WO2020078408A1 - 一种酒石酸氢胆碱及其制备方法 - Google Patents

一种酒石酸氢胆碱及其制备方法 Download PDF

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WO2020078408A1
WO2020078408A1 PCT/CN2019/111617 CN2019111617W WO2020078408A1 WO 2020078408 A1 WO2020078408 A1 WO 2020078408A1 CN 2019111617 W CN2019111617 W CN 2019111617W WO 2020078408 A1 WO2020078408 A1 WO 2020078408A1
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tartrate
trimethylamine
choline
tartaric acid
ethylene oxide
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PCT/CN2019/111617
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French (fr)
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王庆友
王家梁
李民
赵士章
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济南蓬勃生物技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid

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  • the invention relates to a choline and a preparation method thereof, in particular to a choline bitartrate and a preparation method thereof, and belongs to the technical field of chemical synthesis.
  • Choline C 5 H 15 NO 2
  • Streker in 1894, and was officially named Choline in 1962. It is a component of all biofilms and a precursor of acetylcholine in cholinergic neurons. It plays an important role in the process of nerve conduction and membrane growth of organisms, and is widely used in the fields of food nutrition enhancers, medicines, and feed additives.
  • Choline used as a food nutrition enhancer can promote brain development and improve memory capacity, ensure information transmission, promote fat metabolism, promote methyl metabolism in the body, and reduce serum cholesterol. It can be used in the field of medicine to treat fatty liver and liver cirrhosis. It can also be used as a drug intermediate in the nervous system. It is an important part of lecithin in biological cells. Applied to feed additives can maintain the low molecular organic compounds necessary for the physiological functions of animals, regulate the metabolism and conversion of fat, prevent the degeneration of liver and kidney and other tissues caused by fat deposition, promote the regeneration of amino acids, and improve amino acids, especially methionine Utilization rate.
  • choline salts are mainly choline chloride and choline bitartrate (also known as choline tartrate).
  • Choline chloride is mainly produced by the reaction of trimethylamine hydrochloride and ethylene oxide after concentration and purification. Therefore, because its catalyst is not easy to separate and contains highly reducing chloride ions, it must be purified before it can be used as medicine and feed, which affects the application of choline chloride in these two fields.
  • Choline bitartrate is a relatively stable bibasic acid choline salt. As a vitamin product, it is widely used in medicines, health products and food nutrition additives.
  • the preparation methods of choline bitartrate mainly include ion resin exchange method, choline chloride method and ethylene oxide method.
  • the cost of ion resin exchange method is higher and the safety of choline chloride method has hidden dangers.
  • Choline tartrate is widely used in the preparation of ethylene oxide method, from a high concentration of ethylene oxide aqueous solution, at room temperature with trimethylamine to obtain choline, and then dissolved in methanol, add molar ratio of tartaric acid Neutralized, refined by concentration, drying, acetone recrystallization, etc.
  • the choline produced by the reaction of trimethylamine and ethylene oxide is an unstable organic strong base, which is very susceptible to side reactions to form aldehyde products and other polymers; and in a strong alkaline environment, subsequent addition
  • the ethylene oxide in large quantities produces ethylene glycol and ethylene oxide polymers.
  • the components in the system are complex, resulting in a low yield, and the target product, choline bitartrate, cannot be crystallized out of the aqueous solution with many impurities. Therefore, only the organic solvent such as methanol can be used to obtain the target product with higher purity.
  • GB 2760-2014 has banned the use of methanol as a solvent for the production of food additives.
  • choline is used as a nutrient fortifier.
  • the source of the compound is choline chloride and choline bitartrate.
  • the prior art production process of choline bitartrate The use of organic solvents such as methanol cannot be avoided, so the relevant national standards for choline bitartrate have been unable to be formulated.
  • the emission of volatile organic compounds during the production process causes environmental pollution and reduces the safety of the production process.
  • There is methanol residue in the product which greatly limits the production and application of the product.
  • the present invention provides a raw material is easily available, the reaction is stable, green and environmentally friendly, the yield is high, and the production Choline tartrate without adding toxic and harmful substances such as methanol during the process and its preparation method.
  • a choline bitartrate characterized in that the choline bitartrate is one of L + choline bitartrate, DL choline bitartrate, or D-choline bitartrate. Any kind.
  • a preparation method of choline bitartrate includes the following steps:
  • the molar ratio of tartaric acid and trimethylamine in step 1) is 0.8-1.2: 2;
  • the trimethylamine in step 1) is a trimethylamine aqueous solution with a concentration of 30-40% or 99% liquefied trimethylamine;
  • the temperature reduction in step 1) is cooling water cooling or ice water circulation cooling, and the temperature is reduced to 30 ° C to 40 ° C;
  • the molar ratio of trimethylamine tartrate salt and ethylene oxide in step 2) is 1: 2;
  • the ethylene oxide mentioned in step 2) is a liquefied ethylene oxide with a concentration of 99%;
  • the molar ratio of dicholine tartrate to tartaric acid in step 3) is 0.8-1.2: 1, wherein the total amount of tartaric acid added in step 1) and step 3) and the trimethylamine added in step 1)
  • the molar ratio of ethylene oxide added in step 2) is 1: 1: 1 to 1.08.
  • step 3 when the temperature is 40 ° C to 70 ° C, tartaric acid is added to the dicholine tartrate obtained in step 2);
  • the reduced-pressure heating evaporation concentration in step 4) is 70 ° C to 95 ° C;
  • step 4 heating and evaporation under reduced pressure are concentrated to an aqueous solution concentration of 50-95%, and then the temperature is reduced and cooled to 40 ° C to -20 ° C.
  • reaction process is:
  • Trimethylamine tartrate salt reacts with ethylene oxide to form dicholine tartrate:
  • the preparation method of choline bitartrate of the present invention does not use toxic and harmful substances such as methanol in the production process, which eliminates the emission of volatile organic compounds (VOC) during the production process, and effectively avoids the toxic and harmful substances such as methanol in the product. Substitute.
  • the preparation method of choline bitartrate of the present invention does not use methanol in the production process, and the reaction process avoids the strong alkaline environment of the system, effectively reducing the probability of side reactions of ethylene oxide, and the reaction is stable and yield Higher than 98.1%.
  • the preparation method of choline tartrate of the present invention is easy to obtain raw materials, economical, safe, and environmentally friendly.
  • the obtained choline tartrate product has a uniform appearance and good stability, and is added to food nutrition enhancers, medicine, and feed
  • the field has wide application value.
  • Example 1 is an X-ray diffraction (XRD) pattern of L + choline tartrate prepared in Example 1 of the present invention
  • FIG. 2 is an X-ray diffraction (XRD) pattern of DL choline tartrate prepared in Example 2 of the present invention.
  • the obtained sample is 124.1kg (theoretical calculation should get 126.5kg), the yield is 98.1%, and the purity of the inspection is 99.8%. All other indicators meet the standards of food nutrition enhancers, medicines, and feed additives.
  • the specific test results are shown in Table 1. .
  • the obtained sample is 501.5kg (theoretical calculation should obtain 506kg), the yield is 99.1%, and the purity of the inspection is 98.8%. All other indicators meet the standards of food nutrition enhancers, medicines, and feed additives.
  • the specific test results are shown in Table 3.
  • the actual measurement data sent to prove that the preparation method of adding choline bitartrate of the present invention has high yield and high purity, does not contain methanol, and all other indexes meet the standards of food nutrition fortifier, medicine and feed additives.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种酒石酸氢胆碱及其制备方法，属于化工合成技术领域。先用摩尔比0.8～1.2:2的酒石酸和三甲胺反应生成酒石酸三甲胺盐，然后按照酒石酸三甲胺盐和环氧乙烷的摩尔比为1:2的比例向酒石酸三甲胺盐中加入环氧乙烷反应生成酒石酸二胆碱，再按照酒石酸二胆碱和酒石酸的摩尔比为1:0.8～1.2的比例向酒石酸二胆碱加入酒石酸，最后经浓缩、结晶干燥制得白色或无色酒石酸氢胆碱成品。生产过程中不使用甲醇，避免了生产过程中挥发性有机物(VOC)的排放，产品中不含有甲醇等有毒有害物质。方法原料易得、反应稳定、绿色环保、产率高于98.1％，产品形貌均匀，稳定性好，在食品营养强化剂、医药、饲料添加剂领域具有广泛的应用价值。

Description

一种酒石酸氢胆碱及其制备方法 技术领域
本发明涉及一种胆碱及其制备方法，具体涉及一种酒石酸氢胆碱及其制备方法，属于化工合成技术领域。
背景技术
胆碱(C 5H 15NO 2)是一种不稳定的强碱，首次由Streker在1894年从猪胆汁中分离出来，1962年被正式命名为胆碱。是所有生物膜的组成成分和胆碱能神经元中的乙酰胆碱的前体。在生物体神经传导和膜生长过程中起重要作用，广泛应用于食品营养强化剂、医药、饲料添加剂领域。
胆碱应用于食品营养强化剂可以促进脑发育和提高记忆能力、保证信息传递、促进脂肪代谢、促进体内转甲基代谢、降低血清胆固醇。应用于医药领域可以治疗脂肪肝及肝硬化等，亦可作为神经系统药物中间体，是生物细胞中卵磷脂的重要组成部分。应用于饲料添加剂可维持动物体内生理机能所必需的低分子有机化合物，调节脂肪的代谢和转化，预防由脂肪沉积引起的肝脏和肾脏及其他组织变性，促进氨基酸的再生成，提高氨基酸尤其是蛋氨酸的利用率。
目前应用广泛的胆碱盐主要有氯化胆碱和酒石酸氢胆碱(又称重酒石酸胆碱)，氯化胆碱主要由三甲胺盐酸盐与环氧乙烷反应，经浓缩、精制制得，因其催化剂不易分离并且含有还原性比较强的氯离子，必须经过提纯才能作为医药和饲料使用，影响了氯化胆碱在这两个领域的应用。酒石酸氢胆碱，是一种相对稳定的二元酸胆碱盐，作为维生素类产品，广泛地应用于药品、保健品以及食品营养添加剂。
目前，酒石酸氢胆碱制备方法主要有离子树脂交换法、氯化胆碱法和环氧乙烷法，离子树脂交换法成本较高、氯化胆碱法安全性存在隐患，因而现有技术的酒石酸氢胆碱制备应用广泛的是环氧乙烷法，由高浓度的环氧乙烷水溶液，在常温下与三甲胺作用而得胆碱，然后使之溶于甲醇中，按摩尔比加入酒石酸中和，再经浓缩、干燥、丙酮重结晶等精制而成。在此方法中，三甲胺和环氧乙烷反应生成的胆碱为不稳定的有机强碱，自身极易发生副反应生成醛类产物及其他聚合物；且在强碱性环境下，后续加入的环氧乙烷大量生成乙二醇及环氧乙烷聚合物。体系中成份复杂，导致产率很低，且目标产品酒石酸氢胆碱无法在杂质很多的水溶液中结晶析出。故只能用甲醇等有机溶剂才能得到纯度较高的目标产物。GB 2760-2014已禁止将甲醇作为食品添加剂生产溶剂使用，GB 14880-2012中胆碱作为营养强化剂其化合物来源是氯化胆碱和酒石酸氢胆碱，现有技术酒石酸氢胆碱的生产工 艺无法避免甲醇等有机溶剂的使用，所以相关酒石酸氢胆碱的国家标准一直无法制定。生产过程中有挥发性有机物的排放，造成环境污染，也降低了生产过程的安全性。产品中有甲醇残留，在很大程度上限制了产品的生产和应用。
为了保障人民食品药品安全和质量，一种原料易得、反应稳定、绿色环保、产率高，并且生产过程中不添加甲醇等有毒有害物质的酒石酸氢胆碱及其制备方法亟待开发出来。
发明内容
为了解决现有技术的酒石酸氢胆碱制备方法产率低以及产品中残留有甲醇等有毒有害物质的缺陷，本发明提供了一种原料易得、反应稳定、绿色环保、产率高，并且生产过程中不添加甲醇等有毒有害物质的酒石酸氢胆碱及其制备方法。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一种酒石酸氢胆碱，其特征在于：所述的酒石酸氢胆碱为L+酒石酸氢胆碱、DL酒石酸氢胆碱或D-酒石酸氢胆碱三种不同比旋光度的酒石酸氢胆碱中的任意一种。
一种酒石酸氢胆碱的制备方法，包括以下步骤：
1)、将酒石酸加入水中搅拌混匀，加入三甲胺，边加边搅拌，降温至20℃～50℃，保温反应2～6h，得到酒石酸三甲胺盐；
2)、向上述步骤制得的酒石酸三甲胺盐中加入环氧乙烷，温度30℃～70℃，控制Ph＝8～9，生成酒石酸二胆碱；
3)、向上述步骤制得的酒石酸二胆碱中加酒石酸，生成酒石酸氢胆碱，控制温度40℃～70℃，过滤；
4)、浓缩结晶：将上述步骤制得的滤液减压加热蒸发浓缩，然后降温冷却，即有大量白色或无色酒石酸氢胆碱晶体析出，经离心、干燥后得酒石酸氢胆碱成品。
优选的，步骤1)中所述的酒石酸和三甲胺的摩尔比为0.8～1.2:2；
优选的，步骤1)中所述的三甲胺为浓度30～40％的三甲胺水溶液或99％液化三甲胺；
优选的，步骤1)中所述的降温为冷却水降温或冰水循环冷却降温，降温至30℃～40℃；
优选的，步骤2)中所述的酒石酸三甲胺盐和环氧乙烷的摩尔比为1:2；
优选的，步骤2)中所述的环氧乙烷为浓度99％的液化环氧乙烷；
优选的，步骤3)中所述的酒石酸二胆碱和酒石酸的摩尔比为0.8～1.2:1，其中步骤1)和步骤3)中所添加的酒石酸总量与步骤1)中添加的三甲胺和步骤2)中添加的环氧乙烷的摩尔比为1:1:1～1.08。
优选的，步骤3)中当温度40℃～70℃时向步骤2)制得的酒石酸二胆碱中加入酒石酸；
优选的，步骤4)中所述的减压加热蒸发浓缩温度为70℃～95℃；
优选的，步骤4)中减压加热蒸发浓缩到水溶液浓度50～95％后降温冷却至40℃～-20℃。
上述方法中，反应过程为：
(1)、酒石酸和三甲胺反应生成酒石酸三甲胺盐：
Figure PCTCN2019111617-appb-000001
(2)、酒石酸三甲胺盐和环氧乙烷反应生成酒石酸二胆碱：
Figure PCTCN2019111617-appb-000002
(3)、酒石酸二胆碱和酒石酸反应生成酒石酸氢胆碱：
Figure PCTCN2019111617-appb-000003
本发明的有益技术效果：
(1)本发明的酒石酸氢胆碱的制备方法生产过程中不使用甲醇等有毒有害物质，杜绝了生产过程中挥发性有机物(VOC)的排放，同时有效避免了产品中甲醇等有毒有害物 质的代入。
(2)本发明的酒石酸氢胆碱的制备方法生产过程中不使用甲醇，且反应过程避免了体系的强碱性环境，有效减少了环氧乙烷发生副反应的概率，反应稳定、产率高于98.1％。
(3)本发明的酒石酸氢胆碱的制备方法原料易得、经济安全、绿色环保，所制得的酒石酸氢胆碱产品形貌均匀，稳定性好，在食品营养强化剂、医药、饲料添加领域领域具有广泛的应用价值。
附图说明
图1为本发明实施例1制备的L+酒石酸氢胆碱的X射线衍射(XRD)图谱；
图2为本发明实施例2制备的DL酒石酸氢胆碱的X射线衍射(XRD)图谱。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围，具体实施方式不限制本发明。
实施例1：一种L+酒石酸氢胆碱的制备
往反应釜中加入水85kg，然后加入L+酒石酸30kg，L+酒石酸完全溶解，通入29.5kg纯度为99％的液化三甲胺，边加边搅拌，冷却水降温至30℃，保温反应，反应2h，得到L+酒石酸三甲胺盐。继续往反应釜中加入22kg环氧乙烷，控制PH在8～9，温度50℃，边加边搅拌，生成L+酒石酸二胆碱。再向应釜中加入45kg L+酒石酸，生成L+酒石酸氢胆碱；抽滤，将滤液减压加热蒸发浓缩至浓度85％，然后降温冷却至室温，即有大量无色L+酒石酸氢胆碱晶体析出，经离心、干燥后得L+酒石酸氢胆碱成品。
得样品124.1kg(理论计算应该得到126.5kg)，收率为98.1％，送检纯度为99.8％，其它各项指标均满足食品营养强化剂、医药、饲料添加剂的标准，具体检测结果见表1。
表1实施例1L+酒石酸氢胆碱检测结果
Figure PCTCN2019111617-appb-000004
实施例2：一种DL酒石酸氢胆碱的制备
往反应釜中加入去离子水150kg，然后加入DL酒石酸70kg，DL酒石酸不能完全溶解，通入59kg纯度为99％液化三甲胺，边加边搅拌，冷却水降温至30℃，保温反应，反应2h，得到DL酒石酸三甲胺盐。继续往反应釜中加入44kg环氧乙烷，控制PH在8～9，温度50℃，边加边搅拌，生成DL酒石酸二胆碱。再向应釜中加入80kgDL酒石酸，生成DL酒石酸氢胆碱；抽滤，将滤液减压加热蒸发浓缩至溶液浓度90％，然后降温冷却至室温，即有大量白色DL酒石酸氢胆碱晶体析出，经离心、干燥后得DL酒石酸氢胆碱成品。
得样品250.2kg(理论计算应该得到253.0kg)，收率为98.9％，送检纯度为99.3％，其它各项指标均满足食品营养强化剂、医药、饲料添加剂的标准，具体检测结果见表2。
表2实施例2DL酒石酸氢胆碱检测结果
Figure PCTCN2019111617-appb-000005
实施例3：一种DL酒石酸氢胆碱的制备
往反应釜中加入水340kg，然后加入DL酒石酸150kg，DL酒石酸不能完全溶解，通入 118kg纯度为99％的三甲胺水溶液，边加边搅拌，冷却水降温至40℃，保温反应，反应6h，得到DL酒石酸三甲胺盐。继续往反应釜中加入88kg环氧乙烷，控制PH在8～9，温度55℃，边加边搅拌，生成DL酒石酸二胆碱。再向应釜中加入150kg DL酒石酸，生成DL酒石酸氢胆碱；抽滤，将滤液减压加热蒸发浓缩至溶液浓度50％，然后降温冷却至5℃，即有大量无色DL酒石酸氢胆碱晶体析出，经离心、干燥后得DL酒石酸氢胆碱成品。
得样品501.5kg(理论计算应该得到506kg)，收率为99.1％，送检纯度为98.8％，其它各项指标均满足食品营养强化剂、医药、饲料添加剂的标准，具体检测结果见表3。
表3实施例3DL酒石酸氢胆碱检测结果
Figure PCTCN2019111617-appb-000006
实施例4：一种D-酒石酸氢胆碱的制备
往反应釜中加入去离子水170kg，然后加入D-酒石酸60kg，D-酒石酸完全溶解，通入59kg纯度为99％的液化三甲胺，边加边搅拌，冷却水降温至30℃，保温反应，反应2h，得到D-酒石酸三甲胺盐。继续往反应釜中加入44kg环氧乙烷，控制PH在8～9，温度55℃，边加边搅拌，生成D-酒石酸二胆碱。再向应釜中加入90kg D-酒石酸，生成D-酒石酸氢胆碱；抽滤，将滤液减压加热蒸发浓缩至溶液浓度70％，然后降温冷却至-5℃，即有大量无色D-酒石酸氢胆碱晶体析出，经离心、干燥后得D-酒石酸氢胆碱成品。
得样品251.4kg(理论计算应该得到253.0kg)，收率为99.4％，送检纯度为98.2％，其它各项指标均满足食品营养强化剂、医药、饲料添加剂的标准，具体检测结果见表4。
表4实施例4D-酒石酸氢胆碱检测结果
Figure PCTCN2019111617-appb-000007
送检实测数据证明添加本发明的酒石酸氢胆碱的制备方法产率高纯度高，不含甲醇，并且其它各项指标均满足食品营养强化剂、医药、饲料添加剂的标准。
需要指出的是，上述较佳实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种酒石酸氢胆碱，其特征在于：所述的酒石酸氢胆碱为L+酒石酸氢胆碱、DL酒石酸氢胆碱或D-酒石酸氢胆碱三种不同比旋光度的酒石酸氢胆碱中的任意一种。
  2. 根据权利要求1的一种酒石酸氢胆碱的制备方法，其特征在于包括以下步骤：
    1)、将酒石酸加入水中搅拌混匀，加入三甲胺，边加边搅拌，降温至20℃～50℃，反应2～6h，得到酒石酸三甲胺盐；
    2)、向上述步骤制得的酒石酸三甲胺盐中加入环氧乙烷，温度30℃～70℃，控制Ph＝8～9，生成酒石酸二胆碱；
    3)、向上述步骤制得的酒石酸二胆碱中加入酒石酸，生成酒石酸氢胆碱，控制温度40℃～70℃，过滤；
    4)、浓缩结晶：将上述步骤制得的滤液减压加热蒸发浓缩，然后降温冷却，有酒石酸氢胆碱晶体析出，经离心、干燥后得酒石酸氢胆碱成品。
  3. 根据权利要求2所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤1)中所述的酒石酸和三甲胺的摩尔比为0.8～1.2:2。
  4. 根据权利要求2或3任一所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤1)中所述的三甲胺为浓度30～40％的三甲胺水溶液或99％液化三甲胺。
  5. 根据权利要求2所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤1)中所述的降温为冷却水降温或冰水循环冷却降温，降温至30℃～40℃。
  6. 根据权利要求2所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤2)中所述的酒石酸三甲胺盐和环氧乙烷的摩尔比为1:2。
  7. 根据权利要求2或6任一所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤2)中所述的环氧乙烷为浓度99％的液化环氧乙烷。
  8. 根据权利要求2所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤3)中所述的酒石酸二胆碱和酒石酸的摩尔比为0.8～1.2:1，其中步骤1)和步骤3)中所添加的酒石酸总量与步骤1)中添加的三甲胺和步骤2)中添加的环氧乙烷的摩尔比为1:1:1～1.08。
  9. 根据权利要求2所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤4)中所述的减压加热蒸发浓缩温度为70℃～95℃。
  10. 根据权利要求2或9任一所述的一种酒石酸氢胆碱的制备方法，其特征在于：步骤4)中减压加热蒸发浓缩到水溶液浓度50～95％后降温冷却至40℃～-20℃。
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