WO2023236453A1 - Procédé de préparation d'albiflorine-6'-o-benzènesulfonate - Google Patents

Procédé de préparation d'albiflorine-6'-o-benzènesulfonate Download PDF

Info

Publication number
WO2023236453A1
WO2023236453A1 PCT/CN2022/133498 CN2022133498W WO2023236453A1 WO 2023236453 A1 WO2023236453 A1 WO 2023236453A1 CN 2022133498 W CN2022133498 W CN 2022133498W WO 2023236453 A1 WO2023236453 A1 WO 2023236453A1
Authority
WO
WIPO (PCT)
Prior art keywords
paeoniflorin
benzenesulfonate
glycoside
solvent
mixed solvent
Prior art date
Application number
PCT/CN2022/133498
Other languages
English (en)
Chinese (zh)
Inventor
白柏
许文东
刘菊妍
唐顺之
袁诚
韩亚明
彭万才
梁北梅
魏劭恒
傅玉萍
李佳俐
Original Assignee
广州白云山汉方现代药业有限公司
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 广州白云山汉方现代药业有限公司 filed Critical 广州白云山汉方现代药业有限公司
Publication of WO2023236453A1 publication Critical patent/WO2023236453A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of compounds, and specifically relates to a preparation method of paeoniflorin-6'-O-benzenesulfonate.
  • White peony root is the root of Paeonia lactiflora, which has antipyretic and analgesic effects. Modern pharmacology shows that white peony extract also has various pharmacological activities such as anti-inflammatory and immunomodulatory, detoxifying and liver-protecting, anti-mutagenic and anti-tumor. Total glycosides of white peony are also the first to be used in the clinical treatment of rheumatoid joints. It is an anti-inflammatory immunomodulatory drug for inflammation, and has the characteristics of good curative effect, few adverse reactions, and good tolerance.
  • Albiflorin also has a variety of pharmacological effects, such as anti-epileptic, analgesic, detoxification, anti-vertigo, etc. It can also be used to treat rheumatoid arthritis and bacterial infections. Dysentery, enteritis, viral hepatitis, senile diseases, etc.
  • Paeoniflorin is the second most abundant active ingredient in the traditional Chinese medicine white peony root [1].
  • paeoniflorin glycosides have unique pharmacodynamic characteristics that are different from paeoniflorin. It has better pharmacological effects than paeoniflorin in terms of blood enrichment, antidepressant, and potential treatment of diabetes. characteristics, and has anti-convulsant, anti-inflammatory and liver-protecting effects [2].
  • Patent CN102603827 studies the preparation method of the similar compound paeoniflorin-6'-O-benzenesulfonate, using 98% paeoniflorin as the raw material, using pyridine as the acid compress and reaction solvent, DMAP as the catalyst, and slowly adding peony root.
  • the molar ratio of glycosides to benzene sulfonyl chloride dissolved in methylene chloride is 20 hours, after post-treatment, the yield is about 40%.
  • the compound paeoniflorin-6'-O-benzenesulfonate described in this patent can also be synthesized by this method, but there are the following shortcomings: 1.
  • the purity of paeoniflorin required for the reaction raw materials is not less than 98%.
  • Sources are limited, and there are currently no kilogram-level raw materials with a purity of more than 98% on the market; 2.
  • the reaction yield is low, the catalyst, reaction solvent and subsequent purification solvent required for the reaction are large, and the reaction process is not economical and environmentally friendly; 3.
  • the reaction raw materials need to be added step by step, and the raw materials need to be added slowly during the reaction process.
  • the reaction time for large-scale preparation is long and the process is complicated, which is not conducive to industrial production.
  • paeoniflorin-6'-O-benzenesulfonate has the characteristics of strong lipophilicity, difficulty in crystallization, strong hygroscopicity, and poor thermal stability, it significantly increases the difficulty of the drying process. After adopting the process of directly drying the precipitates, the solvent encapsulation phenomenon exists in the finished product, causing the solvent residue to seriously exceed the standard. If the sample is dissolved and dried directly under vacuum, paeoniflorin-6'-O-benzenesulfonate is prone to alcohol degradation, resulting in a significant increase in related substances, which undoubtedly brings challenges to the research on drying processes.
  • the material is heated and dried under low temperature and vacuum conditions, which is suitable for the preparation of heat-sensitive materials.
  • Materials that are soluble and stable in aqueous solution can use water as the sole solvent for this drying procedure, but paeoniflorin-6'-O-benzenesulfonate is not suitable because it is slightly soluble in water.
  • Tert-butanol which has high melting point, high vapor pressure, non-toxicity and is miscible with water, is an excellent choice as a drying solvent for drugs that are difficult to dissolve in water and are heat-labile.
  • Tert-butanol-water co-solvent has been used in a variety of injectable drugs.
  • the production process can improve drying efficiency and shorten drying time, but paeoniflorin-6'-O-benzenesulfonate is unstable in alcohol-containing solvents and prone to degradation, resulting in a greatly reduced quality of the finished product that does not meet the requirements.
  • the present invention provides for the first time a preparation route for paeoniflorin-6'-O-benzenesulfonate.
  • medicinal materials rich in paeoniflorin such as white peony root as raw materials, 80% is obtained through extraction, adsorption and silica gel column chromatography.
  • % or more of paeoniflorin glycosides, through esterification reaction obtain the crude paeoniflorin glycoside-6'-O-benzenesulfonate, and then through chromatographic column separation, purification and drying, finally obtain the medicinal paeoniflorin glycosides -6'-O-benzenesulfonate.
  • the present invention adopts the following technical solutions:
  • a preparation method of paeoniflorin-6’-O-benzenesulfonate comprising the following steps:
  • an organic metal catalyst, an acid binding agent and a chemically active benzenesulfonyl chloride are used to react with paeoniflorin glycoside in S2, so that the reaction can produce paeoniflorin glycoside-6'-O-benzenesulfonic acid.
  • the ester reaches more than 80%, and then is separated and purified by column chromatography and then refined to obtain more than 98% of paeoniflorin-6'-O-benzenesulfonate ester.
  • step S4 the purity of the obtained paeoniflorin-6'-O-benzenesulfonate fine product B has reached more than 98% after testing.
  • the liquid phase solvent does not produce peaks or is subtracted from the background, premium product B actually contains more solvents used in the refining process.
  • the residues of various solvents used in the present invention in the finished drug should basically be controlled below 0.5%, so further drying of S5 is required.
  • step S5 the present invention proposes a ternary solvent system of dimethyl carbonate, C3-4 ketones, and water with a proportion within a certain range.
  • the freezing point is -10-0°C, which meets the solvent requirements of the programmed drying process and is expected to Unexpectedly, while successfully solving the drying problem of fat-soluble paeoniflorin-6'-O-benzenesulfonate, the related substances in the finished product no longer increase compared with before drying, and the solvent residues (including: the good quality used for refining
  • the solvent isopropyl acetate or isobutyl acetate, the drying solvent dimethyl carbonate, acetone can all be lower than the specified value.
  • the mixed solvent consists of dimethyl carbonate, acetone and water, or consists of dimethyl carbonate, butanone and water. Under this combination, the mixed solvent has better solubility for paeoniflorin-6'-O-benzenesulfonate, which can better reduce solvent residues and reduce the increase in related substance content after the drying process.
  • the total solvent residue of paeoniflorin-6'-O-benzenesulfonate is no more than 0.6%.
  • the carbonate residue of paeoniflorin-6'-O-benzenesulfonate is not higher than 0.5%, and the residue of C3 ⁇ 4 ketones is not higher than 0.2%.
  • the content of related substances in paeoniflorin-6'-O-benzenesulfonate increases by no more than 0.2%.
  • steps S1-2 and S3 those skilled in the art know that when column chromatography is used for separation, the starting point for collecting the eluent is when the main component appears, and the end point is when impurities appear or the spots of the main component become smaller.
  • the medicinal materials include one or more of white peony root, red peony root, paeoniae bark, dog head, peony root, and purple peony root, using 80% to 100% ethanol or 80% to 100% ethanol.
  • the extraction method includes one of cold soaking, thermal reflux or microwave-assisted extraction; in step S1-2, the column chromatography separation is silica gel column chromatography separation, and the eluent is an alkane derivative-lower alcohol mixed solvent ;
  • the organometallic catalyst includes one or more of C1 to C4 alkyl tin halides, aryl tin halides, C1 to C4 alkyl tin oxides, and C1 to C4 alkyl tin sulfides
  • the acid binding agent includes one or more of triethylamine, N, N'-diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate
  • the reaction solvent includes One or more of acetonitrile, tetrahydrofuran, acetone, pyridine, methyl ethyl ketone, N,N'-dimethylformamide, 1,4-di
  • step S1-2 compared with the haloalkane-alcohol system, when the alkane derivative-alcohol system is used in the present invention to separate the crude paeoniflorin glycosides by column chromatography, its elution capacity is stronger, and the separation effect is achieved at the same time , the amount of eluent is relatively small, and it is less toxic than chloroform, making the production safer and more environmentally friendly.
  • step S2 chemically active benzenesulfonyl chloride is used as the substrate.
  • Pyridine can be used as both a reaction solvent for S2 and an acid-binding agent.
  • the reaction solvent can be organic solvents such as acetone and acetonitrile
  • the acid binding agent can be organic acid binding agents such as triethylamine, or inorganic acid binding agents such as potassium carbonate.
  • S2 also includes extracting the product with ethyl acetate and water after the reaction is terminated, and then concentrating to obtain the crude paeoniflorin-6'-O-benzenesulfonate ester.
  • the reaction temperature was room temperature, and the reaction time was 2 to 5 hours. It is best to use artificial control to terminate the reaction process. If the reaction is not terminated and the reaction time is too long, more impurities will be produced by side reactions. Add water and ethyl acetate and stir to terminate the reaction and perform extraction at the same time. After stirring, let it stand and separate the layers to take the organic layer.
  • the present invention creatively uses the method of dissolving paeoniflorin-6'-O-benzenesulfonate fine product A in a good solvent and then adding a poor solvent for crystallization in step S4, which can improve the purity of the product and reduce the Impurities.
  • the medicinal material includes one or more of white peony root and red peony root, and is extracted using 95% to 100% ethanol or 95% to 100% methanol.
  • the extraction method includes thermal reflux;
  • Step S1 -2 the mass ratio of the silica gel used for the silica gel column chromatography separation to the crude paeoniflorin glycoside is 10 to 20:1, and the mass ratio of the alkane derivative-lower alcohol mixed solvent to the crude paeoniflorin glycoside
  • the volume to mass ratio is 40 to 65 ml: 1 g; in step S2, the dosage of the benzenesulfonyl chloride is 20% to 60% of the mass of the paeoniflorin glycoside, and the dosage of the organic metal catalyst is the paeoniflorin glycoside.
  • the mass ratio of the silica gel used for the silica gel column chromatography separation to the crude paeoniflorin-6'-O-benzenesulfonate is 6 to 12:1, and the halogenated hydrocarbon-lower alcohol mixed solvent and the crude paeoniflorin-6'-O-benzenesulfonate are
  • the volume to mass ratio of the crude paeoniflorin-6'-O-benzenesulfonate is 55 to 80 ml: 1 g
  • the mass ratio of ethanol or methanol to the medicinal material is 5 to 20:1; in step S1-2, the mass of the silica gel used for silica gel column chromatography separation and the crude paeoniflorin glycosides The ratio is 10-15:1, and the volume-to-mass ratio of the alkane derivative-lower alcohol mixed solvent and the crude paeoniflorin glycoside is 50-60ml:1g; in step S2, the amount of benzene sulfonyl chloride is 25% to 30% of the mass of the paeoniflorin glycoside, the dosage of the organometallic catalyst is 0.5% to 5.0% of the mass of the paeoniflorin glycoside, and the molar ratio of the acid binding agent to the paeoniflorin glycoside It is 1.2 ⁇ 1.6:1; in step S5, the volume mass ratio of the mixed solvent and the paeoniflorin-6'-O-benzenesulfonate fine product B is 1 ⁇ 15mL:1
  • step S1-2 when the amount of filler is larger, the separation effect is better.
  • the amount is 10 to 15 times that of the crude paeoniflorin glycoside, the amount of eluent is relatively small while ensuring a better separation effect. .
  • the mass ratio of ethanol or methanol to the medicinal material is 5 to 10:1; in step S1-2, the mesh number of the silica gel used for silica gel column chromatography separation is 60 to 400 mesh, and the pore size is 60 to 400 mesh.
  • the volume ratio of the alkane derivative to the lower alcohol in the alkane derivative-lower alcohol mixed solvent is 1 to 10:1; in step S2, the amount of the organometallic catalyst is 0.6% to 0.6% of the mass of the paeoniflorin glycosides.
  • step S3 the mesh number of the silica gel used for the silica gel column chromatography separation is 60 to 400 mesh, and the pore diameter is The volume ratio of the halogenated hydrocarbon to the lower alcohol in the halogenated hydrocarbon-lower alcohol mixed solvent is 6 to 12:1; in step S4, the paeoniflorin-6'-O-benzenesulfonate fine product A After dissolving with the good solvent at 50-60°C, the temperature is lowered to 10-20°C and the poor solvent is added for crystallization; in step S5, the programmed drying includes pre-freezing, sublimation drying and analytical drying steps. The temperatures of pre-freezing, the sublimation drying and the analytical drying are increased in sequence.
  • the adsorption includes one or more of stirring adsorption and column chromatography adsorption
  • the adsorbent includes one or more of silica gel and alumina, and is eluted with pure ethanol.
  • the crude paeoniflorin glycoside is obtained; in step S1-2, the volume ratio of the alkane derivative to the lower alcohol in the alkane derivative-lower alcohol mixed solvent is 3 to 7:1; in step S2, the reaction is carried out at room temperature , the reaction time is 2 to 5h; in step S4, after crystallization, it also includes the process of filtration, rinsing, and re-filtration to obtain the paeoniflorin glycoside-6'-O-benzenesulfonate fine product B; in step S5, The temperature of the pre-freezing is -60 ⁇ -10°C, the temperature of the sublimation drying is -10 ⁇ 0°C, and the temperature of the analytical drying is 5 ⁇ 65°C.
  • step S1-1 generally speaking, in addition to more than 20% of paeoniflorin glycosides, the crude paeoniflorin glycosides also contain a large amount of tannins, sugar gums and other impurities. If column chromatography is used directly for separation, it will not only affect The purity of paeoniflorin glycosides also has a great impact on the separation efficiency. Therefore, using adsorbents to remove impurities such as tannins and sugar gums in paeoniflorin glycosides can further improve the purity and separation efficiency of the resulting paeoniflorin glycosides.
  • the adsorbents used in the present invention are low in price and have good separation effects, and can reduce the cost of industrial production of paeoniflorin-6'-O-benzenesulfonate.
  • the crude paeoniflorin glycosides can be dissolved in a solvent consistent with the eluent used in column chromatography before column chromatography.
  • the mass ratio of the adsorbent to the medicinal material extract is 1-4:1, and the volume-mass ratio of pure ethanol to the adsorbent is 2-6ml:1g; step S1-
  • the crude paeoniflorin derivative is dissolved in the alkane derivative-lower alcohol mixed solvent, and the alkane derivative in the alkane derivative-lower alcohol mixed solvent includes ethyl acetate.
  • the lower alcohol in the alkane derivative-lower alcohol mixed solvent includes one or more of methanol, ethanol, and isopropyl alcohol.
  • step S3 before the silica gel column chromatography separation, use the halogenated hydrocarbon-lower alcohol mixed solvent to dissolve the paeoniflorin-6'-O-benzenesulfonate crude product; in step S4, use the Rinse with poor solvent; in step S5, the pre-freezing operation is to cool down to -60 ⁇ -10°C and keep it warm for 30 ⁇ 300min, and the sublimation drying operation is to raise the temperature to -10 ⁇ 0°C within 30 ⁇ 180min and keep it warm for 30 ⁇ 180min. The temperature is maintained for 180 to 720 minutes.
  • the analytical drying operation is to raise the temperature to 5 to 20°C within 30 to 240 minutes and keep the temperature for 60 to 600 minutes, and then raise the temperature to 50 to 65°C within 30 to 240 minutes and keep the temperature for 300 to 1440 minutes.
  • the alkane derivative-lower alcohol mixed solvent is used to dissolve the crude paeoniflorin glycoside in a volume mass ratio of 1 to 3 ml: 1 g, and the alkane derivative is
  • the substance-lower alcohol mixed solvent is an ethyl acetate-methanol mixed solvent or an ethyl acetate-ethanol mixed solvent, and the volume ratio of the alkane derivative to the lower alcohol in the alkane derivative-lower alcohol mixed solvent is 4 to 6:1;
  • step S3 before the silica gel column chromatography separation, use the halogenated hydrocarbon-lower alcohol mixed solvent to dissolve the crude paeoniflorin-6'-O-benzenesulfonate ester in a volume mass ratio of 1 to 3 ml: 1 g.
  • step S5 the pre-freezing operation is to lower the temperature to -40 ⁇ -10°C and keep it warm for 90 ⁇ 300min, and the sublimation drying operation is to raise the temperature to -10 ⁇ 0°C within 60 ⁇ 180min and keep it warm for 240 ⁇ 600min.
  • the operation of analytical drying is to raise the temperature to 5-15°C within 60-180 min and keep it warm for 90-540 min, and then raise the temperature to 50-60°C within 60-180 min and keep it warm for 480-1440 min.
  • a kind of paeoniflorin-6’-O-benzenesulfonate obtained by the preparation method of paeoniflorin-6’-O-benzenesulfonate has the following structure:
  • the obtained paeoniflorin-6'-O-benzenesulfonate has good blood-enriching effect.
  • the present invention proposes for the first time a process route for preparing paeoniflorin-6'-O-benzenesulfonate.
  • the route is simple, the conditions are mild, and it is suitable for industrial production.
  • the synthesis method in the present invention has the advantages of high yield, small amount of catalyst and organic solvent, short reaction time, and no need to drop raw materials.
  • the elution system of ethyl acetate-methanol or ethyl acetate-ethanol is preferably used.
  • the dosage of remover can also improve the safety of people and industrial production.
  • the drying process of the present invention can ensure that the solvent residue of the finished product of paeoniflorin-6'-O-benzenesulfonate is qualified without increasing the content of related substances and ensure that the paeoniflorin-6'-O-benzenesulfonate product is qualified. High quality of finished acid ester products.
  • Figure 1 is a hydrogen spectrum of the product of Example 1 of the present invention.
  • Figure 2 is a carbon spectrum of the product of Example 1 of the present invention.
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 500g of white peony slices, add 4L of 95% ethanol for hot reflux extraction, filter and concentrate to obtain 31.9g of medicinal extract, then add 63.8g of neutral alumina for stirring and adsorption, and add the adsorbed neutral alumina to the chromatography column , use 100 mL ethanol to elute, collect the eluate, and concentrate to obtain 15.4 g of crude paeoniflorin glycoside, with a purity of 25.3%.
  • Example 1 the hydrogen spectrum of the product is shown in Figure 1 and the carbon spectrum is shown in Figure 2. After identification, it was determined that the product had the following structure:
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 500g of white peony slices, add 600ml of 80% ethanol for thermal reflux extraction, filter and concentrate to obtain 37.6g of medicinal extract, then add 112.8g of neutral alumina for stirring and adsorption, and add the adsorbed neutral alumina to the chromatography column , use 150 mL ethanol to elute, collect the eluate, and concentrate to obtain 17.95g of crude paeoniflorin glycoside, with a purity of 22.6%.
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 1kg of white peony slices, add 6L of absolute ethanol for thermal reflux extraction, filter and concentrate to obtain 31g of medicinal extract, then add 183g of neutral alumina for stirring and adsorption, add the adsorbed neutral alumina to the chromatography column, and use Elute with 180 mL of ethanol, collect the eluate, and concentrate to obtain 36.4 g of crude paeoniflorin glycoside, with a purity of 27.3%.
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 5kg of white peony slices, add 50L of 95% ethanol for thermal reflux extraction, filter and concentrate to obtain 401.4g of medicinal extract, then add 600g of neutral alumina for stirring and adsorption, and add the adsorbed neutral alumina to the chromatography column. Use 1.2L ethanol to elute, collect the eluate, and concentrate to obtain 208.5g of crude paeoniflorin glycoside, with a purity of 28.4%.
  • the eluate was collected and concentrated under reduced pressure to obtain 46.25g of paeoniflorin glycoside with a purity of 93.6%.
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 10kg of white peony slices, add 70L of 90% ethanol for thermal reflux extraction, filter and concentrate to obtain 903g of medicinal extract, then add 1.8kg of neutral alumina for stirring and adsorption, and add the adsorbed neutral alumina to the chromatography column. Use 3.6 L of ethanol to elute, collect the eluate, and concentrate to obtain 505 g of crude paeoniflorin glycoside, with a purity of 23.6%.
  • a paeoniflorin-6'-O-benzenesulfonate is prepared.
  • the specific process is:
  • A Take 50kg of white peony slices, add 500L of 95% ethanol for thermal reflux extraction, filter and concentrate to obtain 4.0kg of medicinal extract, then add 8.0kg of neutral alumina for stirring and adsorption, and add the adsorbed neutral alumina to the chromatography column , use 16.0L ethanol to elute, collect the eluate, and concentrate to obtain 1.8 kg of crude paeoniflorin glycoside, with a purity of 20.3%.
  • This comparative example uses paeoniflorin glycoside (purity 98%) instead of peony extract as the starting material to prepare paeoniflorin glycoside-6'-O-benzenesulfonate, which undergoes the following processes:
  • step D is omitted.
  • step D is omitted.
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • Steps A to C are the same as in Embodiment 4, except that step D is as follows:
  • the residues of various solvents used in the present invention in the finished drug should basically be controlled below 0.5%. From the comparison between Example 4 and Comparative Examples 2 to 7, it can be found that using dimethyl carbonate, acetone and water, or a combination of dimethyl carbonate, methyl ethyl ketone and water as the solvent, the effect of paeoniflorin-6-O' - The benzenesulfonate ester is dissolved and then dried in a programmed manner. The solvent residue can meet the standards and there is no significant increase in related substances. The quality of the dried product is guaranteed.
  • Comparative Example 6 a mixed solvent of dimethyl carbonate and acetone was used to perform programmed drying of paeoniflorin-6-O'-benzenesulfonate, and the solvent residue could not be reduced below the standard.
  • Comparative Example 7 used a mixed solvent of tert-butyl alcohol and water to perform programmed drying of paeoniflorin-6-O'-benzenesulfonate. Although the solvent residue could meet the standards, related substances increased significantly. It can be seen that only by using the specific mixed solvent of the present invention can the requirements that the dissolved residues meet the standards and there is no increase in related substances can be met.
  • Comparative Example 8 when a mixed solvent composed of dimethyl carbonate, acetone and water is used as the solvent for programmed drying, not all proportions can obtain qualified finished products.
  • the results of solvent residues and related substances in the finished product are investigated.
  • the acetone:water ratio in the mixed solvent is less than 1:4, as shown in groups 1, 2, and 8 in the table, the mixed system will appear stratified, and the dimethyl carbonate in the finished product will exceed the limit, affecting the drying effect; and when the mixture When the acetone content in the system exceeds 10%, as shown in Group 4, the residual acetone in the finished product exceeds the limit.
  • the mixed solvent system does not stratify, the solvent residues of dimethyl carbonate and acetone meet the specified requirements, and there is no obvious relevant substance after drying Increase. It can be seen that only by using a mixed solvent of dimethyl carbonate, C3 ⁇ 4 ketones and water in a specific ratio can the dissolved residues meet the standards and there is no increase in related substances.
  • mice were randomly divided into 9 groups according to body weight, half male and half female, namely control group, model group, positive drug group, paeoniflorin glycoside, and paeoniflorin glycoside-6'-O-
  • control group model group
  • positive drug group paeoniflorin glycoside
  • 0.5 mL of blood was bled from the fundus venous plexus and administered intragastrically 24 hours later.
  • the positive drug group was intragastrically administered compound donkey-hide gelatin slurry at 20 ml/kg
  • the control and model groups were intragastrically administered distilled water at 120 mg/kg.
  • 30 ⁇ L of blood was collected from the orbit to detect the number of red blood cells (see Table 14).
  • paeoniflorin-6'-O-benzenesulfonate and paeoniflorin can effectively increase the number of red blood cells in mice, and the effect of paeonilide-6'-O-benzenesulfonate is greater. It is better than paeoniflorin glycoside, and the effect of high dose of paeoniflorin glycoside-6'-O-benzenesulfonate is close to that of compound donkey-hide gelatin. Compared with paeoniflorin, the reason why paeonilide-6'-O-benzenesulfonate is more effective may be due to increased lipophilicity and improved in vivo bioavailability.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention relève du domaine des composés, et concerne un procédé de préparation d'albiflorine-6'-O-benzènesulfonate. Le procédé comprend les étapes suivantes consistant à : mettre à disposition un matériau médicinal riche en albiflorine en tant que matériau de départ, le soumettre à une extraction, une adsorption, une séparation et une purification pour obtenir de l'albiflorine ayant une pureté relativement élevée ; et faire réagir un catalyseur métallique organique, un agent de liaison à l'acide et du chlorure de benzènesulfonyle chimiquement actif avec de l'albiflorine, réaliser une séparation par chromatographie sur colonne et un raffinage sur le produit pour obtenir plus de 98 % d'albiflorine-6'-O-benzènesulfonate, le dissoudre dans un solvant mixte, et réaliser un séchage programmé pour obtenir finalement un produit fini d'albiflorine-6'-O-benzènesulfonate. Le procédé a un rendement de réaction élevé, un fonctionnement simple et des conditions modérées, et est très approprié pour la production industrielle d'albiflorine-6'-O-benzènesulfonate.
PCT/CN2022/133498 2022-06-09 2022-11-22 Procédé de préparation d'albiflorine-6'-o-benzènesulfonate WO2023236453A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210647520.6A CN115677804A (zh) 2022-06-09 2022-06-09 一种芍药内酯苷-6’-o-苯磺酸酯的制备方法
CN202210647520.6 2022-06-09

Publications (1)

Publication Number Publication Date
WO2023236453A1 true WO2023236453A1 (fr) 2023-12-14

Family

ID=85060344

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/133498 WO2023236453A1 (fr) 2022-06-09 2022-11-22 Procédé de préparation d'albiflorine-6'-o-benzènesulfonate

Country Status (2)

Country Link
CN (1) CN115677804A (fr)
WO (1) WO2023236453A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677804A (zh) * 2022-06-09 2023-02-03 广州白云山汉方现代药业有限公司 一种芍药内酯苷-6’-o-苯磺酸酯的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603827A (zh) * 2012-02-10 2012-07-25 魏伟 一种芍药苷芳香族酯衍生物、其制备方法及其用途
CN102643316A (zh) * 2011-11-28 2012-08-22 宁波立华制药有限公司 一种酰化苷类化合物及其制法和应用
CN103044503A (zh) * 2012-12-24 2013-04-17 浙江工业大学 一种快速高效提取芍药苷和芍药内酯苷的方法
CN103951717A (zh) * 2014-04-11 2014-07-30 浙江工业大学 一种提取制备苯甲酰芍药苷和苯甲酰芍药内酯苷的方法
CN115677804A (zh) * 2022-06-09 2023-02-03 广州白云山汉方现代药业有限公司 一种芍药内酯苷-6’-o-苯磺酸酯的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102643316A (zh) * 2011-11-28 2012-08-22 宁波立华制药有限公司 一种酰化苷类化合物及其制法和应用
CN102603827A (zh) * 2012-02-10 2012-07-25 魏伟 一种芍药苷芳香族酯衍生物、其制备方法及其用途
CN103044503A (zh) * 2012-12-24 2013-04-17 浙江工业大学 一种快速高效提取芍药苷和芍药内酯苷的方法
CN103951717A (zh) * 2014-04-11 2014-07-30 浙江工业大学 一种提取制备苯甲酰芍药苷和苯甲酰芍药内酯苷的方法
CN115677804A (zh) * 2022-06-09 2023-02-03 广州白云山汉方现代药业有限公司 一种芍药内酯苷-6’-o-苯磺酸酯的制备方法

Also Published As

Publication number Publication date
CN115677804A (zh) 2023-02-03

Similar Documents

Publication Publication Date Title
JP7402696B2 (ja) 合成のための化合物、組成物、及び方法
JP7371006B2 (ja) Ｐ３００及び／又はｃｂｐの調節因子を調製するための方法
WO2023236453A1 (fr) Procédé de préparation d'albiflorine-6'-o-benzènesulfonate
CN110423257B (zh) 一种索菲布韦合成工艺
CN102070699B (zh) 三羟基取代五环三萜类化合物及其制备方法和应用
CN107488156B (zh) 一种无定型葡萄糖醇的合成方法
CN102775450A (zh) 一种1,6-脱水-2-叠氮-2-脱氧-β-D-吡喃葡萄糖的制备方法
CN102101856A (zh) 一种高光学纯度核苷类中间体及其制备方法
CN112500358B (zh) 赛乐西帕晶型及其制备方法
WO2022062401A1 (fr) Procédé de préparation de tianagliflozine
TW202304858A (zh) 單甲基奧瑞他汀e化合物之製備及純化方法
CN102058610B (zh) 三萜皂苷化合物在制备抗高血压药物中的应用
WO2013159285A1 (fr) Procédé de préparation de (s)-oxiracétam
WO2023000517A1 (fr) Procédé de préparation de paéoniflorine-6-o'-benzènesulfonate
CN104610208B (zh) (1s)‑1,6‑二脱氧‑1‑[4‑甲氧基‑3‑(反式‑4‑正丙基环己基)甲基苯基]‑d‑吡喃葡萄糖的晶型a及其制备方法和应用
CN111499653A (zh) 一种单流程制备双氢青蒿素原料药的方法
CN1616474A (zh) 吲哚美辛的乙酰氨基葡萄糖衍生物及其合成方法和应用
CN105884846B (zh) 一种2’-脱氧腺苷的合成方法
CN106977561B (zh) Sutherlandin-5-p-hydroxybenzoate的制备及其在制备治疗类风湿关节炎药物中的应用
CN114920705B (zh) 格列吡嗪酯类杂质的制备方法及其应用
CN104693192A (zh) 一种化合物的晶型a及其制备方法和应用
CA2637815A1 (fr) Formes cristallines de ciclesonide
CN113248464B (zh) 一种c-糖苷类衍生物的合成方法
CN111808157B (zh) 一种腺苷原料药的制备方法
CN108640958A (zh) 异苯并呋喃衍生物、其药物组合物和制剂以及用途

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: 22945581

Country of ref document: EP

Kind code of ref document: A1