WO2015109979A1 - Royal jelly acid derivative, preparation method and application thereof - Google Patents

Royal jelly acid derivative, preparation method and application thereof Download PDF

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WO2015109979A1
WO2015109979A1 PCT/CN2015/071019 CN2015071019W WO2015109979A1 WO 2015109979 A1 WO2015109979 A1 WO 2015109979A1 CN 2015071019 W CN2015071019 W CN 2015071019W WO 2015109979 A1 WO2015109979 A1 WO 2015109979A1
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acid
royal
royal jelly
acid derivative
hydroxy
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PCT/CN2015/071019
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French (fr)
Chinese (zh)
Inventor
赵瑞林
王占喜
张良才
申玉
刘建美
李佳乔
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石家庄维奥化工有限公司
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Publication of WO2015109979A1 publication Critical patent/WO2015109979A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers

Definitions

  • the invention relates to the technical field of chemical synthesis and immunopharmaceutical, in particular to a royal jelly acid derivative, a preparation method thereof and the application of royal jelly acid and its derivatives.
  • the object of the present invention is to provide a royal jelly acid derivative and a preparation method and application thereof for preparing an immunosuppressive agent containing a royal jelly acid or a derivative thereof as a main component which is urgently needed in the prior art.
  • a royal acid derivative wherein the chemical structure of the royal acid derivative is
  • R1 is H, a branched linear hydrocarbon group, a fatty acyl group, an enoyl group, and a single or double of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • One of the fatty acyl esters, or R1 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3-dihydroxypropane, 2,3- A type of mono or diacyl acyl ester of dihydroxypropane.
  • R2 is H, a branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • One of the compounds, or R2 is a linear or branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • X is O or NH.
  • Typical compounds of the royal acid derivative are: E-10-hydroxy-2-decenoic acid, E-10-acetoxy-2-decenoic acid, E-10-propionyloxy-2-indole Alkenoic acid, E-10-butyryloxy-2-decenoic acid, ethyl E-10-hydroxy-2-decenoate, ethyl E-10-acetoxy-2-decenoate, E- Ethyl 10-propionyloxy-2-decenoate, ethyl E-10-butyryloxy-2-decenoate, ethylene glycol E-10-hydroxy-2-decenoate (single or Diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) ethylene glycol ester, E-10-hydroxy-2-decenoic acid glyceride (1, 2, 3 positions) Monoester or diester and triester; and mixed ester with acetic acid, propionic acid, buty
  • a method of making a royal jelly acid derivative comprising the steps of:
  • step A Acylation of a royal acid amide or an ester derivative with an acid halide or an acid anhydride to obtain a final product
  • the royal jelly acid derivative, the reaction formula of step A and step B is as follows:
  • step A in the amidation or esterification reaction, it is necessary to heat the solvent to 60 to 80 ° C, carry out a reflux reaction for 3 to 5 hours, reduce the temperature to 0 to 25 ° C, and then perform a washing operation with water. Drying at 20 to 50 ° C;
  • step B in the acylation reaction, the solvent temperature is heated to 60 to 80 ° C, and the reflux reaction is carried out for 2 to 5 hours. After the temperature is lowered to 0 to 25 ° C, the washing operation is repeated with water, and the washing is repeated. 3 to 5 times, the oil layer is separated and washed to obtain a royal acid derivative.
  • the molar ratio of the royal jelly acid, the petroleum ether, the methanol, and the concentrated sulfuric acid is 1: (3 to 10): 1.5: 0.02, and then heated to reflux at 65 ° C.
  • ethanolamine was added dropwise, stirred and heated to reflux at 65 ° C for 3 hours, cooled to -5 to 10 ° C, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10-hydroxy-2.
  • -decenylamide ethanol in the amidation or esterification reaction, the molar ratio of the royal jelly acid, the petroleum ether, the methanol, and the concentrated sulfuric acid is 1: (3 to 10): 1.5: 0.02, and then heated to reflux at 65 ° C.
  • ethanolamine was added dropwise, stirred and heated to reflux at 65 ° C for 3 hours, cooled to -5 to 10 ° C, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10
  • step B the E-10-hydroxy-2-nonenylamide ethanol obtained in the step A is dissolved in DMF, and one of butyryl chloride or butyryl bromide and butyric anhydride is added dropwise with stirring.
  • the reaction was carried out at 80 ° C for 2 hours, the temperature was lowered to -5 to 10 ° C, poured into 0 to 15 ° C cold water, stirred for 0.5 hours, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10-butyryl.
  • Oxy-2-decenylamide ethanol butyrate is
  • the application is an immunosuppressive agent containing a royal jelly acid derivative as a main component, and the royal jelly acid is derived.
  • the vaccine is produced, it is added to a vaccine preparation of an oil, a liquid or a powder, and the royal jelly acid derivative and the vaccine are thoroughly mixed at a ratio of 0.001% to 2%, and then injected, sprayed or dripped.
  • the application is an immunosuppressive agent containing a royal jelly or a royal jelly or a royal jelly acid derivative as a main component, and is applied to avian H5 influenza, H7 influenza, H9 influenza, Newcastle disease vaccine production or vaccine immunization.
  • the royal jelly acid or the royal jelly or the royal jelly acid derivative is thoroughly mixed with the vaccine in a ratio of 0.001% to 2%.
  • the beneficial effects of the invention are: the royal jelly acid is an unsaturated fatty acid found in royal jelly, non-toxic, and the royal pulp acid has a good biological activity, and the royal pulp acid derivative has physiological characteristics similar to those of the royal jelly acid, and 0.001 is added relative to the commercial vaccine. % ⁇ 2% of royal jelly acid or its derivative, the antibody titer of the body in 2 to 4 days is 1 to 4 (2 1 to 4 ) higher than that of the control group.
  • the invention relates to a royal jelly acid derivative and a preparation method and application thereof.
  • the royal jelly acid is an unsaturated fatty acid found in royal jelly, non-toxic, and the royal pulp acid has good biological activity, and the royal pulp acid derivative has a physiological similar to royal jelly acid.
  • Characteristics Compared with commercial vaccines, 0.001% to 2% of royal jelly acid or its derivatives are added, and the antibody titer of the body in 2 to 4 days is 1 to 4 (2 1 to 4 ) higher than that of the control group.
  • R1 is H, a branched linear hydrocarbon group, a fatty acyl group, an enoyl group, and a single or double of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • One of the fatty acyl esters, or R1 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3-dihydroxypropane, 2,3- A type of mono or diacyl acyl ester of dihydroxypropane.
  • R2 is H, a branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • One of the compounds, or R2 is a linear or branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
  • X is O or NH.
  • Typical compounds of the royal acid derivative are: E-10-hydroxy-2-decenoic acid, E-10-acetoxy-2-decenoic acid, E-10-propionyloxy-2-indole Alkenoic acid, E-10-butyryloxy-2-decenoic acid, ethyl E-10-hydroxy-2-decenoate, ethyl E-10-acetoxy-2-decenoate, E- Ethyl 10-propionyloxy-2-decenoate, ethyl E-10-butyryloxy-2-decenoate, ethylene glycol E-10-hydroxy-2-decenoate (single or Diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) ethylene glycol ester, E-10-hydroxy-2-decenoic acid glyceride (1, 2, 3 positions) Monoester or diester and triester; and mixed ester with acetic acid, propionic acid, buty
  • a method of making a royal jelly acid derivative comprising the steps of:
  • step A Acylation of a royal acid amide or an ester derivative with an acid halide or an acid anhydride to obtain a final product
  • the royal jelly acid derivative, the reaction formula of step A and step B is as follows:
  • the immunoassay 50 mg of the royal jelly acid derivative E-10-acetoxy-2-decenoic acid was added to 250 ml of avian influenza H9 commercial seedlings at a ratio of 0.001% to 2%, and the serum antibody was detected by immunizing 6-week-old SPF chickens. Before and after immunization, 10 randomly selected SPF chickens were used to detect the initial serum antibody level, and the antibody titer was 3.25 times that of the control group (the antibody concentration was 2.25 times of the control group, ie 4.75 times).
  • E-10-hydroxy-2-nonenylamide ethanol was dissolved in DMF, and acetyl chloride (or acetyl bromide, acetic anhydride) was added dropwise with stirring. The reaction was carried out at 80 ° C for 2 hours, and the temperature was lowered to 0 ° C and then poured into 0 to 10 ° C. In cold water, stir for 0.5 hours, filter, and wash 3 times with water. Drying at 50 ° C gave 74.2 g of E-10-acetoxy-2-nonenylamide ethanol acetate, the total yield was 95.1%, and the HPLC detection content was ⁇ 98.0%.
  • Royal jelly acid immunization test according to the ratio of 0.001% to 2%, 250ml of avian influenza H9 commercial seedlings were added with 55mg of royal jelly acid, shaken, immunized 6 weeks old SPF chicken, by serum antibody detection, before and after immunization, SPF chicken randomly selected 10, the initial detection of serum antibody levels, H9 antibody titer is 2.875 times the control group (1.875 antibody concentration is 2 times the control group, i.e., 3.66 times).

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Abstract

The present invention relates to a royal jelly acid derivative, which is characterized in that a chemical formula structure of the royal jelly acid derivative is (I). A beneficial effect of the present invention is: royal jelly acid is unsaturated fatty acid found in royal jelly, and is nontoxic; the royal jelly acid has good biological activity; the royal jelly acid derivative has a physiological characteristic similar to the royal jelly acid; compared with a commercially available vaccine, adding 0.001%-2% of the royal jelly acid or the derivative thereof, antibody titer of a body in 2-4 days is higher than a control group by 1-4(21-4).

Description

一种王浆酸衍生物及其制备方法和应用Royal pulp acid derivative and preparation method and application thereof 技术领域Technical field
本发明涉及化学合成及免疫制药的技术领域，尤其是一种王浆酸衍生物及其制备方法和王浆酸及其衍生物的应用。The invention relates to the technical field of chemical synthesis and immunopharmaceutical, in particular to a royal jelly acid derivative, a preparation method thereof and the application of royal jelly acid and its derivatives.
背景技术Background technique
随着现代生物技术的迅速发展，新的疫苗不断得到开发，然而抗原的免疫原性普遍较弱，为了快速提高抗原的有效性，需要在抗原中添加速效剂，以诱导机体快速免疫反应能力。近几十年来，国内外学者和研究人员对速效剂进行了大量的研究，从不同方面寻找高效低毒的新型免疫速效剂，由于大部分天然物提取物具有毒性低、可代谢的特点，因此，从天然物提取物中寻找新型免疫速效剂的研究，越来越受到重视，而王浆酸或其衍生物毒性低，能够快速使家禽对抗原产生免疫能力，因此王浆酸或其衍生物的制备以及在免疫疫苗领域的应用成为急需解决的问题。With the rapid development of modern biotechnology, new vaccines are continuously developed. However, the immunogenicity of antigens is generally weak. In order to rapidly increase the effectiveness of antigens, it is necessary to add a fast acting agent to the antigen to induce rapid immune response. In recent decades, domestic and foreign scholars and researchers have carried out a lot of research on quick-acting agents, and searched for new high-efficiency and low-toxic immunosuppressive agents from different aspects. Because most natural extracts have low toxicity and metabolism, The research on finding new immune quick-acting agents from natural extracts is getting more and more attention, and the high toxicity of royal jelly acid or its derivatives can quickly make poultry immune to antigens, so the preparation of royal jelly acid or its derivatives And the application in the field of immunization vaccines has become an urgent problem to be solved.
发明内容Summary of the invention
本发明的目的是提供一种王浆酸衍生物及其制备方法和应用，用以制备现有技术急需解决的以王浆酸或其衍生物为主要成分的免疫速效剂。The object of the present invention is to provide a royal jelly acid derivative and a preparation method and application thereof for preparing an immunosuppressive agent containing a royal jelly acid or a derivative thereof as a main component which is urgently needed in the prior art.
为了完成上述目的，本发明采用的技术方案是：In order to accomplish the above object, the technical solution adopted by the present invention is:
一种王浆酸衍生物，所述的王浆酸衍生物的化学式结构为A royal acid derivative, wherein the chemical structure of the royal acid derivative is
Figure PCTCN2015071019-appb-000001
Figure PCTCN2015071019-appb-000001
所述的王浆酸衍生物的结构中，R1为H、带支链的直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R1为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3- 二羟基丙烷的单或双脂酰基酯化物的一种。In the structure of the royal acid derivative, R1 is H, a branched linear hydrocarbon group, a fatty acyl group, an enoyl group, and a single or double of 2,3-dihydroxypropane or 2,3-dihydroxypropane. One of the fatty acyl esters, or R1 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3-dihydroxypropane, 2,3- A type of mono or diacyl acyl ester of dihydroxypropane.
所述的王浆酸衍生物的结构中，R2为H、带支链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R2为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种。In the structure of the royal acid derivative, R2 is H, a branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane. One of the compounds, or R2 is a linear or branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
所述的王浆酸衍生物的结构中，X为O或NH。In the structure of the royal acid derivative, X is O or NH.
所述的王浆酸衍生物的典型化合物为：E-10-羟基-2-癸烯酸、E-10-乙酰氧基-2-癸烯酸、E-10-丙酰氧基-2-癸烯酸、E-10-丁酰氧基-2-癸烯酸、E-10-羟基-2-癸烯酸乙酯、E-10-乙酰氧基-2-癸烯酸乙酯、E-10-丙酰氧基-2-癸烯酸乙酯、E-10-丁酰氧基-2-癸烯酸乙酯、E-10-羟基-2-癸烯酸乙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)乙二醇酯、E-10-羟基-2-癸烯酸甘油酯(1、2、3位的单酯或二酯及三酯；以及与乙酸、丙酸、丁酸的混合酯)、E-10-羟基-2-癸烯酸丙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)丙二醇酯、E-10-羟基-2-癸烯酸丁二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)丁二醇酯、以及E-10-羟基-2-癸烯酰胺基乙醇、E-10-羟基-2-癸烯酰胺基乙醇乙酸(或丙酸、丁酸)酯、E-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯、E-10-丙酰氧基-2-癸烯酰胺基乙醇丙酸酯、E-10-丁酰氧基-2-癸烯酰胺基乙醇丁酸酯中的一种，或铵、钠、钙、镁盐类的王浆酸盐。Typical compounds of the royal acid derivative are: E-10-hydroxy-2-decenoic acid, E-10-acetoxy-2-decenoic acid, E-10-propionyloxy-2-indole Alkenoic acid, E-10-butyryloxy-2-decenoic acid, ethyl E-10-hydroxy-2-decenoate, ethyl E-10-acetoxy-2-decenoate, E- Ethyl 10-propionyloxy-2-decenoate, ethyl E-10-butyryloxy-2-decenoate, ethylene glycol E-10-hydroxy-2-decenoate (single or Diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) ethylene glycol ester, E-10-hydroxy-2-decenoic acid glyceride (1, 2, 3 positions) Monoester or diester and triester; and mixed ester with acetic acid, propionic acid, butyric acid), E-10-hydroxy-2-decenoic acid propylene glycol ester (mono or diester), E-10-hydroxy-2 -decenoic acid acetic acid (or propionic acid, butyric acid) propylene glycol ester, E-10-hydroxy-2-decenoic acid butylene glycol ester (mono or diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) butylene glycol ester, and E-10-hydroxy-2-decenylamide ethanol, E-10-hydroxy-2-decenylamide glycolic acid (or propionic acid, butyric acid) Ester, E-10-acetoxy-2-nonenylamide ethanol acetate, E-10-propionyloxy-2-decenylamide ethanol Ester A butyryloxy-2-decenyl-ethanol amide of butyrate E-10-, or ammonium, sodium, calcium, magnesium salts like jelly.
一种制作王浆酸衍生物的方法，包括以下步骤：A method of making a royal jelly acid derivative comprising the steps of:
A、将王浆酸与含氨(胺)基或羟基的化合物进行酰胺化或酯化反应，得到王浆酸酰胺或酯类衍生物；A, amidation or esterification reaction of a royal acid with a compound containing an amino group or a hydroxyl group to obtain a royal acid amide or an ester derivative;
B、将王浆酸酰胺或酯类衍生物与酰卤或酸酐进行酰化反应得到最终产 品王浆酸衍生物，步骤A和步骤B的反应式如下：B. Acylation of a royal acid amide or an ester derivative with an acid halide or an acid anhydride to obtain a final product The royal jelly acid derivative, the reaction formula of step A and step B is as follows:
Figure PCTCN2015071019-appb-000002
式中：X＝O(CH2)qH或NH(CH2)qH，q＝0、2、4；Y＝Cl、Br；R1＝(CH2)nCH3，n＝0、1、2、3……。
Figure PCTCN2015071019-appb-000002
Wherein: X = O(CH 2 ) q H or NH(CH 2 ) q H, q = 0, 2 , 4; Y = Cl, Br; R1 = (CH 2 ) n CH 3 , n = 0, 1 , 2, 3...
所述的步骤A中，进行酰胺化或酯化反应时，需要将溶剂温度加热到60～80℃，进行3～5小时的回流反应，将温度降低至0～25℃后，用水进行洗涤操作，在20～50℃下进行干燥；In the step A, in the amidation or esterification reaction, it is necessary to heat the solvent to 60 to 80 ° C, carry out a reflux reaction for 3 to 5 hours, reduce the temperature to 0 to 25 ° C, and then perform a washing operation with water. Drying at 20 to 50 ° C;
所述的步骤B中，进行酰化反应时，需要将溶剂温度加热到60～80℃，进行2～5小时的回流反应，将温度降低至0～25℃后，用水进行洗涤操作，重复洗涤3～5次，分出油层，洗涤得到王浆酸衍生物。In the step B, in the acylation reaction, the solvent temperature is heated to 60 to 80 ° C, and the reflux reaction is carried out for 2 to 5 hours. After the temperature is lowered to 0 to 25 ° C, the washing operation is repeated with water, and the washing is repeated. 3 to 5 times, the oil layer is separated and washed to obtain a royal acid derivative.
所述的步骤A中，进行酰胺化或酯化反应时，将王浆酸、石油醚、甲醇、浓硫酸按摩尔比为1：(3～10)：1.5：0.02混合后，加热到65℃回流反应5小时，滴加入乙醇胺，搅拌加热到65℃回流反应3小时，降温到-5～10℃、过滤、用水洗涤，在20～50℃干燥5～10小时，得到E-10-羟基-2-癸烯酰胺基乙醇；In the step A, in the amidation or esterification reaction, the molar ratio of the royal jelly acid, the petroleum ether, the methanol, and the concentrated sulfuric acid is 1: (3 to 10): 1.5: 0.02, and then heated to reflux at 65 ° C. After reacting for 5 hours, ethanolamine was added dropwise, stirred and heated to reflux at 65 ° C for 3 hours, cooled to -5 to 10 ° C, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10-hydroxy-2. -decenylamide ethanol;
所述的步骤B中，将步骤A得到的E-10-羟基-2-癸烯酰胺基乙醇溶于DMF中，搅拌滴加丁酰氯或丁酰溴、丁酸酐中的一种，在加温到80℃时反应2小时，降温-5～10℃后倒入0～15℃冷水中，搅拌0.5小时、过滤、用水洗涤，20～50℃干燥5～10小时，得到E-10-丁酰氧基-2-癸烯酰胺基乙醇丁酸酯。In the step B, the E-10-hydroxy-2-nonenylamide ethanol obtained in the step A is dissolved in DMF, and one of butyryl chloride or butyryl bromide and butyric anhydride is added dropwise with stirring. The reaction was carried out at 80 ° C for 2 hours, the temperature was lowered to -5 to 10 ° C, poured into 0 to 15 ° C cold water, stirred for 0.5 hours, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10-butyryl. Oxy-2-decenylamide ethanol butyrate.
所述的应用为以王浆酸衍生物为主要成分的免疫速效剂，王浆酸衍生 物在疫苗生产时添加到油剂、水剂或粉剂的疫苗制剂中，将王浆酸衍生物与疫苗按0.001％～2％的比例充分混合后进行注射、喷雾或滴鼻点眼使用。The application is an immunosuppressive agent containing a royal jelly acid derivative as a main component, and the royal jelly acid is derived. When the vaccine is produced, it is added to a vaccine preparation of an oil, a liquid or a powder, and the royal jelly acid derivative and the vaccine are thoroughly mixed at a ratio of 0.001% to 2%, and then injected, sprayed or dripped.
所述的应用为以王浆酸或王浆酸盐或王浆酸衍生物为主要成分的免疫速效剂，应用于禽类的H5流感、H7流感、H9流感、新城疫疫苗生产或疫苗免疫使用过程中，将王浆酸或王浆酸盐或王浆酸衍生物与疫苗按0.001％～2％的比例充分混合。The application is an immunosuppressive agent containing a royal jelly or a royal jelly or a royal jelly acid derivative as a main component, and is applied to avian H5 influenza, H7 influenza, H9 influenza, Newcastle disease vaccine production or vaccine immunization. The royal jelly acid or the royal jelly or the royal jelly acid derivative is thoroughly mixed with the vaccine in a ratio of 0.001% to 2%.
本发明的有益效果是：王浆酸是蜂王浆中发现的不饱和脂肪酸，无毒，王浆酸具有很好的生物活性，王浆酸衍生物具有与王浆酸类似的生理特性，相对于商品疫苗，添加0.001％～2％王浆酸或其衍生物，机体在2～4天的抗体滴度比对照组高1～4(21～4)。The beneficial effects of the invention are: the royal jelly acid is an unsaturated fatty acid found in royal jelly, non-toxic, and the royal pulp acid has a good biological activity, and the royal pulp acid derivative has physiological characteristics similar to those of the royal jelly acid, and 0.001 is added relative to the commercial vaccine. %～2% of royal jelly acid or its derivative, the antibody titer of the body in 2 to 4 days is 1 to 4 (2 1 to 4 ) higher than that of the control group.
具体实施方式detailed description
本发明为一种王浆酸衍生物及其制备方法和应用，王浆酸是蜂王浆中发现的不饱和脂肪酸，无毒，王浆酸具有很好的生物活性，王浆酸衍生物具有与王浆酸类似的生理特性，相对于商品疫苗，添加0.001％～2％王浆酸或其衍生物，机体在2～4天的抗体滴度比对照组高1～4(21～4)。The invention relates to a royal jelly acid derivative and a preparation method and application thereof. The royal jelly acid is an unsaturated fatty acid found in royal jelly, non-toxic, and the royal pulp acid has good biological activity, and the royal pulp acid derivative has a physiological similar to royal jelly acid. Characteristics: Compared with commercial vaccines, 0.001% to 2% of royal jelly acid or its derivatives are added, and the antibody titer of the body in 2 to 4 days is 1 to 4 (2 1 to 4 ) higher than that of the control group.
下面结合具体实施例对本发明做进一步说明。The invention will be further described below in conjunction with specific embodiments.
具体实施例1，一种王浆酸衍生物，所述的王浆酸衍生物的化学式结构为Specific Example 1, a royal jelly acid derivative, wherein the chemical formula of the royal jelly acid derivative is
Figure PCTCN2015071019-appb-000003
Figure PCTCN2015071019-appb-000003
所述的王浆酸衍生物的结构中，R1为H、带支链的直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R1为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3- 二羟基丙烷的单或双脂酰基酯化物的一种。In the structure of the royal acid derivative, R1 is H, a branched linear hydrocarbon group, a fatty acyl group, an enoyl group, and a single or double of 2,3-dihydroxypropane or 2,3-dihydroxypropane. One of the fatty acyl esters, or R1 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3-dihydroxypropane, 2,3- A type of mono or diacyl acyl ester of dihydroxypropane.
所述的王浆酸衍生物的结构中，R2为H、带支链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R2为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种。In the structure of the royal acid derivative, R2 is H, a branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane. One of the compounds, or R2 is a linear or branched hydrocarbon group, a fatty acyl group, an enoyl group, and a mono- or di-acyl acyl ester of 2,3-dihydroxypropane or 2,3-dihydroxypropane.
所述的王浆酸衍生物的结构中，X为O或NH。In the structure of the royal acid derivative, X is O or NH.
所述的王浆酸衍生物的典型化合物为：E-10-羟基-2-癸烯酸、E-10-乙酰氧基-2-癸烯酸、E-10-丙酰氧基-2-癸烯酸、E-10-丁酰氧基-2-癸烯酸、E-10-羟基-2-癸烯酸乙酯、E-10-乙酰氧基-2-癸烯酸乙酯、E-10-丙酰氧基-2-癸烯酸乙酯、E-10-丁酰氧基-2-癸烯酸乙酯、E-10-羟基-2-癸烯酸乙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)乙二醇酯、E-10-羟基-2-癸烯酸甘油酯(1、2、3位的单酯或二酯及三酯；以及与乙酸、丙酸、丁酸的混合酯)、E-10-羟基-2-癸烯酸丙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)丙二醇酯、E-10-羟基-2-癸烯酸丁二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)丁二醇酯、以及E-10-羟基-2-癸烯酰胺基乙醇、E-10-羟基-2-癸烯酰胺基乙醇乙酸(或丙酸、丁酸)酯、E-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯、E-10-丙酰氧基-2-癸烯酰胺基乙醇丙酸酯、E-10-丁酰氧基-2-癸烯酰胺基乙醇丁酸酯中的一种，或铵、钠、钙、镁盐类的王浆酸盐。Typical compounds of the royal acid derivative are: E-10-hydroxy-2-decenoic acid, E-10-acetoxy-2-decenoic acid, E-10-propionyloxy-2-indole Alkenoic acid, E-10-butyryloxy-2-decenoic acid, ethyl E-10-hydroxy-2-decenoate, ethyl E-10-acetoxy-2-decenoate, E- Ethyl 10-propionyloxy-2-decenoate, ethyl E-10-butyryloxy-2-decenoate, ethylene glycol E-10-hydroxy-2-decenoate (single or Diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) ethylene glycol ester, E-10-hydroxy-2-decenoic acid glyceride (1, 2, 3 positions) Monoester or diester and triester; and mixed ester with acetic acid, propionic acid, butyric acid), E-10-hydroxy-2-decenoic acid propylene glycol ester (mono or diester), E-10-hydroxy-2 -decenoic acid acetic acid (or propionic acid, butyric acid) propylene glycol ester, E-10-hydroxy-2-decenoic acid butylene glycol ester (mono or diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) butylene glycol ester, and E-10-hydroxy-2-decenylamide ethanol, E-10-hydroxy-2-decenylamide glycolic acid (or propionic acid, butyric acid) Ester, E-10-acetoxy-2-nonenylamide ethanol acetate, E-10-propionyloxy-2-decenylamide ethanol Ester A butyryloxy-2-decenyl-ethanol amide of butyrate E-10-, or ammonium, sodium, calcium, magnesium salts like jelly.
一种制作王浆酸衍生物的方法，包括以下步骤：A method of making a royal jelly acid derivative comprising the steps of:
A、将王浆酸与含氨(胺)基或羟基的化合物进行酰胺化或酯化反应，得到王浆酸酰胺或酯类衍生物；A, amidation or esterification reaction of a royal acid with a compound containing an amino group or a hydroxyl group to obtain a royal acid amide or an ester derivative;
B、将王浆酸酰胺或酯类衍生物与酰卤或酸酐进行酰化反应得到最终产 品王浆酸衍生物，步骤A和步骤B的反应式如下：B. Acylation of a royal acid amide or an ester derivative with an acid halide or an acid anhydride to obtain a final product The royal jelly acid derivative, the reaction formula of step A and step B is as follows:
Figure PCTCN2015071019-appb-000004
式中：X＝O(CH2)qH或NH(CH2)qH，q＝0、2、4；Y＝Cl、Br；R1＝(CH2)nCH3，n＝0、1、2、3……。
Figure PCTCN2015071019-appb-000004
Wherein: X = O(CH 2 ) q H or NH(CH 2 ) q H, q = 0, 2 , 4; Y = Cl, Br; R1 = (CH 2 ) n CH 3 , n = 0, 1 , 2, 3...
王浆酸衍生物E-10-乙酰氧基-2-癸烯酸的制备：Preparation of royal jelly acid derivative E-10-acetoxy-2-decenoic acid:
将王浆酸93.1g、乙酸酐61.5g按摩尔比1:1.2混合，搅拌下于60～80℃反应3小时，降温到0～15℃后倒入0～15℃的水中，分出油层，用水洗涤3次，在20～50℃进行干燥得到产品113.2g，收率97.6％，HPLC检测含量≥98.5％。93.1 g of royal jelly acid and 61.5 g of acetic anhydride were mixed at a molar ratio of 1:1.2, and reacted at 60 to 80 ° C for 3 hours with stirring. After cooling to 0 to 15 ° C, the mixture was poured into water at 0 to 15 ° C to separate the oil layer. After washing 3 times, it was dried at 20 to 50 ° C to obtain 113.2 g of a product, the yield was 97.6%, and the content of HPLC detection was ≥98.5%.
免疫试验，按0.001％～2％的比例，禽流感H9商品苗250ml加入50mg王浆酸衍生物E-10-乙酰氧基-2-癸烯酸，免疫6周龄SPF鸡后，通过检测血清抗体，免疫前后，SPF鸡中随机抽取10只，检测初始血清抗体水平，抗体滴度是对照组的3.25倍(抗体浓度是对照组的22.25倍，即4.75倍)。In the immunoassay, 50 mg of the royal jelly acid derivative E-10-acetoxy-2-decenoic acid was added to 250 ml of avian influenza H9 commercial seedlings at a ratio of 0.001% to 2%, and the serum antibody was detected by immunizing 6-week-old SPF chickens. Before and after immunization, 10 randomly selected SPF chickens were used to detect the initial serum antibody level, and the antibody titer was 3.25 times that of the control group (the antibody concentration was 2.25 times of the control group, ie 4.75 times).
按0.001％～2％的比例，新流(H5)二联商品苗250ml(500羽份)加入50mgE-10-乙酰氧基-2-癸烯酸，免疫63周龄正常产蛋鸡后，通过检测血清抗体，免疫前后，鸡中随机抽取8只鸡蛋，检测鸡蛋的抗体水平，抗体滴度与对照组比较，Re-4高3.125(抗体浓度是对照组的23.125倍，即8.72倍)，Re-6高2.75(抗体浓度是对照组的22.75倍，即6.73倍)，新城疫高2.625(抗体浓度是对照组的22.625倍，即6.16倍)。According to the ratio of 0.001% to 2%, 250ml (500 drops) of new stream (H5) two-way commercial seedlings was added with 50mg of E-10-acetoxy-2-decenoic acid, and after immunization of normal laying hens at 63 weeks of age, Serum antibodies were detected. Before and after immunization, 8 eggs were randomly selected from chickens to detect the antibody level of the eggs. The antibody titer was compared with the control group, and the Re-4 was 3.125 (the antibody concentration was 3.125 times of the control group, ie 8.72 times). Re-6 was 2.75 (antibody concentration was 2.75 times of the control group, ie 6.73 times), Newcastle disease was 2.625 higher (antibody concentration was 2.625 times of the control group, ie 6.16 times).
王浆酸衍生物E-10-丙酰氧基-2-癸烯酸的制备：Preparation of the royal jelly acid derivative E-10-propionyloxy-2-decenoic acid:
将王浆酸93.1g、丙酸酐70.0g按摩尔比1:1.2混合，搅拌下于60～ 80℃反应3小时，降温到0～15℃后倒入0～15℃的水中，分出油层，用水洗涤3次，在20～50℃进行干燥得到产品114.6g，收率96.1％，HPLC检测含量≥98.0％。Mixing 93.1 g of royal jelly acid and 70.0 g of propionic anhydride in a molar ratio of 1:1.2, stirring at 60~ The reaction was carried out at 80 ° C for 3 hours, and the temperature was lowered to 0 to 15 ° C, and then poured into water of 0 to 15 ° C, and the oil layer was separated, washed three times with water, and dried at 20 to 50 ° C to obtain 114.6 g of a product, yield 96.1%, HPLC detection The content is ≥98.0%.
部分化合物合成参数如表3Some compound synthesis parameters are shown in Table 3.
Figure PCTCN2015071019-appb-000005
Figure PCTCN2015071019-appb-000005
实例2Example 2
王浆酸衍生物E-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯的制备：Preparation of royal jelly acid derivative E-10-acetoxy-2-decenylamide ethanol acetate:
将王浆酸46.6g、石油醚200ml、甲醇100g、浓硫酸1ml于反应瓶中加热到65℃搅拌回流反应5小时，滴加入乙醇胺，加热到65℃搅拌回流反应3小时，降温到-5～10℃、过滤、用水洗涤3次，在50℃进行干燥得到E-10-羟基-2-癸烯酰胺基乙醇56.5g。46.6g of royal jelly acid, 200ml of petroleum ether, 100g of methanol and 1ml of concentrated sulfuric acid were heated to 65 ° C in a reaction flask and stirred for reflux for 5 hours. Ethanolamine was added dropwise, heated to 65 ° C, stirred and refluxed for 3 hours, and cooled to -5 to 10 The mixture was filtered, washed with water three times, and dried at 50 ° C to obtain 56.5 g of E-10-hydroxy-2-decenylaminoethanol.
将E-10-羟基-2-癸烯酰胺基乙醇溶于DMF中，搅拌滴加乙酰氯(或乙酰溴、乙酸酐)，80℃反应2小时，降温到0℃后倒入0～10℃冷水中，搅拌0.5小时、过滤、用水洗涤3次。在50℃进行干燥得到E-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯74.2g，总收率95.1％，HPLC检测含量≥98.0％。E-10-hydroxy-2-nonenylamide ethanol was dissolved in DMF, and acetyl chloride (or acetyl bromide, acetic anhydride) was added dropwise with stirring. The reaction was carried out at 80 ° C for 2 hours, and the temperature was lowered to 0 ° C and then poured into 0 to 10 ° C. In cold water, stir for 0.5 hours, filter, and wash 3 times with water. Drying at 50 ° C gave 74.2 g of E-10-acetoxy-2-nonenylamide ethanol acetate, the total yield was 95.1%, and the HPLC detection content was ≥98.0%.
免疫试验，按0.001％～2％的比例，禽流感H9商品苗250ml加入 50mgE-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯，摇匀，免疫6周龄SPF鸡后，通过检测血清抗体，免疫前后，SPF鸡中随机抽取10只，检测初始血清抗体水平，H9抗体滴度是对照组的2.625倍(抗体浓度是对照组的21.625倍，即3.08倍)。In the immunoassay, 50 mg of E-10-acetoxy-2-nonenylamide ethanol acetate was added to 250 ml of avian influenza H9 commercial seedlings at a ratio of 0.001% to 2%, shaken, and 6-week-old SPF chickens were immunized. detection of serum antibodies before and after immunization, the SPF chickens randomly selected 10, the initial detection of serum antibody levels, H9 antibody titer is 2.625 times the control group (1.625 antibody concentration is 2 times the control group, i.e., 3.08 times).
按0.001％～2％的比例，新流(H5)二联商品苗250ml(500羽份)加入50mgE-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯，摇匀，免疫63周龄正常产蛋鸡后，通过检测血清抗体，免疫前后，鸡中随机抽取8只鸡蛋，检测鸡蛋的抗体水平，抗体滴度与对照组比较，Re-4高2.875(抗体浓度是对照组的22.875倍，即7.33倍)，Re-6高2.75(抗体浓度是对照组的22.75倍，即6.73倍)，新城疫高2.25(抗体浓度是对照组的22.25倍，即4.75倍)。Add 50mg of E-10-acetoxy-2-nonenylamide ethanol acetate to 250ml (500 drops) of fresh flow (H5) two-way commercial seedlings at a ratio of 0.001% to 2%, shake and immunize for 63 weeks. After the normal laying of laying hens, serum antibodies were tested. Before and after immunization, 8 eggs were randomly selected from the chickens to detect the antibody level of the eggs. The antibody titer was compared with the control group, and the Re-4 was 2.875 (the antibody concentration was 2 in the control group). 2.875 times, ie 7.33 times), Re-6 was 2.75 (antibody concentration was 2.75 times of the control group, ie 6.73 times), Newcastle disease was 2.25 (antibody concentration was 2.25 times of the control group, ie 4.75 times).
实例3Example 3
王浆酸免疫试验，按0.001％～2％的比例，禽流感H9商品苗250ml分别加入55mg王浆酸，摇匀，免疫6周龄SPF鸡后，通过检测血清抗体，免疫前后，SPF鸡中随机抽取10只，检测初始血清抗体水平，H9抗体滴度是对照组的2.875倍(抗体浓度是对照组的21.875倍，即3.66倍)。Royal jelly acid immunization test, according to the ratio of 0.001% to 2%, 250ml of avian influenza H9 commercial seedlings were added with 55mg of royal jelly acid, shaken, immunized 6 weeks old SPF chicken, by serum antibody detection, before and after immunization, SPF chicken randomly selected 10, the initial detection of serum antibody levels, H9 antibody titer is 2.875 times the control group (1.875 antibody concentration is 2 times the control group, i.e., 3.66 times).
按0.001％～2％的比例，新流(H5)二联商品苗250ml(500羽份)加入55mg王浆酸，摇匀，免疫63周龄正常产蛋鸡后，通过检测血清抗体，免疫前后，鸡中随机抽取8只鸡蛋，检测鸡蛋的抗体水平，抗体滴度与对照组比较，Re-4高2.625(抗体浓度是对照组的22.625倍，即6.16倍)，Re-6高2.25(抗体浓度是对照组的22.25倍，即4.75倍)，新城疫高2.125(抗体浓度是对照组的22.125倍，即4.36倍)。 According to the ratio of 0.001% to 2%, 250ml (500 drops) of the new flow (H5) two-way commercial seedlings is added with 55mg of royal jelly acid, shaken, and immunized with 63 weeks old normal laying hens, by detecting serum antibodies, before and after immunization. Eight eggs were randomly selected from chickens to detect the antibody level of the eggs. The antibody titer was compared with the control group. Re-4 was 2.625 higher (antibody concentration was 2.625 times of the control group, 6.16 times), and Re-6 was 2.25 (antibody). The concentration was 2.25 times of the control group, or 4.75 times, and the Newcastle disease was 2.125 (the antibody concentration was 2.125 times, or 4.36 times, of the control group).

Claims (10)

  1. 一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的化学式结构为A royal acid derivative characterized in that the chemical structure of the royal acid derivative is
    Figure PCTCN2015071019-appb-100001
    Figure PCTCN2015071019-appb-100001
  2. 根据权利要求1所述的一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的结构中，R1为H、带支链的直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R1为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种。A royal jelly acid derivative according to claim 1, wherein in the structure of the royal acid derivative, R1 is H, a branched linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2 a mono- or di-acyl acyl ester of 3-dihydroxypropane or 2,3-dihydroxypropane, or R1 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3-dihydroxypropane. One of the mono- or di-acyl acyl esters of 2,3-dihydroxypropane.
  3. 根据权利要求1所述的一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的结构中，R2为H、带支链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种，或R2为带直链的烃基、脂酰基、烯脂酰以及2,3-二羟基丙烷、2,3-二羟基丙烷的单或双脂酰基酯化物的一种。A royal acid derivative according to claim 1, wherein in the structure of the royal acid derivative, R2 is H, a branched hydrocarbon group, a fatty acyl group, an enoyl group, and 2,3- a mono- or di-fatty acid ester of dihydroxypropane or 2,3-dihydroxypropane, or R2 is a linear hydrocarbon group, a fatty acyl group, an enoyl group, and a 2,3-dihydroxypropane, 2,3 a type of mono or diacyl acyl ester of dihydroxypropane.
  4. 根据权利要求1所述的一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的结构中，X为O或NH。A royal acid derivative according to claim 1, wherein in the structure of the royal acid derivative, X is O or NH.
  5. 根据权利要求1所述的一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的典型化合物为：E-10-羟基-2-癸烯酸、E-10-乙酰氧基-2-癸烯酸、E-10-丙酰氧基-2-癸烯酸、E-10-丁酰氧基-2-癸烯酸、E-10-羟基-2-癸烯酸乙酯、E-10-乙酰氧基-2-癸烯酸乙酯、E-10-丙酰氧基-2-癸烯酸乙酯、E-10-丁酰氧基-2-癸烯酸乙酯、E-10-羟基-2-癸烯酸乙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)乙二醇酯、E-10-羟基-2-癸烯酸甘油酯(1、2、3位的单酯或二酯及三酯；以及与乙酸、丙酸、丁酸的混合酯)、E-10-羟基-2-癸烯酸丙二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙 酸、丁酸)丙二醇酯、E-10-羟基-2-癸烯酸丁二醇酯(单或双酯)、E-10-羟基-2-癸烯酸乙酸(或丙酸、丁酸)丁二醇酯、以及E-10-羟基-2-癸烯酰胺基乙醇、E-10-羟基-2-癸烯酰胺基乙醇乙酸(或丙酸、丁酸)酯、E-10-乙酰氧基-2-癸烯酰胺基乙醇乙酸酯、E-10-丙酰氧基-2-癸烯酰胺基乙醇丙酸酯、E-10-丁酰氧基-2-癸烯酰胺基乙醇丁酸酯中的一种，或铵、钠、钙、镁盐类的王浆酸盐。A royal acid derivative according to claim 1, wherein the typical compound of the royal acid derivative is: E-10-hydroxy-2-decenoic acid, E-10-acetoxy- 2-decenoic acid, E-10-propionyloxy-2-decenoic acid, E-10-butyryloxy-2-decenoic acid, ethyl E-10-hydroxy-2-decenoate, Ethyl E-acetoxy-2-decenoate, ethyl E-10-propionyloxy-2-decenoate, ethyl E-10-butyryloxy-2-decenoate, E-10-hydroxy-2-decenoic acid ethylene glycol ester (mono or diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) ethylene glycol ester, E-10 -hydroxy-2-decenoic acid glyceride (monoester or diester and triester of 1, 2, 3 positions; and mixed ester with acetic acid, propionic acid, butyric acid), E-10-hydroxy-2-indole Propylene acrylate (mono or diester), E-10-hydroxy-2-decenoic acid acetic acid (or C Acid, butyric acid) propylene glycol ester, E-10-hydroxy-2-decenoic acid butylene glycol ester (mono or diester), E-10-hydroxy-2-decenoic acid acetic acid (or propionic acid, butyric acid) Butylene glycol ester, and E-10-hydroxy-2-decenylamide ethanol, E-10-hydroxy-2-decenylamide ethanolic acid (or propionic acid, butyric acid) ester, E-10-acetoxy Ethyl-2-decenylaminoethanol acetate, E-10-propionyloxy-2-decenylamide ethanol propionate, E-10-butyryloxy-2-decenylamide ethanolate One of the acid esters, or the royal jelly salt of ammonium, sodium, calcium, magnesium salts.
  6. 一种制作如权利要求1所述的王浆酸衍生物的方法，其特征在于包括以下步骤：A method of making a royal acid derivative according to claim 1, comprising the steps of:
    A、将王浆酸与含氨(胺)基或羟基的化合物进行酰胺化或酯化反应，得到王浆酸酰胺或酯类衍生物；A, amidation or esterification reaction of a royal acid with a compound containing an amino group or a hydroxyl group to obtain a royal acid amide or an ester derivative;
    B、将王浆酸酰胺或酯类衍生物与酰卤或酸酐进行酰化反应得到最终产品王浆酸衍生物，步骤A和步骤B的反应式如下：B. Acylation of a royal acid amide or an ester derivative with an acid halide or an acid anhydride to obtain a final product of a royal acid acid derivative. The reaction formula of the step A and the step B is as follows:
    Figure PCTCN2015071019-appb-100002
    式中：X＝O(CH2)qH或NH(CH2)qH，q＝0、2、4；Y＝Cl、Br；R1＝(CH2)nCH3，n＝0、1、2、3……。
    Figure PCTCN2015071019-appb-100002
    Wherein: X = O(CH 2 ) q H or NH(CH 2 ) q H, q = 0, 2 , 4; Y = Cl, Br; R1 = (CH 2 ) n CH 3 , n = 0, 1 , 2, 3...
  7. 根据权利要求6所述的一种制作王浆酸衍生物的方法，其特征在于：所述的步骤A中，进行酰胺化或酯化反应时，需要将溶剂温度加热到60～80℃，进行3～5小时的回流反应，将温度降低至0～25℃后，用水进行洗涤操作，在20～50℃下进行干燥；The method for producing a royal jelly acid derivative according to claim 6, wherein in the step A, when the amidation or esterification reaction is carried out, the solvent temperature is heated to 60 to 80 ° C for 3 ～5 hours of reflux reaction, the temperature is lowered to 0 to 25 ° C, and then washed with water, and dried at 20 to 50 ° C;
    所述的步骤B中，进行酰化反应时，需要将溶剂温度加热到60～80℃，进行2～5小时的回流反应，将温度降低至0～25℃后，用水进行洗涤操作， 重复洗涤3～5次，分出油层，洗涤得到王浆酸衍生物。In the step B described above, when the acylation reaction is carried out, it is necessary to heat the solvent to 60 to 80 ° C, carry out a reflux reaction for 2 to 5 hours, lower the temperature to 0 to 25 ° C, and then perform a washing operation with water. The washing was repeated 3 to 5 times, and the oil layer was separated and washed to obtain a royal acid derivative.
  8. 根据权利要求6所述的一种制作王浆酸衍生物的方法，其特征在于：所述的步骤A中，进行酰胺化或酯化反应时，将王浆酸、石油醚、甲醇、浓硫酸按摩尔比为1：(3～10)：1.5：0.02混合后，加热到65℃回流反应5小时，滴加入乙醇胺，搅拌加热到65℃回流反应3小时，降温到-5～10℃、过滤、用水洗涤，在20～50℃干燥5～10小时，得到E-10-羟基-2-癸烯酰胺基乙醇；A method for producing a royal jelly acid derivative according to claim 6, wherein in the step A, when amidation or esterification is carried out, royal acid, petroleum ether, methanol, concentrated sulfuric acid The ratio is 1: (3 ~ 10): 1.5: 0.02 after mixing, heating to 65 ° C reflux reaction for 5 hours, adding ethanolamine dropwise, stirring and heating to 65 ° C reflux reaction for 3 hours, cooling to -5 ~ 10 ° C, filtration, water Washing, drying at 20 to 50 ° C for 5 to 10 hours to obtain E-10-hydroxy-2-decenylamide ethanol;
    所述的步骤B中，将步骤A得到的E-10-羟基-2-癸烯酰胺基乙醇溶于DMF中，搅拌滴加丁酰氯或丁酰溴、丁酸酐中的一种，在加温到80℃时反应2小时，降温-5～10℃后倒入0～15℃冷水中，搅拌0.5小时、过滤、用水洗涤，20～50℃干燥5～10小时，得到E-10-丁酰氧基-2-癸烯酰胺基乙醇丁酸酯。In the step B, the E-10-hydroxy-2-nonenylamide ethanol obtained in the step A is dissolved in DMF, and one of butyryl chloride or butyryl bromide and butyric anhydride is added dropwise with stirring. The reaction was carried out at 80 ° C for 2 hours, the temperature was lowered to -5 to 10 ° C, poured into 0 to 15 ° C cold water, stirred for 0.5 hours, filtered, washed with water, and dried at 20 to 50 ° C for 5 to 10 hours to obtain E-10-butyryl. Oxy-2-decenylamide ethanol butyrate.
  9. 根据权利要求1所述的一种王浆酸衍生物的应用，其特征在于：所述的应用为以王浆酸衍生物为主要成分的免疫速效剂，王浆酸衍生物在疫苗生产时添加到油剂、水剂或粉剂的疫苗制剂中，将王浆酸衍生物与疫苗按0.001％～2％的比例充分混合后进行注射、喷雾或滴鼻点眼使用。The use of a royal jelly acid derivative according to claim 1, wherein the application is an immunosuppressive agent containing a royal jelly acid derivative as a main component, and the royal jelly acid derivative is added to the oil during the production of the vaccine. In the vaccine preparation of the aqueous solution or the powder, the royal jelly acid derivative and the vaccine are thoroughly mixed at a ratio of 0.001% to 2%, and then injected, sprayed or dripped.
  10. 根据权利要求1所述的一种王浆酸衍生物及王浆酸的应用，其特征在于：所述的应用为以王浆酸或王浆酸盐或王浆酸衍生物为主要成分的免疫速效剂，应用于禽类的H5流感、H7流感、H9流感、新城疫疫苗生产或疫苗免疫使用过程中，将王浆酸或王浆酸盐或王浆酸衍生物与疫苗按0.001％～2％的比例充分混合。 The use of a royal jelly acid derivative and a royal jelly acid according to claim 1, wherein the application is an immunosuppressive agent containing a royal jelly or a royal jelly or a royal acid derivative as a main component. In the process of avian H5 influenza, H7 influenza, H9 influenza, Newcastle disease vaccine production or vaccine immunization, the royal jelly or royal jelly or royal acid derivative is thoroughly mixed with the vaccine in a ratio of 0.001% to 2%.
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