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 PDFInfo
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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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- Prior art keywords
- hydroxybenzylamine
- hydrobromic acid
- methoxybenzylamine
- synthesizing
- reaction
- Prior art date
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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
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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
-
- 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
Definitions
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
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 |
序号 | 保留时间(min) | 峰面积 | 浓度(%) |
1 | 3.862 | 5186747 | 100 |
总计 | 5186747 | 100 |
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 |
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 |
Claims (9)
- 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。
- 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%。
- 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。
- 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。
- 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%。
- 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。
- 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%。
- 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。
- 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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JP2022521159A JP7349762B2 (ja) | 2019-11-13 | 2020-09-02 | ヒドロキシベンジルアミンの合成方法 |
DE112020005539.6T DE112020005539T5 (de) | 2019-11-13 | 2020-09-02 | Verfahren zum synthetisieren von hydroxybenzylamin |
US17/639,591 US12024483B2 (en) | 2019-11-13 | 2020-09-02 | Synthesis method of hydroxybenzylamine |
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CN113735740A (zh) * | 2021-08-30 | 2021-12-03 | 珠海润都制药股份有限公司 | 一种去甲基伊托必利亚硝胺的制备方法 |
CN116947596B (zh) * | 2023-07-24 | 2024-02-23 | 山东华氟化工有限责任公司 | 一种六氟丁二烯的制备方法 |
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- 2020-09-02 WO PCT/CN2020/112960 patent/WO2021093426A1/zh active Application Filing
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JP2022541683A (ja) | 2022-09-26 |
CN110803996B (zh) | 2022-01-11 |
US12024483B2 (en) | 2024-07-02 |
JP7349762B2 (ja) | 2023-09-25 |
DE112020005539T5 (de) | 2022-12-29 |
CN110803996A (zh) | 2020-02-18 |
US20220289664A1 (en) | 2022-09-15 |
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