2-氨基-5-氯-N，3-二甲基苯甲酰胺和2-甲基乙酰乙酸乙酯的合成工艺研究
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摘要
2-氨基-5-氯-N,3-二甲基苯甲酰胺(ACBA)是氯虫苯甲酰胺的重要中间体,2-甲基乙酰乙酸乙酯(2-MEA)是抗蚜威的重要中间体。本文详细介绍了2-氨基-5-氯-N,3-二甲基苯甲酰胺和2-甲基乙酰乙酸乙酯的合成工艺研究。
本文确定了两条可行的2-氨基-5-氯-N,3-二甲基苯甲酰胺的合成路线,A路线以2-硝基-3-甲基苯甲酸为原料,依次经催化、环合、甲胺化和氯化合成目标化合物,得到的产品纯度≥97.9%,反应总收率达82.0%,高出文献值15.5%。在2-氨基-3-甲基苯甲酸的合成中,采用Fe O(OH)/C催化水合肼还原法,解决了文献方法对设备要求高等问题。在ACBA合成中,通过实验探究确定了适宜的氯化试剂,避免了文献直接通氯气或采用双氧水/浓盐酸法带来的反应不易控制,产品品质差等问题,此步收率达89.4%,含量≥97.9%。高出文献值17%。此路线合成过程中光气环合,甲胺化和氯化三步反应溶剂一致,我们将这三步一锅进行得到ACBA,总收率约为82%,避免了中间体纯化分离,操作更简单,更适宜工业化生产。B路线依次经催化、氯化、环合和甲胺化合成目标化合物,得到的产品纯度≥97.6%,总收率达84.3%,高出文献值17.8%。
我们确定了两条2-甲基乙酰乙酸乙酯的合成路线,A路线为烯胺合成法,以乙酰乙酸乙酯为原料,经哌啶亲核、酸性脱水,甲基化得到目标化合物。在2-六氢吡啶基丁烯酸乙酯的合成中,采用哌啶为亲核试剂,更有利于下一步合成最终产物,反应收率96.4%,产品含量≥96.0%。此合成方法不需要碱性催化剂,降低了生产成本,避免自身缩合以及多烃化副产反应收率为85.4%,高出文献值5.4%,产品含量≥96.3%。B路线为催化加氢法,经甲醛缩合,在加氢催化剂的作用下通入氢气,经后处理得到目标物。选取了适宜的加氢催化剂,优化了催化剂量,反应时间等反应条件,反应收率为91.7%,产品含量99.0%。此合成方法原料便宜,收率高,后处理简单,易于工业化。
我们对合成目标物以及重要中间体的化学结构均通过MS及H1MNR进行了表征,证实了与目标物及其中间体的分子结构完全相符合。
2-Amino-5-chloro-N,3-dimethylbenzamide is the key intermediate of synth-esis of chlorantraniliprole. Ethyl 2-methylacetoacetate is the key intermediate of synthesis of pirimicarb. This paper has summarized the optimization on the synthesis process of the 2-Amino-5-chloro-N,3-dime-thylbenzamide and ethyl 2-methylacetoacetate.
Two reasonable synthesis routes of 2-Amino-5-chloro-N,3-dimethyl-benza-mide were evaluated in this paper, that were obtained from 3-methyl-2-nitroben-zoic acid. A-route target compound was obtained via catalyzed reduction, cyclization, methylamination and chlorination, the yield and purity of the product was≥82% and≥97.9%, respectively. During the process of preparing 2-amino-3-methyl benzoic acid, high requirements for equipment was resolved by using FeO(OH)/C-catalyzed reduction with hydrazine hydrate. During the process of preparing 2-Amino-5-chloro-N,3-dimethylbenzamide, the suitable chlorination reagent was determined via large quantity of experiment and exploration. From this, the yield and purity of the product was≥89.4% and≥97.9%. The total yield increased about 17%.In the process of synthesis, cyclization, methylamineation and chlorination in one pot because of their solvent was unanimous, which avoided purification of the intermediate product and simplified the process, therefore the route was more suited for industrialization production. B-route TM was obtained via catalyzed reduction, chlorination, cyclization and methylamination, the yield and purity of the product was≥84.3% and≥97.6%. respectively. The total yield increased about 17.8%.
Two reasonable synthesis routes of ethyl 2-methylacetoacetate were explored. A-route was enamine synthesis.2-methylacetoacetate was obtained from methyl aceto acetate, via piperidine nucleophilie, acid dehydration and methylamination. During the process of preparing 2-hexahy dropyridine ethyl crotonate, it was favourable toward the next step reaction by using piperidine as the nucleophilic reagent. The yield and purity of the product was≥96.4%and≥96%. The total yield increased about 5.4%. This method without using basic catalyst, could avoid self-condensation by-products. From this, the yield and purity of the product was≥85.4% and≥96.3%, respectively. B-route was catalytic hydrogenation synthesis. The synthesis of 2-methylacetoacetate was got from formaldehyde condensation and hydrogenation reduction with hydrogenation catalyst. During the process of preparing the target compound, the suitable hydrogenation catalyst was selected and reaction conditions, such as amount of catalyst, reaction time and so on, were optimized. Then the yield and purity of the product was≥91.7% and≥99%. Raw material was cheap, the yield and purity was high, post-treatm-ent was simple. Therefore, the method was more suitable for industrial.
The by-products and its important intermediates were separated, and then characterized by NMR and MS. It's found that the structures of target product and important intermediates were confirmed.
本文确定了两条可行的2-氨基-5-氯-N,3-二甲基苯甲酰胺的合成路线,A路线以2-硝基-3-甲基苯甲酸为原料,依次经催化、环合、甲胺化和氯化合成目标化合物,得到的产品纯度≥97.9%,反应总收率达82.0%,高出文献值15.5%。在2-氨基-3-甲基苯甲酸的合成中,采用Fe O(OH)/C催化水合肼还原法,解决了文献方法对设备要求高等问题。在ACBA合成中,通过实验探究确定了适宜的氯化试剂,避免了文献直接通氯气或采用双氧水/浓盐酸法带来的反应不易控制,产品品质差等问题,此步收率达89.4%,含量≥97.9%。高出文献值17%。此路线合成过程中光气环合,甲胺化和氯化三步反应溶剂一致,我们将这三步一锅进行得到ACBA,总收率约为82%,避免了中间体纯化分离,操作更简单,更适宜工业化生产。B路线依次经催化、氯化、环合和甲胺化合成目标化合物,得到的产品纯度≥97.6%,总收率达84.3%,高出文献值17.8%。
我们确定了两条2-甲基乙酰乙酸乙酯的合成路线,A路线为烯胺合成法,以乙酰乙酸乙酯为原料,经哌啶亲核、酸性脱水,甲基化得到目标化合物。在2-六氢吡啶基丁烯酸乙酯的合成中,采用哌啶为亲核试剂,更有利于下一步合成最终产物,反应收率96.4%,产品含量≥96.0%。此合成方法不需要碱性催化剂,降低了生产成本,避免自身缩合以及多烃化副产反应收率为85.4%,高出文献值5.4%,产品含量≥96.3%。B路线为催化加氢法,经甲醛缩合,在加氢催化剂的作用下通入氢气,经后处理得到目标物。选取了适宜的加氢催化剂,优化了催化剂量,反应时间等反应条件,反应收率为91.7%,产品含量99.0%。此合成方法原料便宜,收率高,后处理简单,易于工业化。
我们对合成目标物以及重要中间体的化学结构均通过MS及H1MNR进行了表征,证实了与目标物及其中间体的分子结构完全相符合。
2-Amino-5-chloro-N,3-dimethylbenzamide is the key intermediate of synth-esis of chlorantraniliprole. Ethyl 2-methylacetoacetate is the key intermediate of synthesis of pirimicarb. This paper has summarized the optimization on the synthesis process of the 2-Amino-5-chloro-N,3-dime-thylbenzamide and ethyl 2-methylacetoacetate.
Two reasonable synthesis routes of 2-Amino-5-chloro-N,3-dimethyl-benza-mide were evaluated in this paper, that were obtained from 3-methyl-2-nitroben-zoic acid. A-route target compound was obtained via catalyzed reduction, cyclization, methylamination and chlorination, the yield and purity of the product was≥82% and≥97.9%, respectively. During the process of preparing 2-amino-3-methyl benzoic acid, high requirements for equipment was resolved by using FeO(OH)/C-catalyzed reduction with hydrazine hydrate. During the process of preparing 2-Amino-5-chloro-N,3-dimethylbenzamide, the suitable chlorination reagent was determined via large quantity of experiment and exploration. From this, the yield and purity of the product was≥89.4% and≥97.9%. The total yield increased about 17%.In the process of synthesis, cyclization, methylamineation and chlorination in one pot because of their solvent was unanimous, which avoided purification of the intermediate product and simplified the process, therefore the route was more suited for industrialization production. B-route TM was obtained via catalyzed reduction, chlorination, cyclization and methylamination, the yield and purity of the product was≥84.3% and≥97.6%. respectively. The total yield increased about 17.8%.
Two reasonable synthesis routes of ethyl 2-methylacetoacetate were explored. A-route was enamine synthesis.2-methylacetoacetate was obtained from methyl aceto acetate, via piperidine nucleophilie, acid dehydration and methylamination. During the process of preparing 2-hexahy dropyridine ethyl crotonate, it was favourable toward the next step reaction by using piperidine as the nucleophilic reagent. The yield and purity of the product was≥96.4%and≥96%. The total yield increased about 5.4%. This method without using basic catalyst, could avoid self-condensation by-products. From this, the yield and purity of the product was≥85.4% and≥96.3%, respectively. B-route was catalytic hydrogenation synthesis. The synthesis of 2-methylacetoacetate was got from formaldehyde condensation and hydrogenation reduction with hydrogenation catalyst. During the process of preparing the target compound, the suitable hydrogenation catalyst was selected and reaction conditions, such as amount of catalyst, reaction time and so on, were optimized. Then the yield and purity of the product was≥91.7% and≥99%. Raw material was cheap, the yield and purity was high, post-treatm-ent was simple. Therefore, the method was more suitable for industrial.
The by-products and its important intermediates were separated, and then characterized by NMR and MS. It's found that the structures of target product and important intermediates were confirmed.
引文
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