CN117886958A - Nine-sugar and preparation method and application thereof - Google Patents

Nine-sugar and preparation method and application thereof Download PDF

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CN117886958A
CN117886958A CN202210975957.2A CN202210975957A CN117886958A CN 117886958 A CN117886958 A CN 117886958A CN 202210975957 A CN202210975957 A CN 202210975957A CN 117886958 A CN117886958 A CN 117886958A
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disaccharide
acceptor
butyl dimethyl
benzoyl
dimethyl silicon
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朱玉亮
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Eliste Hefei Biotechnology Co ltd
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    • 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
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a nine-sugar and a preparation method and application thereof, and relates to a synthesis method of the nine-sugar which has biological activity and can be particularly used as an antitumor drug. The invention firstly prepares a disaccharide acceptor and a disaccharide donor which are connected with 1-3, under the action of Lewis acid, the coupling is carried out to obtain tetrasaccharide which is connected with 1-3, the tetrasaccharide 10 is used for removing tertiary butyl dimethyl silicon to obtain a tetrasaccharide acceptor 14, the tetrasaccharide 14 is used as a glycosyl acceptor, the disaccharide 4 is used as a glycosyl donor, the coupling is carried out to obtain hexasaccharide 19, the 4, 6-benzylidene group is removed to obtain hexasaccharide 20 which is used as a glycosyl acceptor, the hexasaccharide 20 is coupled with the monosaccharide donor 3 to obtain nine-saccharide 21, and all protecting groups are removed to obtain nine-saccharide 22.

Description

Nine-sugar and preparation method and application thereof
Technical Field
The present invention relates to a highly efficient synthesis of biologically active, in particular, nonasaccharide useful as an antitumor agent.
Background
The invention relates to a method for preparing the nine-sugar by adopting a synthesis mode with simple route, convenient operation and high efficiency, and the nine-sugar obtained by the chemical method has high purity, high yield and controllable quality. As reported in the prior art of chemical preparation methods of hexasaccharides and heptasaccharides, for example, beta- (1- > 6) main chain beta- (1- > 3) Branched chain dextran hexasaccharides and dextran heptasaccharides prepared by CN1242371A and CN1340550A, beta- (1- > 6) Branched chain beta- (1- > 3) main chain dextran hexasaccharides prepared by CN1417217A are easy to generate orthoesters during the preparation process, the reaction operability is complex and the operation is difficult, and the articles "Synthesis of beta- (1- > 6) -Branched beta- (1- > 3) -Glucohexaose and Its Analogues Containing an A- (1- > 3) Linked Bond with Antitumor Activity" published by Ning Jun and Kong Fan also indicate that orthoesters are generated when a 2-site acetyl Schmitt reagent is used as a glycosyl donor for coupling with a glycosyl acceptor, so that the post-treatment is complex, the reaction is easy to fail, and the requirements on technical staff are extremely high, and industrialization cannot be realized.
Disclosure of Invention
The invention aims to provide a synthesis method which has extremely simple route, convenient operation and high efficiency, and is used for synthesizing the nine sugar with biological activity, particularly beta- (1-6) branched beta- (1-3) main chain which can be used as an antitumor agent. The method provided by the invention has simple reaction synthesis route, strong selectivity and high raw material utilization rate, the method has low technical requirements on operators and high yield, and is suitable for industrialization. The industrial preparation method of the nine sugar provided by the invention is provided for the first time. The 9-saccharide has strong inhibition effect on chemical carcinogenesis. Few cancer cells produced by MC inoculation are destroyed by injection of 9-sugar enhancing immune function. Sugar 9 also reduces the oncogenic rate of adenovirus from 79% to 41%. The 9-saccharide of the invention not only has the effect of promoting immune rejection and resisting cancer.
In order to solve the technical problems of the invention, the technical proposal is as follows: a nine sugar has the following structural formula:
in order to solve the technical problem of the invention, another technical proposal is as follows:
the tetraose 14 is used as a glycosyl acceptor, the disaccharide 4 is used as a glycosyl donor, the coupling is carried out to obtain hexasaccharide 19, the 4, 6-benzylidene group is removed to obtain hexasaccharide 20 which is used as the glycosyl acceptor, the hexasaccharide 20 is coupled with the monosaccharide donor 3 to obtain nine saccharide 21, and all protecting groups are removed to obtain lentinus edodes nine saccharide 22.
(1) Removing tert-butyl dimethyl silicon group from 4, 6-benzylidene-2-O-benzoyl-3-tert-butyl dimethyl silicon-thioethyl glucose 1 under the action of HF/Py to obtain 4, 6-benzylidene-2-O-benzoyl-thioethyl glucose 2, taking 2 moles of monosaccharide 2 as a glycosyl acceptor and 1 mole of monosaccharide 3 as a glycosyl donor, dissolving the glycosyl donor and the glycosyl acceptor in dichloromethane, adding a catalytic amount of TMSOTF, stirring at 25 ℃, and reacting for 4-8 hours to obtain disaccharide 4.
Bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -; SEt is C 2 H 5 S-；
(2) 4, 6-benzylidene-2-O-benzoyl-3-tert-butyldimethylsilyl-thioethyl glucose 1 is dissolved in dichloromethane, 4, 6-benzylidene-2-O-benzoyl-3-tert-butyldimethylsilyl-O-benzyl glucose 5 is prepared under the action of BnOH, NIS, tfOH, tert-butyldimethylsilyl groups are removed under the action of HF/Py to obtain 4, 6-benzylidene-2-O-benzoyl-O-benzyl glucose 6, 2 moles of monosaccharide 6 are used as glycosyl acceptors, 1 mole of monosaccharide 7 is used as glycosyl donors, the glycosyl donors and glycosyl acceptors are dissolved in dichloromethane, a catalytic amount of TMSOTF is added, stirring is carried out at 25 ℃ for 4-8 hours, and the tert-butyldimethylsilyl groups are removed under the action of HF/Py to obtain disaccharide 9. The following formula is shown:
bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -; SEt is C 2 H 5 S-；
(3) 2.2 mol of disaccharide 4 is taken as a glycosyl donor, 1 mol of disaccharide 9 is taken as a glycosyl acceptor, the glycosyl donor and the glycosyl acceptor are dissolved in methylene dichloride, a catalytic amount of TMSOTF and NIS is added, and stirring is carried out at 0 ℃ for 4-8 hours, and then the tetraose 10 is obtained.
Bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -; SEt is C 2 H 5 S-；
(4) Removing tert-butyl dimethyl silicon group from tetrasaccharide 10 under the action of HF/Py to obtain tetrasaccharide 14;
bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -；
(5) Taking 2 moles of tetraose 14 as a glycosyl acceptor, 1 mole of disaccharide 4 as a glycosyl donor, dissolving the glycosyl donor and the glycosyl acceptor in dichloromethane, adding a catalytic amount of TMSOTF, stirring at 25 ℃, reacting for 4-8 hours to obtain hexasaccharide 19, removing 4, 6-benzylidene groups to obtain hexasaccharide 20, taking 2.2 moles of hexasaccharide 20 as the glycosyl acceptor, taking 1 mole of monosaccharide 3 as the glycosyl donor, dissolving the glycosyl donor and the glycosyl acceptor in dichloromethane, adding the catalytic amount of TMSOTF, stirring at 25 ℃, reacting for 4-8 hours to obtain nine saccharides 21, and removing all protecting groups to obtain lentinus edodes nine saccharides 22.
Bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -; SEt is C 2 H 5 S-；
Detailed Description
The following specific embodiments are used to illustrate the technical solution of the present invention, but the scope of the present invention is not limited thereto:
example 1
Preparation of disaccharide donor 4
4, 6-Benzylidene-2-O-benzoyl-3-t-butyldimethylsilyl-thioethylglucose 1 (2.65 g, 5 mmol) was added to 30ml 80% HF/Py and after stirring at 25℃for 6 hours, thin layer chromatography analysis indicated completion of the reaction. The solvent was distilled off under reduced pressure to give monosaccharide 2. Monosaccharide 2 (4.16 g, 10 mmol) was dissolved in 30ml dichloromethane to give solution A, monosaccharide 3 (3.75 g, 5 mmol) was dissolved in 10 ml dichloromethane to give solution B, A and B were mixed to give solution C, TMSOTF (575. Mu.l, 5 mmol) was added to C, and thenAfter reacting the molecular sieves at 25 ℃ for 8 hours, thin layer chromatography analysis indicated the reaction was complete. Suction filtration, reduced pressure evaporation of the solvent, column chromatography separation, eluting with ethyl acetate/cyclohexane (1/3) as eluent, collecting the corresponding components, and obtaining pure disaccharide 4 with a yield of 96%.
Preparation of disaccharide receptor 9
4, 6-Benzylmethylidene-2-O-benzoyl-3-tert-butyldimethylsilyl-thioethylglucose 1 (2.65 g, 5 mmol) was dissolved in 10 ml dichloromethane, bnOH (0.62 ml, 6 mmol), NIS (0.65 ml, 6 mmol), tfOH (0.48 ml, 6 mmol) were added, and thenAfter reacting the molecular sieves at 0 ℃ for 4 hours, thin layer chromatography analysis indicated the reaction was complete. Suction filtration and reduced pressure evaporation of the solvent gave disaccharide 5. Disaccharide 5 (5.76 g, 10 mmol) was dissolved in 40ml 80% HF/Py and after stirring at 25℃for 7 hours, thin layer chromatography analysis indicated the reaction was complete. The solvent was distilled off under reduced pressure to give monosaccharide 6. Monosaccharide 6 (4.62 g, 10 mmol) was dissolved in 20ml dichloromethane to give solution A, monosaccharide 7 (3.25 g, 5 mmol)Molar) was dissolved in 10 ml of dichloromethane to give solution B, and solution A was mixed with solution B to give solution C, to which TMSOTF (575. Mu.l, 5 mmol) was added, followed by +.>After reacting the molecular sieves at 25 ℃ for 8 hours, thin layer chromatography analysis indicated the reaction was complete. Filtering, evaporating the solvent under reduced pressure, separating by column chromatography, eluting with ethyl acetate/cyclohexane (1/3) as eluent, and collecting the corresponding components to obtain pure disaccharide 8. Disaccharide 8 (10.5 g, 10 mmol) was dissolved in 40ml 80% HF/Py and after stirring at 25℃for 5 hours, thin layer chromatography analysis indicated the reaction was complete. The solvent was distilled off under reduced pressure and the solid was washed with pyridine to give pure disaccharide 9 in 94% yield.
Preparation of tetraose 10
Disaccharide 4 (10.4 g, 10 mmol) was dissolved in 40ml dichloromethane to give solution A, disaccharide 9 (4.26 g, 4.55 mmol) was dissolved in 10 ml dichloromethane to give solution B, solution A was mixed with solution to give solution C, TMSOTF (690. Mu.l, 6 mmol), NIS (0.65 ml, 6 mmol) were added to the C, and thenAfter reacting the molecular sieves at 0 ℃ for 8 hours, thin layer chromatography analysis indicated the reaction was complete. Filtering, evaporating the solvent under reduced pressure, separating by column chromatography, eluting with ethyl acetate/cyclohexane (1/3) as eluent, and collecting the corresponding components to obtain pure tetrasaccharide 10.
Preparation of tetraose 14
Tetraose 10 (18.78 g, 10 mmol) was added to 60ml 80% HF/Py and after stirring at 25℃for 7 hours, thin layer chromatography analysis indicated completion of the reaction. The solvent was distilled off under reduced pressure to give tetraose 14.
Preparation of lentinan 22
Tetrasaccharide 14 (17.64 g, 10 mmol) was dissolved in 60ml dichloromethane to give solution A, disaccharide 4 (5.02 g, 5 mmol) was dissolved in 15 ml dichloromethane to give solution B, solution A was mixed with solution B to give solution C, TMSOTF (805. Mu.l, 7 mmol) was added to the solution C, and thenMolecular sieves, stirred at 25 ℃, after 8 hours of reaction, thin layer chromatography analysis indicated completion of the reaction. Suction filtration, reduced pressure evaporation of the solvent, column chromatography separation, eluting with ethyl acetate/cyclohexane (1/3) as eluent, and collecting the corresponding components to obtain pure hexose 19. Hexasaccharide 19 (27.06 g, 10 mmol) was dissolved in 75 ml 80% aqueous acetic acid and stirred at 25℃for 9 hours, after which thin layer chromatography analysis indicated completion of the reaction. The solvent was distilled off under reduced pressure to give hexose 20. Hexasaccharide 20 (24.42 g, 10 mmol) was dissolved in 80 ml dichloromethane to give solution D, monosaccharide 3 (3.41 g, 4.55 mmol) was dissolved in 10 ml dichloromethane to give solution E, solution D and solution E were mixed to give solution F, TMSOTF (805. Mu.l, 7 mmol) was added to F, and then->Molecular sieves, stirred at 25 ℃, after 8 hours of reaction, thin layer chromatography analysis indicated completion of the reaction. Suction filtration, reduced pressure evaporation of the solvent, column chromatography separation, eluting with ethyl acetate/cyclohexane (1/3) as eluent, and collecting the corresponding components to obtain pure nine-sugar 21, yield 89%. Nine sugar 21 (42.06 g, 10 ng) was dissolved in 100 ml of saturated sodium methoxide solution and Pd (OH) was added 2 (1.13 g, 8 mmol) and stirred at 25℃for 72 hours, the concentrated sephadex LH-20 (methanol) was separated on a column to give lentinan 22 in 94% yield. Nuclear magnetism 1 HNMR：5.23，4.76，4.73， 4.71，4.69，4.65，4.62，4.55，4.48
Example 2
The 9-saccharide prepared in example 1 has obvious effect on the gene expression level and activity of IL-2 and TNF-a in peripheral blood mononuclear cells of healthy human, and the gene expression level and activity are increased with the increase of the concentration in the concentration range of 0.5 mg/L to 15 mg/L to induce immune response.
Preliminary biological activity tests show that the inhibition effect of the nine-sugar mouse liver cancer cell H22, the mouse anus fibrosarcoma cell S180 and the human liver cancer cell HepG2 shows good dose-effect dependence (P <0.05 or P < 0.01).
The tumor inhibition by 9 sugar is shown in Table 1 below
Anticancer and cancer cell metastasis inhibiting effects of table 19 saccharide
From these results, the 9 saccharide in example 1 was found to have a preventive effect not only on allograft cancers such as S180 but also on homologous cancers and spontaneous cancer growth, and also on chemical carcinogenesis and viral carcinogenesis.
The tumor-inhibiting effect of 9-sugar in example 1 is characterized by: there is no direct cytotoxic effect on tumor cells, which depends on the host. Mice such as A/J, DBA/2, CD-1 and the like are sensitive to 9 sugar, and the tumor can completely disappear. No disappearance of C3H/He, BALB/C, CBA, etc. Sensitive mice were inoculated with Methylbile (MC) to establish fibrosarcoma strains, from which tumors disappeared after 9-sugar administration following implantation in inbred mice.
The 9 sugar in example 1 has strong inhibitory effect on chemical carcinogenesis. Almost all mice developed cancer 35 weeks after MC inoculation, but the intraperitoneal administration of 9 sugars was started 2-3 weeks after MC inoculation, and the carcinogenic rate was reduced to about 31%. This is because few cancer cells produced by MC inoculation are destroyed by injection of 9-sugar to enhance immune function. Sugar 9 also reduces the oncogenic rate of adenovirus from 79% to 41%. Indicating that 9-sugar is not only a substance that promotes immune rejection but is a true anticancer substance.
Example 3
1000 mg, 5000 mg and 10000 mg of formula 9 sugar were dissolved in 1000 ml of 1% physiological saline, respectively, to prepare injections of 1 mg/ml, 5 mg/ml and 10 mg/ml, respectively, which are usually prepared at the time of use.
Example 4
Preparation of granule
80g of the pure product of the nine sugar obtained in example 1;
80g of mannitol;
320g of sucrose;
80g of corn starch;
32g of sodium carboxymethylcellulose;
proper amount of 10% starch slurry
The preparation method comprises the following steps: sieving pure product of nine sugar, mannitol, sucrose, corn starch and sodium carboxymethylcellulose with 100 mesh sieve, respectively, weighing according to prescription, mixing, adding 10% starch slurry to obtain soft material, granulating with 14 mesh sieve, drying at 70-80deg.C, sieving with 12 mesh sieve, granulating, and packaging.
Example 5
A preparation method of an immunity-providing anti-tumor health care product capsule comprises the following steps: weighing 50g of the nine-sugar pure product obtained in the example 1, 32.4g of white dextrin and 1.6g of magnesium stearate, fully and uniformly mixing, filling the obtained mixed raw materials into hollow capsule shells, and respectively filling 0.45g of the mixed raw materials into each hollow capsule shell to prepare the immunity and anti-tumor health care capsule product.
The foregoing examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the foregoing examples, and any other modifications that do not depart from the present invention should be equivalent to the above-described examples, and are included in the scope of the present invention.

Claims (6)

1. A nine sugar characterized by the following structural formula:
2. the method for producing a nine sugar according to claim 1, comprising the steps of:
removing tert-butyl dimethyl silicon group from 4, 6-benzylidene-2-O-benzoyl-3-tert-butyl dimethyl silicon-thioethyl glucose 1 to obtain 4, 6-benzylidene-2-O-benzoyl-thioethyl glucose 2 serving as a monosaccharide acceptor, and coupling 2,4, 6-tri-O-benzoyl-3-tert-butyl dimethyl silicon-glucose trichloroacetyl iminoester 3 serving as a glycosyl donor under the action of TMSOTf to obtain a disaccharide donor 4;
4, 6-benzylidene-2-O-benzoyl-3-tertiary butyl dimethyl silicon-thioethyl glucose 1 is used for preparing 4, 6-benzylidene-2-O-benzoyl-3-tertiary butyl dimethyl silicon-O-benzyl glucose 5, tertiary butyl dimethyl silicon is removed to obtain a 4, 6-benzylidene-2-O-benzoyl-O-benzyl glucose 6 monosaccharide acceptor, the 4, 6-tri-O-benzoyl-3-tertiary butyl dimethyl silicon-thioethyl glucose 7 monosaccharide donor is coupled with 2,4, 6-tri-O-benzoyl-3-tertiary butyl dimethyl silicon-thioethyl glucose 7 monosaccharide donor under the action of TMSOTF to obtain disaccharide 8, tertiary butyl dimethyl silicon group is removed to obtain disaccharide acceptor 9, disaccharide donor 4 and disaccharide acceptor 9 are coupled under the action of TMSOTF to obtain tetraose 10, namely tetraose 10 is removed to tertiary butyl dimethyl silicon to obtain tetraose acceptor 14,
coupling with tetraose 14 as glycosyl acceptor, disaccharide 4 as glycosyl donor to obtain hexasaccharide 19, removing 4, 6-benzylidene group to obtain hexasaccharide 20 as glycosyl acceptor, coupling with monosaccharide donor 3 to obtain nonasaccharide 21, removing all protecting groups to obtain nonasaccharide 22;
bz is: c (C) 6 H 5 (c=o) -; TBS is: c (C) 6 H 15 Si-; bn is C 6 H 5 CH 2 -; ph is C 6 H 5 -; SEt is C 2 H 5 S-；
3. The use of the nine sugar according to claim 1 for preparing an anti-tumor, immunity-enhancing drug or health product.
4. The use of the nine sugar according to claim 1 for preparing an anti-tumor, immunity-enhancing drug or health care product, characterized in that: optionally adding pharmaceutically acceptable adjuvants to make into pharmaceutically acceptable dosage forms.
5. The use of the nine sugar according to claim 1 for preparing an anti-tumor or immunity-enhancing drug or health product, characterized in that: the preparation of the medicine or health care product is pill, syrup, mixture, decoction, tablet, powder, paste, capsule, oral liquid, granule or injection.
6. The use of the nine sugar according to claim 1 for preparing an anti-tumor or immunity-enhancing drug or health product, characterized in that: adjuvants may also be added including one or more of propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binding agents, integration agents, permeation promoters, pH regulators, buffers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, and release retarders.
CN202210975957.2A 2022-08-15 2022-08-15 Nine-sugar and preparation method and application thereof Pending CN117886958A (en)

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