WO2022222607A1 - 一种乙酰化透明质酸钠的制备方法 - Google Patents

一种乙酰化透明质酸钠的制备方法 Download PDF

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WO2022222607A1
WO2022222607A1 PCT/CN2022/078460 CN2022078460W WO2022222607A1 WO 2022222607 A1 WO2022222607 A1 WO 2022222607A1 CN 2022078460 W CN2022078460 W CN 2022078460W WO 2022222607 A1 WO2022222607 A1 WO 2022222607A1
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reaction
preparation
sodium hyaluronate
reaction solution
solution
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PCT/CN2022/078460
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English (en)
French (fr)
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刘磊
王春喜
李庆
康传利
孙晶晶
汤丽伟
刘蔷
廉少杰
张美霞
张梦益
李取泉
杜帅
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山东焦点福瑞达生物股份有限公司
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Priority to JP2022560961A priority Critical patent/JP7430944B2/ja
Priority to EP22782444.8A priority patent/EP4119586A4/en
Priority to US17/918,906 priority patent/US20230295351A1/en
Publication of WO2022222607A1 publication Critical patent/WO2022222607A1/zh

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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
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of acetylated sodium hyaluronate.
  • Acetylated sodium hyaluronate is a moisturizing raw material obtained after sodium hyaluronate undergoes an acetylation reaction.
  • the hydrogen on the hydroxyl group of sodium hyaluronate is replaced by an acetyl moiety; while maintaining hydrophilicity, its lipophilicity is improved, which helps to improve the affinity and adsorption properties with the skin.
  • Sodium Acetylated Hyaluronate provides excellent hydration, repairs the skin barrier, improves skin elasticity and keeps skin smooth.
  • acetylated sodium hyaluronate in the prior art, one is prepared by using acetic acid/acetic anhydride as a solvent and catalyzed by concentrated sulfuric acid, and the use of concentrated sulfuric acid as a catalyst is dangerous, and ethanol is required to precipitate the product subsequently.
  • acetylated sodium hyaluronate has high solubility in ethanol, so it needs more anhydrous ethanol to precipitate out, and the consumption is huge.
  • Another method of using DMF as a solvent and acetyl chloride as an acylating agent such as the preparation method of the acetylated sodium hyaluronate disclosed in the Chinese invention patent application with the application number of 2019110154812, under the protective gas, with sodium hyaluronate and hyaluronic acid.
  • Acetyl chloride is reacted in an organic solvent, and the product is separated and purified to form a salt with an alkali to obtain the product.
  • This process does not require corrosive catalysts such as concentrated sulfuric acid or pyridines that are difficult to purify.
  • the technical problem to be solved by the present invention is to aim at the deficiencies of the prior art, and to provide a kind of product with an acetyl substitution degree of 2.7-3.2 that can be effectively avoided to be too high or too low, the reaction raw materials and conditions are mild, and the separation and purification steps are simple.
  • a preparation method of acetylated sodium hyaluronate is characterized in that, comprises the following steps:
  • hyaluronic acid salt and acetic anhydride are added to the organic solvent to catalyze the reaction.
  • a water absorbing agent is added.
  • the reaction solution is subjected to post-treatment, separation, purification and drying to obtain a product.
  • the degree of acetyl substitution was detected at 2.7-3.2.
  • reaction between hyaluronate and acetic anhydride is as follows: dissolving hyaluronate in an organic solvent to a homogeneous phase, adding a water-absorbing agent, cooling the reaction system to -5°C to 10°C, and adding acetic anhydride dropwise to the solution.
  • the DMAP-toluene solution was added dropwise to the reaction solution, and after a certain period of reaction, the reaction was heated to 40-70° C. for a period of time to obtain a light yellow turbid solution.
  • the temperature needs to be lowered and added dropwise, in order to prevent the local acetic anhydride concentration from being too high and the rapid reaction, and the local exotherm will aggravate this phenomenon, resulting in the formation of excessively substituted floc precipitation.
  • it can be controlled by vigorous stirring and cooling dropwise, but magnetic stirring and small mechanical stirring are not effective, so it needs to be added dropwise after cooling, and the system will be stirred evenly, and then naturally return to normal temperature for reaction.
  • the purpose of adding the water absorbing agent during the reaction is to absorb the water contained in the polysaccharide chain as much as possible, so as to prevent the water and acetic anhydride from reacting first to consume part of the acetic anhydride, resulting in a low degree of substitution.
  • the mass ratio of the hyaluronate to acetic anhydride is 1:1-1:5, and the average molecular weight of the hyaluronate is 5KDa-5000KDa; preferably 10KDa-2000KDa; more preferably 20KDa-200KDa.
  • the post-processing process of the reaction solution is as follows: adding water to the reaction solution to quench the remaining acetic anhydride, and filtering to remove the water absorbing agent.
  • the water-absorbing agent adopts molecular sieve, which can be pulverized, but will not participate in the reaction, and can be removed by one-step filtration;
  • the catalyzer adopts DMAP, and the mass ratio of hyaluronate and DMAP is 1:0.05-1: 0.12.
  • the organic solvent adopts toluene, and the solid-liquid ratio is 1:5-1:20.
  • the separation and purification process of the reaction solution is as follows: the reaction solution is subjected to membrane filtration and purification, and a small amount of water is added several times during the purification process until the fraction is colorless and weakly acidic.
  • the membrane used is an organic membrane or a ceramic membrane, which can withstand organic solvents such as toluene, and the membrane pore size is 200KD-5000KD.
  • the pH of the reaction solution is adjusted to 5-7 with alkaline solution, and concentrated.
  • the alkali solution adopts at least one of sodium hydroxide solution, sodium carbonate solution and sodium bicarbonate solution.
  • the drying process adopts low temperature drying, and the temperature is 0-25°C.
  • the process of the present invention adopts the addition of a water-absorbing agent molecular sieve in the reaction process of hyaluronate and acetic anhydride, so that the water-absorbing agent removes the interference of water in the reaction, and prevents water and acetic anhydride from first reacting to consume part
  • the degree of substitution caused by acetic anhydride is low, and at the same time, the problem of too low or too high substitution is solved by controlling the reaction temperature; membrane filtration is used for purification, and a small amount of water is added several times in the process to remove the introduced catalyst and organic solvent.
  • Using a large amount of ethanol for precipitation reduces consumption, and the obtained product has high purity and good state; the overall process conditions are mild in reaction, and the separation and purification steps are simple.
  • acetylated sodium hyaluronate comprises the following steps:
  • reaction solution was purified by membrane filtration, and water was added several times in the purification process until the fraction was colorless and weakly sour, and the volume of the reaction solution after the last purification was 200 mL;
  • the obtained product is in the form of crystals, and the acetyl substitution degree detected by hydroxylamine colorimetry is 2.9, which is within the qualified range of 2.6-3.6.
  • m 1 is the mass of fed HA
  • m 2 is the mass of the obtained AcHA
  • DS is the degree of acetyl substitution.
  • acetylated sodium hyaluronate comprises the following steps:
  • reaction solution is purified by membrane filtration, and a small amount of water is added several times during the purification process until the fraction is colorless and weakly sour, and the volume of the reaction solution after the last purification is about 500 mL;
  • the obtained product is in the form of crystals, and the degree of acetyl substitution detected by hydroxylamine colorimetry is 2.7, which is within the qualified range of 2.6-3.6.
  • acetylated sodium hyaluronate comprises the following steps:
  • reaction solution is purified by membrane filtration, and water is added several times in the purification process until the fraction is colorless and weakly sour, and the volume of the reaction solution after the last purification is 1000 mL;
  • the obtained product is in the form of crystals, and the degree of acetyl substitution detected by hydroxylamine colorimetry is 3.17, which is within the qualified range of 2.6-3.6.
  • the preparation method is the same as that in Example 1, the difference is that no water-absorbing agent is added in the process method, and the obtained acetylated HA substitution degree is 2.21.
  • the preparation method is basically the same as in Example 1, the difference is that the water-absorbing agent molecular sieve is replaced with concentrated sulfuric acid, and as a result, the water-absorbing agent has a great influence on the pH of the system and even directly participates in the reaction.
  • the preparation method is basically the same as in Example 1, except that the water-absorbing agent molecular sieve is replaced by soda lime, and the result is that the water-absorbing agent has a greater influence on the pH of the system and even directly participates in the reaction.
  • the preparation method is basically the same as in Example 1, the difference is that the water-absorbing agent molecular sieve is replaced with anhydrous sodium sulfate, and the experimental result is that the anhydrous sodium sulfate directly forms hard lumps after absorbing water, which affects stirring.
  • the preparation method is basically the same as that of Example 1, except that the temperature in step (1) is controlled to be normal temperature, and other conditions remain unchanged.
  • the results show that it takes a long time to dissolve sodium hyaluronate, and the temperature is not lowered when acetic anhydride is added dropwise, flocs appear at the dropwise addition, and then the reaction system is partially exothermic, and the dropwise additions are more and more floccules. .
  • the flocs were collected and tested, and it was found to be acetylated sodium hyaluronate that was too high and close to 4. The flocs were no longer soluble in water, lost their hydrophilicity, and were unqualified.

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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Abstract

本发明涉及一种乙酰化透明质酸钠的制备方法，属于有机化学合成领域，其特征在于，包括以下步骤：在惰性气体保护下，以透明质酸盐和乙酸酐在有机溶剂中加催化剂催化反应，反应过程中加入吸水剂，反应液经后处理、分离纯化、干燥获得产品；本发明能够有效避免取代度过高或过低从而获得乙酰基取代度在2.7-3.2的产品、反应原料及条件温和、分离纯化步骤简单。

Description

一种乙酰化透明质酸钠的制备方法 技术领域
本发明涉及有机化学合成技术领域，具体涉及一种乙酰化透明质酸钠的制备方法。
背景技术
乙酰化透明质酸钠是透明质酸钠经过乙酰化反应之后而得到一种保湿原料。透明质酸钠羟基上的氢被乙酰基部分取代；保持亲水性的同时提高了它的亲脂性，这有助于提高和皮肤的亲和力和吸附性能。乙酰化透明质酸钠具有清新而不黏腻的感觉，可提供极佳的保湿效果，修复皮肤屏障，改善皮肤弹性并保持皮肤光滑。从AcHA的结构上看，每个双糖单位上有四个羟基氢可被乙酰基取代，因此对一个双糖结构来说取代度范围为0-4，取代度会影响HA亲水亲脂性。乙酰化改性的目的是保持HA亲水的前提下提高亲脂性，因此使HA亲水亲脂达到平衡的取代度才是最适合的。研究表明，乙酰基的取代度在2.6-3.6之间，乙酰化HA亲水亲脂性最佳。
现有技术乙酰化透明质酸钠的制备方法中，一种是以醋酸/醋酸酐为溶剂，经浓硫酸催化而制得，使用浓硫酸作催化剂，危险性较高，后续需要乙醇沉淀出产品，乙酰化透明质酸钠相比于普通透明质酸钠，在乙醇里的溶解性高，因此需要更多的无水乙醇沉淀出来，消耗巨大。
另有一种用DMF做溶剂、乙酰氯做酰化剂的方法，如申请号为2019110154812的中国发明专利申请公布的乙酰化透明质酸钠的和制备方法，保护气体下，以透明酸钠盐和乙酰氯在有机溶剂中反应，产物分离纯化后与碱成盐获得产品。这种工艺不需要浓硫酸等腐蚀性或吡啶类难纯化的催化剂，但是，还存在如下问题：乙酰氯的腐蚀性较强，在工艺生产中容易损耗设备，并且引起产品的铁、铬含量超标；工艺后处理时需要调节pH至12，而碱性环境下酯基容易水解造成乙酰取代度降低，过氧化物除色也会带来很大的安全隐患。
发明内容
本发明所要解决的技术问题是针对现有技术的不足，提供一种有效避免取代度过高或过低从而获得乙酰基取代度在2.7-3.2的产品、反应原料及条件温和、 分离纯化步骤简单的乙酰化透明质酸钠的制备方法。
本发明解决上述技术问题的技术方案如下：一种乙酰化透明质酸钠的制备方法，其特征在于，包括以下步骤：
在惰性气体保护下，以透明质酸盐和乙酸酐在有机溶剂中加催化剂催化反应，反应过程中加入吸水剂，反应液经后处理、分离纯化、干燥获得产品，所得产品经羟胺比色法检测乙酰基取代度在2.7-3.2。
进一步的，透明质酸盐和乙酸酐的反应如下：将透明质酸盐溶于有机溶剂中至均相，加入吸水剂，将反应体系降温至-5℃～10℃，将乙酸酐滴加到反应液中，再将DMAP-甲苯溶液滴加到反应液中，反应一定时间后，再加热至40-70℃反应一段时间，得到淡黄色浑浊溶液。
在加入乙酸酐时需要降温滴加，是为了防止局部乙酸酐浓度过高快速反应，局部放热又加剧这种现象，生成取代度过高的絮状物沉淀。一般可以通过剧烈搅拌与降温滴加来控制，但是磁力搅拌与小机械搅拌效果不好，故需要在降温后滴加，等体系搅拌均匀，再自然回温到常温反应。
反应式如下：
Figure PCTCN2022078460-appb-000001
反应过程中加入吸水剂的目的是，尽可能吸收掉多糖链中包含的水分，防止水和乙酸酐先反应消耗掉部分乙酸酐而导致的取代度较低。
进一步的，所述透明质酸盐与乙酸酐的质量比为1:1-1:5，透明质酸盐的平均分子量为5KDa-5000Kda；优选为10KDa-2000KDa；更优选为20KDa-200KDa。
进一步的，催化反应完毕后，反应液的后处理过程为：向反应液中加水淬灭剩余乙酸酐，过滤除去吸水剂。
进一步的，所述吸水剂采用分子筛，可以被搅碎，但不会参与反应，并且一步过滤就可除去；所述催化剂采用DMAP，透明质酸盐与DMAP的质量比为1:0.05-1:0.12。
进一步的，所述有机溶剂采用甲苯，料液比为1:5-1:20。
进一步的，反应液的分离纯化过程为：将反应液进行膜过滤纯化，纯化过程中多次少量加水，直至馏分无色弱酸味。所用膜采用有机膜或陶瓷膜，可耐受甲苯等有机溶剂，膜孔径在200KD-5000KD。
进一步的，分离纯化后将反应液用碱液调pH到5-7，浓缩。其中，碱液采用氢氧化钠溶液、碳酸钠溶液、碳酸氢钠溶液中的至少一种。
进一步的，所述干燥过程采用低温干燥，温度0-25℃。
本发明的有益效果是：本发明工艺采用在透明质酸盐与乙酸酐的反应过程中加入吸水剂分子筛，使吸水剂除掉水分在反应中的干扰，防止水和乙酸酐先反应消耗掉部分乙酸酐而导致的取代度较低，同时配合控制反应温度，解决了取代度过低或者过高的问题；采用膜过滤纯化，过程中多次少量加水，除掉引入的催化剂和有机溶剂，无需使用大量乙醇沉淀，降低了消耗，并且得到的产品纯度高，状态好；整体工艺条件反应温和、分离纯化步骤简单。
具体实施方式
下面对本发明的原理和特征进行描述，所举实施例只用于解释本发明，并非用于限定本发明的范围。
实施例1
本实施例乙酰化透明质酸钠的制备方法，包括以下步骤：
(1)在氮气保护下，在1000mL的反应瓶中称取50.00g分子量10KDa的HA，加入无水溶剂250mL甲苯中升温到60℃搅拌，直至全溶成为均相，加入分子筛用于反应中吸水；之后将反应体系降温到-5℃，将50mL乙酸酐滴加到反应液里，再将0.25g DMAP用4mL甲苯溶液溶解后滴加到反应液里，常温反应1h后，再加热40℃反应4h得到淡黄色浑浊溶液；
(2)加入等体积的水淬灭剩余乙酸酐，将反应液过滤除去分子筛；
(3)将反应液进行膜过滤纯化，纯化过程中多次少量加水，直至馏分无色弱酸味，最后一次纯化完反应液体积为200mL；
(4)将反应液用氢氧化钠溶液调pH到5-7，浓缩；
(5)干燥得到39.01g乙酰化透明质酸钠，收率为60％。
得到产品状态呈晶状物，经羟胺比色法检测乙酰基取代度为2.9，在2.6-3.6的合格范围内。
其中，收率μ＝401.3*m 2/m 1*(401.3+(43-1)*DS)；
m 1为投料HA质量，m 2为所得到AcHA质量，DS为乙酰基取代度。
实施例2
本实施例乙酰化透明质酸钠的制备方法，包括以下步骤：
(1)在氮气保护下，在1000mL的反应瓶中称取30.00g分子量1000KDa的HA，加入无水溶剂300mL甲苯中升温到70℃搅拌(升温是为了溶解透明质酸钠，分子量越大越难溶)，直至全溶成为均相，加入分子筛用于反应中吸水；之后将反应体系降温到0℃，将90mL乙酸酐滴加到反应液里，再将0.2g DMAP用4mL甲苯溶解后滴加到反应液里，常温反应1h后，再加热50℃反应12h得到淡黄色浑浊溶液；
(2)加入等体积的水淬灭剩余乙酸酐，将反应液过滤除去分子筛；
(3)将反应液进行膜过滤纯化，纯化过程中多次少量加水，直至馏分无色弱酸味，最后一次纯化完反应液体积为500mL左右；
(4)将反应液用碳酸钠溶液调pH到5-7，浓缩；
(5)干燥得到17.5g乙酰化透明质酸钠，收率为58％。
得到产品状态呈晶状物，经羟胺比色法检测乙酰基取代度为2.7，在2.6-3.6的合格范围内。
实施例3
本实施例乙酰化透明质酸钠的制备方法，包括以下步骤：
(1)在氮气保护下，在1000mL的反应瓶中称取20.00g分子量200KDa的HA，加入无水溶剂400mL甲苯中升温到70℃搅拌，直至全溶成为均相，加入分子筛用于反应中吸水；之后将反应体系降温到-5℃，将100mL乙酸酐滴加到反应液里，再将0.24g DMAP用4mL甲苯溶解滴加到反应液里，常温反应1h后，再加热70℃反应48h得到淡黄色浑浊溶液；
(2)加入等体积的水淬灭剩余乙酸酐，将反应液过滤除去分子筛；
(3)将反应液进行膜过滤纯化，纯化过程中多次少量加水，直至馏分无色弱酸味，最后一次纯化完反应液体积为1000mL；
(4)将反应液用碳酸氢钠溶液调pH到5-7，浓缩；
(5)干燥得到13.8g乙酰化透明质酸钠，收率为52％左右。
得到产品状态呈晶状物，经羟胺比色法检测乙酰基取代度为3.17，在2.6-3.6的合格范围内。
对比例1
制备方法同实施例1，所不同的是，工艺方法中未添加吸水剂，得到的乙酰化HA取代度在为2.21。
结果表明，该反应过程也发生了酰化反应，但是取代度较低。其原因为透明质酸钠具有较强的锁水能力，难以在不破坏结构的条件下彻底除去其中的水分，正常化妆品级透明质酸钠的干燥失重在6％-9％之间，透明质酸钠带入反应体系的水会和乙酸酐发生水解反应生成乙酸，消耗掉部分乙酸酐；该酰化反应为羟基氢被酰化取代，也是可逆的酯化反应，体系中含水，会促进后期的逆反应，影响取代度。
对比例2
制备方法基本同实施例1，所不同的是，将吸水剂分子筛替换为浓硫酸，结果吸水剂对体系酸碱度影响较大甚至直接参与反应。
对比例3
制备方法基本同实施例1，所不同的是，将吸水剂分子筛替换为碱石灰，结果吸水剂对体系酸碱度影响较大甚至直接参与反应。
对比例4
制备方法基本同实施例1，所不同的是，将吸水剂分子筛替换为无水硫酸钠，实验结果无水硫酸钠在吸水后直接结成硬块，影响搅拌。
对比例5
制备方法基本同实施例1，所不同的是，步骤(1)中的温度控制为常温，其他条件不变。结果表明，需要很长的时间才能将透明质酸钠溶解，在滴加乙酸酐时未降温，滴加处出现絮状物，接着反应体系局部放热，滴加处絮状物越来越多。该絮状物经收集检测，为取代度过高接近4的乙酰化透明质酸钠，该絮状物不再溶于水，失去亲水性，不合格。

Claims (10)

  1. 一种乙酰化透明质酸钠的制备方法，其特征在于，包括以下步骤：
    在惰性气体保护下，以透明质酸盐和乙酸酐在有机溶剂中加催化剂催化反应，反应过程中加入吸水剂，反应液经后处理、分离纯化、干燥获得产品。
  2. 根据权利要求1所述的乙酰化透明质酸钠的制备方法，其特征在于，透明质酸盐和乙酸酐的反应如下：将透明质酸盐溶于有机溶剂中至均相，加入吸水剂，将反应体系降温至-5℃～10℃，将乙酸酐滴加到反应液中，再将DMAP-甲苯溶液滴加到反应液中，反应一定时间后，再加热至40-70℃反应一段时间；
    所述透明质酸盐与乙酸酐的质量比为1:1-1:5，透明质酸盐的平均分子量为5KDa-5000KDa。
  3. 根据权利要求1或2所述的乙酰化透明质酸钠的制备方法，其特征在于，催化反应完毕后，反应液的后处理过程为：向反应液中加水淬灭剩余乙酸酐，过滤除去吸水剂。
  4. 根据权利要求1或2所述的乙酰化透明质酸钠的制备方法，其特征在于，所述吸水剂采用分子筛，催化剂采用DMAP。
  5. 根据权利要求1或2所述的乙酰化透明质酸钠的制备方法，其特征在于，所述有机溶剂采用甲苯，透明质酸盐在有机溶剂中的料液比为1:5-1:20。
  6. 根据权利要求1所述的乙酰化透明质酸钠的制备方法，其特征在于，反应液的分离纯化过程为：将反应液进行膜过滤纯化，纯化过程中多次少量加水，直至馏分无色弱酸味。
  7. 根据权利要求6所述的乙酰化透明质酸钠的制备方法，其特征在于，所用膜采用有机膜或陶瓷膜，膜孔径在200KD-5000KD。
  8. 根据权利要求1或6所述的乙酰化透明质酸钠的制备方法，其特征在于，分离纯化后将反应液用碱液调pH到5-7，浓缩。
  9. 根据权利要求8所述的乙酰化透明质酸钠的制备方法，其特征在于，所述碱液采用氢氧化钠溶液、碳酸钠溶液、碳酸氢钠溶液中的至少一种。
  10. 根据权利要求1所述的乙酰化透明质酸钠的制备方法，其特征在于，所述干燥过程采用低温干燥，温度0-25℃。
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