硫酸特布他林合成工艺的优化和改进
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河北省重点研发计划项目(18274010D)


Optimization and improvement of the synthesis method of terbutaline sulfate
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    摘要:

    为了提高硫酸特布他林的反应收率和产品质量,对其合成方法进行了优化研究。以3,5-二苄氧基苯乙酮为起始原料,依次经过溴代反应、烷基化反应、羰基还原、催化加氢脱苄得到硫酸特布他林,对反应的条件和参数进行了优化和改进。结果表明:溴代反应中,采用四丁基三溴化铵来代替液溴和溴化铜作为溴代试剂,以四氢呋喃和甲醇为溶剂,n(3,5-二苄氧基苯乙酮)∶n(四丁基三溴化铵)=1∶1.3时,反应时间减少至6 h,收率达到99.1%;缩合反应中,用苄基叔丁胺代替叔丁胺,n(3,5-二苄氧基-α-溴代苯乙酮)∶n(苄基叔丁胺)=1∶3,反应收率达到69.9%;催化加氢脱苄基反应中,以甲醇为溶剂、Raney Ni用量为15%、压力为1.0 MPa、温度为40 ℃时,收率达到90.2%。在此优化条件下,反应总收率为62.4%,产品纯度达到99.90%(HPLC法),单杂均小于0.1%,目标化合物结构经过1H-NMR和13C-NMR得以确证。改进后的合成工艺反应条件温和,操作简单,产品收率高,更加适合工业化生产。

    Abstract:

    In order to obtain high yield and product quality of terbutaline sulfate, the synthetic method of terbutaline sulfate is studied. Terbutaline sulfate is synthesized from 3,5-dibenzyloxyacetophenone by bromination, alkylation reaction, carbonyl reduction and catalytic hydrodebenzylation. The reaction conditions and parameters are optimized and improved. Bromination is optimized,with tetrahydrofuran and methanol as solvents,tetrabutylammonium tribromide is used instead of liquid bromide and copper bromide as bromination reagent, n(3,5-dibenzyloxyacetophenone)∶n(tetrabutyl ammonium bromide)=1∶1.3,the reaction time could be reduced to 6 hours, and the yield is up to 99.1%.In condensation reaction, with benzyl tert-butylamine instead of tert-butylamine,n(3, 5-dibenzyloxy-alpha-Bromoacetophenone)∶n(benzyl tert-butylamine)=1∶3, the yield is 69.9%. In catalytic hydrodebenzylation, the amount of Raney Ni is 15% in solvent methanol, the pressure is 1.0 MPa,temperatuer is 40 ℃,and the yield is up to 90.2%. Under the optimized conditions,the total yield is 62.4%,and the purity is 99.90%(by HPLC), the impurities are less than 0.1%. The structures of the target compound are confirmed by 1H-NMR and 13C-NMR. The improved synthesis process with mild reaction conditions, simple operation, and high yield is more suitable for industrial production.

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赵学斌,谷 岚,李晓梦,董莎莎,姚 军.硫酸特布他林合成工艺的优化和改进[J].河北科技大学学报,2019,40(5):379-384

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  • 收稿日期:2019-06-04
  • 最后修改日期:2019-08-20
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  • 在线发布日期: 2019-10-24
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