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氨基丙磺酸的制备的方法有哪些?
来源:http://www.jnjrh.com 日期:2019-08-30 发布人:admin
基丙磺酸是用于制备γ-氨基丁酸受体冲动剂的一种医药中间体。对该化合物的合成办法,除在Annalen der chemie 565 Bend(22~35)中有所引见外,尚未发现有其它制备奋报导。该文献所报导的合成制备办法,为在乙醇中通入氨气,使其饱和,冷却下参加1,3-丙烷磺内酯,再升温至32℃停止反响,即得到所说的产物。该办法由于运用乙醇作溶剂,反响中生成的产物在乙醇中呈粘状,易夹杂未反响的原料,反响不易完整,且纯化艰难,产物重结晶时的损失较大。实验结果显现,该办法的收率普通为85%左右,且纯度<90%。因而,用该办法制备得到的产物如不经重结晶纯化处置,无法得到纯度大于98%的产品。
Propyl sulfonic acid is a pharmaceutical intermediate used to prepare gamma-aminobutyric acid receptor impulsive agent. The synthetic methods of this compound have not been reported except in Annalen der Chemie 565 Bend (22-35). The synthetic method reported in this paper is to inject ammonia into ethanol, saturate it, take part in 1,3-propane sulfonated lactone under cooling, then raise the temperature to 32 degrees Celsius to stop the reaction, so as to obtain the said product. Because of the use of ethanol as solvent, the products produced in the reaction are sticky in ethanol, easy to mix with unresponsive raw materials, the reaction is not easy to complete, and the purification is difficult, and the loss of product recrystallization is large. The experimental results show that the yield of this method is about 85% and the purity is less than 90%. Therefore, if the product prepared by this method is not recrystallized and purified, the product with purity greater than 98% can not be obtained.
针对上述状况,本创造将提供一种合成制备3-氨基丙磺酸的新办法,使其原料易得,且操作条件温和,工艺过程简单,并合适工业化消费。
In view of the above situation, the invention will provide a new method for synthesizing 3-aminopropionic acid, making its raw material easy to obtain, mild operating conditions, simple process, and suitable for industrial consumption.
本创造制备制备3-氨基丙磺酸的办法,是先向原料3-氨基丙醇中用氯化氢停止氯代反响后,参加乙醇稀释并冷却析晶,得到γ-氯丙胺盐酸盐中间体化合物。然后,将别离得到的该中间体化合物配制成水溶液,再与碱金属的亚硫酸盐类的水溶液在回流下停止磺化反响。反响终了用盐酸停止酸化处置并趁热过滤后,冷却析晶,即得到所说的3-氨基丙磺酸产物。其反响过程如下式所示 在上述的制备办法中,第一步反响中所说的用氯化氢停止的氯代反响,普通能够采用常用的参加浓盐酸的方式停止,也能够采用向原料3-氨基丙醇中通入氯化氢气体至中止吸收时止的方式停止,或采用将两者分离同时运用的方式。
The method of preparing 3-aminopropane sulfonic acid is to stop the chlorination reaction with hydrogen chloride in the raw material 3-aminopropyl alcohol, dilute the ethanol and cool the crystallization to obtain the intermediate compound of gamma-chloropropylamine hydrochloride. Then, the separated intermediate compound was prepared into an aqueous solution, and then the sulfonation reaction was stopped under reflux with the aqueous solution of alkali metal sulfites. At the end of the reaction, the acidification is stopped with hydrochloric acid and filtered while the heat is taken. After cooling and crystallization, the product of 3-aminopropionic sulfonic acid is obtained. The reaction process is shown as follows. In the preparation method mentioned above, the chlorination reaction stopped by hydrogen chloride in the first step can generally be stopped by taking part in concentrated hydrochloric acid, or by introducing hydrogen chloride gas into the raw material 3-aminopropyl alcohol until the absorption is stopped, or by adding hydrogen chloride to the raw material 3-aminopropyl alcohol until the absorption is stopped. The way in which the two are separated and used simultaneously.
实验显现,在完成上述第一步所说的氯代反响后,参加乙醇停止稀释将有利于中间产物的析晶。并且,以采用先将反响物冷却至室温后再用乙醇停止稀释的方式为好。所说的用于稀释的乙醇,普通以采用体积含量85%以上的乙醇,以至是无水乙醇的效果为好。乙醇的稀释用量普通采用为反响物体积的1-5倍即可,其中优选的为2-3倍。乙醇稀释的用量过多或过少都会影响收率进一步,实验显现,对反响物用乙醇稀释后,以析晶方式得到γ-氯丙胺盐酸盐中间体化合物时,普通使析晶的冷却温度控制在降至15℃以下较为理想,能够使析晶到达尽量完整的水平,进步中间体化合物的收率。
Experiments show that after completing the chlorination reaction mentioned in the first step mentioned above, the participation of ethanol to stop dilution will be conducive to the crystallization of intermediate products. Moreover, it is better to cool the reactant to room temperature and then stop the dilution with ethanol. The said ethanol used for dilution is generally better to use ethanol with volume content of more than 85%, or even absolute ethanol. The dilution dosage of ethanol is usually 1-5 times of the volume of the reactor, of which the optimum is 2-3 times. Excessive or little ethanol dilution will affect the yield further. Experiments show that when the reaction substance is diluted with ethanol and the intermediate compound of gamma-chloropropylamine hydrochloride is obtained by crystallization, the cooling temperature of crystallization is usually controlled below 15 C, which can make the crystallization reach as complete as possible. The yield of step intermediate compounds.
实验结果还显现,在上述的制备办法中,为停止第二步的磺化反响,将所说的用γ-氯丙胺盐酸盐中间体化合物配制成的水溶液重量浓度范围以控制在70%~80%为好。配制成的水溶液浓渡过高或过低,都会对产物的收率有不利影响。并且,所说的该磺化反响,普通以采用使中间体化合物与碱金属亚硫酸盐类为1~2∶1的摩尔比的条件下停止反响为好。
The experimental results also show that in order to stop the sulfonation reaction in the second step, it is better to control the weight concentration range of the water solution prepared by the intermediate compound of gamma-chloropropylamine hydrochloride at 70%-80%. Excessive or low concentration of the prepared water solution will have a negative impact on the yield of the product. In addition, the sulfonation reaction mentioned above is usually stopped under the condition that the molar ratio of intermediate compound to alkali metal sulfite is 1-2:1.
停止所说的磺化反响时,作为磺化试剂运用的上述碱金属的亚硫酸盐类的水溶液,作为可供施行时参考方式之一的,采用钾或钠的亚硫酸盐或亚硫酸氢盐等常用易得的盐类化合物的水溶液即可。
氨基磺酸
When the reaction of sulfonation is stopped, the aqueous solution of the sulfite of the alkali metals mentioned above, which is used as a sulfonation reagent, can be used as one of the reference methods for implementation, and the aqueous solution of the commonly available salts such as potassium or sodium sulfite or bisulfite can be used.
普通状况下,磺化反响后用盐酸停止酸化处置时,普通将反响物调理至pH6~7,即,使所得的产物成为游离胺的状态即可。酸化处置后即趁热过滤。此处对所说趁热过滤时的温度控制范围并无非常严厉的请求,例如在50%-100℃范围内均可,主要目的是以尽可能地减少因过滤过程中有结晶的析出而影响过滤的顺利停止及影响产物的收率。停止冷却析晶时的是使温度至少降至0℃或更低,以保证析晶完整。
Under normal conditions, when acidification is stopped with hydrochloric acid after sulfonation reaction, the reactant is usually conditioned to pH 6-7, that is, the product is in the state of free amine. After acidification disposal, it is filtered while the temperature is high. There is no strict requirement for the temperature control range of thermal filtration, for example, in the range of 50% - 100 (?) C. The main purpose is to minimize the influence of crystalline precipitation during the filtration process on the smooth stop of filtration and the yield of products. When cooling crystallization is stopped, the temperature is reduced to at least 0 C or lower to ensure the integrity of crystallization.
采用本创造上述制备办法的两步反响后,关于所得到的3-氨基丙磺酸终产物粗品,还能够用目前对该化合物的常规方式停止重结晶的纯化处置。例如,可作为一种详细施行时的参考方式,是采用50~95%的乙醇停止重结晶的纯化处置。
After the two-step reaction of the above-mentioned preparation method, the crude end product of 3-aminopropionic sulfonic acid can be purified and disposed of in the conventional way of Recrystallization at present. For example, as a reference method for detailed implementation, 50-95% ethanol is used to stop recrystallization of purified disposal.
由上述制备办法的过程能够看出,本创造合成制备3-氨基丙磺酸的办法,以3-氨基丙醇为起始原料,其原料易得,且制备过程中的氯代和磺化两步反响条件温和,操作简单,十分合适于工业化的消费。
It can be seen from the above-mentioned preparation process that the method of synthesizing 3-aminopropane sulfonic acid is easy to obtain with 3-aminopropanol as the starting material, and the reaction conditions of chlorination and sulfonation in the preparation process are mild, the operation is simple, and it is very suitable for industrial consumption.