CN111909089A - Preparation method of mikui ammonium chloride reference substance - Google Patents
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 239000013558 reference substance Substances 0.000 title claims abstract description 20
- 235000019270 ammonium chloride Nutrition 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 54
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 20
- 238000000926 separation method Methods 0.000 claims abstract description 19
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 10
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 10
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000010262 high-speed countercurrent chromatography Methods 0.000 claims abstract description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical group CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940090181 propyl acetate Drugs 0.000 claims abstract description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940035429 isobutyl alcohol Drugs 0.000 claims abstract 2
- 239000007787 solid Substances 0.000 claims description 17
- 239000003957 anion exchange resin Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000006228 supernatant Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 4
- 238000013375 chromatographic separation Methods 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000002427 irreversible effect Effects 0.000 abstract description 3
- -1 quaternary ammonium salt compounds Chemical class 0.000 abstract description 3
- 238000001179 sorption measurement Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 206010021118 Hypotonia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IZTUINVRJSCOIR-UHFFFAOYSA-N benzylisoquinoline Chemical compound N=1C=CC2=CC=CC=C2C=1CC1=CC=CC=C1 IZTUINVRJSCOIR-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Abstract
The invention discloses a preparation method of a mikui ammonium chloride reference substance, and relates to the technical field of separation and purification of large-polarity quaternary ammonium salt compounds. The preparation method comprises the steps of carrying out reflux reaction on R- (+) -5' -methoxylapatin, 3-chloro-1-propanol, sodium iodide and sodium carbonate in an organic solvent to obtain a crude product, carrying out high-speed countercurrent chromatographic separation on the crude product, and carrying out separation by using a solvent in a volume ratio of 1-5: 1-10: 1-10 parts of a solvent A, a solvent B and a solvent C form a high-speed counter-current solvent system, wherein the solvent A is ethyl acetate, propyl acetate or butyl acetate, the solvent B is n-butyl alcohol or isobutyl alcohol, the solvent C is water, the upper phase is a stationary phase, and the lower phase is a mobile phase, and the mickey ammonium chloride reference substance is obtained by separation. The micstore ammonium chloride reference substance 950U77 is prepared by adopting a high-speed counter-current chromatography, and compared with the traditional column chromatography separation, the method has the advantages of no irreversible adsorption, sample loss avoidance, short separation time, good separation effect, small solvent consumption and mass production.
Description
Technical Field
The invention belongs to the field of separation and purification of large-polarity quaternary ammonium salt compounds, and particularly relates to a preparation method of a micaceous ammonium chloride reference substance.
Background
Mickoamine, also known as mevisone, is a benzylisoquinoline short-acting non-depolarizing neuromuscular blocker, mainly used for tracheal intubation and muscle relaxation maintenance. Because the mickey ammonium chloride structure contains two chiral carbons and two chiral nitrogens, wherein the configuration of the chiral carbons is a fixed R type, and the molecules are symmetrical structures, the finally synthesized mickey ammonium chloride consists of three non-separated diastereoisomers, and the ratio of the three diastereoisomers in the current commercially available patent medicine is cis-cis: cis-trans: trans-trans ≈ 5:40: 55. Since the final product is a mixture without separation, and the ratio of the three will have small deviation due to different process operations, the hydrolysate 950U77 (trans-hydrolysate) is selected as the reference substance when the content is calibrated, so as to increase the accuracy of content determination.
The micakammonium chloride has the following structural formula:
micaka ammonium chloride control 950U77 has the following structural formula:
in the patent US4761418, the 950U77 crude product is dissolved by water, then is frozen to 0 ℃, the solid is pumped out, and then is adsorbed by macroporous resin, and the residual isomer is removed by DMF, namely 950U77, and the practical operation shows that the separation of the two isomers can not be realized. In the prior art, a conventional column chromatography separation method is generally adopted to obtain a micstore ammonium chloride reference substance 950U77 through separation, the quaternary ammonium salt compound has high polarity, and the polarity of 950U77 is close to that of a cis-diastereoisomer generated in the reaction process, so that the separation process is time-consuming and labor-consuming, the silica gel of a stationary phase separated by column chromatography has an irreversible adsorption effect on a sample, and the sample is partially degraded due to long-time contact with the silica gel, so that the final yield is not high. High-speed countercurrent chromatography (HSCCC) is a continuous high-efficiency and rapid liquid-liquid distribution chromatographic separation technology without a solid support, has the advantages of no sample loss, no pollution, high efficiency, rapidness and the like, and is widely applied to the preparation, separation and purification of chemical substances in the fields of biology, medicine and the like.
Disclosure of Invention
The invention aims to provide a method for preparing a micstore ammonium chloride reference substance by utilizing high-speed counter-current chromatography separation and purification, which can quickly and efficiently separate and purify the micstore ammonium chloride reference substance.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a preparation method of micrbammonium chloride reference substance comprises the following steps:
(1) carrying out reflux reaction on R- (+) -5' -methoxy laudanosine, 3-chloro-1-propanol, sodium iodide and sodium carbonate in an organic solvent, filtering, and evaporating filtrate to dryness to obtain a solid A;
(2) preparing a crude product of a micaceium chloride reference substance: dissolving the solid A obtained in the step (1) with water, adding anion exchange resin, stirring, performing suction filtration, exchanging the filtrate with the anion exchange resin once, adding sodium chloride into the water to separate out a product, extracting with an extractant, and evaporating to dryness to obtain a reference product crude product of mikul ammonium chloride;
(3) and (3) purifying the crude product of the micaceium chloride reference substance: forming a high-speed counter-current solvent system by using a solvent A, a solvent B and a solvent C, fully mixing the high-speed counter-current solvent system, standing, separating an upper phase and a lower phase, taking the upper phase as a stationary phase and the lower phase as a mobile phase, filling the stationary phase into a multi-layer coil separation column of a high-speed counter-current chromatograph, and then injecting the mobile phase; dissolving the crude product of the micstore ammonium chloride reference substance obtained in the step (2) by using a lower phase, then injecting a sample, collecting a first peak in an effluent liquid, adding sodium chloride into a collected liquid to separate out a product, extracting by using an extracting agent, adding diethyl ether after drying by distillation to separate out a solid, pouring out a supernatant, and drying the solid to obtain the micstore ammonium chloride reference substance;
preferably, the solvent A is ethyl acetate or propyl acetate or butyl acetate, the solvent B is n-butanol or isobutanol, and the solvent C is water.
Preferably, the solvent A is ethyl acetate, and the solvent B is n-butanol.
Preferably, the volume ratio of the solvent A, the solvent B and the solvent C is as follows: solvent A: solvent B: solvent C ═ (1-5): (1-10): (1-10).
Preferably, the volume ratio of the solvent A, the solvent B and the solvent C is as follows: solvent A: solvent B: solvent C ═ 1:4: 6.
preferably, in the step (1), the molar ratio of R- (+) -5' -methoxylapatin, 3-chloro-1-propanol, sodium iodide and sodium carbonate is as follows: r- (+) -5' -methoxylapatin: 3-chloro-1-propanol: sodium iodide: sodium carbonate 1: (1-2.5): (1-2.5): (0.1-1), the ratio of the volume of the organic solvent to the mass of the R- (+) -5' -methoxylapatin is (5-20): 1mL/g, and the organic solvent is at least one of acetone, acetonitrile and ethyl acetate.
Preferably, in the step (2), the anion exchange resin is a strongly basic anion exchange resin.
Preferably, in the step (2), the strongly basic anion exchange resin is a 201 × 7 strongly basic anion exchange resin.
Preferably, in the step (3), the wavelength of the high-speed counter-current chromatograph ultraviolet detector is set to be 254-300 nm, and the mobile phase is injected at a flow rate of 2-10 mL/min at a rotation speed of 500-1000 r/min.
Preferably, in the step (3), the wavelength of the ultraviolet detector in the high-speed countercurrent chromatograph is 279 nm.
Preferably, in the step (3), the rotating speed is 800 r/min.
Compared with the prior art, the invention has the beneficial effects that: the separation process of the invention can be continuously carried out, the operation is simple and convenient, and the efficiency is high; and the method adopts high-speed counter-current chromatography preparation, has no irreversible adsorption, avoids sample loss, and has the characteristics of good separation effect, small solvent consumption, no pollution, high efficiency and high speed.
Drawings
FIG. 1 is a liquid chromatogram of crude 950U77 prepared in example 1;
FIG. 2 is a high-speed countercurrent chromatographic separation of 950U77 prepared in example 1;
FIG. 3 is a liquid chromatogram of purified 950U77 prepared in example 1.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
Example 1
In an embodiment of the preparation method of the present invention, the preparation method of this embodiment includes the following steps:
1) adding 5.0g R- (+) -5' -methoxylapatin into a 100mL single-neck bottle, adding 75mL acetone to dissolve, sequentially adding 2.8g sodium iodide and 0.25g sodium carbonate, 2.2g of 3-chloro-1-propanol, heating and refluxing for 96h, detecting by thin-layer chromatography (TLC) that the reaction is complete, stopping the reaction, filtering the reaction solution, evaporating the filtrate to dryness to obtain a light yellow foamy solid 7.7g, adding 38ml of deionized water to dissolve the solid, adding 15.4g of 201X 7 strong base anion exchange resin, stirring at room temperature for 30min, carrying out suction filtration, exchanging the filtrate with 15.4g of 201X 7 strong base anion exchange resin once, adding 14.0g of sodium chloride into the water to separate out the product, extracting with dichloromethane (30ml X3 times), drying the dichloromethane layer, and evaporating to dryness to obtain 6.8g of light yellow foamy solid, namely the micstore ammonium chloride reference 950U77 crude product.
And detecting the purity of the obtained crude product by using a high performance liquid chromatograph. Particulate porous Silica gel as filler (Partisil 5Silica) (5 μm, 250 mm. times.4.6 mm); acetonitrile-water (acetonitrile: water 70:30, v/v) is used as a mobile phase; the column temperature was 35 ℃ and the flow rate was 1mL/min, the detection wavelength was 279 nm. The HPLC chromatogram is shown in FIG. 1, the ratio of the two peak areas is about 1:3, compared with the positive control, the 2 nd peak from left to right is 950U77, and the liquid phase content is 72.72%.
2) High-speed counter-current chromatography was applied to separate 950U 77: mixing ethyl acetate, n-butanol and purified water according to a volume ratio of 1:4:6, standing after full mixing, separating an upper phase from a lower phase, wherein the upper phase is a stationary phase, the lower phase is a mobile phase, pumping the stationary phase into a high-speed counter-current chromatograph, starting the high-speed counter-current chromatograph after a plurality of layers of coil separation columns are completely filled, setting the wavelength of an ultraviolet detector of the high-speed counter-current chromatograph to be 279nm, adjusting the rotating speed to be 800r/min (positive rotation), pumping the mobile phase, receiving by a conversion cylinder, and indicating that the system is well balanced when the upper phase of the mobile phase at a receiving position is not. 100mg of the 950U77 crude product obtained in example 1 is taken, dissolved by 6mL of lower phase and then injected, the injection is carried out again every 25min after the injection, the detected spectrogram of an ultraviolet detector is shown in figure 2, the first peak in the double peaks is collected and combined (87 mL for 4 times), 31g of sodium chloride is added into the collected liquid, dichloromethane (50mL multiplied by 3 times) is used for extraction, anhydrous sodium sulfate is dried, oil is obtained by evaporation, 1.2g of oil is obtained, 20mL of ether is added to precipitate white solid, the white solid is left to stand and then the supernatant is removed, and the solid is dried to obtain 162mg of the solid.
3) The purity of the obtained pure product was measured by using a high performance liquid chromatograph. Particulate porous Silica gel as filler (Partisil 5Silica) (5 μm, 250 mm. times.4.6 mm); acetonitrile-water (70:30, v/v) is used as a mobile phase; the column temperature was 35 ℃ and the flow rate was 1mL/min, the detection wavelength was 279 nm. The high performance liquid chromatogram thereof is shown in fig. 3, and the liquid phase purity of 950U77 is 99.67%, and the isomer content is 0.28%.
Example 2
An example of the preparation method of the present invention, compared with example 1, has the following differences: in the step (1), 1.94g of sodium iodide, 0.14g of sodium carbonate, 1.22g of 3-chloro-1-propanol and 25mL of acetone were used.
The purity of the pure product obtained in example 2 was measured by using a high performance liquid chromatograph in the same manner as in example 1, and the liquid phase purity of 950U77 was 99.23%.
Example 3
An example of the preparation method of the present invention, compared with example 1, has the following differences: in the step (1), 4.83g of sodium iodide, 1.37g of sodium carbonate, 3.05g of 3-chloro-1-propanol and 100mL of acetone were used.
The purity of the pure product obtained in example 3 was measured by using a high performance liquid chromatograph in the same manner as in example 1, and the liquid phase purity of 950U77 was 99.35%.
Example 4
An example of the preparation method of the present invention, compared with example 1, has the following differences: in the step (2), the anion exchange resin is a type 202 strong base resin.
The purity of the pure product obtained in example 4 was measured by using a high performance liquid chromatograph in the same manner as in example 1, and the liquid phase purity of 950U77 was 97.50%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The preparation method of the micrbammonium chloride reference substance is characterized by comprising the following steps:
(1) carrying out reflux reaction on R- (+) -5' -methoxy laudanosine, 3-chloro-1-propanol, sodium iodide and sodium carbonate in an organic solvent, filtering, and evaporating filtrate to dryness to obtain a solid A;
(2) preparing a crude product of a micaceium chloride reference substance: dissolving the solid A obtained in the step (1) with water, adding anion exchange resin, stirring, performing suction filtration, exchanging the filtrate with the anion exchange resin once, adding sodium chloride into the water to separate out a product, extracting with an extractant, and evaporating to dryness to obtain a reference product crude product of mikul ammonium chloride;
(3) and (3) purifying the crude product of the micaceium chloride reference substance: forming a high-speed counter-current solvent system by using a solvent A, a solvent B and a solvent C, fully mixing the high-speed counter-current solvent system, standing, separating an upper phase and a lower phase, taking the upper phase as a stationary phase and the lower phase as a mobile phase, filling the stationary phase into a multi-layer coil separation column of a high-speed counter-current chromatograph, and then injecting the mobile phase; dissolving the crude product of the micstore ammonium chloride reference substance obtained in the step (2) by using a lower phase, then injecting a sample, collecting a first peak in an effluent liquid, adding sodium chloride into a collected liquid to separate out a product, extracting by using an extracting agent, adding diethyl ether after drying by distillation to separate out a solid, pouring out a supernatant, and drying the solid to obtain the micstore ammonium chloride reference substance;
the solvent A is ethyl acetate, propyl acetate or butyl acetate, the solvent B is n-butyl alcohol or isobutyl alcohol, and the solvent C is water.
2. The process according to claim 1, wherein the solvent A is ethyl acetate and the solvent B is n-butanol.
3. The method according to claim 1, wherein the volume ratio of the solvent A, the solvent B and the solvent C is: solvent A: solvent B: solvent C ═ (1-5): (1-10): (1-10).
4. The method according to claim 3, wherein the volume ratio of the solvent A, the solvent B and the solvent C is: solvent A: solvent B: solvent C ═ 1:4: 6.
5. the preparation method according to claim 1, wherein in the step (1), the molar ratio of R- (+) -5' -methoxylapatin, 3-chloro-1-propanol, sodium iodide and sodium carbonate is: r- (+) -5' -methoxylapatin: 3-chloro-1-propanol: sodium iodide: sodium carbonate 1: (1-2.5): (1-2.5): (0.1-1), the ratio of the volume of the organic solvent to the mass of the R- (+) -5' -methoxylapatin is (5-20): 1mL/g, and the organic solvent is at least one of acetone, acetonitrile and ethyl acetate.
6. The method according to claim 1, wherein in the step (2), the anion exchange resin is a strongly basic anion exchange resin.
7. The method according to claim 6, wherein in the step (2), the strongly basic anion exchange resin is a 201 x 7 strongly basic anion exchange resin.
8. The method according to claim 1, wherein in the step (3), the wavelength of the UV detector of the high-speed countercurrent chromatography is set to 254-300 nm, and the mobile phase is injected at a flow rate of 2-10 mL/min at a rotation speed of 500-1000 r/min.
9. The method according to claim 8, wherein in the step (3), the wavelength of the ultraviolet detector in the high-speed countercurrent chromatograph is 279 nm.
10. The method according to claim 8, wherein in the step (3), the rotation speed is 800 r/min.
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2020
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