WO2021093426A1 - 一种羟基苄胺的合成方法 - Google Patents

一种羟基苄胺的合成方法 Download PDF

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WO2021093426A1
WO2021093426A1 PCT/CN2020/112960 CN2020112960W WO2021093426A1 WO 2021093426 A1 WO2021093426 A1 WO 2021093426A1 CN 2020112960 W CN2020112960 W CN 2020112960W WO 2021093426 A1 WO2021093426 A1 WO 2021093426A1
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hydroxybenzylamine
hydrobromic acid
methoxybenzylamine
synthesizing
reaction
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PCT/CN2020/112960
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English (en)
French (fr)
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徐昌平
贾彦荣
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台州市创源工业技术有限公司
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Priority to JP2022521159A priority Critical patent/JP7349762B2/ja
Priority to DE112020005539.6T priority patent/DE112020005539T5/de
Priority to US17/639,591 priority patent/US12024483B2/en
Publication of WO2021093426A1 publication Critical patent/WO2021093426A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

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  • the invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing hydroxylbenzylamine.
  • Hydroxybenzylamine also called aminomethylphenol, it is an important organic intermediate, which is used in many fields.
  • 2-hydroxybenzylamine has been used in silk dyeing in recent years to treat atherosclerosis and hypertension.
  • 3-hydroxybenzylamine is used in the research of hair dyes, antibacterial agents and anti-tumor drugs
  • 4-hydroxybenzylamine is an important middle of the digestive system drug itopride.
  • hydroxybenzylamine The existing synthetic methods of hydroxybenzylamine are roughly divided into the hydroxybenzaldehyde method from the raw materials; the hydroxybenzonitrile method and the methoxybenzylamine method. Most of the first two methods have their own unique advantages, but there are also some unsatisfactory ones. Disadvantages, such as: need high pressure; expensive catalyst; product is not easy to separate and purify, etc.
  • the purpose of the present invention is to provide a synthesis method that can be completed under normal pressure without a catalyst, which has simple process, low raw material consumption, short reaction time, and high purity and yield of the final product. High advantages.
  • the former chemists Just use the commercially available hydrobromic acid with the highest concentration of 48% and increase the dosage, which leads to increased raw material consumption, increased processing volume, and increased sodium hydroxide dosage during subsequent neutralization, but the effect received is limited.
  • the present application is made to address this problem.
  • step S3 Continue to distill the materials in step S2 to recover excess hydrobromic acid, and stop when the temperature in the reactor reaches 132°C or higher;
  • step S4 Cool the reactor of step S3 slightly, add water to it, add dropwise sodium hydroxide aqueous solution under cooling to cause precipitation, continue to dropwise until the precipitation completely disappear; the amount of water should not be too much, so that the subsequent cooling It is enough not to cause difficulty in stirring due to the appearance of hydroxybenzylamine hydrobromide crystals;
  • step S5 Extract the alkali-insoluble organic matter in step S4, then recover the extractant from the organic phase, and save the aqueous phase;
  • step S6 Under cooling, adjust the pH value of the water phase in step S5 with hydrochloric acid, crystallize with ice, filter with suction, wash, and dry in vacuum to obtain the finished product.
  • the method for synthesizing hydroxybenzylamine is characterized in that the mass concentration of hydrobromic acid in the S1 step is more than 1%, preferably 10%-48%.
  • the method for synthesizing hydroxybenzylamine is characterized in that: in step S1, methoxybenzylamine is 2-methoxybenzylamine, 3-methoxybenzylamine or 4-methoxybenzylamine.
  • the target product obtained by 2-methoxybenzylamine is 2-hydroxybenzylamine
  • the target product obtained by 3-methoxybenzylamine is 3-hydroxybenzylamine
  • 4-methoxybenzylamine is obtained
  • the target product is 4-hydroxybenzylamine monohydrate, because it is easy to lose one molecule of water, and the temperature and vacuum degree during the subsequent vacuum drying can be controlled, and 4-hydroxybenzylamine can be obtained close to anhydrous state.
  • the method for synthesizing hydroxybenzylamine is characterized in that: in the S1 and S2 steps, the excess water is distilled off until the top temperature of the distillate reaches 120°C, and the heating power is reduced to make it into a reflux state or extremely Distillation at a slow rate.
  • the purpose of this operation is to increase the concentration of hydrobromic acid in the reaction mixture and increase the reaction temperature, so that the temperature in the reactor is maintained above 126°C, which is conducive to a more thorough reaction, and speeds up the reaction speed, thereby shortening Reaction time.
  • the purpose of continuing the distillation in the S3 step is also to further increase the reaction temperature and make the reaction more complete, and also to recover excess hydrobromic acid, reduce the consumption of raw hydrobromic acid and the processing capacity and hydrogen in subsequent steps. Consumption of sodium oxide.
  • the method for synthesizing hydroxybenzylamine is characterized in that the concentration of sodium hydroxide dropped in step S4 is 1%-60%, preferably 10%-50%.
  • the method for synthesizing hydroxybenzylamine is characterized in that the extractant for extracting alkali-insoluble organic matter in step S5 is an ether substance or a homologue of benzene, and the ether substance is preferably ethyl ether, propyl ether, Isopropyl ether, butyl ether or methyl tert-butyl ether; the homologue of benzene is preferably benzene, toluene or xylene.
  • the method for synthesizing hydroxybenzylamine is characterized in that the concentration of hydrochloric acid in the S6 step is 1%-37.5%, preferably 10%-37.5%.
  • the method for synthesizing hydroxybenzylamine is characterized in that the pH value is adjusted to 9-10 in the S6 step.
  • the method for synthesizing hydroxybenzylamine is characterized in that the vacuum drying conditions in the S6 step are: absolute pressure is less than 10 mmHg, rotating and vacuum drying at room temperature for 2 hours, and then heating at 10°C/hour Raise the speed to 80°C and bake to constant weight.
  • the methoxybenzylamine and hydrobromic acid are heated and distilled to remove excess water under the reflux state to increase the concentration of hydrobromic acid in the reaction mixture and increase the reaction temperature, thereby enhancing the hydrobromic acid to methyl
  • the demethylation effect of oxybenzylamine further shortens the reaction time and improves the conversion rate; another advantage of the present invention is that low-concentration hydrobromic acid can be used instead of high-concentration hydrobromic acid.
  • step S2 The use of organic solvents to absorb or refrigerate the methyl bromide gas produced in step S2 is beneficial to environmental protection and resource recycling;
  • the present invention has the advantages of simple process, short reaction time, easy purification of products, low consumption of raw materials, high reaction yield and the like.
  • FIG. 1 Schematic diagram of the process flow of the present invention
  • FIG. 1 Gas chromatogram of 2-hydroxybenzylamine in Example 1;
  • Figure 8 Liquid chromatogram of 4-hydroxybenzylamine in Example 4.
  • the generated gas is absorbed by a solvent or recovered by a freezing method to protect the environment.
  • increase the heating rate again continue to distill, and recover excess hydrobromic acid until the temperature in the reactor reaches 132°C or higher.
  • Aqueous solution make precipitation, drop again, until the precipitation completely disappeared, use 50 ml of benzene to extract and wash twice, the organic phase recovers the benzene, the water phase is ice-cooled with 36.5% hydrochloric acid to adjust the pH: 9-10, stir to crystallize, and filter with suction.
  • the filter cake was washed with 250 ml of water, drained, and dried in a vacuum. The absolute pressure is less than 10 mmHg. After rotating and vacuum drying for 2 hours at room temperature, the cake is then heated to 80°C at a rate of 10°C/hour, and dried.
  • Example 3 Put 231 grams (1.27 moles) of 44.5% of the hydrobromic acid recovered in Example 3 into a 0.5L reactor equipped with a thermometer, a dropping funnel, an adjustable power heating jacket, a stirrer and a distillation device, and stir under the stirrer. Use a dropping funnel to slowly add 43.56 grams (0.3175 moles) of 4-methoxybenzylamine. After the addition is completed, the excess water is removed by heating and distillation until the distillation temperature reaches 120°C or more (the temperature in the reactor reaches 126°C at this time) Above), reduce the heating rate, make it into a reflux state or distill out at a very slow rate, and keep the temperature in the reactor above 126°C.
  • the generated gas is absorbed by a solvent or recovered by a freezing method to protect the environment.
  • gas When gas is generated again, increase the heating rate again, continue distillation, and recover excess hydrobromic acid until the temperature in the reactor reaches 132°C or more. Cool slightly, add 60 milliliter of water, and drop the pre-cooled mass under water cooling.
  • the involved equipment and instruments such as adjustable power heating jackets, stirrers, reactors, etc., are all commonly used equipment and instruments in the prior art.

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

Abstract

一种羟基苄胺的合成方法，属于有机合成技术领域。该方法原理为：甲氧基苄胺在氢溴酸作用下的去甲基化反应，本发明的特点是：甲氧基苄胺和氢溴酸在回流状态下，蒸馏除去多余的水份以提高反应温度，增加反应混合物中氢溴酸的浓度，从而增强氢溴酸对甲氧基苄胺的去甲基化作用，进而缩短反应时间，提高转化率；当观察不到再有溴甲烷气体产生后继续蒸馏，回收过量的氢溴酸以进一步提高反应温度、提高转化率,同时减小原材料氢溴酸的消耗，又可减少后续步骤的处理量及原料氢氧化钠的消耗量，因此本发明具有工艺过程简单；反应时间短；产物易提纯；原材料消耗少；反应收率高等优点。

Description

一种羟基苄胺的合成方法 技术领域
本发明属于有机合成技术领域，具体涉及一种羟基苄胺的合成方法。
背景技术
羟基苄胺：又叫氨甲基苯酚，是一类重要的有机中间体，被应用于多个领域，如：2-羟基苄胺近年被应用于丝绸染色,治疗动脉粥样硬化及高血压等药物的研究上；3-羟基苄胺被应用于染发剂，抗菌剂及抗肿瘤药物等的研究上；4-羟基苄胺则是消化系统药物伊托必利(itopride)的重要中间。
羟基苄胺现有合成方法从原料上分大致有羟基苯甲醛法；羟基苯腈法以及甲氧基苄胺法，前二种方法中大多有其独到的优点，但也有一些不太如人意的缺点，如：需高压；昂贵的催化剂；产物不易分离提纯等,甲氧基苄胺法中有人采用三溴化硼去甲基化法合成羟基苄胺,但收率不高,也有人采用氢溴酸去甲基化法合成的,但因没有在反应时蒸馏除去多余的水份和回收过量的氢溴酸而导致反应温度不高,反应速度及转化率不理想,为了弥补该点不足,只好采用市售最高浓度48％的氢溴酸并加大用量,这就直接导致原材料消耗大,处理量大,后续中和时的氢氧化钠用量增大等缺点,但尽管如此,产生的效果还是不太理想,收率不到90％。
发明内容
鉴于现有技术存在的问题，本发明的目的在于提供一种无需催化剂常压下就能完成的合成方法，具有工艺简单，原材料消耗少，反应时间较短，最终得到的产物纯度高且收率高的优点。
本发明的实验原理：甲氧基苄胺在氢溴酸的作用下去甲基化反应，以3-羟 基苄胺为例,其反应方程式如下：
Figure PCTCN2020112960-appb-000001
从上面的反应式可知:当氢溴酸滴加入反应器中时,首先发生的是成盐反应,这步反应会消耗掉一当量的氢溴酸,从而多余出了这一当量氢溴酸所对映的水份,而当去甲基化反应发生时,又会有一当量的氢溴酸慢慢地消耗掉,从而又多余出了这一当量氢溴酸所对映的水份,这样就使体系中的氢溴酸浓度降低,同时也使反应时的回流温度降低,最终会弱化氢溴酸的去甲基化作用,导致反应时间加长,产物收率降低,因此,以往的化学工作者就采用市售最高浓度48％的氢溴酸并加大用量,这就导致原材料消耗增大,处理量增大,后续中和时的氢氧化钠用量增大,但收到的效果却有限,本发明申请正是针对这一问题而提出的。
所述的一种羟基苄胺的合成方法，其特征在于：包括以下步骤：
S1：取氢溴酸加至配备有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中，搅拌下滴加甲氧基苄胺，直至甲氧基苄胺滴加完毕，开始升温，蒸馏除去其中多余的水份；
S2：当馏出顶温达120℃以上时，降低加热速率，使成回流状态或以极慢的速率馏出，以保持反应器内温度在126℃以上，产生的气体采用有机溶剂吸收或冷冻回收，直至观察不到再有气体生成；
S3：将S2步骤中的物料继续蒸馏，回收过量的氢溴酸，至反应器内温度达 132℃以上时停止；
S4：将S3步骤的反应器稍冷，向其中加入水，冷却下滴加氢氧化钠水溶液，使产生沉淀，继续滴加，至沉淀完全消失；其中加水量不宜过多,使得在后续的冷却时不至因出现羟基苄胺氢溴酸盐结晶而使搅拌困难即可；
S5：将S4步骤中不溶于碱的有机物进行萃取，然后有机相回收萃取剂，水相留用；
S6:冷却下，将S5步骤中的水相用盐酸调节pH值，冰冷结晶，抽滤，洗涤，真空干燥即得成品。
所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中氢溴酸的质量浓度为1％以上，优选10％-48％。
所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中甲氧基苄胺为2-甲氧基苄胺、3-甲氧基苄胺或4-甲氧基苄胺中的一种；其中，2-甲氧基苄胺得到的目标产物为2-羟基苄胺，3-甲氧基苄胺得到的目标产物为3-羟基苄胺，4-甲氧基苄胺得到的目标产物为4-羟基苄胺一水合物,因其容易失去一分子水,控制好后续真空干燥时的温度及真空度,可以得到接近无水状态的4-羟基苄胺。
所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中投料摩尔比为：甲氧基苄胺:氢溴酸＝1:2-1:4，优选1:2.5-1:4。
所述一种羟基苄胺的合成方法，其特征在于：所述S1及S2步骤中蒸馏除去多余的水份至馏出顶温达120℃时,调低加热功率,使成回流状态或以极慢的速率馏出，如此操作的目的是为了增加反应混合物中氢溴酸的浓度以及提高反应温度,使反应器内温度保持在126℃以上，有利于反应更彻底,并加快反应速度,进而缩短反应时间。所述S3步骤中继续蒸馏的目的也是为了进一步提高反应温度,使反应更进一步地趋向完全,同时也是为了回收过量的氢溴酸,降低原料氢溴酸的消耗量及后续步骤的处理量和氢氧化钠的消耗量。
所述一种羟基苄胺的合成方法，其特征在于：所述S4步骤中滴加的氢氧化钠浓度为1％-60％,优选10％-50％。
所述一种羟基苄胺的合成方法，其特征在于：所述S5步骤中萃取不溶于碱的有机物的萃取剂是醚类物质或苯的同系物，所述醚类物质优选乙醚、丙醚、异丙醚、丁醚或甲基叔丁基醚；所述苯的同系物优选苯、甲苯或二甲苯。
所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中盐酸的浓度为1％-37.5％，优选10％-37.5％。
所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中调节pH值至9-10。
所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中真空干燥条件为：绝对压力小于10毫米汞柱，室温下旋转真空干燥2小时后，再按10℃/小时的升温速率升至80℃,烘至恒重即可。
本发明工艺流程见图1所示。
本发明的有益效果：
所述S2步骤中甲氧基苄胺和氢溴酸在回流状态下，加热蒸馏除去多余水份的目的就是为了增加反应混合物中氢溴酸的浓度，提高反应温度，从而增强氢溴酸对甲氧基苄胺的去甲基化作用，进而缩短反应时间，提高转化率；本发明还有一个优点就是可以采用低浓度的氢溴酸,而无须高浓度的氢溴酸。
所述采用有机溶剂吸收或冷冻回收S2步骤中产生的溴甲烷气体，有利于环境的保护和资源的回收利用；
所述S3步骤中,在观察不到再有气体产生时继续蒸馏，以进一步提高反应温度,使反应更趋完全,同时回收过量的氢溴酸以减小原材料的消耗，又可减少后续步骤的处理量及原料氢氧化钠的消耗量；
因此本发明具有工艺过程简单、反应时间短、产物易提纯、原材料消耗少、 反应收率高等优点。
附图说明
图1：本发明工艺流程示意图；
图2：实施例1中的2-羟基苄胺气相色谱图；
图3：实施例1中的2-羟基苄胺的核磁图谱；
图4：实施例2中的3-羟基苄胺的气相色谱图；
图5：实施例2中的3-羟基苄胺的核磁图谱；
图6：实施例3中的4-羟基苄胺的液相色谱图；
图7：实施例3中的4-羟基苄胺的核磁图谱；
图8：实施例4中的4-羟基苄胺的液相色谱图；
图9：实施例4中的4-羟基苄胺的核磁图谱。
具体实施方式
下面结合附图及具体实施例对本发明作进一步的说明，但本发明保护的范围不局限于所述范围。
实施例1：2-羟基苄胺的合成
在0.5L的带有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中投入252.8克(1.5摩尔)48％氢溴酸，在搅拌器搅拌下利用滴液漏斗缓慢滴加入68.6克(0.5摩尔)2-甲氧基苄胺，滴加完，升温蒸馏除去多余的水份至馏出顶温达120℃以上(此时反应器内温度达126℃以上)，然后降低加热速率，使成回流状态或以极慢的速率馏出，保持反应器内温度维持在126℃以上，所产生的气体用溶剂吸收或用冷冻法回收以保护环境，至观察不到再有气体产生时，重新提高加热速率，继续蒸馏，回收过量的氢溴酸，至反应器内温度达132℃以上时为止，稍冷，加入80ml水，水冷下滴加预先冷却的质量浓度33.3％氢氧化钠水溶液，使产生沉淀，再滴，至沉淀完全消失，用30毫升异丙醚萃取 洗涤2次，有机相回收异丙醚,水相冰冷下用30.0％的盐酸调节PH：9-10，搅拌结晶，抽滤，滤饼用120毫升水洗涤后抽干，真空干燥，即为绝对压力小于10毫米汞柱的状态，室温下旋转真空干燥2小时后,再按10℃/小时的升温速率升至80℃,烘至恒重，即得成品，共计:58.3克，卡尔·费休法测定含水量为：0.43％,摩尔收率：94.0％，通过图2及图3可知所得产品确实为2-羟基苄胺，气相色谱含量达到99.0％以上。图2气相色谱图各组分数据如下:
序号 保留时间(min) 峰面积 浓度(％)
1 3.058 4393 0.1646
2 3.313 4084 0.153
3 3.596 2661392 99.68
总计   2669869 100
实施例2：3-羟基苄胺的合成
在1L的带有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中投入708.0克(3.5摩尔)40％氢溴酸，在搅拌器搅拌下利用滴液漏斗缓慢滴加入137.2克(1.0摩尔)3-甲氧基苄胺，滴加毕，升温蒸馏除去多余的水份至馏出温度达120℃以上(此时反应器内温度达126℃以上)，降低加热速率，使成回流状态或以极慢的速率馏出，保持反应器内温度维持在126℃以上，所产生的气体用溶剂吸收或用冷冻法回收以保护环境，至观察不到再有气体产生时，重新提高加热速率，继续蒸馏，回收过量的氢溴酸，至反应器内温度达132℃以上时止，稍冷，加入0毫升水，水冷下滴加预先冷却的质量浓度30％氢氧化钠水溶液，使产生沉淀，再滴，至沉淀完全消失，用50毫升苯萃取洗涤2次，有机相回收苯,水相冰冷下用36.5％的盐酸调节PH：9-10，搅拌结晶,抽滤，滤饼用250毫升水洗涤后抽干，真空干燥，即为绝对压力小于10毫米汞柱的状态，室温下旋转真空干燥2小时后,再按10℃/小时的升温速率升至80℃,烘至恒重， 即得成品，共计：119.3克，卡尔·费休法测定含水量为：1.53％，摩尔收率:95.4％，通过图4及图5可知所得产品确实为3-羟基苄胺，气相色谱含量达到99.0％以上。图4气相色谱图各组分数据如下:
序号 保留时间(min) 峰面积 浓度(％)
1 3.862 5186747 100
总计   5186747 100
实施例3：4-羟基苄胺的合成
在1L的带有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中投入970.9克(3.0摩尔)25％氢溴酸，在搅拌器搅拌下利用滴液漏斗缓慢滴加入103.7克(0.7558摩尔)4-甲氧基苄胺，滴加毕，升温蒸馏除去多余的水份至馏出温度达120℃以上(此时反应器内温度达126℃以上)，降低加热速率，使成回流状态或以极慢的速率馏出，保持反应器内温度维持在126℃以上，所产生的气体用溶剂吸收或用冷冻法回收以保护环境，至观察不到再有气体产生时，重新提高加热速率，继续蒸馏，回收过量的氢溴酸，至反应器内温度达132℃以上时止，稍冷，加入200毫水，水冷下滴加预先冷却的质量浓度40％氢氧化钠水溶液，使产生沉淀，再滴，至沉淀完全消失，用50毫升甲苯萃取洗涤2次，有机相回收甲苯,水相冰冷下用30.0％的盐酸调节PH：9-10,搅拌结晶,抽滤，滤饼用240毫升水洗涤后抽干，真空干燥，即为绝对压力小于10毫米汞柱时的状态，室温下旋转真空干燥2小时后,再按10℃/小时的升温速率升至80℃,烘至恒重，即得成品，共计：86.9克，卡尔·费休法测定含水量为：0.2％，摩尔收率：92.5％，通过图6及图7可知所得产品确实为4-羟基苄胺，液相色谱含量达到99.0％以上。图6液相色谱图各组分数据如下:
序号 保留时间(min) 峰面积 浓度(％)
1 1.58 8920.50 99.24
2 2.27 68.53 0.76
总计   8989.03 100
实施例4：4-羟基苄胺的合成
在0.5L的带有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中投入231克(1.27摩尔)44.5％实施例3回收的氢溴酸，在搅拌器搅拌下利用滴液漏斗缓慢滴加入43.56克(0.3175摩尔)4-甲氧基苄胺，滴加毕，升温蒸馏除去多余的水份至馏出温度达120℃以上(此时反应器内温度达126℃以上)，降低加热速率，使成回流状态或以极慢的速率馏出，保持反应器内温度维持在126℃以上，所产生的气体用溶剂吸收或用冷冻法回收以保护环境，至观察不到再有气体产生时，重新提高加热速率，继续蒸馏，回收过量的氢溴酸，至反应器内温度达132℃以上时止，稍冷，加入60毫水，水冷下滴加预先冷却的质量浓度25％氢氧化钠水溶液，使产生沉淀，再滴，至沉淀完全消失，用30毫升甲基叔丁基醚萃取洗涤2次，有机相回收甲基叔丁基醚,水相冰冷下用30.0％的盐酸调节PH：9-10，搅拌结晶,抽滤，滤饼用200毫升水洗涤后抽干，真空干燥，即为绝对压力小于10毫米汞柱时的状态，室温下旋转真空干燥2小时后,再按10℃/小时的升温速率升至80℃,烘至恒重，即得成品，共计：37.7克，卡尔·费休法测定含水量为：3.56％，摩尔收率：92.4％，通过图8及图9可知所得产品确实为4-羟基苄胺，液相色谱含量达到99.0％以上。图8液相色谱图各组分数据如下:
序号 保留时间(min) 峰面积 浓度(％)
1 1.28 3.78 0.0600
2 1.40 6676.74 99.40
3 1.88 36.56 0.5400
总计   6717.07 100
上述实施例中，涉及的设备、器械，如可调功率加热套、搅拌器、反应器等，均为现有技术中常用的设备和器械。

Claims (9)

  1. 一种羟基苄胺的合成方法，其特征在于：包括以下步骤：
    S1：取氢溴酸加至配备有温度计、滴液漏斗、可调功率加热套、搅拌器及蒸馏装置的反应器中，搅拌下滴加甲氧基苄胺，直至甲氧基苄胺滴加完毕，开始升温，蒸馏除去其中多余的水份；
    S2：当馏出顶温达120℃以上时，降低加热速率，使成回流状态或以极慢的速率馏出，以保持反应器内温度在126℃以上，产生的气体采用有机溶剂吸收或冷冻回收，直至观察不到再有气体产生；
    S3：将S2步骤中的物料继续蒸馏，回收过量的氢溴酸，至反应器内温度达132℃以上时停止；
    S4：将S3步骤的反应器稍冷，向其中加入水，冷却下滴加氢氧化钠水溶液，使产生沉淀，继续滴加，至沉淀完全消失；
    S5：将S4步骤中不溶于碱的有机物用萃取剂进行萃取，然后有机相回收萃取剂，水相留用；
    S6:冷却下，将S5步骤中的水相用盐酸调节pH值，冰冷结晶，抽滤，洗涤，真空干燥即得成品。
  2. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中氢溴酸的质量浓度为1％以上，优选10％-48％。
  3. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中甲氧基苄胺为2-甲氧基苄胺、3-甲氧基苄胺或4-甲氧基苄胺中的一种。
  4. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S1步骤中投料摩尔比为：甲氧基苄胺:氢溴酸＝1:2-1:4，优选1:2.5-1:4。
  5. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S4 步骤中滴加的氢氧化钠浓度为1％-60％,优选10％-50％。
  6. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S5步骤中萃取不溶于碱的有机物的萃取剂是醚类物质或苯的同系物，所述醚类物质优选乙醚、丙醚、异丙醚、丁醚或甲基叔丁基醚；所述苯的同系物优选苯、甲苯或二甲苯。
  7. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中盐酸的浓度为1％-37.5％，优选10％-37.5％。
  8. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中调节pH值至9-10。
  9. 根据权利要求1所述一种羟基苄胺的合成方法，其特征在于：所述S6步骤中真空干燥条件为绝对压力小于10毫米汞柱，室温下旋转真空干燥2小时后,再按10℃/小时的升温速率升至80℃,烘至恒重即可。
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