盐酸维拉佐酮的合成工艺改进研究
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摘要
目的对盐酸维拉佐酮的合成工艺进行改进。方法以4-(4-乙酰基哌嗪-1-基)苯酚为起始原料,经Duff反应、取代、环化、脱保护、酰胺化得到关键中间体5-(1-哌嗪基)-苯并呋喃-2-甲酰胺,再与3-(4-氯丁酰基)-1H-吲哚-5-甲氰缩合、成盐得到盐酸维拉佐酮。结果合成了目标化合物盐酸维拉佐酮,并利用~1H-NMR、MS确证了结构,质量分数为99.8%,该路线的总收率为22.5%。结论该合成工艺原料廉价易得、操作简单,适于工业化生产。
Objective To improve the process for synthesis of vilazodone hydrochloride. Methods The key intermediate 5-(1-piperazinyl)benzofuran-2-carboxamide was prepared from 4-(4-acetylpiperazine-1-yl)phenol by Duff reaction, substitution, cyclization, deprotection, and amidation. Vilazodone hydrochloride was synthesized from 5-(1-piperazinyl)benzofuran-2-carboxamide and 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile by substitution and salification. Results The target compound vilazodone hydrochloride was synthesized and characterized by ~1H-NMR and MS. The purity was 99.8%, and the total yield of this synthetic route was 22.5%. Conclusion The synthetic process with facile material and simple operation simplified method is applicable to industrial production.
Objective To improve the process for synthesis of vilazodone hydrochloride. Methods The key intermediate 5-(1-piperazinyl)benzofuran-2-carboxamide was prepared from 4-(4-acetylpiperazine-1-yl)phenol by Duff reaction, substitution, cyclization, deprotection, and amidation. Vilazodone hydrochloride was synthesized from 5-(1-piperazinyl)benzofuran-2-carboxamide and 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile by substitution and salification. Results The target compound vilazodone hydrochloride was synthesized and characterized by ~1H-NMR and MS. The purity was 99.8%, and the total yield of this synthetic route was 22.5%. Conclusion The synthetic process with facile material and simple operation simplified method is applicable to industrial production.
引文
[1]王来海,张瑞玲,李焕芬.新型抗抑郁药维拉唑酮的药理与临床评价[J].中国新药杂志,2011,20(18):1729-1731.
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[4]Heinrich T,B?ttcher H,Gericke R,et al.Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT1A receptor agonists and serotonin reuptake inhibitors[J].J Med Chem,2004,47(19),4684-4692.
[5]A·巴瑟,S·埃莫特,B·海尔夫特,等.通过过渡金属催化的氨基化反应制备5-(1-哌嗪基)-苯并呋喃-2-甲酰胺的方法[P].中国:1232519,2005-12-21.
[6]竺伟,陈宇,袁利.一种制备维拉佐酮中间体5-哌嗪基-2-酰基取代苯并呋喃的方法[P].中国:103145664,2011-12-06.
[7]薛小平,刘长欢,邓国昌.5-氨基苯并呋喃-2-甲酸酯及其中间体的制备方法[P].中国:102108070,2011-01-26.
[8]郑广兵.酚类化合物的催化邻甲酰基化研究[D].大连:大连理工大学,2012.
[9]王志龙,康江鹏,潘毅,等.盐酸维拉佐酮的合成工艺研究[J].现代药物与临床,2015,30(7):753-756.
[10]钱定权,曹如珍.Vilsmeier试剂近年来在有机合成中的应用[J].有机化学,2000,20(1):30-43.
[11]程青芳,王启发,邱峰,等.盐酸维拉佐酮的合成方法改进[J].中国新药杂志,2013,22(2):226-229.
[2]Sorbera L A,Rabasseda X,Silvestre J,et al.Vilazodone hydrochloride[J].Drugs Fut,2001,26(3):247-252.
[3]A·巴斯,B·海尔福特,H·博特彻尔,等.苯并呋喃类[P].中国:1181067,2004-12-22.
[4]Heinrich T,B?ttcher H,Gericke R,et al.Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT1A receptor agonists and serotonin reuptake inhibitors[J].J Med Chem,2004,47(19),4684-4692.
[5]A·巴瑟,S·埃莫特,B·海尔夫特,等.通过过渡金属催化的氨基化反应制备5-(1-哌嗪基)-苯并呋喃-2-甲酰胺的方法[P].中国:1232519,2005-12-21.
[6]竺伟,陈宇,袁利.一种制备维拉佐酮中间体5-哌嗪基-2-酰基取代苯并呋喃的方法[P].中国:103145664,2011-12-06.
[7]薛小平,刘长欢,邓国昌.5-氨基苯并呋喃-2-甲酸酯及其中间体的制备方法[P].中国:102108070,2011-01-26.
[8]郑广兵.酚类化合物的催化邻甲酰基化研究[D].大连:大连理工大学,2012.
[9]王志龙,康江鹏,潘毅,等.盐酸维拉佐酮的合成工艺研究[J].现代药物与临床,2015,30(7):753-756.
[10]钱定权,曹如珍.Vilsmeier试剂近年来在有机合成中的应用[J].有机化学,2000,20(1):30-43.
[11]程青芳,王启发,邱峰,等.盐酸维拉佐酮的合成方法改进[J].中国新药杂志,2013,22(2):226-229.