1673736 A CN1673736 A CN 1673736A CN 200510049524 CN200510049524 CN 200510049524 CN 200510049524 A CN200510049524 A CN 200510049524A CN 1673736 A CN1673736 A CN 1673736A
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Abstract
The three-zone supercritical fluid analog movable bed chromatographic equipment includes 3-36 stuffing columns connected successively with back pressure regulator, with the output of the last stuffing column being connected to the input of the first one with back pressure regulator. All the inlets of the stuffing columns are connected with the flow phase inlet pipeline and sample feeding port pipeline, all the outlets of the stuffing columns are connected with extracting port pipeline and residue port pipeline, and the outlets of the extracting port pipeline and the residue port pipeline have cyclonic separators connected separately. The flow phase is supercritical fluid, and the present invention may operate in either pressure gradient operation mode or modifier gradient operation mode. The present invention has supercritical CO2 fluid as the flow phase and chiral fixed phase as stuffing, and may be used in splitting chiral medicine raceme in large scale.
Description
Technical field
The present invention relates to include the preparing chromatograph in industry tripping device of handling supercritical fluid with adsorbent, relate in particular to a kind of supercritical fluid simulated movable bed chromatography device that is used for three subregions of resolving chiral medicine raceme.
Background technology
Food and Drug Administration (FDA) has issued the chiral drug governing principle in March, 1992, has proposed to develop the strategy of the littler single enantiomer medicine of toxic and side effect.Therefore, the raceme 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 enantiomorph 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 enantiomorph.But utilization factor that there is stationary phase in preparative liquid chromatography is low, the moving phase consumption is big, intermittently operated, separation costs height, shortcoming such as seriously polluted, has hindered its further application in commercial production.
Preparation type supercritical fluid chromatography be owing to can remedy problems such as preparative liquid chromatography moving phase consumption is big, seriously polluted effectively, emerged many compelling achievements at aspects such as the analysis of chiral drug and preparations.Supercritical fluid chromatography be adopt near or surpass the chromatographic separation technology of the high-pressure fluid of critical temperature (TC) and emergent pressure (PC) as moving phase, 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 stratographic analysis 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 moving 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 mutual solubility, under operating conditions stable modifier such as ethanol, just can significantly improve the dissolving power 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 adsorptive power in the chiral stationary phase, so even a spot of modifier also can obviously improve the eluting power of moving phase.Not only contain supercritical carbon dioxide fluid but also contain separated material in the moving phase of supercritical fluid chromatography outlet, 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 the stationary phase utilization factor is on the low side, separation costs is higher still exists, and has hindered its application in commercial production.
Low in order to solve preparative liquid chromatography stationary phase utilization factor, 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 stationary phase utilization factor height, continued operation, the liquid phase simulated moving bed chromatography 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 simulated moving bed chromatography 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 Journal of Chromatography A of liquid phase simulated moving bed chromatography 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 simulated moving bed chromatography is 20 times of preparative liquid chromatography based on the productive capacity of unit mass chiral stationary phase, and the moving phase consumption that obtains the unit mass product then has only the latter's 1/20.Although the liquid phase simulated moving bed chromatography has shown the performance of excellence like this, but produce the per kilogram product and still need to consume 439 liters of organic solvent moving phases, 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 simulated moving bed chromatography is when carrying out the industrial 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 simulated moving bed chromatography have 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 researchist 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 three 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, be moving phase particularly, 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 raceme safely with the supercritical carbon dioxide fluid.
The technical solution used in the present invention is:
It comprises 3 to 36 packed columns, is connected successively with the entrance point of a back packed column by the endpiece of last packed column, and the entrance point of the endpiece of last root packed column and first packed column is formed by connecting; The open-close type valve that the entrance point of every packed column passes through separately respectively is connected with moving phase entrance pipe, injection port pipeline; Open-close type valve by separately and output are enriched with the extract port pipeline of the fluid of strong retained fraction to the endpiece of every packed column respectively, the remaining mouthful pipeline of fluid that output is enriched with weak retained fraction is connected; On the pipeline of the entrance point of an endpiece that connects last packed column and a back packed column, be connected to open-close type valve or non-return valve; On the pipeline of the entrance point of the endpiece that connects last root packed column and first packed column, be connected to open-close type valve or non-return valve; On the pipeline of the entrance point of an endpiece 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 endpiece 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 endpiece of the endpiece of extract port pipeline, remaining mouthful pipeline is connected to cyclone separator respectively; The modifier pipeline inserts the moving phase entrance pipe 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 moving phase entry position, the extract port position, the injection port position, remaining mouthful position, thereby all packed columns three 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 moving phase entry position, the extract port position, the injection port position, pass along the packed column that is directed downwards that fluid flows respectively remaining mouthful position, same three subregions are also passed to next root packed column thereupon, thereby form the effect that moving phase and packed column filler move round about, realize the continued operation of detachment process.
Above-mentioned three subregions are finished different functions respectively.Packed column between moving phase entry position and extract port position belongs to subregion I, and 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.
Above-mentioned moving phase adopts temperature, pressure to surpass the supercritical fluid of critical temperature, emergent pressure, perhaps adopts temperature, the pressure subcritical fluids a little less than critical temperature, emergent 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 moving phase, can solve the liquid phase simulated moving bed chromatography because organic solvent high flow rate, the high pollution problem that adopts organic solvent to bring as moving phase;
3. the supercritical fluid simulated movable bed chromatography device can be implemented gradient operation mode easily, and especially pressure gradient operator scheme and modifier gradient operation mode significantly improve the separation efficiency of device;
4. product separates easily with moving phase, extract port and the remaining mouthful of moving phases that flow out can by heat up, the effect of step-down, will be as the supercritical fluid moment gasification of moving phase, and the cyclonic separation effect by cyclone separator, obtain product easily;
5. for supercritical carbon dioxide fluid as for the supercritical fluid simulated movable bed chromatography device of moving phase, 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 run 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.
6. four subregions of the general existence of traditional simulated moving bed chromatography, promptly also dispose packed column more than one as subregion IV remaining mouthful of back, position, main effect is that weak retained fraction is adsorbed fully, make in the moving phase outlet fluid and do not contain the component that will separate, being convenient to moving phase, to get back to subregion I recycling; The supercritical fluid simulated movable bed chromatography device of three subregions provided by the invention, by steps such as remaining mouthful of pipeline intensification, step-down, cyclonic separation, when obtaining weak retained fraction product, realize purifying moving phase for recycling purpose, thereby omit the subregion IV that mainly plays the effect of purifying moving phase, its advantage is: technological process is simple and clear, the equipment complexity reduces, device reliability improves, and investment is saved, and 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 exchange and the recycling principle schematic of moving phase among the present invention;
Fig. 3 is the supercritical fluid simulated movable bed chromatography device that subregion I, II, III comprise three subregions of 1,2,3 packed column respectively, in two adjacent valve switching cycles, the situation of movement synoptic diagram of moving phase entry position, extract port position, injection port position, remaining mouthful position;
Fig. 4 is the principle schematic that the supercritical fluid simulated movable bed chromatography device of subregion I, II, III three subregions that comprise 1,2,3 packed column is respectively implemented pressure gradient operator scheme and modifier gradient operation mode.
Among the figure: 1, the moving phase wet tank, 2, the export pipeline of moving phase wet tank, 3, constant pressure pump, 4, surge tank, 5, the heated constant temperature groove, 6, the moving phase entrance pipe, 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 heated constant temperature case, 17, the heated constant temperature groove, 18, the exit gas main pipe rail, 19, activated-charcoal column, 20, the moving phase steel cylinder, 21, the cyclinder gas pipeline, 22, low temperature thermostat bath, 23, computer control system.
Embodiment
The supercritical fluid simulated movable bed chromatography device of a kind of three 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 three packed column Z1, Z2, Z3, endpiece by first packed column Z1 is connected with the entrance point of second packed column Z2 through open-close type valve VE1, pressure transducer PZ1, back pressure regulator VPZ1 successively, endpiece by second packed column Z2 is connected with the entrance point of the 3rd packed column Z3 through open-close type valve VE2, pressure transducer PZ2, back pressure regulator VPZ2 successively, is connected with the entrance point of first packed column Z1 through open-close type valve VE3, pressure transducer PZ3, back pressure regulator VPZ3 successively by the endpiece of the 3rd packed column Z3; The entrance point of every packed column Z1, Z2, Z3 open-close type valve VA1, the VA2 by separately, VA3 respectively is connected with injection port pipeline 7, moving phase entrance pipe 6 with open-close type valve VB1, VB2, the VB3 by separately respectively; The endpiece of every packed column Z1, Z2, Z3 open-close type valve VC1, the VC2 by separately, VC3 respectively is connected with extract port pipeline 14, a remnants mouth pipeline 15 with open-close type valve VD1, VD2, the VD3 by separately respectively; On extract port pipeline 14, be connected to mass flowmeter F2, flow control valve VR2, pressure transducer PE, back pressure regulator VPE, heated constant temperature groove 17 and cyclone separator S1 successively; On remaining mouthful pipeline 15, be connected to mass flowmeter F3, flow control valve VR3, pressure transducer PR, back pressure regulator VPR, heated constant temperature groove 17 and cyclone separator S2 successively; Open-close type valve VS1, VS2 that the outlet at bottom of cyclone separator S1, S2 passes through separately respectively are connected with recycling can L1, L2; Open-close type valve VL1, VL2 that the outlet at bottom of recycling can L1, L2 passes through respectively separately connect non-pressure vessel; The top exit gas main pipe rail 18 of cyclone separator S1, S2, behind pressure transducer PS, back pressure regulator VPS, activated-charcoal column 19, converge with the cyclinder gas pipeline 21 that is connected to reduction valve VG, pressure transducer PG, open-close type valve VH from moving phase steel cylinder 20 successively, behind low temperature thermostat bath 22, enter moving phase wet tank 1; On the export pipeline 2 of moving 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 moving phase entrance pipe 6, 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 respectively by open-close type valve VB1, VB2, VB3; Another road is an injection port pipeline 7, behind reduction valve VJ, pressure transducer 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 flowmeter F1, flow control valve VR1, be connected with packed column Z1, Z2, Z3 respectively by open-close type valve VA1, VA2, VA3.
In said apparatus, with the on off state of three packed column Z1, Z2, direct-connected all open-close type valves of Z3 3 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, VE1, VE2; Closing valve VA1, VA2, VB2, VB3, VC2, VC3, VD1, VD2, VE3; At this moment, the packed column that is in subregion I, II, III is respectively packed column Z1, Z2, Z3.
2. open valve VA1, VB2, VC2, VD1, VE2, VE3; Closing valve VA2, VA3, VB1, VB3, VC1, VC3, VD2, VD3, VE1; At this moment, the packed column that is in subregion I, II, III is respectively packed column Z2, Z3, Z1.
3. open valve VA2, VB3, VC3, VD2, VE1, VE3; Closing valve VA1, VA3, VB1, VB2, VC1, VC2, VD1, VD3, VE2; At this moment, the packed column that is in subregion I, II, III is respectively packed column Z3, Z1, Z2.
In above-mentioned and packed column Z1, Z2, direct-connected all open-close type valves of Z3, VE1, VE2, VE3 also can replace with non-return valve 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 non-return valve is controlled automatically by the pressure of fluid in the pipeline, and is consistent all the time with the on off state of VE1, VE2, VE3.In addition, these open-close type valves are not limited to two general formula valves, and they also can be the combinations of T-valve or multiport 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 16.
And the safety valve VK1, the VK2 that install at the device diverse location, VK3 can further guarantee the pressure security of total system owing to be totally independent of computer control system 23.
The structural representation of Fig. 1 according to the present invention, moving phase state exchange and recycling principle schematic in conjunction with Fig. 2, at being moving phase with the supercritical carbon dioxide fluid, being 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 moving 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 a moving phase entrance pipe 6, 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 the moving 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 reduction 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 raceme sample, the flow measuring and controlling assembly that is made of mass flowmeter 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 flowmeter 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 17 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.From the temperature, pressure that converges after the top of cyclone separator S1, S2 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 19 adsorption cleanings and low temperature thermostat bath 22 cooling liquefaction, becoming temperature, pressure is (T1, liquid CO P1)
2, it is recycling to enter moving phase wet tank 1.The on-stream pressure PS of above-mentioned cyclone separator S1, S2 unifies control by the back pressure regulator VPS in downstream.The outlet at bottom of cyclone separator S1, S2 connects recycling can L1, L2 respectively, and then connect non-pressure vessel respectively, by the alternation switch state of gauge tap formula valve VS1, VS2 and open-close type valve VL1, VL2, 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 moving phase steel cylinder 20
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 36.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 1,2,3 packed column respectively at subregion I, II, III, 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 and make moving phase entry position, extract port position, injection port position, remaining mouthful position pass and move 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 comprise three subregions of 1,2,3 packed column respectively, in two adjacent valve switching cycles, the situation of movement synoptic diagram of moving phase entry position, extract port position, injection port position, remaining mouthful position; Fig. 3 (a) is the desired location of current period moving phase inlet, extract port, injection port, remaining mouth; Fig. 3 (b) is the desired location of next cycle moving phase inlet, extract port, injection port, remaining mouth.
In addition, the supercritical fluid simulated movable bed chromatography device of three subregions can also be implemented gradient operation mode easily, significantly improves separation efficiency.The basic thought of gradient operation mode is, along subregion I on the direction of subregion III, the eluting power that forms moving phase by strong to weak gradient, or the gradient that grows from weak to strong of the affinity that forms solute and stationary phase, control by the precision of operating parameter simultaneously, above-mentioned gradient is kept and all the time along with valve switches dynamically translation of flow direction along moving phase, strong retained fraction is flowed out at the complete wash-out of subregion I quilt and from extract port, adsorbed fully and the smooth wash-out of weak retained fraction quilt at the then strong retained fraction of subregion III simultaneously.The gradient operation mode that the supercritical fluid simulated movable bed chromatography device can conveniently be implemented comprises pressure gradient operator scheme and modifier gradient operation mode.
The principle of pressure 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 subtle change of pressure will cause the density generation marked change of supercritical fluid, and the density of supercritical fluid almost can be compared with liquid phase at this moment.The solubleness 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 solubleness of solute increases, and the eluting power of moving phase strengthens.Therefore, the present invention proposes to utilize supercritical fluid to have the dull corresponding relation of pressure-density-solubleness-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 pressure gradient operator scheme at subregion III.
The principle of modifier gradient operation mode is: the adding of modifier, both can significantly improve solubleness, 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 moving 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 has the modifier gradient operation mode of low modifier concentration.
The supercritical fluid simulated movable bed chromatography device pressure gradient operator scheme of three 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, three subregions that III comprises 1,2,3 packed column respectively as an example, principle schematic in conjunction with Fig. 4 is described as follows:
When implementing the pressure gradient operator scheme, the back pressure regulator standard-sized sheet of each subregion inside between adjacent chromatographic column, and three back pressure regulators of each subregion end are in adjustment state, make the stepped successively reduction of supercritical fluid pressure of moving phase inlet, extract port, injection port, remaining mouth.In the pressure gradient operator scheme, in fact the formation of pressure gradient have two factors: one is back pressure regulator is regulated generation to each subregion pressure pressure drop; The resistance to flow pressure drop that another is moving phase resistance to flow causes when subregion I flows to subregion III, this means under the situation of all back pressure regulator standard-sized sheets, also there is pressure gradient in the supercritical fluid simulated moving bed chromatography, but this pressure gradient is difficult to regulate, and effect neither highly significant.So the pressure gradient operator scheme mainly refers to the pressure 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 moving phase entrance pipe 6 is greater than the modifier concentration in the supercritical fluid of injection port pipeline 7.From the structural representation 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.
Be moving phase with the supercritical carbon dioxide fluid, be packed column filler, the three subregion supercritical fluid simulated movable bed chromatography devices that adopt pressure gradient operator scheme and modifier gradient operation mode with the chiral stationary phase, can be efficiently, low consumption, cleaning, resolving chiral medicine raceme 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 adsorptive separation solid filling agents 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, the moving phase that the present invention relates to is not limited in the supercritical fluid that temperature, pressure surpass critical temperature, emergent pressure, also can be temperature, the pressure subcritical fluids a little less than critical temperature, emergent pressure.
Claims (7)
1, a kind of supercritical fluid simulated movable bed chromatography device of three subregions, it comprises 3 to 36 packed columns, endpiece by last packed column is connected successively with the entrance point of a back packed column, and the entrance point of the endpiece of last root packed column and first packed column is formed by connecting; The open-close type valve that the entrance point of every packed column passes through separately respectively is connected with moving phase entrance pipe, injection port pipeline; Open-close type valve by separately and output are enriched with the extract port pipeline of the fluid of strong retained fraction to the endpiece of every packed column respectively, the remaining mouthful pipeline of fluid that output is enriched with weak retained fraction is connected; It is characterized in that: on the pipeline of the entrance point of an endpiece that connects last packed column and a back packed column, be connected to open-close type valve or non-return valve; On the pipeline of the entrance point of the endpiece that connects last root packed column and first packed column, be connected to open-close type valve or non-return valve; On the pipeline of the entrance point of an endpiece 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 endpiece 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 endpiece of the endpiece of extract port pipeline, remaining mouthful pipeline is connected to cyclone separator respectively; The modifier pipeline inserts the moving phase entrance pipe 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 three subregions according to claim 1, it is characterized in that: it comprises three packed column (Z1, Z2, Z3), by the endpiece of first packed column (Z1) successively through open-close type valve (VE1), pressure transducer (PZ1), back pressure regulator (VPZ1) is connected with the entrance point of second packed column (Z2), by the endpiece of second packed column (Z2) successively through open-close type valve (VE2), pressure transducer (PZ2), back pressure regulator (VPZ2) is connected with the entrance point of the 3rd packed column (Z3), by the endpiece of the 3rd packed column (Z3) successively through open-close type valve (VE3), pressure transducer (PZ3), back pressure regulator (VPZ3) is connected with the entrance point of first packed column (Z1); The entrance point of every packed column (Z1, Z2, the Z3) open-close type valve (VA1, VA2, VA3) by separately respectively is connected with injection port pipeline (7), moving phase entrance pipe (6) with the open-close type valve (VB1, VB2, VB3) by separately respectively; The endpiece of every packed column (Z1, Z2, Z3) respectively the open-close type valve (VC1, VC2, VC3) by separately and respectively the open-close type valve (VD1, VD2, VD3) by separately be connected with extract port pipeline (14), remnants mouth pipelines (15); On extract port pipeline (14), be connected to mass flowmeter (F2), flow control valve (VR2), pressure transducer (PE), back pressure regulator (VPE), heated constant temperature groove (17) and cyclone separator (S1) successively; On remaining mouthful of pipeline (15), be connected to mass flowmeter (F3), flow control valve (VR3), pressure transducer (PR), back pressure regulator (VPR), heated constant temperature groove (17) and cyclone separator (S2) successively; The open-close type valve (VS1, VS2) that the outlet at bottom of cyclone separator (S1, S2) passes through separately respectively is connected with recycling can (L1, L2); The open-close type valve (VL1, VL2) that the outlet at bottom of recycling can (L1, L2) passes through respectively separately connects non-pressure vessel; The top exit gas main pipe rail (18) of cyclone separator (S1, S2), behind pressure transducer (PS), back pressure regulator (VPS), activated-charcoal column (19), converge with the cyclinder gas pipeline (21) that is connected to reduction valve (VG), pressure transducer (PG), open-close type valve (VH) from moving phase steel cylinder (20) successively, behind low temperature thermostat bath (22), enter moving phase wet tank (1); On the export pipeline (2) of moving 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 moving phase entrance pipe (6), 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) respectively by open-close type valve (VB1, VB2, VB3); Another road is injection port pipeline (7), behind reduction valve (VJ), pressure transducer (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 flowmeter (F1), flow control valve (VR1), be connected with packed column (Z1, Z2, Z3) respectively by open-close type valve (VA1, VA2, VA3).
3, the supercritical fluid simulated movable bed chromatography device of a kind of three 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 T-valve or multiport valve or rotary valve.
4, the supercritical fluid simulated movable bed chromatography device of a kind of three 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 three subregions according to claim 1 and 2, it is characterized in that: moving phase is the supercritical fluid that temperature, pressure surpass critical temperature, emergent pressure, perhaps is temperature, the pressure subcritical fluids a little less than critical temperature, emergent pressure.
6, the supercritical fluid simulated movable bed chromatography device of a kind of three subregions according to claim 1 and 2 is characterized in that: moving phase is supercritical carbon dioxide fluid.
7, the supercritical fluid simulated movable bed chromatography device of a kind of three 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 (6)
| 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 |
| CN101732890B (en) * | 2009-12-08 | 2012-01-18 | 辽宁科技大学 | Three-section simulated moving bed chromatography device |
| CN102445503A (en) * | 2011-09-22 | 2012-05-09 | 中国海洋大学 | Combined analytic device for subcritical fluid extraction-liquid chromatography (LC) |
| CN108728247A (en) * | 2017-04-13 | 2018-11-02 | 义守大学 | The method of purified conjugate linolenic acid |
| TWI716829B (en) * | 2019-03-12 | 2021-01-21 | 喬璞科技有限公司 | Method of purifying 6-gingerol |
| 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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| TWI641585B (en) * | 2017-04-17 | 2018-11-21 | 義守大學 | Method of purifying solanesol |
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2005
- 2005-03-31 CN CN 200510049524 patent/CN1276251C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101732890B (en) * | 2009-12-08 | 2012-01-18 | 辽宁科技大学 | Three-section simulated moving bed chromatography device |
| CN102445503A (en) * | 2011-09-22 | 2012-05-09 | 中国海洋大学 | Combined analytic device for subcritical fluid extraction-liquid chromatography (LC) |
| CN108728247A (en) * | 2017-04-13 | 2018-11-02 | 义守大学 | The method of purified conjugate linolenic acid |
| TWI716829B (en) * | 2019-03-12 | 2021-01-21 | 喬璞科技有限公司 | Method of purifying 6-gingerol |
| 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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| CN1276251C (en) | 2006-09-20 |
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