WO2012019500A1 - Bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation - Google Patents

Bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2012019500A1
WO2012019500A1 PCT/CN2011/076902 CN2011076902W WO2012019500A1 WO 2012019500 A1 WO2012019500 A1 WO 2012019500A1 CN 2011076902 W CN2011076902 W CN 2011076902W WO 2012019500 A1 WO2012019500 A1 WO 2012019500A1
Authority
WO
WIPO (PCT)
Prior art keywords
chiral
separation
hpce
column
oxo
Prior art date
Application number
PCT/CN2011/076902
Other languages
English (en)
Chinese (zh)
Inventor
沈静茹
Original Assignee
中南民族大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中南民族大学 filed Critical 中南民族大学
Publication of WO2012019500A1 publication Critical patent/WO2012019500A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/29—Chiral phases
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8877—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample optical isomers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44704—Details; Accessories
    • G01N27/44747—Composition of gel or of carrier mixture

Definitions

  • the present invention relates to bis-[6-oxo-(2-m-carboxybenzenesulfonyl-succinic acid 1,4 monoester-4)]- ⁇ -cyclodextrin and a preparation method thereof and as a chiral selector in high performance capillary electrophoresis (HPCE) is the preparation of chiral HPCE electrophoresis columns and mobile phase chiral additives for the separation of chiral materials.
  • HPCE high performance capillary electrophoresis
  • HPCE Hign Performance Capillary Electrophoresis
  • Chiral separation is difficult to achieve in an achiral environment.
  • some chiral environments such as optically active reagents and solvents, and in stereospecific biological systems, they show great differences. Therefore, the key to chiral separation is to establish a chiral environment.
  • Natural cyclodextrin is often used as a chiral additive for HPCE, which has both advantages and disadvantages.
  • Natural cyclodextrin has three kinds of a-CD, ⁇ -CD and ⁇ -CD: ⁇ -CD has small pores, usually only encapsulates smaller guest substances, and has a narrow application range; ⁇ -CD The molecular cavity is large and can enclose a larger molecular object, but the production cost of ⁇ -CD is high, and it cannot be mass-produced industrially; the molecular cavity size of ⁇ -CD is moderate, so that the inclusion range is wide, and The production cost is low, and it is the only cyclodextrin product produced on an industrial scale. However, the low solubility of ⁇ -CD in water limits its application range.
  • ⁇ -CD can be modified by a derivatization reaction to achieve the following objectives:
  • ⁇ -CD derivatives Existing as a HPCE mobile phase chiral additive ⁇ -CD derivatives are (1) anion-modified CDs, and negatively charged CD derivatives are the most commonly used chiral selectors. Generally, it can be divided into sulfoalkyl ether-derived CDs, sulfonated CDs, and carboxyl-derived CDs. (2) Neutral CDs, such derivatives are mainly methylated CD (Me-CD), hydroxypropyl CD (HP-CD), hydroxyethyl CD (HE-CD). (3) Cation-modified CDs, mainly CDs containing amino and alkoxy groups.
  • Binary CD system which uses a binary CD system, including a highly sulfonated ( ⁇ -, ⁇ -, ⁇ -HSCD) and a neutral CD, any one of seven (2, 3, 6) -3-0-methyl)- ⁇ -CD (TMCD), hepta-(2,6-bis--0-methyl)- ⁇ -CD (DMCD) or hydroxypropyl- ⁇ -CD (HPCD), can be separated 25 different acid-basic drugs (16 alkaline drugs, 8 acidic drugs, 1 neutral drug) showed that the binary CD system is very effective in separating chiral substances and HP-CD alone cannot be separated sufficiently. ,
  • TMCD highly sulfonated
  • DMCD hepta-(2,6-bis--0-methyl)- ⁇ -CD
  • HPCD hydroxypropyl- ⁇ -CD
  • Clark Desiderio uses antibiotics as a chiral selector to separate chiral substances.
  • Jun Haginaka uses protein as a chiral selector to separate chiral drugs, including albumin (BSA, HSA) and other types of serum albumin, glycoproteins and so on.
  • BSA albumin
  • human serum albumin as a chiral selector for the separation of bupivacaine enantiomers in HPCE coated with cetyltrimethylamine bromide.
  • the derivatization of charged groups on CD facilitates the resolution of neutral and oppositely charged enantiomers. This finding further extends the range of applications for CDs, due to the increased charge effect on oppositely charged enantiomers. Generally, the splitting effect can be improved. Therefore, positively charged CDs are often used to resolve anionic enantiomers, while negatively charged CDs are commonly used to resolve cationic enantiomers.
  • the pharmacological action of chiral drugs is achieved by strict chiral recognition and matching with macromolecules in the body. In many cases, there is a significant difference in the pharmacological activity, metabolic processes, metabolic rate, and toxicity of a pair of enantiomers of a compound. In addition, the toxicity of drugs combines many factors, such as the selectivity of receptors, the in vivo processes of drugs and their metabolites, and the selectivity of metabolites for side effects, so racemates and enantiomers, enantiomers and Correct The toxicity between the morphogens can vary widely. Attention should be paid to the pharmacological effects of the different isomers and preferably in the form of a single enantiomer.
  • the drug is converted into a chiral drug (chiral conversion).
  • chiral conversion For the application of a new racemic drug, detailed physiological activity and toxicological data must be provided for both enantiomers and should not be treated as the same substance.
  • the global single enantiomer drug continues to grow, with sales reaching $96.4 billion in 1998. According to the US Chemical and Engineering Weekly report on October 1, 2001, sales in 2000 were $133 billion, and it is estimated that in 2008 Reached 200 billion US dollars. According to 1998 statistics, the world's 500 quietest drugs. More than half of the chiral drugs sold as a single isomer accounted for 52% of their total sales. In recent years, through the conversion of racemates, the conversion of drugs sold as racemates into chiral drugs sold as single isomers has created more substantial benefits.
  • the present invention provides a novel ⁇ -CD derivative: bis-[6-oxo-(2-m-carboxybenzenesulfonyl-succinic acid 1,4 monoester-4)]- ⁇ -CD (p-CD- B 2 ) and preparation method and use.
  • Separation of the chiral substances phenylglycine, anisodamine, isoproterenol and propafenone using P-CD-B 2 as the HPCE mobile phase chiral additive, can achieve baseline separation; preparation of the hand using the ⁇ -CD derivative
  • the HPCE column which can separate chiral substances such as chlorpheniramine, bupivacaine, procaine, atenolol, anisodamine, propafenone and lobeline, can achieve baseline separation.
  • a new method for the quantitative determination of single enantiomers of chiral substances by HPCE was established.
  • the present invention provides a novel meta-carboxybenzenesulfonyl group (OOCC 6 H 5 S0 2 ) and succinate
  • the chiral HPCE column is prepared by chemically bonding the synthesized P-CD-B 2 through an "arm" to the inner surface of the capillary column to form a whole. The column was opened and characterized by scanning electron microscopy to confirm that P-CD-B 2 was bonded to the inner surface of the capillary column. This column method has not been reported in the literature. The column separation efficiency was examined using P-CD-B 2 HPCE columns with different concentrations of bonding (5%, 8%, 12%, 20%, 25%, 30%). Both chlorpheniramine and bupivacaine achieved baseline separation on this new type of chiral HPCE column.
  • the maximum resolution of chlorpheniramine was 3.98, and the bupivacaine resolution was 3.19, which was 17.19 within 4 minutes. Complete the separation; and characterize with the control. Procaine resolution ⁇ 3 ⁇ 4 up to 10.20, anisodamine maximum resolution ⁇ 3 ⁇ 4 up to 1.38, qualitative comparison with the control. The maximum resolution of atenolol is ⁇ 3 ⁇ 4 up to 22.04. Baseline separation can be achieved with both propafenone and lobeline. In contrast to the blank column, the separation could not be achieved under the same conditions.
  • the method for preparing the HPCE column is effective, and the P-CD-B 2 derivative can be successfully bonded to the inner surface of the HPCE column, which further indicates that the open-tube capillary preparation method is feasible, and various The separation of chiral substances is ideal.
  • the invention utilizes this derivative as a chiral selector to establish a new qualitative qualitative and quantitative method for HPCE of a plurality of chiral substance single enantiomers.
  • a new report was issued by the Wuhan Science and Technology Research and Search Center of the Chinese Academy of Sciences, and no literature has been reported.
  • the instruments and reagents used in the present invention are:
  • the K band (219 nm) absorption peak of m-carboxybenzenesulfonyl chloride is present in a molar ratio above a certain ratio, but the structural difference is The maximum absorption peak has a certain blue shift (230 nm:).
  • the concentration of each batch was l.Ox lO- 3 mol'L- 1 , the injection volume was ⁇ , using gradient elution mode, 35-40% acetonitrile content, 40 min elution time, column temperature 30.0 ° C, flow rate was 0.3ml'min- C18 column, detection wavelength 230nm
  • the collected sample was distilled under reduced pressure at 42 ° C (ensure that there was no acetonitrile in the sample), and lyophilized to obtain a pale yellow solid powder, which was further characterized.
  • the diffraction angle (2 ⁇ ) of P-CD, P-CD-A2, and P-CD-B2 is from 10-70 °, nitrogen protection (Cu gram).
  • P-CD-B2 has been purified. It can be seen from Fig. 6 that many diffraction peaks appear in ⁇ -CD. As the reaction progresses, the -OH group is substituted, and the diffraction peak is significantly reduced. It can also be seen that P-CD-B2 and ⁇ -CD and P-CD -A2 has a significant difference in structure.
  • reaction materials P-CD, P-CD-A 2 and product P-CD-B 2 were further identified by nuclear magnetic resonance means, including: 13 C NMR, 'H NMR and HMBC (1H detection of heteronuclear multiple bonds) Related tests), HSQC (1H test).
  • Figure 7 is a 13 C NMR nuclear magnetic map of ⁇ -CD, which can be obtained as C1: 102.573 C2: 73.693 C3: 73.014 C4: 82.162 C5: 72.674 C6: 60.569, the position of the substitution reaction can be preliminarily judged by the chemical shift change of C.
  • Figure 9 is a 13 C NMR nuclear magnetic diagram of P-CD-B 2 , which gives: Chemical shifts of 6 C corresponding to ⁇ -CD: CI: 102.450; C2: 73.955; C3: 73.085; C4: 77.393; C5 : 72.646; C6: 61.552, phenyl ring Ar (C7-C12): 130.080, 127.158, 131.036, 130.448, 130.781, 128.906 long chain C13: 167.295; C14: 149.225; C15: 97.571; C16: 92.965; C17: 167.663.
  • Figure 10 is a 13 C NMR nuclear magnetic diagram of P-CD-B 2 , which can be obtained: 6 Cs on the benzene ring are split into 2s4d 6 peaks, C8 and C12 are s peaks, C7, C9, C10, C11 are d peak.
  • Figure 2.14 shows that C1 on the CD ring is directly related to HI: ⁇ 4.646, C2 is directly related to ⁇ 2: ⁇ 3.573, C3 is directly related to ⁇ 3: ⁇ 3.158, and C4 is directly related to ⁇ 4: S3.301 , C5 is directly related to ⁇ 5: S3.250, C6 is directly related to H6a: S3.429; H6b: ⁇ 3.573.
  • the aromatic ring contains four CH directly related carbons: C7, C9, C10, C11 are directly related to H7: 58.158, H9: 56.271, H10: 57.43-7.48, Hll: S7.80-7.89, and branches C15 and H15 : 54.895, C16 is directly related to H16: S4.895.
  • C1 on the CD ring is remotely related to H5 and H4 due to the chair structure of the CD and the influence of the substituent group, and C2 is remotely related to H5.
  • C7 is remotely related to H9, H10, Hll on the aromatic ring
  • C9 is remotely related to H7 and Hll
  • C10 is remotely related to H7
  • C11 is remotely related to H7 and H9
  • C8 is remotely related to H10 and Hl
  • C12 is remotely related to H10 and H9
  • C13 is remotely related to H7, H9, H10, Hll.
  • the obtained derivative was purified by mass spectrometry (Fig. 12), and the following information was obtained: 1699 is a molecular ion peak, and the fragment peaks present in the mass spectrum are 1212.1, 863.1, 486.6, 309.9, 242.4, 185.4.
  • the way in which the substituent group can be broken is shown by the two paths shown below: 301, 1213, 243, 185 in the first mode can be found in the mass spectrum
  • the first and second ways to replace the way the group may break
  • the benzene ring may only be added to the C16 position, and the hydrogen is added to the C15, which is also a double substitution. If the addition is at C15, the following fracture mode should be used: The m/z 257, 1442 fragment peak is not found in the mass spectrum.
  • the double substitution occurs on the 1,4 ring of ⁇ -CD.
  • 486, 1213, 350, and 863 have peaks in the mass spectrum.
  • the ⁇ -CD derivatives have more molecular ion fragments that are split in the mass spectrum.
  • other substitution patterns are substituted by 1,2; the fragment ions required for 1,3 substitution do not appear. Such as 1,2 replaced possible.
  • the present invention provides a novel ⁇ -CD derivative: bis-[6-oxo-(2-m-carboxybenzenesulfonyl-succinic acid 1,4 monoester-4)]- ⁇ -CD (p-CD- B 2 ) and preparation method and use.
  • Separation of the chiral substances phenylglycine, anisodamine, isoproterenol and propafenone using P-CD-B 2 as the HPCE mobile phase chiral additive, can achieve baseline separation; preparation of the hand using the ⁇ -CD derivative
  • the HPCE column which can separate chiral substances such as chlorpheniramine, bupivacaine, procaine, atenolol, anisodamine, propafenone and lobeline, can achieve baseline separation.
  • a new method for the quantitative determination of single enantiomers of chiral substances by HPCE was established. A new report was issued by the Wuhan Science and Technology Research and Search Center of the Chinese Academy of Sciences, and no literature has been reported.
  • Figure 2 is a UV scan of P-CD-B 2 under different conditions.
  • 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, and 3i are respectively liquid chromatographic separation diagrams of the product P-CD-B 2 under different conditions.
  • Figure 4 shows the UV scan of the product 1x10-5 mol -1 .
  • Figure 5 is an infrared diagram of P-CD-B 2 .
  • Figure 6 is a comparison of XRD of P-CD, P-CD-A 2 and P-CD-B 2 , wherein aP-CD, bP-CD-A 2 , cP-CD-B 2 .
  • Figure 7 shows the ⁇ -CD nuclear magnetic map (DMSO 150 MHz).
  • Figure 8 is a P-CD-A 2 nuclear magnetic map (DMSO 150 MHz) P-CD-A 2 was not purified.
  • Figure 9 is a P-CD-B 2 nuclear magnetic diagram (DMSO 150 MHz), product synthesis conditions: raw material ratio of 1:30, 25 mL H20, 8 h, purified.
  • Figure 10 is a nuclear magnetic diagram of P-CD-B 2 HSQC.
  • Product synthesis conditions Raw material ratio is 1:30, 25mL H20,
  • Figure 11 is a P-CD-B 2 HMBC nuclear magnetic diagram, product synthesis conditions: raw material ratio of 1:30, 25mL H20,
  • Figure 12 is a mass spectrum of P-CD-B 2 .
  • Figure 13 is a 13C NMR chart of the product.
  • the product was synthesized in a ratio of 1 : 20, 25 mL H20, 6 h, purified.
  • Figure 14a is an electron microscopy scan of the HPCE column and the blank column with a P-CD-B 2 concentration of 8% (1000 times).
  • FIG. 14c Blank column (7500 times) without P-CD-B 2 coated. Electron micrograph of HPCE column and blank column.
  • Figure 15a is an electron microscopy scan of the HPCE column at a P-CD-B 2 concentration of 8% 1000 times.
  • FIG 15 c 2 is the concentration of P-CD-B of FIG HPCE SEM column at 12% of 5000 times.
  • Figure 16 is a scanning electron micrograph of the P-CD-B 2 concentration of 12% 75000 times. (The left side of the figure is the inner surface of the capillary column, and the right side is glass)
  • Figure 17 shows the HPCE plot of bupivacaine separated by 8% chiral column at injection time lOmin.
  • Figure 18 shows the separation of bupivacaine in a blank column.
  • Figure 19a is a plot of bupivacaine in a 8% chiral column at a P-CD-B 2 concentration.
  • Figure 19b is a separation diagram of bupivacaine in a 12% chiral column of P-CD-B 2 concentration.
  • Figure 19c is a separation diagram of bupivacaine in a 20% chiral column of P-CD-B 2 concentration.
  • Figure 20 is a diagram showing the separation of bupivacaine as a chiral stationary phase of P-CD-B 2 .
  • Figure 21 shows the separation of chiral additives for bupivacaine.
  • Figure 22a is a bupivacaine separation diagram of a P-CD-B 2 chiral HPCE electrophoresis column.
  • Figure 22b is a diagram showing the separation of bupivacaine in a blank electrophoresis column.
  • Figure 23a shows the separation of procaine in a 12% P-CD-B 2 HPCE column.
  • Figure 23b shows the separation of procaine in a blank electrophoresis column.
  • Figure 24a is a diagram showing the separation of bupivacaine from a P-CD-B 2 chiral electrophoresis column after injection of 150 needles.
  • Figure 24b is an electrophoretic separation diagram of a new P-CD-B 2 column.
  • Figure 25 is an electrophoresis separation diagram of chlorpheniramine.
  • Figure 26 is an electrophoresis separation diagram of chlorpheniramine chiral additive.
  • Figure 27 shows the HPCE separation of the anisodamine drug.
  • Figure 28a is an electrophoretic separation diagram of anisodamine in a HPCE column with a control P-CD-B 2 concentration of 20%.
  • Figure 28b is an electrophoretic separation diagram of anisodamine in a blank column of the control.
  • Figure 29a is a DL-phenylglycine separation plot for the Tris-H3P04 additive.
  • Figure 29b shows the separation of DL-phenylglycine from the ⁇ -CD chiral additive.
  • Figure 29c is a DL-phenylglycine separation plot for the P-CD-A 2 chiral additive.
  • Figure 29 d is a DL-phenylglycine separation plot for the P-CD-B 2 chiral additive.
  • Figure 30a is a separation diagram of propafenone under the borax buffer additive.
  • Figure 30b is a plot of propafenone separation under the ⁇ -CD chiral additive.
  • Figure 30c is a separation diagram of propafenone under the P-CD-A 2 chiral additive.
  • Figure 30 d is a separation diagram of propafenone under the P-CD-B 2 chiral additive.
  • Figure 31 a is a separation diagram of isoproterenol under the borax buffer additive.
  • Figure 31b is a plot of isoproterenol separation under the ⁇ -CD chiral additive.
  • Figure 31c is a plot of isoproterenol separation under the P-CD-A 2 chiral additive.
  • Figure 31 d is an isoproterenol separation plot for the P-CD-B 2 chiral additive.
  • Figure 32 a is a separation diagram of anisodamine from Tris-citric acid additive.
  • Figure 32b shows the separation of anisodamine from the ⁇ -CD chiral additive.
  • Figure 32c is a separation diagram of anisodamine for the P-CD-A 2 chiral additive.
  • Figure 32 is a separation diagram of anisodamine from the P-CD-B 2 chiral additive.
  • ⁇ -cyclodextrin is abbreviated as ⁇ -CD, as follows The steps are as follows: (1), 100 g of benzoic acid powder and 140 g of chlorosulfonic acid are stirred and mixed, and the temperature is raised to 120 ° C.
  • High-performance capillary electrophoresis HPCE column was prepared by using ⁇ -CD-B 2, a novel chiral separation material synthesized by our. The preparation conditions were optimized. Scanning electron microscopy confirmed that the inner surface of the capillary column had been bonded with ⁇ -CD-B 2 . Specific methods: A 75 ⁇ chiral capillary electrophoresis column was prepared by physical coating, chemical bonding and preparation of a monolithic column. Using a static coating device, the capillary electrophoresis column is pretreated by chemical bonding to expose more silicon hydroxyl groups on the inner wall of the tube. According to the principle of sol-gel, a suitable "arm" coupling agent is selected and connected.
  • the column was packed with a coupling agent methanol solution, sealed with a rubber pad, placed in an oven at a temperature of 50 ° C for 12 hours, then washed with methanol and acetone, and dried with nitrogen.
  • PB-B-B 2 dissolved in different concentrations was filled into the pretreated capillary column, sealed at both ends, heated at 70 ° C for 12 h, rinsed with methanol and water, and then treated with HC1-methanol. Pressurize (pressure about 9000 Pa) into the column to hydrolyze the remaining epoxy groups to diol and rinse with water. Remove residual acid from inside. A suitable observation window was made by flame ablation at the end of the coated capillary column 10 cm. The effective length of the capillary column was 40 cm.
  • the prepared -CD-B 2 concentration of 8%, 12% and blank HPCE column was sent to the School of Physics and Telecommunication Engineering of Huazhong Normal University, and analyzed by JSM-6700F field emission scanning electron microscopy.
  • the obtained electron microscope scanning chart is shown in Figure 14a. 14b, Figure 14c.
  • Fig. 14a, Fig. 14b, and Fig. 14c under the 1000-fold microscope, 8% and 12% of the inner surface of the HPCE column has a derivative layer, and the derivative layer is partially peeled off due to vibration when the column is cut. The inner glass surface is exposed. Under the 7500 high power microscope, only the glass slag is lifted on the inner surface of the blank column.
  • the HPCE open column was bonded with a self-synthesized P-CD-B 2 bond.
  • the inner surface of the HPCE column is pretreated, and then an "arm" is connected between the ⁇ -CD derivative and the inner surface of the column to form a whole by chemical bonding, so that the ⁇ -CD derivative is not easily eluted.
  • the chiral separation factor is increased. It can be seen from the comparison in Fig. 17 and Fig. 18 that the HPCE chiral open tubular column of ⁇ -CD derivative can achieve the baseline separation of bupivacaine enantiomers. .
  • the advantage of the open column is that the preparation process is simple and the column efficiency is high. The use of it in HPCE for the separation of chiral substances, such as drugs and biological substances, should be a meaningful work.
  • the chiral drug procaine hydrochloride and bupivacaine hydrochloride are common local anesthetics and antiarrhythmic drugs.
  • Samir Cherkaoui et al. used HPCE-coated MSPE to separate the cloth by HPCE-mass spectrometry (MS). Cain, lidocaine, mabivacaine, ketamine, chiral separation of four drugs within 12 minutes.
  • Ivanildo Jos6 da Silva et al. used HPLC to prepare the compound as the stationary phase, and n-hexan-2-propanol/acetonitrile/triethylamine as the mobile phase to separate bupivacaine, and the diastereomer was separated in 15 minutes. The resolution is 3.50.
  • the prepared P-CD-B 2 bonded HPCE chiral column was used to separate two kinds of caffeine procaines such as procaine hydrochloride and bupivacaine hydrochloride.
  • Baseline separation was achieved on bupivacaine hydrochloride on 8%, 12%, and 20% P-CD-B 2 electrophoresis columns. The 8% column resolution was the smallest, and was also 14.71.
  • P/ACETM MDQ high performance capillary electrophoresis apparatus (BECKMAN, USA); quartz capillary 50cmx75 m(id) (Hebei Yongnian Optical Fiber Factory); effective length 40cm; pHs-3c type acidity meter (Shanghai Weiye Instrument Factory); 85-2 Type thermostatic magnetic stirrer (Jintan Kexing Instrument Factory); ES-120J electronic analysis Tianping (Shenyang Longteng Electronic Weighing Instrument Co., Ltd.); 0.22 ⁇ Microporous Membrane (Shanghai Xinya Purification Device Factory) 1.2 Reagent
  • Procaine hydrochloride injection drug, Shandong Fangming Pharmaceutical Co., Ltd.
  • bupivacaine hydrochloride injection drug, Shanghai Zhaohui Pharmaceutical Co., Ltd.
  • the injection of the auxiliary material is water for injection (containing phosphate, Indium chloride
  • the buffer ionic strength, buffer pH value, separation voltage change, procaine hydrochloride, bupivacaine hydrochloride chiral drug separation were investigated, and the optimal conditions were explored.
  • the procaine hydrochloride injection (20g_L-, bupivacaine hydrochloride injection g ⁇ 1 ) was filtered, and different concentrations of boric acid-NaOH buffer were set. The pH value was adjusted according to the separation and used as the running medium for electrophoresis.
  • the HPCE column was washed with deionized water for 3 min, 0.1 mol*L-1Hcl for 5 min, deionized water for 5 min, and background electrolyte for 5 min.
  • the solution was filtered through a 0.22 ⁇ microporous membrane. Using pressure injection, 0.5 psi injection for 5 s, separation voltage of 20 kV, detection wavelength of 214 nm, temperature of 20 °C.
  • Bupivacaine hydrochloride also known as carbamazepine, is a long-acting local anesthetic for local anesthesia and post-operative pain relief.
  • Bupivacaine is a racemic form of a mixture of a left-handed body and a right-handed body.
  • the central nervous system and cardiotoxicity are mainly derived from the right-handed body.
  • Its bupivacaine L-body S-(-)-body is an amide local anesthetic and is a long-lasting local anesthetic widely used for spinal anesthesia.
  • the molecular structure of the left and right spine is the same as that of the cardiocaine, but the central nervous system toxicity and cardiotoxicity are significantly different.
  • the toxicity of levobupivacaine is significantly lower. Since synthetic drugs are mostly sold in the form of racemates, the enantiomers of chiral drugs have different pharmacological and toxicological effects, sometimes with toxic side effects. Therefore, the separation of the chiral drug bupivac
  • P-CD-B 2 was isolated as a chiral additive.
  • the separation of bupivacaine was Rsl.30, and the baseline separation was not achieved.
  • 8%P-CD-B 2 was bonded to the capillary column.
  • the inner wall as a chiral electrophoresis stationary phase to separate bupivacaine has a resolution Rs of 17.19, which is superior to P-CD-B 2 as a chiral additive for separating the separation effect of bupivacaine.
  • Optimum separation conditions in a 20% P-CD-B 2 chiral column or empty column, buffer concentration 50 mmol / L, injection 1.5 psi, 15 sec, ⁇ ⁇ . ⁇ , separation voltage 25kV, detection wavelength 280 nm , temperature 20 ° C.
  • Figure 22b separation of bupivacaine in a blank electrophoresis column.
  • Example 3 P-CD-B 2 as a chiral stationary phase for separation of chiral drugs in HPCE
  • Chlorpheniramine injection chlorpheniramine (drug, Hubei Huazhong Pharmaceutical Co., Ltd., chlorpheniramine maleate, reference substance, lOOmg China National Institute for the Control of Pharmaceutical and Biological Products), anisodamine (pharmaceutical, Hangzhou Minsheng Pharmaceutical Group Co., Ltd.) Company); Propafenone (drug, Jiangsu Yunyang Group Pharmaceutical Co., Ltd.); DL-phenylglycinol (purity: 99%) (Shanghai Qide Biochemical Co., Ltd.); D ⁇ -phenylglycinol (purity) : 98.5%); Tris AR, Amreso Pack; H 3 P0 4 AR (Tianjin Jinnan Chemical Reagent Factory); Citric Acid AR, (China National Pharmaceutical Group Shanghai Chemical Reagent Company); Boric Acid A (China Yunling Chemical Plant); NaOHAR (Tianjin Komiou Chemical Reagent Co., Ltd.)
  • Mixer-type left-handed body and right-handed body such as racemic form, right-handed chlorpheniramine is mainly used to prevent urticaria, drug eruption, asthma, allergic rhinitis, contact dermatitis, hay fever, insect bites, itchy skin, cold , serum disease and prevention of transfusion reactions.
  • the left-handed body has a greater toxic effect on the human body. Since synthetic drugs are mostly sold in the form of racemates, the enantiomers of chiral drugs have different pharmacological and toxicological effects, sometimes with toxic side effects. Therefore, the separation of the drug Bupivacaine is of great significance.
  • a HPCE column was prepared using 12% P-CD-B 2 as the chiral stationary phase. Dissolve chlorpheniramine in ultrapure water (0.4g/L), configure different concentrations of Tris-phosphate buffer, adjust the pH value according to separation, and use it as the running medium for electrophoresis. Capillaries should be used before each run. Ion water was washed for 3 min, 0.1 mol*L-1Hcl was rinsed for 5 min, deionized water was rinsed for 5 min, background electrolyte was rinsed for 5 min, and the solution used was filtered through a 0.22 ⁇ microporous membrane. Pressure injection, 0.5 s injection for 5 s, separation voltage of 20 kV, detection wavelength of 214 nm, temperature of 20 ° C.
  • P-CD-B 2 separated as chlorpheniramine chiral additive are: concentration of P-CD-B 7g / L, The buffer concentration was 50 mM, pH 2.3, separation voltage 25 kV, temperature 20 °C.
  • the electropherogram is shown in Figure 26.
  • P-CD-B 2 as a chiral additive for the separation of chlorpheniramine did not reach baseline separation, and 12% P-CD-B chiral HPCE column separation of chlorpheniramine reached baseline separation.
  • Anisodamine is a white crystal or a crystalline powder, which is odorless and bitter. It is extracted from plant hawthorn or artificially synthesized from furan.
  • An anticholinergic agent that blocks the M-choline receptor. It is clinically used to treat acute microcirculatory disorders and organic phosphorus poisoning. It is also used to treat toxic shock, vertigo and vascular diseases (cerebral thrombosis, cerebral vasospasm). For toxic shock, vascular disorders, neuralgia, retinal diseases.
  • the standard of the anisodamine was compared under the electrophoresis conditions of a buffer concentration of 40 mmol/LTris-citric acid, pH 4.5, a separation voltage of 25 kV, an injection volume of 0.5 psi to 5 s, and a temperature of 20 °C.
  • the standard concentration is 0.5 g/mL.
  • the components in the separated anisodamine tablets are the same as those in the standard.
  • a blank column without a P-CD-B 2 derivative was not isolated from the anisodamine.
  • Example 4 P-CD-B 2 as an HPCE mobile phase chiral additive for separation of DL-phenylglycinol
  • HPCE mobile phase consists of P-CD-B 2 concentration of 7g / L and Tris-H 3 P0 4 buffer concentration of 50mmol / L, separation voltage of 25kV, detection wavelength of 254nm, 3 ⁇ 4 reached 5.32, qualitative and quantitative separation analysis DL - Benzylglycol, giving the linear range of each of the single enantiomer and the racemate.
  • Example 5 P-CD-B 2 as a mobile phase chiral additive baseline separation of chiral drugs
  • P-CD-B 2 derivatives were used as chiral additives to separate three kinds of chiral drugs, anisodamine, isoproterenol and propafenone, and compared with pure buffer, other chiral additives or standards, against background
  • the separation conditions such as electrolyte, buffer concentration, pH value, chiral selector concentration, and separation voltage were optimized.
  • Propafenone, anisodamine and isoproterenol can achieve baseline separation, and the reference substance has been used to establish a new method for quantitative determination of related drugs.
  • Propafenone is also known as: propyl acetophenone; altama; hydroxypropiophenone; propofol hydrochloride; heart rhythm. Indications: for the prevention or treatment of ventricular or supraventricular ectopic pulsation, ventricular or supraventricular tachycardia, pre-excitation syndrome, ventricular fibrillation after electrical cardioversion, etc., caused by coronary heart disease, hypertension The arrhythmia has a good effect.
  • Propafenone (PPF) is an antiarrhythmic drug. It is clinically administered as a racemate, but S-(+)-PPF is more toxic than R-0-PPF.
  • the main hydroxylation pathway in humans is catalyzed by CYP2D6, which is preferentially metabolized by the S-enantiomer, but this enzyme has a greater affinity for the R-enantiomer.
  • CYP2D6 which is preferentially metabolized by the S-enantiomer
  • This enzyme has a greater affinity for the R-enantiomer.
  • the two enantiomers inhibit each other, but the R-enantiomer has stronger competitive inhibition of S-enantiomer metabolism, which can attenuate the elimination of S-enantiomers and increase the concentration of S-type blood. Adverse reactions that cause beta blockade.
  • the borax buffer solution with P-CD-B 2 as the chiral additive was used as the running medium for electrophoresis.
  • the capillary was rinsed with 0.1 mol_L- ⁇ aOH for 5 min, deionized water for 5 min, and the background electrolyte for 5 min before each run. It was filtered through a 0.22 ⁇ microporous membrane. Using a pressure injection, 0.3 psi injection for 3 s, the separation voltage was 25 kV, the detection wavelength was 254 nm, and the temperature was 20 °C.
  • Fig. 30a, Fig. 30b, Fig. 30c, Fig. 30d a comparative test for separating propafenone with borax buffer and P-CD, p-CD-A 2 and P-CD-B 2 as chiral additives, respectively.
  • Fig. 30a and Fig. 30b there is only one strong peak under pure buffer and only ⁇ -CD.
  • Fig. 30c only the non-linear peak appears in the buffer system with P-CD-A 2 added. There are also peaks.
  • the two peaks reached baseline separation with a resolution of 3.36.
  • Isoproterenol is commonly used as a white or off-white crystalline powder; it is odorless, slightly bitter, and has a gradual color in light and air, and is more susceptible to discoloration in an alkaline solution. Soluble in water, slightly soluble in ethanol, insoluble in chloroform or ether. Indications: (1) Bronchial Asthma: It is suitable for the control of acute asthma attacks. It is usually administered by aerosol inhalation. The effect is fast and strong, but the duration is short. (2) Cardiac aggregation: used to treat cardiac arrest caused by various causes such as drowning, electric shock, surgical accidents and drug poisoning. When necessary, it can be used in combination with adrenaline and norepinephrine. (3) Atrioventricular block.
  • Anti-shock It can be used for cardiogenic shock and septic shock.
  • (-)-Isoproterenol is a ⁇ -quinone receptor agonist, and its (+)-isomer is a competitive antagonist of (-)-body with approximately equivalent affinity.
  • a comparative test for separating isoproterenol is known.
  • the separation is not ideal without the addition of additives and the addition of ⁇ -CD to Figure 31a and Figure 31b.
  • the peak time of the sample was fast and the response signals of both peaks were strong.
  • Figure 31c shows that the P-CD-A 2 derivative also has a chimeric effect after sandwiching isoproterenol molecules.
  • Anisodamine is also known as 6-hydroxypurine, racemic anisodamine. It is a white crystalline or crystalline powder, odorless and bitter. It is extracted from plant hawthorn or artificially synthesized from furan.
  • An anticholinergic agent that blocks the M-choline receptor. Clinically used to treat acute microcirculatory disorders and organophosphate poisoning. It is also used to treat toxic shock, vertigo and vascular diseases (cerebral thrombosis, cerebral vasospasm). For toxic shock, vascular disease, neuralgia, fundus retina Ill.
  • the preparations are tablets and injections.
  • P-CD-B 2 A certain amount of P-CD-B 2 was weighed and dissolved in a prepared 50 mmol/L Tris-citrate buffer as a running medium.
  • the capillary was rinsed with 0.1 mol_L- ⁇ aOH for 5 min, deionized water for 5 min, background electrolyte rinse for 5 min, pressure injection, l.Opsi injection for 8 s, separation voltage of 25 kV, detection wavelength of 254 nm, temperature 20 before each run. °C.
  • the hydrogen bond between the carboxyl group 0 on the P-CD-A 2 and the hydroxyl group in the anisodamine molecule separates the enantiomer, and
  • the peak elution intensity is equivalent, the peak shape is symmetrical but the baseline separation is not achieved;
  • P-CD-B 2 is used as the chiral additive, there is a chimeric effect of the ⁇ -CD hydrophobic cavity and the anisodamine molecule, and P- Hydrogen bonding and dipolar action of carbonyl or carboxyl group 0 on CD-B 2 and S on the branch and the hydroxy group of anisodamine molecule, superconducting of benzene ring on phenyl ring and anisodamine molecule on P-CD-B 2
  • the yoke acts to complete the baseline separation of the enantiomer molecules 9 minutes before.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Materials Engineering (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation comme sélecteur chiral dans une électrophorèse capillaire (HPCE), notamment la préparation d'une colonne d'électrophorèse chirale et un additif chiral dans une phase mobile que l'on utilise dans l'isolement de substances chirales. La formule de la bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine est : C64H84049S2. L'utilisation de β-CD-B2 comme additif chiral dans une phase mobile d'une HPCE pour l'isolement de substances chirales 2-amino-2-phénylglycylol, d'anisodamine, d'isoprotérénol et de propafénone permet un isolement de référence. La colonne HPCE préparative chirale P-CD-B2 permet d'isoler les dérivés de la chlorphéniramine, la bupivacaïne, la procaïne, l'aténolol, l'anisodamine, la propafénone et la lobeline, entre autres, afin de garantir un isolement de référence, d'où l'élaboration d'un nouveau procédé de détermination quantitative par HPCE d'énantiomères purs et simples à partir d'une pluralité de substances chirales.
PCT/CN2011/076902 2010-08-12 2011-07-06 Bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation WO2012019500A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN 201010254099 CN101928356B (zh) 2010-08-12 2010-08-12 双-[6-氧-(2-间羧基苯磺酰基-丁二酸1,4单酯-4)]-β-环糊精及制备方法和用途
CN201010254099.X 2010-08-12

Publications (1)

Publication Number Publication Date
WO2012019500A1 true WO2012019500A1 (fr) 2012-02-16

Family

ID=43367822

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/076902 WO2012019500A1 (fr) 2010-08-12 2011-07-06 Bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN101928356B (fr)
WO (1) WO2012019500A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965376A (zh) * 2014-05-19 2014-08-06 中南民族大学 双-（6-氧-间硝基苯磺酰基）-β-环糊精及制备方法和用途
CN110530992A (zh) * 2019-08-30 2019-12-03 珠海润都制药股份有限公司 一种盐酸左布比卡因注射液光学异构体的检验方法
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101928356B (zh) * 2010-08-12 2013-06-05 中南民族大学 双-[6-氧-(2-间羧基苯磺酰基-丁二酸1,4单酯-4)]-β-环糊精及制备方法和用途
CN103472119B (zh) * 2013-06-16 2016-01-20 德州学院 给毛细管内壁涂层电动增压在线富集毛细管电泳分析芳香族羧酸的方法
CN104557682A (zh) * 2014-08-12 2015-04-29 江苏汉邦科技有限公司 模拟移动床色谱拆分扑尔敏对映体的方法
CN104297316B (zh) * 2014-10-24 2016-11-02 常州大学 一种基于β-环糊精的手性传感器及其制备方法
CN106984291B (zh) * 2017-03-31 2020-04-21 中南民族大学 双[-6-氧-(3-脱氧柠檬酸单酯-4)]-β-环糊精HPLC柱材料的制备和用途
CN110508135B (zh) * 2019-07-16 2021-12-21 沈阳化工大学 一种分离泮托拉唑消旋体的毛细管电色谱方法
CN114034759B (zh) * 2020-07-21 2024-07-26 中国计量科学研究院 一种用于药物布洛芬分子手性结构分析的试剂和方法
CN113117657B (zh) * 2021-04-14 2022-12-13 中南民族大学 β-环糊精金属有机骨架材料HPLC柱的制备及应用
CN114486444B (zh) * 2022-02-07 2024-02-20 洛阳师范学院 一种阿替洛尔非外消旋体混合物的毛细管电泳分离方法
CN115850125B (zh) * 2022-11-18 2024-06-21 爱斯特（成都）生物制药股份有限公司 一种连续流制备苯磺酰氯类化合物的方法
CN117723680B (zh) * 2024-02-08 2024-05-03 苏州博研医药科技有限公司 一种盐酸洛贝林杂质的分离检测方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624599B1 (fr) * 1993-05-13 1997-07-30 L'oreal Dérivés de mono (6-amino 6-désoxy)cyclodextrine substituée en position 6 par un reste d'alpha-aminoacide, leur procédé de préparation et leurs utilisations
CN101015789A (zh) * 2007-01-05 2007-08-15 中国农业大学 新型β－环糊精衍生物毛细管气相色谱手性固定相及其制备方法
CN101928356A (zh) * 2010-08-12 2010-12-29 中南民族大学 双-[6-氧-(2-间羧基苯磺酰基-丁二酸1,4单酯-4)]-β-环糊精及制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100335507C (zh) * 2002-04-29 2007-09-05 西巴特殊化学品控股有限公司 反应性环糊精衍生物的水成液组合物和使用所述组合物的整理工艺
CN1232539C (zh) * 2002-05-10 2005-12-21 刘云清 有机药物与倍他环糊精衍生物的配合物及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624599B1 (fr) * 1993-05-13 1997-07-30 L'oreal Dérivés de mono (6-amino 6-désoxy)cyclodextrine substituée en position 6 par un reste d'alpha-aminoacide, leur procédé de préparation et leurs utilisations
CN101015789A (zh) * 2007-01-05 2007-08-15 中国农业大学 新型β－环糊精衍生物毛细管气相色谱手性固定相及其制备方法
CN101928356A (zh) * 2010-08-12 2010-12-29 中南民族大学 双-[6-氧-(2-间羧基苯磺酰基-丁二酸1,4单酯-4)]-β-环糊精及制备方法和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEI, SHUANGSHUANG: "Application of bis[-6-oxygen-(-2-m-carboxyl benzenesulfonyl- succinic acid-1, 4-monoester-4-)-]-p-cyclodextrin to high performance capillary electrophoresis separating chiral drug", CHINA MASTER THESES FULL-TEXT DATABASE, ENGINEERING SCIENCE AND TECHNOLOGY, vol. 1, no. 6, 15 June 2009 (2009-06-15), pages 13 - 15, PP. 29 TO 30 *
REN, WEIHENG ET AL.: "Research on construction of succinate dehydrogenase with (beta-CD", ORGANIC CHEMISTRY, vol. 18, no. 1, February 1998 (1998-02-01), pages 66 - 70 *
SHEN, JINGRU ET AL.: "Preparation of bis[-6-oxygen-(-2-m-carboxyl benzenesulfonyl- succinic acid-1, 4-monoester-4-)-]-p-cyclodextrin chiral HPCE column separating drug", JOURNAL OF SOUTH-CENTRAL UNIVERSITY FOR NATIONALITIES (NATURAL SCIENCE EDITION), vol. 128, no. 4, December 2009 (2009-12-01) *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965376A (zh) * 2014-05-19 2014-08-06 中南民族大学 双-（6-氧-间硝基苯磺酰基）-β-环糊精及制备方法和用途
CN103965376B (zh) * 2014-05-19 2016-05-04 中南民族大学 双-(6-氧-间硝基苯磺酰基)-β-环糊精及制备方法和用途
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof
CN110530992A (zh) * 2019-08-30 2019-12-03 珠海润都制药股份有限公司 一种盐酸左布比卡因注射液光学异构体的检验方法
CN110530992B (zh) * 2019-08-30 2022-05-10 珠海润都制药股份有限公司 一种盐酸左布比卡因注射液光学异构体的检验方法

Also Published As

Publication number Publication date
CN101928356B (zh) 2013-06-05
CN101928356A (zh) 2010-12-29

Similar Documents

Publication Publication Date Title
WO2012019500A1 (fr) Bis[6-oxygène-(2-m-carboxybenzène-acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation
Li et al. Preparation and evaluation of a novel N-benzyl-phenethylamino-β-cyclodextrin-bonded chiral stationary phase for HPLC
Shuang et al. Preparation of a stilbene diamido-bridged bis (β-cyclodextrin)-bonded chiral stationary phase for enantioseparations of drugs and pesticides by high performance liquid chromatography
Long et al. Helical chirality induces a substrate-selectivity switch in carbohydrates recognitions
JP4594298B2 (ja) 高純度フォンダパリヌクスナトリウム組成物
Shuang et al. Preparation and evaluation of an ethylenediamine dicarboxyethyl diamido-bridged bis (β-cyclodextrin)-bonded chiral stationary phase for high performance liquid chromatography
Wang et al. Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor
US11473115B2 (en) Exopolysaccharide from Rhodopseudomonas palustris and method for preparing and use thereof
Pan et al. Rapid and efficient isolation platform for plasma extracellular vesicles: EV‐FISHER
CN112645809A (zh) 一种基于甲萘醌结构的新型冠状病毒3cl蛋白酶抑制剂
Zhang et al. Preparation of a novel bridged bis (β-cyclodextrin) chiral stationary phase by thiol–ene click chemistry for enhanced enantioseparation in HPLC
CN106226426A (zh) 一种高效液相色谱拆分卡格列净五元环杂质对映体的方法
CN111747881A (zh) 两种具有α-葡萄糖苷酶抑制作用的异戊烯基取代吲哚生物碱及其制备方法和应用
Niu et al. A squaramide-catalysed asymmetric cascade Michael addition/acyl transfer reaction between unsaturated benzothiophenones and α-nitroketones
CN111904965B (zh) 白桦脂酸衍生物在制备抗肾病变药物中的应用
CN109985043B (zh) 白桦醇及其衍生物在具有抗肝纤维化作用药物中的应用
WO2012019499A1 (fr) Bis[6-oxygène-(3-m-nitrobenzène acide sulfonyl-succinique-1,4 monoester-4)]-β-cyclodextrine, son procédé de préparation et son utilisation
CN104628892B (zh) 6‑苄基苯乙胺衍生化β‑环糊精键合SBA‑15的制备方法及用途
CN107686492A (zh) 一种使用大孔吸附树脂提取纯化发酵液中红景天苷的方法
EP2755757A1 (fr) Sorbant comprenant sur sa surface un système cyclique aromatique possédant un groupe anionique ou déprotonable, pour la purification de molécules organiques
CN112300155A (zh) 一种海洋来源的抗老年痴呆化合物的制备方法及应用
Li et al. Application of hydrophobic eutectic solvent in efficient biotransformation of total flavonoids of Herba Epimedii
Delattre et al. Purification of oligouronides by immobilized L-histidine pseudoaffinity chromatography
CN111574486B (zh) 香叶基三羟基色酮及其在制备肝x受体激动剂中的应用
WO2024193472A1 (fr) Dérivé de 1h-pyrrole-2-amide et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11816059

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11816059

Country of ref document: EP

Kind code of ref document: A1