CN114177650B - Continuous chromatographic separation method and application - Google Patents
Continuous chromatographic separation method and application Download PDFInfo
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- CN114177650B CN114177650B CN202111384994.8A CN202111384994A CN114177650B CN 114177650 B CN114177650 B CN 114177650B CN 202111384994 A CN202111384994 A CN 202111384994A CN 114177650 B CN114177650 B CN 114177650B
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 238000013375 chromatographic separation Methods 0.000 title abstract description 13
- 238000000926 separation method Methods 0.000 claims abstract description 82
- 239000003480 eluent Substances 0.000 claims abstract description 64
- 239000007788 liquid Substances 0.000 claims abstract description 64
- 230000008569 process Effects 0.000 claims abstract description 7
- 229940045997 vitamin a Drugs 0.000 claims description 96
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 76
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 76
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 76
- 239000011719 vitamin A Substances 0.000 claims description 76
- 235000019155 vitamin A Nutrition 0.000 claims description 76
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000945 filler Substances 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000000741 silica gel Substances 0.000 claims description 16
- 229910002027 silica gel Inorganic materials 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- 150000002266 vitamin A derivatives Chemical class 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- 239000012452 mother liquor Substances 0.000 claims description 10
- 238000012856 packing Methods 0.000 claims description 10
- 239000012527 feed solution Substances 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 229920005990 polystyrene resin Polymers 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000010924 continuous production Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000007599 discharging Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 230000005526 G1 to G0 transition Effects 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008929 regeneration Effects 0.000 description 6
- 238000011069 regeneration method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000010413 mother solution Substances 0.000 description 4
- 150000004492 retinoid derivatives Chemical class 0.000 description 4
- 210000002925 A-like Anatomy 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- FPIPGXGPPPQFEQ-HWCYFHEPSA-N 13-cis-retinol Chemical class OC/C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-HWCYFHEPSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a continuous chromatographic separation method and application, wherein separation bed liquid circularly flows along a mixed liquid feed port, a raffinate discharge port, an eluent feed port, an extract discharge port and a mixed liquid feed port, and the mixed liquid feed port, the raffinate discharge port, the eluent feed port and the extract discharge port move along the liquid flow direction after each time t passes. The method has the advantages of simple process, high separation degree, high yield, low energy consumption and low production cost, and is suitable for industrial continuous production.
Description
Technical Field
The invention belongs to the technical field of chemical separation, and particularly relates to a continuous chromatographic separation method and application.
Background
Chromatographic separation is a method of using the differences in the physical and chemical properties of the components in a sample to distribute the components in two phases to different extents, one of the phases being a stationary phase and the other phase flowing through the stationary phase, known as a mobile phase, and moving the components at different rates to achieve separation.
Column chromatography is often used for separating complex organic systems, but has the characteristics of intermittent operation, small treatment capacity and incapability of large-scale industrial production.
Vitamin A is an important nutritional chemical, and vitamin A isomers are contained in industrially synthesized vitamin A crude products, and the current method for separating vitamin A and vitamin A isomers is a solution low-temperature crystallization method. Dissolving the vitamin A crude product in methanol or ethanol, cooling to below-25 ℃ for crystallization, centrifuging and drying to obtain vitamin A solid, and converting vitamin A isomer in mother liquor into vitamin A through an isomerization process. However, the low-temperature crystallization energy consumption is high, and the product purity and the crystallization yield in the crystallization process are contradictory, and the crystallization yield of the vitamin A is only about 80% on the premise of meeting the purity index of the commercial product. The residual vitamin a in the mother liquor may cause a decrease in conversion rate of isomers when undergoing isomerization reaction, further decreasing separation efficiency.
High Performance Liquid Chromatography (HPLC) is commonly used for separating and analyzing vitamin A, but HPLC stationary phase has low utilization rate and small treatment capacity, the sample injection concentration is usually hundreds to thousands ppm, and the method is batch operation, and can only process mg-level samples at a time, so that the method can not be applied to industrial production obviously.
In order to overcome the defects of the existing separation technology and separate vitamin A and vitamin A isomer more efficiently, the invention provides a novel continuous chromatographic separation method and application.
Disclosure of Invention
The invention aims to provide a novel continuous chromatographic separation method and application thereof, which can separate substances which are difficult to separate in industrial production by utilizing the chromatographic separation method, and has the advantages of simple method, high separation degree, high yield and low energy consumption, and is suitable for industrial production.
In order to solve the problems, the invention provides a continuous chromatographic separation method, which comprises a separation device, wherein the separation device comprises a separation bed, a mixed liquor feed port, a raffinate discharge port, an eluent feed port and an extract discharge port, the separation bed is provided with a plurality of separation beds, the separation bed is divided into four areas, the four areas are connected in series to form a closed system, a III area is arranged between the mixed liquor feed port and the raffinate discharge port, a IV area is arranged between the raffinate discharge port and the eluent feed port, a I area is arranged between the eluent feed port and the extract discharge port, and a II area is arranged between the extract discharge port and the mixed liquor feed port; the liquid of the separation bed circularly flows along the mixed liquid feed port, the raffinate discharge port, the eluent feed port, the extract discharge port and the mixed liquid feed port, the raffinate discharge port, the eluent feed port and the extract discharge port move along the liquid flowing direction after each time t passes.
Preferably, each zone may comprise 1 or more separation beds, preferably comprising 1 to 4 separation beds.
Preferably, the separation bed is filled with packing.
Preferably, the mixed liquor feed port, the raffinate discharge port, the eluent feed port, and the extract discharge port are moved to the next separation bed along the liquid flow direction every time t passes.
Preferably, the time t is chosen between the residence times of the two components to be separated in the separation bed. For example, the residence time of component A in the separation bed is T1, the residence time of component B in the separation bed is T2, T1 < T < T2 if component A and component B are to be separated.
Preferably, the flow rate Q of the extract E Flow rate Q of feed liquid F Flow rate Q of raffinate R Flow rate Q of eluent D 。
Different fillers and organic solvents, eluents and the like can be selected according to different requirements of the substances to be separated.
The utility model is formed by connecting a plurality of separating beds in series, and the end to end forms a closed system. The four inlets and outlets of the feed liquid inlet, the eluent inlet, the extract liquid outlet and the raffinate outlet divide all the separation beds into four areas with different flow rates and respectively bear different functions. The mobile phase and stationary phase countercurrent is simulated by periodically switching the four inlets and outlets, so that the continuity is realized, the separation efficiency and the production efficiency are improved, and the production cost is reduced.
A method for separating vitamin a and vitamin a isomers comprising the steps of:
(1) Dissolving a mixture containing vitamin A and vitamin A isomer in an organic solvent to prepare a feed liquid;
(2) By adopting the chromatographic separation method, the feed liquid and the eluent are continuously introduced into the chromatographic separation device, and the extract liquid and the raffinate are respectively collected;
(3) Separating and purifying the extract and raffinate respectively.
In the invention, the filler filled in the separation bed is one or more of polystyrene resin, phenyl bonded silica gel, octyl silane bonded silica gel and octadecyl silane bonded silica gel; octadecylsilane chemically bonded silica gel is preferred;
in the invention, the diameter of the silica gel filler is 5-200 mu m, and the aperture is 10-100 nm;
the separation bed is filled with filling materials such as bonding silica gel, and the filling materials such as bonding silica gel and the like with the surfaces rich in nonpolar groups can have hydrophobic interaction with a long carbon chain and an aliphatic hydrocarbon main ring in the vitamin A according to the principle of similar compatibility, so that the difference of cis-trans of double bonds between the vitamin A and isomers is identified. The packing is used as a stationary phase, the types and the proportion of eluent are regulated, and the proper flow rate and the switching time of each region are designed, so that the continuous separation of vitamin A and vitamin A isomers can be realized.
In the present invention, each zone contains 1 to 3 separation beds;
in the invention, the positions of a feed liquid inlet, an eluent inlet, an extract outlet and a raffinate outlet are respectively moved to the next bed along the flowing direction at the same time when the time t1 passes;
in the invention, the time t1 is 10 to 60 minutes; preferably 15-30 minutes;
in the invention, the organic solvent in the step (1) and the eluent in the step (2) are one or a mixture of any two of alcohol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate and dichloromethane with C1-C4;
in the invention, the organic solvent in the step (1) has the same composition as the eluent in the step (2);
in the invention, the concentration of the feed liquid is 20-200 g/L; preferably 50-100 g/L;
in the invention, the flow rate Q of the feed liquid F At a flow rate Q of the eluent of 0.1-0.5 BV/h D At a flow rate Q of the extract of 1-10 BV/h E ＝Q F Flow rate Q of raffinate R ＝Q D The method comprises the steps of carrying out a first treatment on the surface of the Preferably, Q F 0.2-0.3 BV/h, Q D 2-5 BV/h;
in the invention, the temperature of the separation bed is 10-50 ℃; preferably 20 to 30 ℃;
in the invention, the diameter of the separation bed is 10-500 mm, and the length is 100-1000 mm;
in the invention, the extraction liquid and the raffinate are respectively subjected to vacuum distillation to remove the organic solvent, so as to respectively obtain vitamin A and vitamin A isomer, wherein the distillation temperature is 20-40 ℃, and the vacuum degree is 5-30 KPaA.
The long carbon chain and the aliphatic hydrocarbon main ring in the vitamin A have hydrophobic interaction with the nonpolar groups on the filler, the filler has relatively strong effect on the vitamin A, has relatively weak effect on the vitamin A isomer, and has almost no effect on the polar eluent.
After the vitamin A and the isomer solution thereof are fed from the feed inlet, the vitamin A isomer is more easily taken away by the fast flowing eluent, the relative content of the vitamin A isomer is higher and higher along with the flowing direction of the liquid in the zone III, when the liquid reaches the raffinate discharge outlet, the relative concentration of the isomer reaches the highest, and the isomer solution is obtained after discharging.
For vitamin a, it stays more easily on the packing, with the "counter-current" packing (achieved by switching the outlet) being brought into zone II. In the zone II, the relative content of vitamin A is higher against the flowing direction of the liquid, the relative concentration of vitamin A reaches the highest at the discharge port of the extracting solution, and the vitamin A solution is obtained after discharging.
The I zone and the IV function as regeneration zones to realize the regeneration of the eluent and the filling (regeneration means no vitamin A and isomers thereof).
The invention also provides a purification method of the vitamin A mother solution, which comprises the following steps:
(a) Dissolving vitamin A mother liquor containing vitamin A and isomers thereof in an organic solvent to prepare a feed liquid;
(b) By adopting the chromatographic separation method, the feed liquid and the eluent are continuously introduced into the chromatographic separation device, and the extract liquid containing vitamin A and isomers thereof is collected from the discharge port of the extract liquid;
in some preferred embodiments of the invention, the vitamin A and its isomers can be separated from other impurity components by selecting the filler, the total mass content of the vitamin A and its isomers in the vitamin A mother liquor is 10% -50%, and when the content of the vitamin A and its isomers is low, the method has better separation effect than other methods, and can improve the effective utilization rate of the vitamin A.
In the invention, the filler filled in the separation bed is silica gel or alumina;
in the invention, the diameter of the filling material filled in the separation bed is 10-200 mu m, and the pore diameter of the filling material is 10-100 nm;
in the invention, a feed liquid inlet, an eluent inlet, an extract liquid outlet and a raffinate liquid outlet respectively move to the next bed along the flowing phase direction at the same time when the time t2 passes;
in the invention, the time t2 is 5-50 minutes; preferably 10 to 20 minutes;
in the present invention, the organic solvent of step (a) is the same as the eluent of step (b);
in the present invention, the organic solvent of step (a) and the eluent of step (b) are C5-C8 alkanes, cycloalkanes, and mixtures thereof;
in the invention, the concentration of the feed liquid is 200-500 g/L; preferably 300 to 400g/L.
In the invention, the flow rate Q of the feed liquid F At a flow rate Q of the eluent of 0.2-1 BV/h D The flow rate Q of the extract liquid is 2-8 BV/h E ＝Q F Flow rate Q of raffinate R ＝Q D The method comprises the steps of carrying out a first treatment on the surface of the Preferably, Q F 0.4-0.6 BV/h, Q D 4-6 BV/h;
in the invention, the temperature of the multistage series beds is 0-30 ℃; preferably 20 to 30 ℃;
in the invention, the diameter of the multistage series bed is 10-500 mm, and the length is 500-2000 mm.
The vitamin A and the isomers thereof and the retinoid impurities have different adsorption effects on the surface of the polar filler due to the polarity difference, the filler has relatively strong effects on the vitamin A and the isomers thereof, has relatively weak effects on the retinoid impurities, and has almost no effects on the nonpolar eluent.
After the vitamin A mother solution is fed from the feed inlet, the vitamin A-like impurities are more easily taken away by the fast flowing eluent, the relative content of the vitamin A-like impurities is higher and higher along with the flowing direction of the liquid in the area III, when the liquid reaches the raffinate discharge outlet, the relative concentration of the vitamin A-like impurities reaches the highest, and the impurity solution almost containing the vitamin A and isomers thereof is obtained after discharging.
For vitamin a and its isomers, it stays more easily on the packing, with the "counter-current" packing (achieved by switching the outlet) being brought into zone II. In zone II, the relative content of vitamin A and its isomer is higher against the flow direction of the liquid, the relative concentration of vitamin A and its isomer is highest at the outlet of the extract, and the purified solution rich in vitamin A and its isomer is obtained after discharging.
The I zone and the IV function as regeneration zones to realize the regeneration of the eluent and the filler (regeneration refers to the absence of vitamin A and isomers and retinoid impurities).
Compared with the existing vitamin A separation method, the method has the following positive effects:
a. compared with the prior art, the device is simpler, and the relative movement of the stationary phase is realized by switching the outlets at intervals of t time, so that different substances are separated. Continuous operation, mild conditions and easy realization of industrial production;
b. the separation degree of the vitamin A and the isomer thereof is improved by utilizing the adsorption capability difference of the vitamin A and the isomer thereof in the filler, and the separation efficiency of the vitamin A and the vitamin A isomer is obviously improved; the purity and the yield of the obtained vitamin A are high;
drawings
Fig. 1 is a schematic diagram of the structure of a multistage series separation bed provided in the present invention (taking 3 beds per functional zone as an example).
In fig. 1, each square represents a separation bed, a zone iii is formed between the mixed liquor feed port and the raffinate feed port, a zone iv is formed between the raffinate feed port and the eluent feed port, a zone i is formed between the eluent feed port and the extract feed port, and a zone ii is formed between the extract feed port and the mixed liquor feed port.
Detailed Description
The process according to the invention is further illustrated by the following specific examples, but the invention is not limited to the examples listed but encompasses any other known modifications within the scope of the claims.
The solvents used in the invention are all industrial grade, and vitamin A isomer are self-produced.
Analysis of vitamin a and vitamin a isomers was performed using High Performance Liquid Chromatography (HPLC) under the following conditions:
shimadzu LC-20A, a SIL-20A autosampler, a CTO-10ASvp column incubator, an SPD-M20A detector, or an instrument with the same performance. Liquid chromatography conditions: sample injection amount is 1 mu L, UV detection wavelength is 328nm, column temperature box: 40 ℃, flow rate: and (3) quantifying by an external standard method at 0.4 ml/min.
Example 1
1. A mixture containing vitamin a and 11-cis vitamin a isomer (60% of vitamin a, 35% of 11-cis isomer, and 5% of the other) was dissolved in methanol to prepare a 50g/L feed solution;
2. the four functional zones of the multistage tandem bed respectively contain 3/3/3/3 beds, and the size of each bed is 10mm multiplied by 100mm; wherein, the octyl silane bonding silica gel filler with the diameter of 5-20 mu m and the aperture of 10-20 nm is filled; the eluent is methanol.
3. Series separation bed operating conditions:
1) Temperature: 20 ℃;
2) Flow rate of feed liquid: 0.2BV/h, flow rate of extract = feed flow rate; methanol eluent flow rate 5BV/h, raffinate flow rate = methanol eluent flow rate;
3) Time for switching positions of feeding and discharging ports: and (3) moving the positions of the feed inlet and the discharge outlet to the next separation bed along the liquid flowing direction for 15min at intervals of 15 min.
4. After the operation is stable, continuously collecting an extract containing vitamin A from an extract discharge port, removing methanol from the extract at 40 ℃ under the condition of 10-22 KPaA to obtain vitamin A, and analyzing by HPLC, wherein the purity is 98.2%, and the yield is 96%; the raffinate was stripped of methanol under the same conditions to give the 11-cis isomer, which was analyzed by HPLC and had a vitamin A content of 2.5%.
Example 2
1. A mixture containing vitamin a and 9-cis vitamin a isomer (75% of vitamin a, 18% of 9-cis isomer, and 7% of the other) was dissolved in ethanol to prepare a 200g/L feed solution;
2. the same multistage tandem separation bed as in example 1 was employed, with the main difference that the four functional groups of the multistage tandem separation bed each contained 2/3/3/2 beds each having a size of 500mm×1000mm; wherein octadecylsilane chemically bonded silica filler with the diameter of 150-200 mu m and the aperture of 80-100 nm is filled; the eluent is ethanol.
3. Tandem bed operating conditions:
1) Temperature: 30 ℃;
2) Flow rate of feed liquid: 0.5BV/h; flow rate of extract = feed flow rate; the flow rate of the ethanol eluent is 10BV/h; flow rate of raffinate = eluent flow rate;
3) Time for switching positions of feeding and discharging ports: 30min.
4. After the operation is stable, continuously collecting an extract containing vitamin A from an extract discharge port, removing ethanol from the extract at 40 ℃ under the condition of 5-18 KPaA to obtain vitamin A, and analyzing by HPLC, wherein the purity is 98.6%, and the yield is 98%; the raffinate was stripped of ethanol under the same conditions to give the 9-cis isomer, which was analyzed by HPLC and contained 1.1% vitamin A.
Example 3
1. A mixture containing vitamin a and 13-cis vitamin a isomer (80% of vitamin a, 10% of 13-cis isomer, and 10% of the other) was dissolved in acetone to prepare a feed solution of 100g/L;
2. the four functional groups of the multistage tandem beds respectively contain 2/2/2/2 beds, and the size of each bed is 100mm multiplied by 500mm, wherein octadecylsilane chemically bonded silica filler with the diameter of 60-80 mu m and the pore diameter of 30-50 nm is filled in the beds; the eluent is acetone.
3. Tandem bed operating conditions:
1) Temperature: 40 ℃;
2) Flow rate of feed liquid: 0.3BV/h, flow rate of extract = feed flow rate; acetone eluent flow rate 2BV/h, raffinate flow rate = eluent flow rate;
3) Time for switching positions of feeding and discharging ports: and 60min.
4. After the operation is stable, continuously collecting an extract containing vitamin A from an extract discharge port, removing acetone from the extract at 20 ℃ under the condition of 15-25 KPaA to obtain vitamin A, and analyzing by HPLC, wherein the purity is 98.0%, and the yield is 95%; acetone was removed from the raffinate under the same conditions to give the 13-cis isomer, which was analyzed by HPLC, wherein the vitamin A content was 4.5%.
Examples 4-7 are vitamin A and its isomers separated from their mother liquor by the process of the present invention, and finally a mixture of vitamin A and its isomers is obtained.
Example 4
1. Dissolving mother solution containing vitamin A (total mass content of vitamin A and 9-cis isomer is 10%, and the balance is retinoid impurity and vitamin A modified product) in hexane to prepare 200g/L feed solution;
2. the four functional groups of the multistage separation bed respectively comprise 2/4/4/2 beds, and each bed has a size of 10mm multiplied by 500mm; wherein, the silica gel filler with the diameter of 10-20 mu m and the aperture of 10-20 nm is filled; the eluent is hexane.
3. Series separation bed operating conditions:
1) Temperature: 0 ℃;
2) Flow rate of feed liquid: 0.2BV/h; hexane eluent flow rate 8BV/h; flow rate of extract = feed flow rate, flow rate of raffinate = eluent flow rate.
3) Time for switching positions of feeding and discharging ports: 50min.
4. After the operation is stable, continuously collecting the extract containing vitamin A and the isomer thereof from the extract outlet, and analyzing the extract by HPLC, wherein the purity of the vitamin A and the isomer thereof is 88 percent, and the yield is 93 percent.
Example 5
1. Dissolving vitamin A mother liquor (total mass content of vitamin A and 13-cis isomer is 50%) in heptane to prepare 500g/L feed liquor;
2. four functional groups of the multistage series separation beds each contain 2/4/3/3 beds, each bed size 100mm x 2000mm; wherein, alumina filler with the diameter of 80-120 mu m and the aperture of 80-100 nm is filled;
3. tandem bed operating conditions:
1) Temperature: 30 ℃;
2) Flow rate of feed liquid: 1BV/h; the flow rate of the heptane eluent is 4BV/h; flow rate of extract = feed flow rate, flow rate of raffinate = eluent flow rate.
3) Time for switching positions of feeding and discharging ports: 20min.
4. After the operation is stable, continuously collecting the extract containing vitamin A and the isomer thereof from the extract outlet, and analyzing the extract by HPLC, wherein the purity of the vitamin A and the isomer thereof is 92 percent, and the yield is 96 percent.
Example 6
1. Dissolving vitamin A mother solution (vitamin A and 9-cis isomer content is 30%) in petroleum ether with boiling range of 60-90 ℃ to prepare 300g/L feed solution;
2. four functional groups of the multistage tandem beds respectively contain 2/4/2/2 beds, and each bed has a size of 500mm multiplied by 500mm; wherein, alumina filler with the diameter of 50-80 mu m and the aperture of 40-60 nm is filled;
3. tandem bed operating conditions:
1) Temperature: 20 ℃;
2) Flow rate of feed liquid: 0.4BV/h; the flow rate of petroleum ether eluent is 2BV/h; flow rate of extract = feed flow rate, flow rate of raffinate = eluent flow rate.
3) Time for switching positions of feeding and discharging ports: 5min.
4. After the operation is stable, continuously collecting the extract containing vitamin A and the isomer thereof from the extract discharge port, and analyzing the extract by HPLC, wherein the purity of the vitamin A and the isomer thereof is 90 percent, and the yield is 96 percent.
Example 7
1. Dissolving vitamin A mother liquor (vitamin A and 11-cis isomer content 20%) in isooctane to prepare 400g/L feed liquor;
2. the four functional zones of the multistage tandem bed respectively contain 4/4/4/4 beds, each bed size being 200mm by 1000mm; wherein, the silica gel filler with the diameter of 150-200 mu m and the aperture of 80-100 nm is filled;
3. tandem bed operating conditions:
1) Temperature: 10 ℃;
2) Flow rate of feed liquid: 0.6BV/h; the flow rate of the isooctane eluent is 6BV/h; flow rate of extract = feed flow rate, flow rate of raffinate = eluent flow rate;
3) Time for switching positions of feeding and discharging ports: and 10min.
4. After the operation is stable, continuously collecting the extract containing vitamin A and the isomer thereof from the extract discharge port, and analyzing the extract by HPLC, wherein the purity of the vitamin A and the isomer thereof is 93 percent, and the yield is 97 percent.
All modifications and equivalent substitutions to the technical proposal of the invention are included in the protection scope of the invention without departing from the scope of the technical proposal of the invention.
Claims (32)
1. A method for separating vitamin a from vitamin a isomers comprising the steps of:
(1) Dissolving a mixture containing vitamin A and vitamin A isomer in an organic solvent to prepare a feed liquid;
(2) Separating vitamin A and vitamin A isomer by the following separation method, and collecting extract and raffinate respectively;
in the separation method, a separation device comprises a separation bed, a mixed liquor feed port, a raffinate discharge port, an eluent feed port and an extract discharge port, wherein the separation bed is provided with a plurality of separation beds, the separation bed is divided into four areas, the four areas are connected in series to form a closed system, a III area is arranged between the mixed liquor feed port and the raffinate discharge port, a IV area is arranged between the raffinate discharge port and the eluent feed port, a I area is arranged between the eluent feed port and the extract discharge port, and a II area is arranged between the extract discharge port and the mixed liquor feed port; the liquid of the separation bed circularly flows along a mixed liquid feed port, a raffinate discharge port, an eluent feed port, an extract discharge port and a mixed liquid feed port, and the mixed liquid feed port, the raffinate discharge port, the eluent feed port and the extract discharge port move along the liquid flowing direction after each time t passes;
(3) Separating and purifying the extract and raffinate respectively;
the separation bed is filled with a packing; the filler filled in the separation bed is one or more of polystyrene resin, phenyl bonding silica gel, octyl silane bonding silica gel and octadecyl silane bonding silica gel;
the mixed liquid feed port, the raffinate discharge port, the eluent feed port and the extract discharge port move to the next separation bed along the liquid flow direction after each time t passes;
the time t is chosen between the residence times of the two components to be separated in the separation bed.
2. The separation process of claim 1 wherein each zone comprises 1 or more separation beds.
3. The separation process of claim 2, wherein each zone comprises 1-4 separation beds.
4. The separation process according to claim 1, wherein the flow rate Q of the extract E Flow rate Q of feed liquid F Flow rate Q of raffinate R Flow rate Q of eluent D 。
5. The separation method according to claim 1, wherein the packing packed in the separation bed is octadecylsilane chemically bonded silica.
6. The separation method according to claim 1, wherein the silica gel filler has a diameter of 5 to 200 μm and a pore diameter of 10 to 100nm.
7. The separation process of claim 1, wherein each zone contains from 1 to 3 separation beds.
8. The separation method according to claim 1, wherein the organic solvent and the eluent in the step (1) are one or a mixture of any two of C1-C4 alcohols, acetonitrile, acetone, tetrahydrofuran, ethyl acetate and dichloromethane.
9. The separation method according to claim 1, wherein the organic solvent of step (1) is the same composition as the eluent.
10. The separation method according to claim 1, wherein the feed liquid inlet, the eluent inlet, the extract liquid outlet and the raffinate outlet are simultaneously moved to the next bed in the mobile phase direction for a time t1 of 10 to 60 minutes, respectively, every time t1 passes.
11. The separation method according to claim 10, wherein the time t1 is 15-30 minutes.
12. The separation method according to claim 1, wherein the concentration of the feed solution is 20 to 200g/L.
13. The separation method according to claim 12, wherein the concentration of the feed solution is 50 to 100g/L.
14. The separation method according to claim 1, wherein the flow rate Q of the feed liquid F At a flow rate Q of the eluent of 0.1-0.5 BV/h D At a flow rate Q of the extract of 1-10 BV/h E ＝Q F Flow rate Q of raffinate R ＝Q D 。
15. The separation method according to claim 1, wherein Q F 0.2-0.3 BV/h, Q D Is 2-5 BV/h.
16. The separation method according to claim 1, wherein the temperature of the separation bed is 10 to 50 ℃.
17. The separation process according to claim 16, wherein the temperature of the separation bed is 20-30 ℃.
18. The separation method according to claim 1, wherein the separation bed has a diameter of 10 to 500mm and a length of 100 to 1000mm.
19. A method for purifying a vitamin a mother liquor comprising the steps of:
(a) Dissolving vitamin A mother liquor containing vitamin A and isomers thereof in an organic solvent to prepare a feed liquid;
(b) The separation method according to claim 1, wherein the feed liquid and the eluent are introduced, and the extract liquid containing vitamin A and isomers thereof is collected from the outlet of the extract liquid; the feed liquid inlet, the eluent inlet, the extract liquid outlet and the raffinate outlet are respectively moved to the next bed along the flowing phase direction at the same time every time of the passing time t 2;
the packing filled in the separation bed is silica gel or alumina; the pore diameter of the filler is 10-100 nm.
20. The method of claim 19, wherein the total mass content of vitamin a and its isomers in the vitamin a mother liquor is 10% to 50%.
21. The method according to claim 19, wherein the packed bed is packed with a packing diameter of 10 to 200 μm.
22. The method of claim 19, wherein the time t2 is from 5 to 50 minutes.
23. The method of claim 22, wherein the time t2 is 10 to 20 minutes.
24. The method of claim 19, wherein the organic solvent of step (a) is the same as the eluent of step (b).
25. The process of claim 19 wherein the organic solvent of step (a) and the eluent of step (b) are C5 to C8 alkanes, cycloalkanes, and mixtures thereof.
26. The method of claim 19, wherein the feed solution has a concentration of 200 to 500g/L.
27. The method of claim 26, wherein the feed solution has a concentration of 300 to 400g/L.
28. The method of claim 19, wherein the feed liquid has a flow rate Q F At a flow rate Q of the eluent of 0.2-1 BV/h D The flow rate Q of the extract liquid is 2-8 BV/h E ＝Q F Flow rate Q of raffinate R ＝Q D 。
29. The method of claim 28, wherein Q F 0.4-0.6 BV/h, Q D 4-6 BV/h.
30. The method of claim 28, wherein the temperature of the multistage tandem beds is between 0 and 30 ℃.
31. The method of claim 30, wherein the temperature of the multistage tandem beds is 20-30 ℃.
32. The method of claim 31, wherein the multistage tandem beds have a diameter of 10 to 500mm and a length of 500 to 2000mm.
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| CN101391159A (en) * | 2008-10-13 | 2009-03-25 | 浙江大学宁波理工学院 | Improved simulated moving bed separation method |
| CN102336792A (en) * | 2010-07-22 | 2012-02-01 | 辽宁科技大学 | Three-zone simulated moving bed chromatography method for separating and purifying paeoniflorin |
| CN103570512A (en) * | 2013-11-12 | 2014-02-12 | 华东理工大学 | Method for separating guaiacol glyceryl ether enantiomer through simulated moving bed chromatography technology |
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| CN101391159A (en) * | 2008-10-13 | 2009-03-25 | 浙江大学宁波理工学院 | Improved simulated moving bed separation method |
| CN102336792A (en) * | 2010-07-22 | 2012-02-01 | 辽宁科技大学 | Three-zone simulated moving bed chromatography method for separating and purifying paeoniflorin |
| CN103570512A (en) * | 2013-11-12 | 2014-02-12 | 华东理工大学 | Method for separating guaiacol glyceryl ether enantiomer through simulated moving bed chromatography technology |
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