WO2015109979A1 - 一种王浆酸衍生物及其制备方法和应用 - Google Patents

一种王浆酸衍生物及其制备方法和应用 Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
acid
royal
royal jelly
acid derivative
hydroxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/071019
Other languages
English (en)
French (fr)
Inventor
赵瑞林
王占喜
张良才
申玉
刘建美
李佳乔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHIJIAZHUANG WEIAO CHEMICAL Ltd Co
Original Assignee
SHIJIAZHUANG WEIAO CHEMICAL Ltd Co
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 SHIJIAZHUANG WEIAO CHEMICAL Ltd Co filed Critical SHIJIAZHUANG WEIAO CHEMICAL Ltd Co
Publication of WO2015109979A1 publication Critical patent/WO2015109979A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Mycology (AREA)
  • Pulmonology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Jellies, Jams, And Syrups (AREA)

Abstract

本发明涉及一种王浆酸衍生物，其特征在于：所述的王浆酸衍生物的化学式结构为（I）。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）。

Description

一种王浆酸衍生物及其制备方法和应用 技术领域
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。
背景技术
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。
发明内容
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。
为了完成上述目的，本发明采用的技术方案是：
一种王浆酸衍生物，所述的王浆酸衍生物的化学式结构为
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。
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。
所述的王浆酸衍生物的结构中，X为O或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。
一种制作王浆酸衍生物的方法，包括以下步骤：
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；
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：
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……。
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；
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。
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；
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。
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。
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。
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)。
具体实施方式
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)。
下面结合具体实施例对本发明做进一步说明。
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
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。
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。
所述的王浆酸衍生物的结构中，X为O或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。
一种制作王浆酸衍生物的方法，包括以下步骤：
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；
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：
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……。
王浆酸衍生物E-10-乙酰氧基-2-癸烯酸的制备：
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％。
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)。
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)。
王浆酸衍生物E-10-丙酰氧基-2-癸烯酸的制备：
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％。
部分化合物合成参数如表3
Figure PCTCN2015071019-appb-000005
实例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：
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。
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％。
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)。
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)。
实例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)。
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)。

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
    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。
  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。
  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。
  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。
  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、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；
    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：
    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……。
  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；
    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。
  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；
    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。
  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。
  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。
PCT/CN2015/071019 2014-01-21 2015-01-19 一种王浆酸衍生物及其制备方法和应用 Ceased WO2015109979A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410027304.7 2014-01-21
CN201410027304.7A CN103787879B (zh) 2014-01-21 2014-01-21 一种王浆酸衍生物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2015109979A1 true WO2015109979A1 (zh) 2015-07-30

Family

ID=50663995

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/071019 Ceased WO2015109979A1 (zh) 2014-01-21 2015-01-19 一种王浆酸衍生物及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN103787879B (zh)
WO (1) WO2015109979A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018074327A1 (ja) * 2016-10-20 2018-04-26 株式会社山田養蜂場本社 粘膜免疫調節剤
CN115806923A (zh) * 2022-10-12 2023-03-17 齐鲁工业大学 一种含有脂酰辅酶a氧化酶基因的工程菌及其在制备10-羟基-2-癸烯酸中的应用
CN115806924A (zh) * 2022-10-12 2023-03-17 齐鲁工业大学 一种基因工程菌及其在制备10-羟基-2-癸烯酸中的应用
CN115819216A (zh) * 2022-12-28 2023-03-21 昆明博鸿科技有限公司 一种10-羟基-2-癸烯酸的制备方法
CN116217377A (zh) * 2023-02-08 2023-06-06 珠海市柏瑞医药科技有限公司 一种王浆酸的合成工艺

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103787879B (zh) * 2014-01-21 2016-05-11 石家庄维奥化工有限公司 一种王浆酸衍生物及其制备方法和应用
CN107988023A (zh) * 2017-12-19 2018-05-04 石家庄颐瑞堂蜂业有限公司 一种保健酒及其应用
CN116790685B (zh) * 2023-08-21 2023-12-01 山东福瑞达生物股份有限公司 一种生物合成法制备王浆酸及其在护肤中的应用
CN118985775B (zh) * 2024-09-25 2025-03-21 齐鲁工业大学(山东省科学院) 王浆酸在蛋鸡饲料添加剂中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1280121A (zh) * 1999-07-12 2001-01-17 云南大学合成化学研究所 一种合成王浆酸的方法
CN102206151A (zh) * 2010-03-30 2011-10-05 上海灏翔生物科技有限公司 王浆酸的合成方法
CN102267893A (zh) * 2011-06-15 2011-12-07 嘉兴学院 王浆酸的制备方法
CN103787879A (zh) * 2014-01-21 2014-05-14 石家庄维奥化工有限公司 一种王浆酸衍生物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5231784B2 (ja) * 2006-11-09 2013-07-10 学校法人近畿大学 不飽和脂肪酸誘導体の製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1280121A (zh) * 1999-07-12 2001-01-17 云南大学合成化学研究所 一种合成王浆酸的方法
CN102206151A (zh) * 2010-03-30 2011-10-05 上海灏翔生物科技有限公司 王浆酸的合成方法
CN102267893A (zh) * 2011-06-15 2011-12-07 嘉兴学院 王浆酸的制备方法
CN103787879A (zh) * 2014-01-21 2014-05-14 石家庄维奥化工有限公司 一种王浆酸衍生物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XU, XIONG ET AL.: "Fatty Acid Composition of Royal Jelly", FOOD SCIENCE, vol. 30, no. 14, 31 December 2009 (2009-12-31), pages 213 - 214 *
ZHANG, YANBIN ET AL.: "Recent Progress in the Synthesis of 10-HDA", GUANGZHOU CHEMICAL INDUSTRY, vol. 41, no. 9, 31 May 2013 (2013-05-31), pages 20 - 22, XP055215515 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018074327A1 (ja) * 2016-10-20 2018-04-26 株式会社山田養蜂場本社 粘膜免疫調節剤
JPWO2018074327A1 (ja) * 2016-10-20 2019-07-25 株式会社山田養蜂場本社 粘膜免疫調節剤
US11089805B2 (en) 2016-10-20 2021-08-17 Yamada Bee Company, Inc. Mucosal immunomodulator
CN115806923A (zh) * 2022-10-12 2023-03-17 齐鲁工业大学 一种含有脂酰辅酶a氧化酶基因的工程菌及其在制备10-羟基-2-癸烯酸中的应用
CN115806924A (zh) * 2022-10-12 2023-03-17 齐鲁工业大学 一种基因工程菌及其在制备10-羟基-2-癸烯酸中的应用
CN115819216A (zh) * 2022-12-28 2023-03-21 昆明博鸿科技有限公司 一种10-羟基-2-癸烯酸的制备方法
CN116217377A (zh) * 2023-02-08 2023-06-06 珠海市柏瑞医药科技有限公司 一种王浆酸的合成工艺

Also Published As

Publication number Publication date
CN103787879A (zh) 2014-05-14
CN103787879B (zh) 2016-05-11

Similar Documents

Publication Publication Date Title
CN103787879A (zh) 一种王浆酸衍生物及其制备方法和应用
CN103232369B (zh) 一种芴甲氧羰酰谷氨酸-5-叔丁酯的制备方法
WO2015123905A1 (zh) 六氢β-酸单酯、内络盐或单酯盐及其做为动物饲料添加剂的应用
CN104341357A (zh) 一种甲氧苄啶半抗原t2制备完全抗原的方法及应用
JPS6253966A (ja) 新規ピリジン誘導体
CN101723846B (zh) 新型18f标记对硝基苯甲酰基氨基酸类衍生物、制备方法和在肿瘤显像中的应用
CN114751846A (zh) 一种氟苯尼考的缬氨酸脂盐的制备方法
WO2023019839A1 (zh) 一种5-氨基酮戊酸酯化物的制备及后处理方法
CN109678771A (zh) 一种叶黄素甘氨酸酯及其盐酸盐的制备方法
Neifert et al. Hexahydroxybenzene and Some of its Derivatives1
JP2000026365A (ja) シキミ酸およびその誘導体の製造方法
Bickel The addition of malonic esters to an acetylenic ketone
SU486505A3 (ru) Способ получени эфиров /3,4-диалканилоксифенил/аланина
SU751328A3 (ru) Способ получени ацилпроизводных геллебригенина или их солей
US2411611A (en) Manufacture of nu-(polyhydroxyalkyl)-arylamines
US1457675A (en) Pharmaceutical product
Barry et al. Antitubercular Substances: I. Monoalkyl Succinic Acids
SU958452A1 (ru) Способ получени монокарбоцианиновых красителей
CN102659639A (zh) 一种益母草碱的制备工艺
CN101619041A (zh) 一种二酮基含氮环化合物的合成方法及其中间体
US2386640A (en) Bis esters of iodinated phenyl aliphatic carboxylic acids
Benedict et al. X-ray diffraction analysis of synthetic unsaturated diacid diglycerides
WO2015100800A1 (zh) β-酸单酯盐及其做为动物饲料添加剂的应用
SU130519A1 (ru) Способ получени диалкиловых эфиров бис-(карбоксифенил)-метилфосфината
US2515240A (en) Nitrophenyl ketonic amino alcohols

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: 15740765

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15740765

Country of ref document: EP

Kind code of ref document: A1