技术领域Technical field
本发明属于氨磺必利中间体合成技术领域，更具体的，涉及4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的制备方法。The invention belongs to the technical field of amisulpride intermediate synthesis, and more specifically, relates to a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid.
背景技术Background technique
氨磺必利(Amisulpride)是一种常见的抗精神病药物，一般用于治疗精神分裂症，这种药物对于精神分裂症的谱系都是有效的，比如精神分裂症、妄想性障碍、幻觉症等，小剂量用药即可改善精神分裂症的阴性症状，比如孤僻、懒散、退缩、淡漠、不与人交往等，大剂量用药能够改善一系列阳性症状，可改善幻觉，消除幻想，控制冲动攻击行为等。Amisulpride is a common antipsychotic drug, generally used to treat schizophrenia. This drug is effective for the spectrum of schizophrenia, such as schizophrenia, delusional disorder, hallucinations, etc. , small doses of medication can improve the negative symptoms of schizophrenia, such as withdrawal, laziness, withdrawal, indifference, and lack of interaction with others. Large doses of medication can improve a series of positive symptoms, such as hallucinations, elimination of fantasies, and control of impulsive and aggressive behaviors. wait.
其中4-氨基-5-乙磺酰基-2-甲氧基苯甲酸是合成氨磺必利的重要中间体，早期的方法是以4-氨基水杨酸为原料，先经硫酸二甲酯处理得到4-氨基-2-甲氧基-苯甲酸甲酯，进一步用硫代氰酸钾处理，再通过溴乙烷处理得到中间产物，其进一步通过过氧化氢和乙酸氧化转化即可获得阿米酸，溴乙烷处理后副产物较难处理并且产物纯度不高，所以该方法用的越来越少。Among them, 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is an important intermediate for the synthesis of amisulpride. The early method was to use 4-aminosalicylic acid as raw material and first treat it with dimethyl sulfate. 4-Amino-2-methoxy-benzoic acid methyl ester is further treated with potassium thiocyanate and then treated with ethyl bromide to obtain an intermediate product, which is further oxidized and converted by hydrogen peroxide and acetic acid to obtain amic acid. , the by-products after treatment with ethyl bromide are difficult to handle and the product purity is not high, so this method is used less and less.
在专利文献CN114230497A中，公开了一种4-氨基-5-乙基磺酰基-2-甲氧基苯甲酸的制备方法，该专利以对氨基水杨酸为原料，在碱的存在下与硫酸二甲酯发生反应，再与硫氰酸铵及液溴发生反应得到得到化合物4-氨基-2-甲氧基-5-硫氰基苯甲酸甲酯，然后与硫化钠醇溶液及硫酸二乙酯反应得到化合物4-氨基-5-乙硫基-2-甲氧基苯甲酸甲酯，再与过氧化物进行反应后加入碱液，即可得到最终产物4-氨基-5-乙基磺酰基-2-甲氧基苯甲酸，这条路线步骤较长，而且反应过程中使用催化剂较多，生成的副产物较难二次利用，间接提高了生产的成本。In the patent document CN114230497A, a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is disclosed. The patent uses p-aminosalicylic acid as raw material, and mixes it with sulfuric acid in the presence of a base. The dimethyl ester reacts, and then reacts with ammonium thiocyanate and liquid bromine to obtain the compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester, which is then reacted with sodium sulfide alcohol solution and diethyl sulfate. The ester reaction obtains the compound 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester, which is then reacted with peroxide and then added with alkali solution to obtain the final product 4-amino-5-ethylsulfonate. Acyl-2-methoxybenzoic acid, this route has longer steps, and more catalysts are used during the reaction. The generated by-products are difficult to reuse, which indirectly increases the cost of production.
因此，目前亟需寻找一种产品纯度高、反应路线短、生产成本低的合成方法。Therefore, there is an urgent need to find a synthesis method with high product purity, short reaction route, and low production cost.
发明内容Contents of the invention
本发明针对以上现有技术中存在的缺陷，提供一种4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的制备方法，解决的问题是如何实现提高产品纯度、降低生产成本的制备方法。In view of the defects existing in the above prior art, the present invention provides a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid. The problem solved is how to improve product purity and reduce production costs. Preparation.
本发明以4-氨基水杨酸为原料，在催化剂的作用下与碳酸二甲酯发生酯化反应生成式IV化合物，避免使用剧毒化合物硫酸二甲酯，再与硫氰酸钠通过卤素引发剂的的催化发生合成反应生成式III化合物，其再与还原剂及硫酸二乙酯发生取代反应，生成式II化合物，此步骤生成的副产物硫氰酸钠在过滤提纯后可以用于前部反应，减少生产成本，最后在将式II化合物与过氧化物反应后再与碱液反应即可得到式I化合物阿米酸，总合成路线为：The present invention uses 4-aminosalicylic acid as raw material, undergoes an esterification reaction with dimethyl carbonate under the action of a catalyst to generate a compound of formula IV, avoids the use of the highly toxic compound dimethyl sulfate, and then reacts with sodium thiocyanate through halogen The catalytic synthesis reaction of the agent generates the compound of formula III, which then undergoes a substitution reaction with the reducing agent and diethyl sulfate to generate the compound of formula II. The by-product sodium thiocyanate generated in this step can be used in the front part after filtration and purification. reaction to reduce production costs. Finally, the compound of formula II is reacted with peroxide and then reacted with alkali to obtain the compound of formula I, amic acid. The total synthesis route is:
该方法包括以下步骤：The method includes the following steps:
S1：4-氨基水杨酸(式V化合物)与碳酸二甲酯在酯化反应催化剂及中和剂的作用下发生反应，生成4-氨基-2-甲氧基苯甲酸甲酯(式IV化合物)；S1: 4-aminosalicylic acid (compound of formula V) reacts with dimethyl carbonate under the action of esterification reaction catalyst and neutralizing agent to generate 4-amino-2-methoxybenzoic acid methyl ester (formula IV compound);
S2：在醇溶液中4-氨基-2-甲氧基苯甲酸甲酯(式IV化合物)与硫氰酸钠在引发剂的作用下发生反应，生成4-氨基-2-甲氧基-5-氰硫基苯甲酸甲酯(式III化合物)；S2: In alcohol solution, 4-amino-2-methoxybenzoic acid methyl ester (compound of formula IV) reacts with sodium thiocyanate under the action of initiator to generate 4-amino-2-methoxy-5 -Methyl cyanothiobenzoate (compound of formula III);
S3：4-氨基-2-甲氧基-5-氰硫基苯甲酸甲酯(式III化合物)在还原剂的作用下与及硫酸二乙酯反应，生成4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯(式II化合物)与硫氰酸钠，硫氰酸钠过滤提纯后可重复利用；S3: 4-amino-2-methoxy-5-cyanothiobenzoic acid methyl ester (compound of formula III) reacts with diethyl sulfate under the action of reducing agent to generate 4-amino-2-methoxy -Methyl 5-ethylthiobenzoate (compound of formula II) and sodium thiocyanate. Sodium thiocyanate can be reused after filtration and purification;
S4：4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯(式II化合物)在催化剂的作用下与过氧化物反应后，再与碱性溶液反应生成4-氨基-5-乙磺酰基-2-甲氧基苯甲酸(式I化合物)。S4: 4-amino-2-methoxy-5-ethylthiobenzoic acid methyl ester (compound of formula II) reacts with peroxide under the action of a catalyst, and then reacts with an alkaline solution to generate 4-amino-5 -Ethanesulfonyl-2-methoxybenzoic acid (compound of formula I).
进一步的，所述步骤S1中，酯化反应催化剂可选用对甲苯磺酸、四丁基溴化铵或二甲基磷酸等其中一种。Further, in step S1, the esterification reaction catalyst may be one of p-toluenesulfonic acid, tetrabutylammonium bromide or dimethylphosphoric acid.
作为优选，选用对甲苯磺酸作为酯化反应催化剂，酯化反应的速率更大，且反应结束后容易分离副产物。As a preference, p-toluenesulfonic acid is selected as the esterification reaction catalyst, the esterification reaction rate is greater, and the by-products are easily separated after the reaction is completed.
进一步的，所述S1步骤中，中和剂可选用氢氧化钾、碳酸氢钠或乙醇胺等其中一种。Further, in the step S1, the neutralizing agent may be one of potassium hydroxide, sodium bicarbonate or ethanolamine.
作为优选，选用氢氧化钾作为中和剂，更容易中和反应产生的酸性物质，有助于维持反应体系的适宜pH范围，加强酯化反应的速率和效果。As a preference, potassium hydroxide is selected as the neutralizing agent, which can more easily neutralize the acidic substances produced by the reaction, help maintain the appropriate pH range of the reaction system, and enhance the rate and effect of the esterification reaction.
进一步的，所述S2步骤中，引发剂可选用溴、氯或碘其中一种。Furthermore, in the step S2, one of bromine, chlorine or iodine can be selected as the initiator.
作为优选，选用溴作为引发剂，对设备的腐蚀性较小同时成本更低。As a preference, bromine is used as the initiator, which is less corrosive to the equipment and lower in cost.
进一步的，所述S2步骤中，硫氰酸钠与引发剂的摩尔比为2:1～1.2。Further, in the step S2, the molar ratio of sodium thiocyanate to initiator is 2:1 to 1.2.
作为优选，硫氰酸钠与引发剂的摩尔比为2:1，减少引发剂与其他基团反应生成副产物。Preferably, the molar ratio of sodium thiocyanate to initiator is 2:1 to reduce the reaction between the initiator and other groups to produce by-products.
进一步的，所述S2步骤中，反应温度为5～20℃。Further, in the step S2, the reaction temperature is 5-20°C.
作为优选，反应温度为5℃，能够更好的维持反应的稳定性，避免受温度影响产生不可控副反应或产生更多副产物。Preferably, the reaction temperature is 5°C, which can better maintain the stability of the reaction and avoid uncontrollable side reactions or the generation of more by-products due to the influence of temperature.
进一步的，所述S3步骤中，还原剂可选用九水合硫化钠、亚硫酸钠或亚硫酸氢钠等其中一种。Further, in the step S3, the reducing agent may be one of sodium sulfide nonahydrate, sodium sulfite or sodium bisulfite.
作为优选，选用九水合硫化钠作为还原剂，反应后产物容易分离处理。Preferably, sodium sulfide nonahydrate is used as the reducing agent, and the product after the reaction can be easily separated and processed.
进一步的，所述S3步骤中，式III化合物与还原剂的摩尔比为1:1.2～1.5。Further, in the step S3, the molar ratio of the compound of formula III to the reducing agent is 1:1.2-1.5.
作为优选，式III化合物与还原剂的摩尔比为1:1.5，减少其他副产物的生成，便于过滤处理可重复利用的副产物。Preferably, the molar ratio of the compound of formula III to the reducing agent is 1:1.5, which reduces the formation of other by-products and facilitates the filtration and processing of reusable by-products.
进一步的，所述S3步骤中，式III化合物与硫酸二乙酯的摩尔比为1:1～1.5。Further, in the step S3, the molar ratio of the compound of formula III to diethyl sulfate is 1:1 to 1.5.
作为优选，式III化合物与硫酸二乙酯的摩尔比为1:1.2，底物完全反应的同时副产物生成较少，产物收率较高。Preferably, the molar ratio of the compound of formula III to diethyl sulfate is 1:1.2. When the substrate is completely reacted, less by-products are generated and the product yield is higher.
进一步的，所述S4步骤中，催化剂可选用钴酸钠、钼酸铵或钨酸钠等其中一种。Further, in the step S4, the catalyst may be one of sodium cobaltate, ammonium molybdate, or sodium tungstate.
作为优选，催化剂选用钴酸钠，提高反应的选择性与产物收率。As a preferred catalyst, sodium cobaltate is used to improve the selectivity of the reaction and the product yield.
综上所述，本发明与现有技术相比，具有以下优点：To sum up, compared with the prior art, the present invention has the following advantages:
本发明中通过使用硫氰酸钠代替硫氰酸铵与4-氨基-2-甲氧基苯甲酸甲酯进行反应，在后续的反应中4-氨基-2-甲氧基-5-氰硫基苯甲酸甲酯与还原剂如九水合硫酸钠及硫酸二乙酯反应后，生成副产物硫氰酸钠，经过过滤提纯后能够再次加入前部反应体系中作为催化剂使用，减少了购买原料的成本，同时通过调整式III化合物与还原剂的投料比，能够减少其他副产物的生成，使生成的副产物仅有硫氰酸钠，方便处理的同时也提高了产物纯度与产物收率。In the present invention, sodium thiocyanate is used instead of ammonium thiocyanate to react with 4-amino-2-methoxybenzoic acid methyl ester. In the subsequent reaction, 4-amino-2-methoxy-5-cyanothiocyanate After the reaction of methyl benzoate with reducing agents such as sodium sulfate nonahydrate and diethyl sulfate, the by-product sodium thiocyanate is generated. After filtration and purification, it can be added to the front reaction system again as a catalyst, reducing the cost of purchasing raw materials. At the same time, by adjusting the feeding ratio of the compound of formula III to the reducing agent, the generation of other by-products can be reduced, so that the only by-product generated is sodium thiocyanate, which not only facilitates processing, but also improves product purity and product yield.
附图说明Description of the drawings
图1为本发明合成路线；Figure 1 is the synthetic route of the present invention;
图2为本发明对比例合成路线。Figure 2 is a synthesis route of a comparative example of the present invention.
具体实施方式Detailed ways
下面通过具体实施例，对本发明的技术方案作进一步具体的说明，但是本发明并不限于这些实施例。The technical solutions of the present invention will be further described in detail below through specific examples, but the present invention is not limited to these examples.
实施例1Example 1
三口瓶中将15.31g4-氨基水杨酸(0.1mol)溶于100mL丙酮，加入1.72g对甲苯磺酸(0.01mol)，搅拌溶解，控温25℃加入14.03g氢氧化钾(0.25mol)，溶解后缓慢滴加19.82g碳酸二甲酯(0.22mol)，升温至30℃继续反应1h，加入盐酸溶液淬灭反应，减压蒸除丙酮，加入200mL冰水析晶，抽滤，使用100mL冷水清洗晶体，真空烘干，得到15.79g式IV化合物4-氨基-2-甲氧基苯甲酸甲酯，产物收率为87.2％，产物纯度为98.6％。Dissolve 15.31g 4-aminosalicylic acid (0.1mol) in 100mL acetone in a three-necked flask, add 1.72g p-toluenesulfonic acid (0.01mol), stir to dissolve, control the temperature to 25°C and add 14.03g potassium hydroxide (0.25mol). After dissolution, slowly add 19.82g dimethyl carbonate (0.22mol) dropwise, raise the temperature to 30°C and continue the reaction for 1 hour. Add hydrochloric acid solution to quench the reaction, evaporate the acetone under reduced pressure, add 200mL ice water to crystallize, filter with suction, and use 100mL cold water. The crystals were washed and dried under vacuum to obtain 15.79g of formula IV compound 4-amino-2-methoxybenzoic acid methyl ester. The product yield was 87.2% and the product purity was 98.6%.
实施例2Example 2
三口瓶中将18.1g式IV化合物(0.1mol)和12.16g硫氰酸钠(0.15mol)溶于150mL乙醇中，降温至5℃，将12g液溴(0.075mol)稀释到50mL乙醇中，控温5℃，缓慢滴加至三口瓶内溶液中，滴加完毕后继续反应1h，加入饱和碳酸氢钠水溶液淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水清洗有机相，减压脱溶，使用甲醇重结晶，过滤后真空烘干，得到21.92g式III化合物4-氨基-2-甲氧基-5-硫氰基苯甲酸甲酯，产物收率为92.1％，产物纯度为99％。Dissolve 18.1g formula IV compound (0.1mol) and 12.16g sodium thiocyanate (0.15mol) in 150mL ethanol in a three-necked flask, cool to 5°C, dilute 12g liquid bromine (0.075mol) into 50mL ethanol, and control The temperature was 5°C, and slowly added dropwise to the solution in the three-necked flask. After the dropwise addition, the reaction was continued for 1 hour. Add saturated sodium bicarbonate aqueous solution to quench the reaction, evaporate the solution under reduced pressure, extract 3 times with 100mL ethyl acetate, and combine the organic phases. , use 100mL cold water to wash the organic phase, remove the solvent under reduced pressure, use methanol to recrystallize, filter and dry under vacuum to obtain 21.92g of formula III compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester, The product yield was 92.1% and the product purity was 99%.
实施例3Example 3
三口瓶中将36.03g九水合硫化钠(0.15mol)溶于200mL乙醇，降温至15℃，分批加入23.8g式III化合物(0.1mol)，加入后搅拌，控温反应30min，缓慢加入18.5g硫酸二乙酯(0.12mol)，降温至10℃继续反应1h，反应完成后加入清水淬灭反应，减压脱溶，加入200mL冰水析晶，抽滤，滤液回收硫氰酸钠重复利用，使用100mL冷水清洗晶体，真空烘干，得到21.09g式II化合物4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯，产物收率为87.5％，产物纯度为99.1％。Dissolve 36.03g sodium sulfide nonahydrate (0.15mol) in 200mL ethanol in a three-necked flask, cool to 15°C, add 23.8g formula III compound (0.1mol) in batches, stir after addition, control temperature for 30 minutes, slowly add 18.5g Diethyl sulfate (0.12 mol), cool to 10°C and continue the reaction for 1 hour. After the reaction is completed, add water to quench the reaction, remove the solution under reduced pressure, add 200 mL of ice water to crystallize, filter with suction, and recover sodium thiocyanate from the filtrate for reuse. Use 100 mL of cold water to wash the crystals and dry them in a vacuum to obtain 21.09g of formula II compound 4-amino-2-methoxy-5-ethylthiobenzoic acid methyl ester. The product yield is 87.5% and the product purity is 99.1%.
实施例4Example 4
三口瓶中将24.1g式II化合物(0.1mol)和0.21g钴酸钠(0.001mol)溶于100mL乙醇，降温至5℃，缓慢滴加30mL30％的双氧水，滴加完毕后升温至30℃反应,1h，冰浴下缓慢滴加10％的硫代硫酸钠水溶液去除双氧水，双氧水除尽后，减压脱除乙醇，使用100mL乙酸乙酯萃取，合并有机相，使用100mL冷水洗涤有机相，减压脱溶，降温析晶，过滤后真空烘干，得到白色固体；Dissolve 24.1g of the compound of formula II (0.1mol) and 0.21g of sodium cobaltate (0.001mol) in 100mL of ethanol in a three-necked flask, cool the temperature to 5°C, slowly add 30mL of 30% hydrogen peroxide dropwise, and after completion of the dropwise addition, raise the temperature to 30°C for reaction. , 1h, slowly add 10% sodium thiosulfate aqueous solution dropwise in an ice bath to remove the hydrogen peroxide. After the hydrogen peroxide is removed, remove the ethanol under reduced pressure, extract with 100mL of ethyl acetate, combine the organic phases, wash the organic phase with 100mL of cold water, and reduce Press to remove the solution, cool down to crystallize, filter and dry under vacuum to obtain a white solid;
将16g氢氧化钠溶于200mL水得到碱液，将27.3g白色固体悬浮在碱液中，升温至50℃，搅拌溶解后继续反应1h，降温至10℃，加入质量分数为10％的盐酸溶液调节反应液pH为4.0～4.5淬灭反应，减压蒸馏除去绝大部分水，降温至5℃析晶，抽滤，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水洗涤有机相，减压脱溶，使用四氢呋喃重结晶，过滤后真空干燥，得到23.05g式I化合物4-氨基-5-乙基磺酰基-2-甲氧基苯甲酸，产物收率为89％，产物纯度为99.6％。Dissolve 16g sodium hydroxide in 200mL water to obtain lye. Suspend 27.3g white solid in the lye, raise the temperature to 50°C, stir and dissolve, continue the reaction for 1 hour, cool to 10°C, and add 10% hydrochloric acid solution. Adjust the pH of the reaction solution to 4.0~4.5 to quench the reaction, remove most of the water by distillation under reduced pressure, cool to 5°C to crystallize, filter with suction, extract three times with 100 mL of ethyl acetate, combine the organic phases, and wash the organic phase with 100 mL of cold water. , decomposed under reduced pressure, recrystallized using tetrahydrofuran, filtered and dried under vacuum to obtain 23.05g of formula I compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, product yield was 89%, product purity is 99.6%.
实施例5Example 5
三口瓶中将15.31g4-氨基水杨酸(0.1mol)溶于100mL丙酮，加入3.22g四丁基溴化铵(0.01mol)，搅拌溶解，控温25℃加入21g碳酸氢钠(0.25mol)，溶解后缓慢滴加19.82g碳酸二甲酯(0.22mol)，升温至30℃继续反应1h，加入盐酸溶液淬灭反应，减压蒸除丙酮，加入200mL冰水析晶，抽滤，使用100mL冷水清洗晶体，真空烘干，得到15.57g式IV化合物4-氨基-2-甲氧基苯甲酸甲酯，产物收率为86％，产物纯度为99.3％。Dissolve 15.31g 4-aminosalicylic acid (0.1mol) in 100mL acetone in a three-necked flask, add 3.22g tetrabutylammonium bromide (0.01mol), stir to dissolve, control the temperature to 25°C and add 21g sodium bicarbonate (0.25mol) , after dissolving, slowly add 19.82g dimethyl carbonate (0.22mol) dropwise, raise the temperature to 30°C and continue the reaction for 1 hour, add hydrochloric acid solution to quench the reaction, evaporate the acetone under reduced pressure, add 200mL ice water to crystallize, filter with suction, use 100mL The crystals were washed with cold water and dried under vacuum to obtain 15.57g of formula IV compound 4-amino-2-methoxybenzoic acid methyl ester. The product yield was 86% and the product purity was 99.3%.
实施例6Example 6
三口瓶中将15.31g4-氨基水杨酸(0.1mol)溶于100mL丙酮，加入0.94g二甲基磷酸(0.01mol)，搅拌溶解，控温25℃加入15.27g乙醇胺(0.25mol)，溶解后缓慢滴加19.82g碳酸二甲酯(0.22mol)，升温至30℃继续反应1h，加入盐酸溶液淬灭反应，减压蒸除丙酮，加入200mL冰水析晶，抽滤，使用100mL冷水清洗晶体，真空烘干，得到15.52g式IV化合物4-氨基-2-甲氧基苯甲酸甲酯，产物收率为85.7％，产物纯度为99.1％。Dissolve 15.31g 4-aminosalicylic acid (0.1mol) in 100mL acetone in a three-necked flask, add 0.94g dimethylphosphoric acid (0.01mol), stir to dissolve, control the temperature to 25°C, add 15.27g ethanolamine (0.25mol), and dissolve Slowly add 19.82g dimethyl carbonate (0.22mol) dropwise, raise the temperature to 30°C and continue the reaction for 1 hour. Add hydrochloric acid solution to quench the reaction, evaporate acetone under reduced pressure, add 200mL ice water to crystallize, filter with suction, and use 100mL cold water to clean the crystals. , vacuum drying to obtain 15.52g of formula IV compound 4-amino-2-methoxybenzoic acid methyl ester, the product yield is 85.7%, and the product purity is 99.1%.
实施例7Example 7
三口瓶中将18.1g式IV化合物(0.1mol)和12.16g硫氰酸钠(0.15mol)溶于150mL乙醇中，降温至5℃，将19g碘(0.075mol)溶于50mL乙醇中，控温5℃，缓慢滴加至三口瓶内溶液中，滴加完毕后继续反应1h，加入饱和碳酸氢钠水溶液淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水清洗有机相，减压脱溶，使用甲醇重结晶，过滤后真空烘干，得到21.95g式III化合物4-氨基-2-甲氧基-5-硫氰基苯甲酸甲酯，产物收率为92.2％，产物纯度为99.1％。Dissolve 18.1g formula IV compound (0.1mol) and 12.16g sodium thiocyanate (0.15mol) in 150mL ethanol in a three-necked flask, cool to 5°C, dissolve 19g iodine (0.075mol) in 50mL ethanol, and control the temperature 5°C, slowly add dropwise to the solution in the three-necked flask. After the dropwise addition is completed, continue the reaction for 1 hour. Add saturated sodium bicarbonate aqueous solution to quench the reaction, evaporate the solution under reduced pressure, extract 3 times with 100mL ethyl acetate, and combine the organic phases. Use 100 mL of cold water to wash the organic phase, remove the solvent under reduced pressure, use methanol to recrystallize, filter and dry under vacuum to obtain 21.95g of formula III compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester, the product The yield was 92.2% and the product purity was 99.1%.
实施例8Example 8
三口瓶中将18.1g式IV化合物(0.1mol)和12.16g硫氰酸钠(0.15mol)溶于150mL乙醇中，降温至5℃，将14.38g液溴(0.09mol)稀释到50mL乙醇中，控温20℃，缓慢滴加至三口瓶内溶液中，滴加完毕后继续反应1h，加入饱和碳酸氢钠水溶液淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水清洗有机相，减压脱溶，使用甲醇重结晶，过滤后真空烘干，得到21.66g式III化合物4-氨基-2-甲氧基-5-硫氰基苯甲酸甲酯，产物收率为91％，产物纯度为99％。Dissolve 18.1g formula IV compound (0.1mol) and 12.16g sodium thiocyanate (0.15mol) in 150mL ethanol in a three-necked flask, cool to 5°C, and dilute 14.38g liquid bromine (0.09mol) into 50mL ethanol. Control the temperature at 20°C and slowly add it dropwise to the solution in the three-necked flask. After the dropwise addition, continue the reaction for 1 hour. Add saturated aqueous sodium bicarbonate solution to quench the reaction. Evaporate the solution under reduced pressure. Extract 3 times with 100 mL of ethyl acetate. Combine the organic acids. Phase, use 100mL cold water to wash the organic phase, remove the solvent under reduced pressure, use methanol to recrystallize, filter and dry under vacuum to obtain 21.66g of formula III compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester. , the product yield is 91%, and the product purity is 99%.
实施例9Example 9
三口瓶中将18.9g亚硫酸钠(0.15mol)溶于200mL乙醇，降温至15℃，分批加入23.8g式III化合物(0.1mol)，加入后搅拌，控温反应30min，缓慢加入18.5g硫酸二乙酯(0.12mol)，降温至10℃继续反应1h，反应完成后加入大量清水淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL饱和食盐水洗涤有机相，减压脱溶，滤液回收硫氰酸钠重复利用，使用甲醇重结晶，过滤后真空烘干，得到20.56g式II化合物4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯，产物收率为85.3％，产物纯度为99.1％。Dissolve 18.9g sodium sulfite (0.15mol) in 200mL ethanol in a three-necked flask, cool to 15°C, add 23.8g formula III compound (0.1mol) in batches, stir after addition, control temperature for 30 minutes, slowly add 18.5g diethyl sulfate ester (0.12 mol), cool to 10°C and continue the reaction for 1 hour. After the reaction is completed, add a large amount of water to quench the reaction, evaporate the solution under reduced pressure, extract three times with 100 mL of ethyl acetate, combine the organic phases, and wash the organic phase with 100 mL of saturated brine. phase, decomposed under reduced pressure, recovered sodium thiocyanate from the filtrate for reuse, recrystallized with methanol, filtered and dried under vacuum to obtain 20.56g of formula II compound 4-amino-2-methoxy-5-ethylthiobenzoic acid. Methyl ester, the product yield is 85.3%, and the product purity is 99.1%.
实施例10Example 10
三口瓶中将15.61g亚硫酸氢钠(0.15mol)溶于200mL乙醇，降温至15℃，分批加入23.8g式III化合物(0.1mol)，加入后搅拌，控温反应30min，缓慢加入18.5g硫酸二乙酯(0.12mol)，降温至10℃继续反应1h，反应完成后加入大量清水淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL饱和食盐水洗涤有机相，减压脱溶，滤液回收硫氰酸钠重复利用，使用甲醇重结晶，过滤后真空烘干，得到20.42g式II化合物4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯，产物收率为84.7％，产物纯度为99％。Dissolve 15.61g sodium bisulfite (0.15mol) in 200mL ethanol in a three-necked flask, cool to 15°C, add 23.8g formula III compound (0.1mol) in batches, stir after addition, control temperature for 30 minutes, slowly add 18.5g Diethyl sulfate (0.12 mol), cool to 10°C and continue the reaction for 1 hour. After the reaction is completed, add a large amount of water to quench the reaction, evaporate the solution under reduced pressure, extract three times with 100 mL of ethyl acetate, combine the organic phases, and use 100 mL of saturated salt. Wash the organic phase with water, remove it under reduced pressure, recover the sodium thiocyanate from the filtrate and reuse it, recrystallize it with methanol, filter it and dry it in a vacuum to obtain 20.42g of formula II compound 4-amino-2-methoxy-5-ethyl sulfide. methyl benzoate, the product yield was 84.7%, and the product purity was 99%.
实施例11Example 11
三口瓶中将28.82g九水合硫化钠(0.12mol)溶于200mL乙醇，降温至15℃，分批加入23.8g式III化合物(0.1mol)，加入后搅拌，控温反应30min，缓慢加入15.42g硫酸二乙酯(0.1mol)，降温至10℃继续反应1h，反应完成后加入大量清水淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL饱和食盐水洗涤有机相，减压脱溶，滤液回收硫氰酸钠重复利用，使用甲醇重结晶，过滤后真空烘干，得到20.73g式II化合物4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯，产物收率为86％，产物纯度为98.8％。Dissolve 28.82g sodium sulfide nonahydrate (0.12mol) in 200mL ethanol in a three-necked flask, cool to 15°C, add 23.8g formula III compound (0.1mol) in batches, stir after addition, control temperature for 30 minutes, slowly add 15.42g Diethyl sulfate (0.1 mol), cool to 10°C and continue the reaction for 1 hour. After the reaction is completed, add a large amount of water to quench the reaction, evaporate the solution under reduced pressure, extract three times with 100 mL of ethyl acetate, combine the organic phases, and use 100 mL of saturated salt. Wash the organic phase with water, remove it under reduced pressure, recover the sodium thiocyanate from the filtrate and reuse it, recrystallize it with methanol, filter it and dry it in a vacuum to obtain 20.73g of compound II compound 4-amino-2-methoxy-5-ethyl sulfide. methyl benzoate, the product yield was 86%, and the product purity was 98.8%.
实施例12Example 12
三口瓶中将36.03g九水合硫化钠(0.15mol)溶于200mL乙醇，降温至15℃，分批加入23.8g式III化合物(0.1mol)，加入后搅拌，控温反应30min，缓慢加入23.12g硫酸二乙酯(0.15mol)，降温至10℃继续反应1h，反应完成后加入大量清水淬灭反应，减压蒸除溶液，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL饱和食盐水洗涤有机相，减压脱溶，滤液回收硫氰酸钠重复利用，使用甲醇重结晶，过滤后真空烘干，得到21g式II化合物4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯，产物收率为87.1％，产物纯度为99.2％。Dissolve 36.03g sodium sulfide nonahydrate (0.15mol) in 200mL ethanol in a three-necked flask, cool to 15°C, add 23.8g formula III compound (0.1mol) in batches, stir after addition, control temperature for 30 minutes, slowly add 23.12g Diethyl sulfate (0.15 mol), cool down to 10°C and continue the reaction for 1 hour. After the reaction is completed, add a large amount of water to quench the reaction, evaporate the solution under reduced pressure, extract three times with 100 mL of ethyl acetate, combine the organic phases, and use 100 mL of saturated salt. Wash the organic phase with water, remove it under reduced pressure, recover the sodium thiocyanate from the filtrate and reuse it, recrystallize it with methanol, filter it and dry it under vacuum to obtain 21g of compound II compound 4-amino-2-methoxy-5-ethylthio. Methyl benzoate, the product yield is 87.1%, and the product purity is 99.2%.
实施例13Example 13
三口瓶中将24.1g式II化合物(0.1mol)和0.2g钼酸铵(0.001mol)溶于100mL乙醇，降温至5℃，缓慢滴加30mL30％的双氧水，滴加完毕后升温至30℃反应,1h，冰浴下缓慢滴加10％的硫代硫酸钠水溶液去除双氧水，双氧水除尽后，减压脱除乙醇，使用100mL乙酸乙酯萃取，合并有机相，使用100mL冷水洗涤有机相,抽滤，降温析晶，过滤后真空烘干，得到白色固体；Dissolve 24.1g of formula II compound (0.1mol) and 0.2g ammonium molybdate (0.001mol) in 100mL of ethanol in a three-necked flask, cool to 5°C, slowly add 30mL of 30% hydrogen peroxide dropwise, and after completion of the dropwise addition, raise the temperature to 30°C for reaction. , 1h, slowly add 10% sodium thiosulfate aqueous solution dropwise in an ice bath to remove the hydrogen peroxide. After the hydrogen peroxide is removed, remove the ethanol under reduced pressure, extract with 100mL of ethyl acetate, combine the organic phases, wash the organic phase with 100mL of cold water, and pump Filter, cool down to crystallize, filter and dry in vacuum to obtain a white solid;
将16g氢氧化钠溶于200mL水得到碱液，将27.3g白色固体悬浮在碱液中，升温至50℃，搅拌溶解后继续反应1h，降温至10℃，加入质量分数为10％的盐酸溶液调节反应液pH为4.0～4.5淬灭反应，减压蒸馏除去绝大部分水，降温至5℃析晶，抽滤，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水洗涤有机相，减压脱溶，使用四氢呋喃重结晶，过滤后真空干燥，得到22.97g式I化合物4-氨基-5-乙基磺酰基-2-甲氧基苯甲酸，产物收率为88.7％，产物纯度为99.6％。Dissolve 16g sodium hydroxide in 200mL water to obtain lye. Suspend 27.3g white solid in the lye, raise the temperature to 50°C, stir and dissolve, continue the reaction for 1 hour, cool to 10°C, and add 10% hydrochloric acid solution. Adjust the pH of the reaction solution to 4.0~4.5 to quench the reaction, remove most of the water by distillation under reduced pressure, cool to 5°C to crystallize, filter with suction, extract three times with 100 mL of ethyl acetate, combine the organic phases, and wash the organic phase with 100 mL of cold water. , decomposed under reduced pressure, recrystallized using tetrahydrofuran, filtered and dried under vacuum to obtain 22.97g of formula I compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, product yield was 88.7%, product purity is 99.6%.
实施例14Example 14
三口瓶中将24.1g式II化合物(0.1mol)和0.18g钨酸钠(0.001mol)溶于100mL乙醇，降温至5℃，缓慢滴加30mL30％的双氧水，滴加完毕后升温至30℃反应,1h，冰浴下缓慢滴加10％的硫代硫酸钠水溶液去除双氧水，双氧水除尽后，减压脱除乙醇，使用100mL乙酸乙酯萃取，合并有机相，使用100mL冷水洗涤有机相,抽滤，降温析晶，过滤后真空烘干，得到白色固体；Dissolve 24.1g of the compound of Formula II (0.1mol) and 0.18g of sodium tungstate (0.001mol) in 100mL of ethanol in a three-necked flask, cool the temperature to 5°C, slowly add 30mL of 30% hydrogen peroxide dropwise, and after completion of the dropwise addition, raise the temperature to 30°C for reaction. , 1h, slowly add 10% sodium thiosulfate aqueous solution dropwise in an ice bath to remove the hydrogen peroxide. After the hydrogen peroxide is removed, remove the ethanol under reduced pressure, extract with 100mL of ethyl acetate, combine the organic phases, wash the organic phase with 100mL of cold water, and pump Filter, cool down to crystallize, filter and dry in vacuum to obtain a white solid;
将16g氢氧化钠溶于200mL水得到碱液，将27.3g白色固体悬浮在碱液中，升温至50℃，搅拌溶解后继续反应1h，降温至10℃，加入质量分数为10％的盐酸溶液调节反应液pH为4.0～4.5淬灭反应，减压蒸馏除去绝大部分水，降温至5℃析晶，抽滤，使用100mL乙酸乙酯萃取3次，合并有机相，使用100mL冷水洗涤有机相，减压脱溶，使用四氢呋喃重结晶，过滤后真空干燥，得到22.93g式I化合物4-氨基-5-乙基磺酰基-2-甲氧基苯甲酸，产物收率为88.5％，产物纯度为99.6％。Dissolve 16g sodium hydroxide in 200mL water to obtain lye. Suspend 27.3g white solid in the lye, raise the temperature to 50°C, stir and dissolve, continue the reaction for 1 hour, cool to 10°C, and add 10% hydrochloric acid solution. Adjust the pH of the reaction solution to 4.0~4.5 to quench the reaction, remove most of the water by distillation under reduced pressure, cool to 5°C to crystallize, filter with suction, extract three times with 100 mL of ethyl acetate, combine the organic phases, and wash the organic phase with 100 mL of cold water. , decomposed under reduced pressure, recrystallized using tetrahydrofuran, filtered and dried under vacuum to obtain 22.93g of formula I compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, product yield was 88.5%, product purity is 99.6%.
对比例Comparative ratio
4-氨基-2-甲氧基苯甲酸甲酯(化合物2)的合成：Synthesis of 4-amino-2-methoxybenzoic acid methyl ester (compound 2):
向1L三口瓶中加人对氨基水杨酸75.0g(0.49mol)、四丁基溴化铵75g(23mmol)和丙酮500mL，维持温度为20～25℃，先加入氢氧化钾700g(125mol)，然后滴加硫酸二甲酯126g(1.00mol)，搅拌反应约30min后再加入氢氧化钾130g(023mol)和硫酸二甲酯22g(18mol)维持温度20～25℃继续搅拌约1.0h。TLC显示反应(展开剂:V(石油醚):V(乙酸乙酯)＝2:1)完全后减压蒸出丙酮。向残留物中加入冰水300mL，搅拌、过滤、干燥，得白色粉末固体750g，收率为85％，熔点为157～160℃(文献值[12]158～160℃)。Add 75.0g (0.49mol) of para-aminosalicylic acid, 75g (23mmol) of tetrabutylammonium bromide and 500mL of acetone to a 1L three-necked flask. Maintain the temperature at 20-25°C. First add 700g of potassium hydroxide (125mol). , then add 126g (1.00mol) of dimethyl sulfate dropwise, stir for about 30 minutes, then add 130g (023mol) of potassium hydroxide and 22g (18mol) of dimethyl sulfate, maintaining the temperature at 20-25°C and continue stirring for about 1.0h. TLC showed that the reaction (developing agent: V (petroleum ether): V (ethyl acetate) = 2:1) was complete, and then the acetone was evaporated under reduced pressure. Add 300 mL of ice water to the residue, stir, filter, and dry to obtain 750 g of white powder solid with a yield of 85% and a melting point of 157 to 160°C (literature value [12] 158 to 160°C).
4-氨基-2-甲氧基-5-氰硫基苯甲酸甲酯(化合物3)的合成：Synthesis of 4-amino-2-methoxy-5-cyanothiobenzoic acid methyl ester (compound 3):
向1L三口瓶中加入中间体(化合物2)64.0g(0.35mol)、硫氰酸铵64.0g(0.84mol)和甲醇440mL维持温度0～5℃，滴加含有溴素670g(0.42mol)的200mL甲醇溶液，滴加完毕后升温至5～10℃继续搅拌约2.5h。TLC显示反应(展开剂:V(石油醚):V(乙酸乙酯)＝2∶1)完全后，滴加饱和的碳酸氢钠水溶液，调节pH值至中性，过滤、干燥，得白色粉末固体78.0g收率为92％，熔点为181～184℃(文献[13]值为180～184℃)。Add 64.0g (0.35mol) of intermediate (compound 2), 64.0g (0.84mol) of ammonium thiocyanate and 440mL of methanol into a 1L three-necked flask to maintain the temperature at 0~5°C, and dropwise add 670g (0.42mol) of bromine. 200 mL methanol solution, after the dropwise addition is completed, raise the temperature to 5~10°C and continue stirring for about 2.5 hours. After TLC shows that the reaction (developing agent: V (petroleum ether): V (ethyl acetate) = 2:1) is complete, add saturated sodium bicarbonate aqueous solution dropwise, adjust the pH value to neutral, filter and dry to obtain white powder. The yield of 78.0 g of solid was 92%, and the melting point was 181 to 184°C (the value in literature [13] was 180 to 184°C).
4-氨基-2-甲氧基-5-乙硫基苯甲酸甲酯(化合物4)的合成：Synthesis of 4-amino-2-methoxy-5-ethylthiobenzoic acid methyl ester (compound 4):
向1L三口瓶中加入九水合硫化钠80.0g(0.34mol)和DMF300mL，维持温度15～20℃，将中间体(化合物3)50.0g(021mol)分批加入到反应液中，加入完毕后继续搅拌约0.5h维持温度20～25℃，滴加硫酸二乙酯39.0g(0.25mol)，继续搅拌约1.0h。TLC显示反应(展开剂:V(石油醚):V(乙酸乙酯)＝1:1)完全后，向反应液中缓慢加入400mL冰水，搅拌、过滤、干燥，得浅黄色粉末固体44.0g，收率为87％，熔点为108～111℃。Add 80.0g (0.34mol) sodium sulfide nonahydrate and 300mL DMF to a 1L three-necked flask, maintain the temperature at 15-20°C, add 50.0g (021mol) of the intermediate (compound 3) into the reaction solution in batches, and continue after the addition is complete. Stir for about 0.5h to maintain the temperature at 20-25°C, dropwise add 39.0g (0.25mol) of diethyl sulfate, and continue stirring for about 1.0h. TLC shows that the reaction (developing agent: V (petroleum ether): V (ethyl acetate) = 1:1) is complete, slowly add 400 mL of ice water to the reaction solution, stir, filter, and dry to obtain 44.0 g of light yellow powder solid. , the yield is 87%, and the melting point is 108~111℃.
4-氨基-5-乙磺酰基-2-甲氧基苯甲酸甲酯(化合物5)的合成：Synthesis of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester (compound 5):
向1L三口瓶中加入中间体(化合物4)72.0g(030mol)、钨酸钠0.36g(0001mol)和甲醇300mL，维持温度10℃以下，缓慢滴加90mL30％(体积分数)的双氧水，滴加完毕后升温至30～35℃继续搅拌约1.0h。TLC显示反应(展开剂:V(石油醚):V(乙酸乙酯)＝2:1)完全后，冰浴下缓慢滴加10％(质量分数)的硫代硫酸钠水溶液，用淀粉碘化钾试纸显示，当过量的双氧水除尽后，再经搅拌、过滤、干燥，得白色粉末固体760g，收率为92％，熔点为139～142℃。Add 72.0g (030mol) of intermediate (compound 4), 0.36g (0001mol) of sodium tungstate and 300mL of methanol into a 1L three-necked flask. Maintain the temperature below 10°C and slowly add 90mL of 30% (volume fraction) hydrogen peroxide dropwise. After completion, raise the temperature to 30~35℃ and continue stirring for about 1.0h. After TLC shows that the reaction (developing agent: V (petroleum ether): V (ethyl acetate) = 2:1) is complete, slowly add 10% (mass fraction) sodium thiosulfate aqueous solution dropwise in an ice bath, and use starch potassium iodide test paper It shows that after the excess hydrogen peroxide is removed, and then stirred, filtered, and dried, 760g of white powder solid is obtained, with a yield of 92% and a melting point of 139 to 142°C.
4-氨基-5-乙磺酰基-2-甲氧基苯甲酸(化合物1)的合成：Synthesis of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1):
向500mL三口瓶中加入氢氧化钠16.0g(0.40mol)和水150mL，搅拌至澄清，然后将中间体(化合物5)55.0g(0.20mol)悬浮到碱溶液中，维持温度在50℃左右，搅拌约1.0h。TLC显示反应(展开剂:V(石油醚):V(乙酸乙酯)＝1:1)完全后，控制温度10℃以下，滴加稀盐酸调节pH值至4.5左右，搅拌、过滤、干燥，得类白色固体45.0g，收率为88％，熔点为148～152℃(文献[12]值为148～152℃)。Add 16.0g (0.40mol) of sodium hydroxide and 150mL of water to a 500mL three-necked flask, stir until clear, and then suspend 55.0g (0.20mol) of the intermediate (compound 5) into the alkaline solution, maintaining the temperature at about 50°C. Stir for about 1.0h. After TLC shows that the reaction (developing agent: V (petroleum ether): V (ethyl acetate) = 1:1) is complete, control the temperature below 10°C, add dropwise dilute hydrochloric acid to adjust the pH to about 4.5, stir, filter, and dry. 45.0 g of off-white solid was obtained, with a yield of 88% and a melting point of 148 to 152°C (the value in literature [12] is 148 to 152°C).
对比本发明中的制备方法，此实施例中制备成本偏高，且收率仍旧存在微小差距。Compared with the preparation method in the present invention, the preparation cost in this embodiment is relatively high, and there is still a slight gap in the yield.
本发明的实施方式并不限于上述实施例所述，在不偏离本发明的精神和范围的情况下，本领域普通技术人员可以在形式和细节上对本发明做出各种改变和改进，而这些均被认为落入了本发明的保护范围。The implementation of the present invention is not limited to the above-described embodiments. Without departing from the spirit and scope of the present invention, those of ordinary skill in the art can make various changes and improvements in the form and details of the present invention, and these All are considered to fall within the protection scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311217481.7ACN117185969A (en) | 2023-09-20 | 2023-09-20 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311217481.7ACN117185969A (en) | 2023-09-20 | 2023-09-20 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
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| CN117185969Atrue CN117185969A (en) | 2023-12-08 |
| Application Number | Title | Priority Date | Filing Date |
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| CN202311217481.7APendingCN117185969A (en) | 2023-09-20 | 2023-09-20 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB514203A (en)* | 1938-03-29 | 1939-11-02 | Manchester Oxide Co Ltd | Process for the introduction of the thiocyano group into organic compounds |
| US20130096319A1 (en)* | 2010-06-17 | 2013-04-18 | Lupin Limited | Process for preparation of amisulpride |
| CN103319384A (en)* | 2013-06-18 | 2013-09-25 | 苏州诚和医药化学有限公司 | Method for preparing 2-methoxyl-4-amino-5-ethylsulfonyl methyl benzoate |
| CN106661047A (en)* | 2014-05-27 | 2017-05-10 | 拜耳制药股份公司 | Benzothiadiazolamines |
| CN112521318A (en)* | 2019-09-19 | 2021-03-19 | 北京万全德众医药生物技术有限公司 | Preparation method of amisulpride important intermediate |
| CN114230497A (en)* | 2021-10-21 | 2022-03-25 | 广东省科学院生物与医学工程研究所 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB514203A (en)* | 1938-03-29 | 1939-11-02 | Manchester Oxide Co Ltd | Process for the introduction of the thiocyano group into organic compounds |
| US20130096319A1 (en)* | 2010-06-17 | 2013-04-18 | Lupin Limited | Process for preparation of amisulpride |
| CN103319384A (en)* | 2013-06-18 | 2013-09-25 | 苏州诚和医药化学有限公司 | Method for preparing 2-methoxyl-4-amino-5-ethylsulfonyl methyl benzoate |
| CN106661047A (en)* | 2014-05-27 | 2017-05-10 | 拜耳制药股份公司 | Benzothiadiazolamines |
| CN112521318A (en)* | 2019-09-19 | 2021-03-19 | 北京万全德众医药生物技术有限公司 | Preparation method of amisulpride important intermediate |
| CN114230497A (en)* | 2021-10-21 | 2022-03-25 | 广东省科学院生物与医学工程研究所 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
| Title |
|---|
| 刘磊 等: "4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成", 精细化工中间体, vol. 38, no. 3, 30 June 2008 (2008-06-30), pages 29 - 32* |
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