Ivacaftor关键中间体2,4-二叔丁基-5-氨基苯酚的合成工艺研究
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摘要
以2,4-二叔丁基苯酚为起始原料,经亚硝化、还原两步反应制备目标产品2,4-二叔丁基-5-氨基苯酚,其结构经1H NMR和MS确证,总收率为75. 3%,粒径主要分布于20～40μm。通过单因素试验获得了较优的工艺条件,亚硝化反应:n(2,4-二叔丁基苯酚)∶n(亚硝酸钠)=1. 0∶1. 6,反应时间2～3 h;还原反应:n(2,4-二叔丁基-5-亚硝基苯酚)∶n(硫代硫酸钠)=1. 0∶2. 6,反应温度为50～60℃。该路线操作简单、反应条件温和,易于放大生产,具有较好的应用价值。
This paper presents the synthesis process study of 2,4-di-tert-butyl-5-aminophenol. The target product 2,4-di-tert-butyl-5-aminophenol(Ⅰ) was synthesized from the 2,4-di-tert-butyl phenol(Ⅱ) via nitrosation reaction and reduction reaction. The structure was confirmed by 1H NMR and MS. The overall yield amounts to 75. 3% and the particle size is mainly distributed into 20 ～ 40 μm. The effects of material ratio,reaction temperature and reaction time were studied by single factor experiment. The preferential experimental results showed that the optimal reaction condition as follows. The nitrosation reaction: n(Ⅱ) : n(sodium nitrite) = 1. 0: 1. 6,the reaction time is 2 ～ 3 h. The reduction reaction: n(Ⅲ) :n(sodium thiosulfate) = 1. 0: 2. 6,and the reaction temperature is 50 ～ 60 ℃. This synthetic route has the advantages of easy preparation and mild reaction conditions,which is suitable for further application and good for practical application values.
This paper presents the synthesis process study of 2,4-di-tert-butyl-5-aminophenol. The target product 2,4-di-tert-butyl-5-aminophenol(Ⅰ) was synthesized from the 2,4-di-tert-butyl phenol(Ⅱ) via nitrosation reaction and reduction reaction. The structure was confirmed by 1H NMR and MS. The overall yield amounts to 75. 3% and the particle size is mainly distributed into 20 ～ 40 μm. The effects of material ratio,reaction temperature and reaction time were studied by single factor experiment. The preferential experimental results showed that the optimal reaction condition as follows. The nitrosation reaction: n(Ⅱ) : n(sodium nitrite) = 1. 0: 1. 6,the reaction time is 2 ～ 3 h. The reduction reaction: n(Ⅲ) :n(sodium thiosulfate) = 1. 0: 2. 6,and the reaction temperature is 50 ～ 60 ℃. This synthetic route has the advantages of easy preparation and mild reaction conditions,which is suitable for further application and good for practical application values.
引文
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[3] DE B K,ZOLIN A,CUPPENS H,et al. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis[J]. Journal of Cystic Fibrosis,2014,13(4):403-409.
[4]王昊,徐保平,申昆玲.囊性纤维化及中国儿童特点[J].首都医科大学学报,2016,37(5):588-592.
[5]米勒M T,安德森C,阿鲁穆加姆V,等.囊性纤维化跨膜转导调节因子调节剂:中国,107690281A[P]. 2018-02-13.
[6] HORSLEY A,BARRY P. Orkambi in patients with severe disease-bumps in the road to CFTR modulation.[J]. Journal of the European Cystic Fibrosis Society,2017,16(3):311-312.
[7] FLUME P,OWEN C A,BINER R F,et al. WS15. 6 A phase3,open-label study of tezacaftor/ivacaftor(TEZ/IVA)therapy:interim analysis of pooled safety,and efficacy in patients heterozygous for F508del-CFTR and a residual function mutation[J]. Journal of Cystic Fibrosis,2018,17:29-30.
[8]商青姿.囊性纤维化治疗新药Ivacaftor的合成[J].精细化工中间体,2014,44(2):28-33.
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