WO2016058283A1 - 一种多不饱和脂肪酸钙的制备方法 - Google Patents

一种多不饱和脂肪酸钙的制备方法 Download PDF

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WO2016058283A1
WO2016058283A1 PCT/CN2015/000686 CN2015000686W WO2016058283A1 WO 2016058283 A1 WO2016058283 A1 WO 2016058283A1 CN 2015000686 W CN2015000686 W CN 2015000686W WO 2016058283 A1 WO2016058283 A1 WO 2016058283A1
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polyunsaturated fatty
fatty acid
calcium
water
reaction
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PCT/CN2015/000686
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English (en)
French (fr)
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项学兵
许新德
邵斌
孟玉芳
李冲
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浙江医药股份有限公司新昌制药厂
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Priority to EP15851044.6A priority Critical patent/EP3208259B1/en
Priority to US15/519,086 priority patent/US10035750B2/en
Publication of WO2016058283A1 publication Critical patent/WO2016058283A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C07C57/12—Straight chain carboxylic acids containing eighteen carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C1/00—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids
    • C11C1/02—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils
    • C11C1/025—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils by saponification and release of fatty acids
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
    • C11C3/12—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by hydrogenation
    • C11C3/126—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by hydrogenation using catalysts based principally on other metals or derivates

Definitions

  • the invention relates to a preparation method of polyunsaturated fatty acid calcium, in particular to various forms of polyunsaturated fatty acid raw materials for preparing polyunsaturated fatty acid calcium products.
  • the main description creatively utilizes water-soluble calcification to directly react with polyunsaturated fatty acid raw materials to obtain polyunsaturated fatty acid calcium salt.
  • the process is very simple, the reaction temperature is low, and the destruction of polyunsaturated fatty acid raw materials is small, and the application of water-soluble calcium
  • the degree of calcification reaction is greatly promoted, the reaction time is shortened, the reaction yield is improved, and the quality of the polyunsaturated fatty acid obtained is finally good.
  • polyunsaturated fatty acids have a very important position in the market, whether as a raw material for medicines. Or as a dietary additive, or feed additives, etc., have broad development and application prospects.
  • Polyunsaturated fatty acids are the constituents of cell membranes and are important material basis for the body's activities, especially in infants and young children. They mainly maintain cell membrane fluidity, promote cholesterol esterification, lower cholesterol and triglycerides, and reduce blood viscosity. Degree, improve blood circulation and other physiological functions, but also improve human thinking and enhance memory, the lack of polyunsaturated fatty acids will lead to more congenital or acquired diseases, but the body itself can not synthesize polyunsaturated fatty acids (PUFA), It must be taken through channels such as diet.
  • PUFA polyunsaturated fatty acids
  • PUFAs polyunsaturated fatty acids
  • PUFAs including omega-3 polyunsaturated fatty acids (PUFA) ( ⁇ -3 PUFA), omega-6 polyunsaturated fatty acids (PUFA) ( ⁇ -6 PUFA), ⁇ -9 polyunsaturated Fatty acid (PUFA) ( ⁇ -9PUFA) and other forms of conjugated linoleic acid, such as alpha-linolenic acid (ALA), eicosapentaenoate (EPA), docosahexaenoic acid (DHA), Docosapentaenoic acid (DPA), linoleic acid (LA), conjugated linoleic acid (CLA), ⁇ -linolenic acid (GLA), arachidonic acid (AA), etc.
  • ALA alpha-linolenic acid
  • EPA eicosapentaenoate
  • DHA docosahexaenoic acid
  • DPA Docosapenta
  • omega-3 polyunsaturated fatty acids which are mainly represented by pentenoic acid (EPA) and docosahexaenoic acid (DHA), are well known and accepted, and have improved and promoted human and animal health. The effect is also the most obvious.
  • EPA pentenoic acid
  • DHA docosahexaenoic acid
  • Polyunsaturated fatty acids are mainly derived from algae extracts and aquatic animal oils.
  • One important source is fish oil.
  • the liquid raw materials used in the polyunsaturated fatty acid products directly supplemented by the human body mainly include free polyunsaturated fatty acids, ethyl ester polyunsaturated fatty acids or glyceride polyunsaturated fatty acids, etc. These raw materials have related functions as well as series.
  • the defects, first of all, the form of these products is liquid, and have a certain fishy smell, which has certain resistance to some people, may not be accepted by the general public, but also has certain limitations on its scope of use, and secondly, some The product is not sufficiently absorbed and utilized in the body, and the bioavailability is low.
  • Polyunsaturated fatty acid calcium products can make up for the above-mentioned deficiencies to a certain extent. Firstly, in addition to not destroying the corresponding effects of polyunsaturated fatty acids, polyunsaturated fatty acid calcium products can also be used as a high-quality calcium source to supplement the calcium nutrients needed by the human body. Polyunsaturated fatty acid calcium products exist in the form of free-flowing powdered products, which relatively broaden the polyunsaturated fatty acids. The scope of application, as well as the product has the advantages of no odor, good stability, etc., and may improve the bioavailability of polyunsaturated fatty acids in the body to some extent.
  • the existing techniques for preparing calcium products of polyunsaturated fatty acids mainly include directly reacting glyceride-type polyunsaturated fatty acids with calcium oxide or calcium hydroxide to obtain calcium polyunsaturated fatty acids; or free polyunsaturated fatty acids and calcium oxide or Calcium hydroxide melts to obtain calcium polyunsaturated fatty acid; or various ester type polyunsaturated fatty acids are first saponified to obtain polyunsaturated fatty acid sodium, and then ion exchange of sodium and calcium to obtain polyunsaturated fatty acid calcium product, the above process Both have certain defects.
  • One type of process directly uses calcium oxide or calcium hydroxide to calcify the polyunsaturated fatty acid calcium product in a molten state with a glyceride-type polyunsaturated fatty acid or a free polyunsaturated fatty acid, and the process temperature is high first. , reaching 200-300 ° C or more, at this temperature, polyunsaturated fatty acids are easily oxidized, decomposed or polymerized; secondly, calcium oxide or calcium hydroxide is poorly soluble, and is substantially insoluble in the reaction system, resulting in a reaction. The degree of not high degree, long reaction time, low reaction yield, etc., the quality of the polyunsaturated fatty acid calcium product obtained is poor.
  • Another type of process first saponification reaction of various polyunsaturated fatty acids including methyl ester type, ethyl ester type or glyceride type with liquid alkali to obtain sodium polyunsaturated fatty acid or re-acidification to obtain free polyunsaturated fatty acid, and then
  • the polyunsaturated fatty acid calcium is obtained by reacting sodium polyunsaturated fatty acid or free polyunsaturated fatty acid with various calcifications, and various calcifications include calcium oxide, calcium hydroxide, calcium acetate, calcium lactate, calcium chloride, etc.
  • the route is more complicated, in which the process is carried out in the first step of the saponification reaction, due to the addition of a large amount of liquid alkali, under the condition of strong alkali, the polyunsaturated fatty acid is destroyed in a large amount, resulting in the obtained intermediate and final product.
  • the color becomes darker and the product quality deteriorates.
  • calcium oxide and calcium hydroxide are substantially insoluble in water or various organic solvents or various polyunsaturated fatty acids in the reaction system, so the reaction degree is small, the yield is low, etc.
  • the whole process includes saponification reaction, pickling/water washing, solvent recovery, calcification reaction, filtration, drying/pulverization, etc.
  • the process is complicated, and finally the product quality is poor, the yield is low, and the process generates a large amount of waste water.
  • Patent US5382678 uses glyceride-type fish oil polyunsaturated fatty acid and calcium oxide or calcium hydroxide to directly carry out calcification reaction, the reaction temperature reaches 250 ° C, although the use of glyceride-type polyunsaturated fatty acids (higher boiling point, slightly better antioxidant performance) can To some extent, to overcome the influence of high temperature on raw materials, but the process reaction is still insufficient, the reaction yield is low, and the final product has a glyceride-type fish oil content of more than 10%, which also leads to the product being sticky and unable to form a free-flowing Powdered product.
  • Patent US60724644 and US60775664 mention a process in which calcium oxide or calcium hydroxide is directly subjected to calcification reaction with free polyunsaturated fatty acids or various ester polyunsaturated fatty acids, the reaction temperature is high, the reaction degree is low, and the product quality is not good enough; Various ester-type polyunsaturated fatty acids are first saponified to obtain polyunsaturated fatty acid sodium, and then ion exchange is carried out to obtain a polyunsaturated fatty acid calcium process, the process route is long, the process produces more wastewater, and the reaction yield is not high.
  • Patent US09675745 relates to heating a polyunsaturated fatty acid first, then slowly adding a hydrate of calcium oxide, and finally evaporating the water and the like, the reaction is carried out under a special environment, and the process is slightly complicated, since the calcium oxide is insoluble in water, the reaction time Longer, less reactive, The quality of the products obtained is low.
  • the patent CN1270160 is first saponified and then acidified to obtain free fatty acid.
  • the purified free fatty acid is then reacted with calcium hydroxide to obtain a polyunsaturated fatty acid calcium product. Since the calcium hydroxide is substantially insoluble, the reaction time is longer and the reaction degree is lower. The yield is not high.
  • the patent CN102417444 uses fatty acid to directly react with calcium hydroxide or calcium oxide to obtain fatty acid calcium.
  • the process is carried out in a continuous mode, and the reaction yield is improved by continuously analyzing the mode of the fatty acid calcium product, and finally the process yield is about 80-85%.
  • the process produces a large amount of wastewater, and the obtained product is not high in purity.
  • the patents CN1752064 and CN1685921 use saponification reaction of fatty acid and liquid alkali to obtain sodium fatty acid, and then ion exchange with calcium chloride to obtain fatty acid calcium product.
  • the process route is complicated, and the yield of the process product is slightly lower, about 80%. A large amount of chlorine-containing wastewater is produced, which is highly polluting to the environment.
  • the main raw materials for preparing polyunsaturated fatty acid calcium products are polyunsaturated fatty acids and calcifications
  • polyunsaturated fatty acid raw materials include free polyunsaturated fatty acids and various ester polyunsaturated fatty acids, which contain more Double-bonded groups, so polyunsaturated fatty acid substances are not stable enough, and free-type polyunsaturated fatty acids have lower boiling points and are resistant
  • the oxidation is the least, followed by methyl ester or ethyl ester polyunsaturated fatty acids.
  • the glyceride polyunsaturated fatty acid has the highest boiling point and is relatively stable. However, when the temperature is higher than 260 ° C, polymerization is easy to form a polymer. At the same time, polyunsaturated fatty acids are sensitive to strong acid or alkali environment, and are prone to structural damage. The appearance is darkened in color and solidified in material state.
  • the present invention creatively uses an aqueous solution of a water-soluble calcified raw material to directly react with a polyunsaturated fatty acid to obtain a calcium polyunsaturated fatty acid. Since the obtained polyunsaturated fatty acid calcium is insoluble in the reaction system, the precipitation is continuously formed during the reaction. The reaction proceeds well, the degree of reaction is high, and the polyunsaturated fatty acid raw material includes Free polyunsaturated fatty acids or various ester-type polyunsaturated fatty acids have good reactivity and high degree of reaction.
  • the invention relates to a preparation method of polyunsaturated fatty acid calcium, in particular to various forms of polyunsaturated fatty acid fish oil raw materials for preparing polyunsaturated fatty acid calcium products.
  • the preparation method of the polyunsaturated fatty acid calcium according to the present invention comprises the following steps:
  • Feeding/reaction feeding polyunsaturated fatty acid raw materials, adding calcified aqueous solution under stirring, maintaining certain reaction conditions, reacting for a period of time, and the reaction is completed.
  • the product quality is good and the yield is high.
  • the "certain reaction conditions" described in the present invention are relatively mild, and the reaction temperature is -20 to 100 ° C, and preferably 20 to 100 ° C.
  • the reaction time is from 0.5 to 10 hr, preferably from 0.5 to 3 hr.
  • the molar amount of fatty acids in the polyunsaturated fatty acid raw material and the polyunsaturated fatty acid calcium product in the present invention is carried out by a certain detection method: the sample to be tested is completely saponified and then acidified to obtain a complete free polyunsaturated fatty acid sample, and titrated The acid value is calculated from the average molar mass of the acid value so that the molar amount of the sample can be obtained.
  • Detection step take about 1.0g sample Wg, put into a jar, add 20ml ethanol and 2-3 drops of phenolphthalein indicator, shake well, titrate with about 0.1mol / L potassium hydroxide standard solution (C mol / L) , consumption standard solution V ml, get sample acid value (56 * C * V) / W (single The position is mgKOH/g), the average molar mass of the sample is (1000*W) / (C*V), and the molar amount of fatty acid in the final sample is the ratio of mass to average molar mass.
  • the treatment of waste water and by-products in the present invention includes the following measures: the filtrate obtained during the filtration of the reaction liquid mainly contains water, a trace amount of organic acid and an alcohol substance, and the organic matter is separated by atmospheric distillation or vacuum distillation. Organic matter can be used, and wastewater can be discharged directly to discharge standards without causing pollution and harm to the environment.
  • polyunsaturated fatty acid raw materials in the present invention is broad, and basically includes various forms of polyunsaturated fatty acids or mixtures thereof, such as free polyunsaturated fatty acids and methyl esters.
  • the structural formula is Polyunsaturated fatty acids (wherein R 1 is a C 6 -C 40 alkenyl group, R 2 is H or a C 1 -C 4 alkyl group) and the structural formula is Polyunsaturated fatty acids (wherein R 3 , R 4 , and R 5 are a hydroxyl group or a C 1 -C 4 carboxylic acid group or a C 6 -C 40 polyunsaturated fatty acid group, and R 3 , R 4 , and R 5 may not all be A hydroxy group or a C 1 -C 4 carboxylic acid group, R 3 , R 4 , and R 5 may be the same or different) and a mixture of one or more of them.
  • polyunsaturated fatty acid raw material refers to various contents of fish oil (directly extracted omega-3 polyunsaturated fatty acid), algal oil (fermentation-derived omega-3 polyunsaturated fatty acid), linoleic acid, total One or more polyunsaturated fatty acid mixtures of conjugated linoleic acid, linolenic acid, arachidonic acid, etc., wherein the total content of polyunsaturated fatty acids is from 10 to 100% by weight.
  • the process has no limitations on the source of polyunsaturated fatty acid raw materials, including algae.
  • the polyunsaturated fatty acid materials derived from extracts such as extracts and aquatic animal oils (such as fish oil) have good reactivity, and the polyunsaturated fatty acid content (10-100%) in the polyunsaturated fatty acid raw materials does not react to the process and The yield has a large influence, and the polyunsaturated fatty acid calcium product with higher yield and better quality can be obtained basically.
  • the calcification used in the present invention is a water-soluble calcification, and the feeding mode is in the form of an aqueous solution of a water-soluble calcification, which can greatly promote the reaction degree of the calcification reaction of the process, improve the quality of the calcium product of the polyunsaturated fatty acid, and reduce the process by reducing the process.
  • the conditions are high efficiency, energy saving, safety and environmental protection.
  • the "water-soluble calcification raw material” includes one or more of calcium acetate, calcium lactate, calcium chloride, calcium nitrate, calcium citrate and calcium fumarate. kind of mixture.
  • the ratio of the feed ratio in the process is as follows: the molar equivalent of the water-soluble calcification raw material is 0.1 to 0.9, preferably 0.5 to 0.7, relative to the molar amount of the polyunsaturated fatty acid; and the water amount of the dissolved water-soluble calcification is the water-soluble calcification weight. 1 to 40 times.
  • the amount of water in which the water-soluble calcification is dissolved depends mainly on the solubility of the corresponding calcification in water, which is basically the water or excess water required for the complete dissolution of the calcification, wherein the excess water has substantially no effect on the process reaction.
  • the invention creatively utilizes the water-soluble calcification to directly react with the polyunsaturated fatty acid raw material to obtain the polyunsaturated fatty acid calcium salt, and the process is very simple, and the main steps are dissolved into Decalcification, calcification, filtration, drying/pulverization, etc., the reaction temperature is low, and the destruction of polyunsaturated fatty acid materials is small.
  • the application of water-soluble calcium greatly promotes the degree of calcification reaction, shortens the reaction time, and improves the reaction. The rate, the final product obtained, the quality of polyunsaturated fatty acids is better.
  • the process of the invention adopts the calcification/aqueous solution and fully contacts and reacts with the polyunsaturated fatty acid raw material during the reaction process, thereby greatly promoting the reaction degree of the calcification reaction, the reaction time is short, the reaction yield is high, and the use is strong. Alkali or strong acid environment, while the reaction temperature is lower, the reaction conditions are milder, so the raw polyunsaturated fatty acid is basically not destroyed, and the quality of the obtained process product is better.
  • the wastewater and by-products produced by the process are less.
  • the wastewater is mainly derived from the water required to dissolve the calcification, and the by-products are organic acids, alcohols and the like.
  • the filtrate obtained by filtration is separated by simple recovery and the like. Products and by-products can be used, and wastewater can be directly discharged from direct discharge standards without causing environmental pollution.
  • the process of the invention is simple and easy to operate, has good reaction activity, short reaction time, high reaction degree, mild reaction condition, good product quality, high yield and process stability. better.
  • the process is generally safe and environmentally friendly, making it ideal for large-scale industrial production.
  • the filtrate obtained by filtration is subjected to simple distillation or vacuum distillation to obtain a small amount of available organic matter and treated wastewater, and the treated wastewater reaches discharge standards and is directly discharged.
  • the fish oil polyunsaturated fatty acid calcium product has been tested.
  • the molar content of fish oil polyunsaturated fatty acid calcium product is 0.95mol, and the total polyunsaturated fatty acid calcium content is 62.9%, of which EPA 33.9%, DHA 23.2%, total free type
  • the saturated fatty acid content is 0.1%, the yield is 94.5%, the product color is white, and the quality is good.
  • the fish oil polyunsaturated fatty acid calcium product has been tested, the molar amount of the fish oil polyunsaturated fatty acid calcium product is 0.63 mol, and the total polyunsaturated fatty acid calcium content is 10.7%, wherein EPA 11.2%, DHA 6.1%, total free polyunsaturated fatty acid content was 12.3%, yield was 10.7%, product quality was poor.
  • the process of the invention is adopted, and the calcium acetate/aqueous solution is obtained by selecting the water-soluble calcium acetate raw material to be dissolved in water, and the relatively mild process and reaction conditions are adopted, and in the case of low temperature, The free fish oil raw material reacts to obtain a fish oil polyunsaturated fatty acid calcium product.
  • the overall process is simple and easy to operate, the reaction level is high, the process yield is high, and the product quality is good.
  • Comparing Comparative Example 2 the reaction was not carried out under the low temperature condition by the reaction of the conventional calcium oxide raw material, and the process temperature condition of 250 ° C was selected, and finally the fish oil polyunsaturated fatty acid calcium product was obtained. Due to the poor solubility of calcium oxide, the degree of reaction is low, and the free fish oil raw material is destroyed at high temperature. The final product of fish oil polyunsaturated fatty acid calcium is obviously low (a large part of raw materials or products are destroyed). The yield is also very low and the product quality is poor.
  • a calcium acetate/aqueous solution is obtained by selecting a water-soluble calcium acetate raw material dissolved in water, using a relatively mild process and reaction conditions, and at a low temperature, and being free.
  • the fish oil raw material reacts to obtain a fish oil polyunsaturated fatty acid calcium product.
  • the overall process is simple and easy to operate, the degree of reaction is very high, the process yield is above 93.4%, and the product quality is good.

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Abstract

本发明涉及一种多不饱和脂肪酸钙的制备方法，主要是通过将多不饱和脂肪酸原料与水溶性钙化物直接反应得到多不饱和脂肪酸钙盐。本发明的工艺过程较为简单，反应时间较短，反应收率较高，得到的多不饱和脂肪酸钙产品品质较好，同时产生较少的副产物和废水。工艺整体上环保和安全风险很小，非常适合于规模化生产。

Description

一种多不饱和脂肪酸钙的制备方法 技术领域
本发明涉及一种多不饱和脂肪酸钙的制备方法，特别是涉及各种形式的多不饱和脂肪酸原料制备多不饱和脂肪酸钙产品。主要描述创造性地利用水溶性钙化物直接与多不饱和脂肪酸原料反应得到多不饱和脂肪酸钙盐，工艺过程十分简单，反应温度较低，对多不饱和脂肪酸原料破坏较小，水溶性钙的应用大大促进钙化反应的程度，缩短反应时间，提高反应收率，最终得到的产品多不饱和脂肪酸品质较好。
背景技术
随着人们对健康以及健康饮食投入越来越多的关注，许多相关的产品得到了广泛的认同和接受，其中多不饱和脂肪酸类产品在市场上占有很重要的地位，无论是作为药品的原料，还是作为膳食添加剂，或者饲料添加剂等，均具有广阔的开发应用前景。
多不饱和脂肪酸是细胞膜的构成成分，是机体特别是婴幼儿期大脑发育等活动的重要物质基础，主要起到保持细胞膜流动性，促使胆固醇酯化，降低胆固醇和甘三酯，降低血液粘稠度，改善血液循环等生理功能，同时还具备改善人类思维和增强记忆力等作用，缺乏多不饱和脂肪酸则会导致较多的先天或后天疾病，但人体自身无法合成多不饱和脂肪酸(PUFA)，必须通过饮食等渠道进行摄取。
多不饱和脂肪酸(PUFA)种类繁多，主要包括ω-3多不饱和脂肪酸(PUFA)(ω-3PUFA)、ω-6多不饱和脂肪酸(PUFA)(ω-6PUFA)、ω-9多不饱和脂肪酸(PUFA)(ω-9PUFA)以及其他类共轭亚油酸等形式，如α-亚麻酸(ALA)、二十碳五烯酯(EPA)、二十二碳六烯酸(DHA)、二十二碳五烯酸(DPA)、亚油酸(LA)、共轭亚油酸(CLA)，γ-亚麻酸(GLA)、花生四烯酸(AA)等，其中尤以二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)为主要代表的ω-3多不饱和脂肪酸(ω-3PUFA)最为大众所熟知和接受，对人体和动物健康具备的改善和促进作用也最明显，部分多不饱和脂肪酸物质的分子结构式如下：
Figure PCTCN2015000686-appb-000001
Figure PCTCN2015000686-appb-000002
多不饱和脂肪酸主要来源于藻类提取物和水产动物油，其中一个重要来源为鱼油。
人体直接补充的多不饱和脂肪酸产品所使用的液态原料主要包括游离型多不饱和脂肪酸、乙酯型多不饱和脂肪酸或者甘油酯型多不饱和脂肪酸等，这些原料具备相关功能的同时也具有系列的缺陷，首先这些产品的形态为液态，而且具有一定的鱼腥味，对于部分人群具有一定的抗拒心理，可能不是被普遍大众所接受，也对其使用范围存在一定的局限性，其次某些产品在机体内吸收利用也不够充分等，生物利用率较低等等。
多不饱和脂肪酸钙产品一定程度上能够弥补上述不足，首先多不饱和脂肪酸钙产品除了不会破坏多不饱和脂肪酸相应功效外，还能作为一种优质钙源补充人体所需的钙营养，其次多不饱和脂肪酸钙产品以自由流动的粉末状态产品形式存在，相对拓宽了多不饱和脂肪酸的 应用范围，还有产品具有无异味、稳定性较好等优点，而且可能一定程度上能提高机体对多不饱和脂肪酸的生物利用率等。
现有制备多不饱和脂肪酸钙产品的技术主要包括使用甘油酯型多不饱和脂肪酸与氧化钙或氢氧化钙熔融直接进行反应得到多不饱和脂肪酸钙；或者游离型多不饱和脂肪酸与氧化钙或氢氧化钙熔融进行反应得到多不饱和脂肪酸钙；或者各种酯型多不饱和脂肪酸先皂化得到多不饱和脂肪酸钠，然后再进行钠与钙的离子交换得到多不饱和脂肪酸钙产品，上述工艺均具有一定的缺陷。
其中一类工艺直接使用氧化钙或氢氧化钙等原料熔融状态下与甘油酯型多不饱和脂肪酸或游离型多不饱和脂肪酸等进行钙化反应得到多不饱和脂肪酸钙产品，首先工艺温度均较高，达到200～300℃以上，在此温度下对多不饱和脂肪酸很容易造成氧化、分解或聚合等破坏作用；其次氧化钙或者氢氧化钙具有难溶性，在反应体系中基本不溶解，导致反应程度不高，反应时间较长，反应收率较低等缺点，最终得到的多不饱和脂肪酸钙产品品质较差。
另一类工艺先将包括甲酯型、乙酯型或甘油酯型的各型多不饱和脂肪酸与液碱进行皂化反应得到多不饱和脂肪酸钠或再酸化后得到游离型多不饱和脂肪酸，然后利用多不饱和脂肪酸钠或游离型多不饱和脂肪酸与各类钙化物反应得到多不饱和脂肪酸钙，各类钙化物包括氧化钙、氢氧化钙、乙酸钙、乳酸钙、氯化钙等，工艺路线较为复杂，其中工艺在第一步先进行的皂化反应时，由于加入大量液碱，在强碱条件下，多不饱和脂肪酸被大量破坏，导致得到的中间体和最终产品 颜色变深，产品品质变差；其次氧化钙和氢氧化钙基本不溶于水或各类有机溶剂或反应体系中的各类多不饱和脂肪酸，所以反应程度较小，收率较低等，工艺整体上包括皂化反应、酸洗/水洗、回收溶剂、钙化反应、过滤、干燥/粉碎等工序，工艺较为复杂，最终得到产品品质较差，收率较低，同时工艺会产生大量废水等。
在现有公开文献中，出现了系列相关多不饱和脂肪酸钙产品的制备方法，如
专利US5382678使用甘油酯型鱼油多不饱和脂肪酸与氧化钙或氢氧化钙直接进行钙化反应，反应温度达到250℃，虽然选用甘油酯型多不饱和脂肪酸(沸点较高，抗氧化性能略好)能够一定程度克服高温对原料带来的影响，但工艺反应还是不够充分，反应收率较低，最后得到的产品中甘油酯型鱼油含量大于10％，因此也导致产品较粘，无法形成自由流动的粉末状产品。
专利US60724644、US60775664提到氧化钙或氢氧化钙与游离多不饱和脂肪酸或者各种酯类多不饱和脂肪酸直接进行钙化反应的工艺，反应温度较高，反应程度较低，产品品质不够好；或者采取各种酯型多不饱和脂肪酸先皂化得到多不饱和脂肪酸钠，再进行离子交换得到多不饱和脂肪酸钙工艺，工艺路线较长，工艺产生较多废水，反应收率不高。
专利US09675745涉及先将多不饱和脂肪酸加热，再缓慢加入氧化钙的水合物，最后将水蒸干等程序，反应在特殊环境下进行，工艺略显复杂，由于氧化钙不溶于水，所以反应时间较长，反应程度较低， 得到的产品品质较低等。
专利CN1270160先皂化再酸化得到游离脂肪酸，纯化后的游离脂肪酸再与氢氧化钙反应，得到多不饱和脂肪酸钙产品，由于氢氧化钙基本不溶解，所以反应时间较长，反应程度较低，工艺收率不高。
专利CN102417444采用脂肪酸直接与氢氧化钙或氧化钙反应，得到脂肪酸钙，其中工艺采用连续化模式进行，通过不断析出脂肪酸钙产品的模式提高反应收率，最后得到工艺收率约80～85％，但工艺产生大量废水，得到的产品纯度不高。
专利CN1752064、CN1685921采用先将脂肪酸与液碱进行皂化反应，得到脂肪酸钠，再与氯化钙进行离子交换得到脂肪酸钙产品，工艺路线较为复杂，工艺的产品收率略低，约80％，同时产生大量含氯废水，对环境的污染较大。
总体上现有公开文献中所表述的多不饱和脂肪酸钙产品制备方法中，大部分主要存在以下问题之一或全部：1)使用氧化钙或氢氧化钙作原料，存在氧化钙或氢氧化钙无法溶解的问题导致反应程度较小，反应时间较长，收率较低等问题；2)使用高温条件或液碱环境等，导致原料多不饱和脂肪酸被大量破坏，得到的产品品质较差，等等。
一般来说制备多不饱和脂肪酸钙产品的主要原料为多不饱和脂肪酸和钙化物，多不饱和脂肪酸原料存在包括游离型多不饱和脂肪酸和各种酯类多不饱和脂肪酸，由于含有较多的双键基团，所以多不饱和脂肪酸物质都不够稳定，其中游离型多不饱和脂肪酸沸点较低，抗 氧化性最小，甲酯型或乙酯型多不饱和脂肪酸次之，甘油酯型多不饱和脂肪酸沸点最高，也相对较稳定，但在温度大于260℃时，也容易发生聚合反应形成聚合物，同时多不饱和脂肪酸对于强酸或者强碱环境比较敏感，容易发生物质结构破坏，外观表现为颜色变深，物质状态固化等。
对于钙化物的选择都有一定局限性，其中最常用的是氧化钙或者氢氧化钙，具有一定的碱性，理论上最容易与多不饱和脂肪酸反应，但由于氧化钙或者氢氧化钙物质本身的物理难溶性，多不饱和脂肪酸与钙化物不能充分接触(液相与固相的非均相反应)，反应程度很小，甚至生成的多不饱和脂肪酸钙产物由于也具有难溶性，将原料钙化物包裹，从而阻碍反应的继续进行，最终导致反应时间很长，得到的产品含量较低等。
另外水溶性钙化物选择相对较少，主要原因是相应工艺均选择先将多不饱和脂肪酸进行皂化反应得到多不饱和脂肪酸钠，在此过程中需要使用大量液碱和水，最终造成多不饱和脂肪酸原料被破坏，产品品质下降，而且产生大量废水等。
发明内容
为了避免上述缺陷，本发明创造性采用水溶性钙化物原料的水溶液直接与多不饱和脂肪酸反应得到多不饱和脂肪酸钙，由于得到的多不饱和脂肪酸钙在反应体系中不溶，反应过程中不断的析出，该反应得以较好的进行，反应程度较高，而且对于多不饱和脂肪酸原料包括 游离型多不饱和脂肪酸或者各种酯型多不饱和脂肪酸等，均具有较好的反应活性和较高的反应程度。
本发明涉及一种多不饱和脂肪酸钙的制备方法，特别是涉及各种形式的多不饱和脂肪酸鱼油原料制备多不饱和脂肪酸钙产品。
本发明所述一种多不饱和脂肪酸钙的制备方法包括以下步骤：
1)溶解钙化物原料：取适当摩尔当量的水溶性钙化物原料，溶解于一定量的水中，得到钙化物水溶液；
2)投料/反应：投料多不饱和脂肪酸原料，搅拌状态下，加入钙化物水溶液，保持一定反应条件，反应一段时间，反应完成。
3)处理得到产品：反应毕，直接过滤反应液得到多不饱和脂肪酸钙固体，再经过干燥、粉碎，即得到多不饱和脂肪酸钙产品。
通过相关质量检测，产品品质良好，收率较高。
本发明中描述的“一定反应条件”比较温和，反应温度为-20～100℃，其中优选20～100℃。而反应时间则为0.5～10hr，优选0.5～3hr。
本发明中的多不饱和脂肪酸原料以及多不饱和脂肪酸钙产品中的脂肪酸摩尔量采用一定的检测方法进行：将待测样品完全皂化后再酸化得到完全的游离型多不饱和脂肪酸样品，滴定其酸值，根据其酸值计算其平均摩尔质量，从而能够得到样品的摩尔量。
检测步骤：取约1.0g样品Wg，放入广口瓶，加入20ml乙醇和2～3滴酚酞指示剂，摇匀，使用约0.1mol/L氢氧化钾标准液(C mol/L)进行滴定，消耗标准液V ml，得到样品酸值为(56*C*V)/W(单 位为mgKOH/g)，样品的平均摩尔质量为(1000*W)/(C*V)，最终样品中的脂肪酸摩尔量为质量与平均摩尔质量的比值。
本发明中对废水和副产物的处理包括以下措施，过滤反应液过程中得到的滤液主要包含水、微量有机酸和醇类物质等，通过常压蒸馏或减压蒸馏等方式将其中有机物分离出来，有机物可以加以利用，废水可达到排放标准直接排放，不会对环境等产生污染和危害等。
由于工艺反应具有良好的溶解和反应活性，本发明中对多不饱和脂肪酸原料的选择范围较为广泛，基本包括各种形式的多不饱和脂肪酸或其混合物，如游离型多不饱和脂肪酸、甲酯型多不饱和脂肪酸、乙酯型多不饱和脂肪酸、甘油酯类多不饱和脂肪酸等等。具体的包括结构式为
Figure PCTCN2015000686-appb-000003
的多不饱和脂肪酸(其中R1为C6～C40的烯基，R2为H或C1～C4的烷基)和结构式为
Figure PCTCN2015000686-appb-000004
的多不饱和脂肪酸(其中R3、R4、R5为羟基或C1～C4羧酸基或C6～C40的多不饱和脂肪酸基，R3、R4、R5不能全部为羟基或C1～C4羧酸基，R3、R4、R5可以相同也可以不同)等其中一种或几种的混合物。
本发明描述中“多不饱和脂肪酸原料”指各种含量的鱼油(直接提取的ω-3多不饱和脂肪酸)、藻油(发酵来源的ω-3多不饱和脂肪酸)、亚油酸、共轭亚油酸、亚麻酸、花生四烯酸等其中一种或多种多不饱和脂肪酸混合物，其中多不饱和脂肪酸总含量为10～100重量％。
而且工艺对多不饱和脂肪酸原料来源基本没有局限性，对包括藻 类提取物和水产动物油(如鱼油)等来源的多不饱和脂肪酸原料均具有良好的反应活性，其中多不饱和脂肪酸原料中多不饱和脂肪酸含量(10～100％)也不会对工艺反应以及收率有较大的影响，基本能得到较高收率和较好品质的多不饱和脂肪酸钙产品。
本发明中所使用的钙化物为水溶性钙化物，投料模式采用水溶性钙化物的水溶液形式，这样能够大大促进本工艺钙化反应的反应程度，提高多不饱和脂肪酸钙产品的品质，通过降低工艺条件达到工艺的高效、节能、安全、环保等目的，其中“水溶性钙化物原料”包括乙酸钙、乳酸钙、氯化钙、硝酸钙、柠檬酸钙、富马酸钙等其中一种或几种的混合物。
工艺中的投料比情况如下：相对于多不饱和脂肪酸摩尔量，水溶性钙化物原料摩尔当量为0.1～0.9，其中优选为0.5～0.7；而溶解水溶性钙化物的水量为水溶性钙化物重量的1～40倍。其中当多不饱和脂肪酸原料与水溶性钙化物原料按照反应当量或者水溶性钙物质过量时，钙化反应的收率较高，过量的钙化物溶解在水中不会对产品含量等品质造成影响，而当时多不饱和脂肪酸原料过量时，过量的多不饱和脂肪酸能够通过后期回收以及套用间接达到提高收率减少损耗的目的。另外溶解水溶性钙化物的水量主要取决于相应钙化物在水中的溶解度，基本为钙化物完全溶解时所需的水或过量的水，其中过量的水对工艺反应基本没有影响。
本发明创造性地利用水溶性钙化物直接与多不饱和脂肪酸原料反应得到多不饱和脂肪酸钙盐，工艺过程十分简单，主要步骤分为溶 解钙化物、钙化反应、过滤、干燥/粉碎等步骤，工艺反应温度较低，对多不饱和脂肪酸原料破坏较小，水溶性钙的应用大大促进钙化反应的程度，缩短反应时间，提高反应收率，最终得到的产品多不饱和脂肪酸品质较好。
本发明工艺过程由于采用钙化物/水溶液，在反应过程中与多不饱和脂肪酸原料充分接触和反应，所以大大促进了钙化反应的反应程度，反应时间较短，反应收率较高；避免使用强碱或强酸环境，同时反应温度较低，反应条件较为温和，所以对原料多不饱和脂肪酸基本没有破坏，最终得到的工艺产品品质较好。
而且工艺产生的废水和副产物较少，废水主要来源于溶解钙化物所需的水，副产物为有机酸、醇类等物质，反应完成后将过滤得到的滤液通过简单回收等措施分离出副产物，副产物可以加以利用，废水则能达到直接排放标准直接排放，不会对环境造成污染。
相比其他工艺，本发明的工艺较为简单和易于操作，反应活性较好，反应时间较短，反应程度较高，反应条件较为温和，得到的产品品质较好，收率较高，工艺稳定性较好。工艺总体上安全性和环保性较好，非常适合大规模工业化生产。
具体实施方式
下面用实施例来进一步说明本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明。
实施例1
取0.5mol乙酸钙(79.9g)，加入200g水，使其完全溶解，得到乙酸钙/水溶液，在反应瓶中加入游离型鱼油原料1.0mol(EPA34.7％，DHA23.6％，总游离型多不饱和脂肪酸含量为63.2％)，搅拌，加热至40℃，加入钙化物的水溶液，开始反应，反应2.0小时，反应毕，过滤得到滤饼固体，再经过干燥，粉碎等处理程序，得到自由流动的鱼油多不饱和脂肪酸钙产品。
过滤得到的滤液经过简单蒸馏或减压蒸馏，得到少量可利用有机物和处理废水，处理废水达到排放标准，直接排放。
鱼油多不饱和脂肪酸钙产品经过检测，鱼油多不饱和脂肪酸钙产品的摩尔量为0.95mol，总多不饱和脂肪酸钙含量为62.9％，其中EPA33.9％，DHA 23.2％，总游离型多不饱和脂肪酸含量为0.1％，收率94.5％，产品颜色为白色，品质较好。
比较实施例2
在反应瓶中加入游离型鱼油原料1.0mol(EPA34.7％，DHA 23.6％，总游离型多不饱和脂肪酸含量为63.2％)，0.5mol氧化钙，搅拌，加热至250℃，反应2.0小时，反应毕，冷却得到的固体再经过干燥，粉碎等处理程序，得到鱼油多不饱和脂肪酸钙产品，产品黏性较大，颜色较深。
鱼油多不饱和脂肪酸钙产品经过检测，鱼油多不饱和脂肪酸钙产品的摩尔量为0.63mol，总多不饱和脂肪酸钙含量为10.7％，其中 EPA11.2％，DHA 6.1％，总游离型多不饱和脂肪酸含量为12.3％，收率10.7％，产品品质较差。
通过比较可以看出，实施例1中采用本发明工艺，通过选择水溶性乙酸钙原料溶于水得到乙酸钙/水溶液，采用比较温和的工艺过程和反应条件，在温度较低的情况下，与游离型鱼油原料反应得到鱼油多不饱和脂肪酸钙产品。整体工艺简单和易于操作，反应程度很高，工艺收率较高，产品品质较好。
对比比较实施例2，通过常规的氧化钙原料反应，反应在低温条件下无法进行，选取250℃工艺温度条件，反应最后得到鱼油多不饱和脂肪酸钙产品。由于氧化钙溶解性很差，反应的程度较低，同时游离型鱼油原料在高温下破坏较严重，最终得到的鱼油多不饱和脂肪酸钙产品含量明显偏低(较大一部分原料或产品被破坏)，收率也很低，产品品质较差。
实施例3～10
下表中列出了实施例3～10的实施对象和相关参数。
Figure PCTCN2015000686-appb-000005
通过实施例3～15看出，采用本发明工艺，通过选择水溶性乙酸钙原料溶于水得到乙酸钙/水溶液，采用比较温和的工艺过程和反应条件，在温度较低的情况下，与游离型鱼油原料反应得到鱼油多不饱和脂肪酸钙产品。整体工艺简单和易于操作，反应程度很高，工艺收率在93.4％以上，产品品质较好。
本发明通过上面的实施例进行举例说明，但是，应当理解，本发明并不限于这里所描述的特殊实例和实施方案。在这里包含这些特殊实例和实施方案的目的在于帮助本领域中的技术人员实践本发明。任何本领域中的技术人员很容易在不脱离本发明精神和范围的情况下进行进一步的改进和完善，因此本发明只受到本发明权利要求的内容和范围的限制，其意图涵盖所有包括在由附录权利要求所限定的本发明精神和范围内的备选方案和等同方案。

Claims (10)

  1. 一种多不饱和脂肪酸钙的制备方法，所述制备方法包括以下步骤：
    (i)将一种水溶性钙化物原料或几种水溶性钙化物原料混合物，溶解于适量水中以得到钙化物水溶液；
    (ii)在温度-20～100℃下，在多不饱和脂肪酸原料中加入所述钙化物水溶液，开始反应；多不饱和脂肪酸原料包括下述一种或几种物质混合物：结构式为
    Figure PCTCN2015000686-appb-100001
    的多不饱和脂肪酸，其中R1为C6～C40的烯基，R2为H或C1～C4的烷基；和结构式为
    Figure PCTCN2015000686-appb-100002
    的多不饱和脂肪酸，其中R3、R4、R5表示羟基或C1～C4羧酸基或含1个或多个双键的具有C6～C40的羧酸基，R3、R4、R5为相同或不同，R3、R4、R5不能全部为羟基或C1～C4羧酸基；
    (iii)反应完毕后，过滤得到多不饱和脂肪酸钙固体；和
    (iv)过滤得到多不饱和脂肪酸钙固体，经过干燥、粉碎，得到自由流动的多不饱和脂肪酸钙产品。
  2. 根据权利要求1所述的方法，其中，所述多不饱和脂肪酸原料包括游离型多不饱和脂肪酸、甲酯型多不饱和脂肪酸、乙酯型多不饱和脂肪酸、甘油酯型多不饱和脂肪酸等其中一种或几种的混合物。
  3. 根据权利要求2所述的方法，其中，所述多不饱和脂肪酸原料包括鱼油、藻油、亚油酸、共轭亚油酸、亚麻酸、花生四烯酸等其 中一种或多种多不饱和脂肪酸混合物。
  4. 根据权利要求1～3任一所述的方法，其中，所述多不饱和脂肪酸原料中多不饱和脂肪酸含量为10～100重量％。
  5. 根据权利要求1所述的方法，其中，所述水溶性钙化物原料选自由乙酸钙、乳酸钙、氯化钙、硝酸钙、柠檬酸钙、富马酸钙组成的组。
  6. 根据权利要求5所述的方法，其中，相对于多不饱和脂肪酸摩尔当量，所述水溶性钙化物原料摩尔量为0.1～0.9。
  7. 根据权利要求6所述的方法，其中，相对于多不饱和脂肪酸摩尔当量，所述水溶性钙化物原料摩尔量为0.5～0.7。
  8. 根据权利要求6所述的方法，其中，相对于水溶性钙化物原料的重量当量，溶解水溶性钙化物原料的水重量为1～40。
  9. 根据权利要求1～8任一所述的方法，其中，反应温度为-20～100℃，优选为反应温度为20～100℃。
  10. 根据权利要求9所述的方法，其中，反应时间为0.5～10hr，优选为反应时间为0.5～3hr。
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