微波辅助合成氘标记班布特罗-D_9盐酸盐
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摘要
以3',5'-二(二甲氨基甲酰氧基)-α-溴苯乙酮(Ⅰ)为初始原料,经还原反应得1-[双-(3',5'-N,N-二甲氨基甲酰氧基)苯基]-2-溴乙醇(Ⅱ),Ⅱ再与叔丁胺-D_9在微波辅助下进行胺化反应,最后合成了氘标记1-[双-(3',5'-N,N-二甲氨基甲酰氧基)苯基]-2-N-叔丁基氨基乙醇-D_9盐酸盐(班布特罗-D_9盐酸盐)。对还原反应中硼氢化钠用量,胺化反应的物料配比、反应温度和反应时间进行了考察。结果表明:n(Na BH4)∶n(Ⅰ)=2.0∶1.0,乙醇为溶剂时,Ⅱ的收率最高,达87.1%;胺化产物可以起到缚酸剂的作用,与常规加热方法相比,微波辅助的胺化反应速率显著提高,反应时间由16~24 h缩短到30 min。在n(Ⅱ)∶n(叔丁胺-D_9)=1.0∶1.2,反应温度100℃,反应时间为30 min时,叔丁胺-D_9利用率可达74.4%(常规加热方法叔丁胺-D_9利用率不超过40%),班布特罗-D_9盐酸盐的收率为89.3%。产物经1HNMR、MS和UPLC进行了结构表征和性能测试,产物高效液相色谱纯度超过99.0%,氘丰度大于98.5 atom%D,班布特罗-D_9盐酸盐可用作食品安全检测的同位素内标试剂。
A reduction reaction of 5-(bromoacetyl)-1,3-phenylene bis(dimethylcarbamate)(Ⅰ) led to 1-[bis(3',5'-N,N-dimethylcarbamoyloxy) phenyl]-2 bromoethanol(Ⅱ).Intermediate was obtained by an amination reaction with tert-butylamine-D_9 under microwave irradiation(MWI) Subsequently,treatment of the intermediate with hydrochloric acid afforded deuterium labelled bambuterol-D_9 hydrochloride.At the same time,the factors affecting the reduction reaction,such as dosage of sodium borohydride,mole ratio of reactants,reaction temperature and time,were investigated.It was found that when mole ratio of sodium borohydride to compound I was 2.0∶1.0 and ethanol was used as solvent,the yield of compound Ⅱ reached 87.1%.The product from amination acts as acid-binding agent.Microwave irradiation obviously enhanced the speed of amination compared with conventional heating,and the reaction time decreased from 16 ~ 24 h to 30 min.Furthermore,when the molar ratio of compound Ⅱ to tert-butyamine D_9 was 1.0∶1.2 and the reaction was carried out at 100 ℃ for 30 min,the yield of the targeted product reached 89.3%,and the utilization rate of tert-butyamine D_9 (74.4%)was higher than that by conventional heating(less than 40%).The product was confirmed by ~1HNMR,MS and UPLC,with a purity of more than 99.0% and deuterium enrichment over 98.5 atom% D,It could be used as internal standard in the field of food safety.
A reduction reaction of 5-(bromoacetyl)-1,3-phenylene bis(dimethylcarbamate)(Ⅰ) led to 1-[bis(3',5'-N,N-dimethylcarbamoyloxy) phenyl]-2 bromoethanol(Ⅱ).Intermediate was obtained by an amination reaction with tert-butylamine-D_9 under microwave irradiation(MWI) Subsequently,treatment of the intermediate with hydrochloric acid afforded deuterium labelled bambuterol-D_9 hydrochloride.At the same time,the factors affecting the reduction reaction,such as dosage of sodium borohydride,mole ratio of reactants,reaction temperature and time,were investigated.It was found that when mole ratio of sodium borohydride to compound I was 2.0∶1.0 and ethanol was used as solvent,the yield of compound Ⅱ reached 87.1%.The product from amination acts as acid-binding agent.Microwave irradiation obviously enhanced the speed of amination compared with conventional heating,and the reaction time decreased from 16 ~ 24 h to 30 min.Furthermore,when the molar ratio of compound Ⅱ to tert-butyamine D_9 was 1.0∶1.2 and the reaction was carried out at 100 ℃ for 30 min,the yield of the targeted product reached 89.3%,and the utilization rate of tert-butyamine D_9 (74.4%)was higher than that by conventional heating(less than 40%).The product was confirmed by ~1HNMR,MS and UPLC,with a purity of more than 99.0% and deuterium enrichment over 98.5 atom% D,It could be used as internal standard in the field of food safety.
引文
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[19]Shi Hongxin(史鸿鑫),Qiu Xiaoli(邱小丽),Wu Hongke(武宏科),et al.Synthesis and properties of ammonium salts of perfluorohexylsulfonamides[J].Fine Chemicals(精细化工),2012,29(5):438-442.
[20]Zhang Laiguo,Luo Shineng,Liu Xiaoya,et al.The synthesis of N,N'-bismethyl-N,N'-bis-(2,3,4,5,6-pentahydroxyhexyl)-2,3,5,6-tetraiodoterephthalamide[J].Chemical Reagents(化学试剂),2006,28(7):423-425.
[21]Yu Tingting(喻婷婷),Wu Tingting(武婷婷),Zeng Runsheng(曾润生),et al.Study on the cycle reaction between l-benzoyl-5-phernyl-2-thiobiuret and 2-bromo-l-phenylethanone[J].Journal of Suzhou University(苏州大学学报),2005,21(2):70-72.
[22]Xu Lubin(徐鲁斌).Studies on the reaetion of bromoallenes with l,3-diearbonyl compounds and Ti(Ⅲ)-mediated intramolecular radieal cyelization of epoxy Allene[D].Hangzhou(杭州):Zhejiang University(浙江大学),2006.
[23]TU Y,ZHONG J,WANG H,et al.Synthesis of stable isotope labeled D9-mabuterol,D9-bambuterol,and D9-cimbuterol[J].J Labelled Comp Radiopharm,2016,59(13):546-551.
[24]Wang Yucheng(王玉成),Wang Suhui(王苏惠),Cai Peijun(蔡佩君),et al.Improved synthesis of bambuterol[J].Chin J Pharm(中国医药工业杂志),1999,30(8):337-338.
[25]de la HOZ A,DIAZ-ORTIZ A,MORENO A.Microwaves in organic synthesis.Thermal and non-thermal microwave effects[J].Chem Soc Rev,2005,34(2):164-178.
[26]Feng Gang(冯刚).Study on microwave assisted organic synthesis and the nonthermal microwave effect in chemical reactions[D].Chongqing(重庆):Chongqing University(重庆大学),2009.
[27]Xu Zhongjie(徐仲杰),Lu Weijing(卢伟京),Lu Hao(卢浩).The synthesis of D-Xylose-U-C5[J].Journal of Isotopes(同位素),2012,25(4):209-213.
[2]OLSSON O A,SVENSSON L A,WETTERLIN K,et al.1-(dihydroxyphenyl)-2-amino ethanol derivatives,their compositions and intermediates:EP0043807[P].1982-01-13.
[3]Bai Xiaoliang(白晓亮).Damage identification of lean meat powder[J].Chin J Animal Husb Veter Med(畜牧兽医科技信息),2011,5:93-94.
[4]Peng Tao(彭涛),Lai Weihua(赖卫华),Zhang Fusheng(张富生),et al.Research progress of properties and detection methods of20β2-agonist[J].Food&Machinery(食品与机械),2013,29(3):254-260.
[5]Chan Jimmy,Fang Yanyan(方晏燕),Li Ping(李平).Rapid confirmation and quantization fo multi-residue ofβ2-agonist[J].Chin J Instrum Anal(分析测试学报),2008,27(S1):200-202.
[6]Wang Peilong(王培龙).β-agonists and its detection[J].Quality Safety Agro-Products(农产品质量与安全),2014,(1):44-52.
[7]FAN S,MIAO H,ZHAO Y,et al.Simultaneous detection of residues of 25β2-agonists and 23β-blockers in animal foods by high-performance liquid chromatography coupled with linear ion trap mass spectrometry[J].J Agric Food Chem,2012,60(8):1898-1905.
[8]DU X,WU Y,YANG H,et al.Simultaneous determination of 10β2-agonists in swine urine using liquid chromatography-tandem mass spectrometry and multi-walled carbon nanotubes as a reversed dispersive solid phase extraction sorbent[J].J Chromatogr A,2012,1260:25-32.
[9]ASAMI K,MACHIDA T,JUNG S,et al.Synthesis of(R)-bambuterol based on asymmetric reduction of 1-[3,5-bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone with incubated whole cells of Williopsis californica JCM 3600[J].J Mol Catal B Enzym,2013,97:106 109.
[10]TAJBAKHSH M,HOSSEINZADEH R,ALINEZHAD H,et al.Catalyst-free one-pot reductive alkylation of primary and secondary amines and N,N-dimethylation of amino acids using sodium borohydride in 2,2,2-trifluoroethanol[J].Cheminform,2011,42(23):490-496.
[11]Zhang Xueli(张雪利),Hong Weiliang(洪伟良),Liu Jianhong(刘剑洪),et al.Improvement of synthesis process for bambuterol[J].J Shenzhen Uni Sci Eng(深圳大学学报,理工版),2005,22(3):269-271.
[12]Wu Haihong(吴海虹),Zhang Xueli(张雪利),Zhu Xueyan(朱雪焱),et al.Sdudy on synthesis of bambuterol[J].Chin J Synthetic Chemistry(合成化学),2000,8(2):146150.
[13]Su Guoqiang(苏国强),Hou Jianyin(侯建英),Zhu Chongquan(朱崇泉),et al.The synthesis of bambuterol[J].J Chin Pharm Uni(中国医科大学学报),1999,30(4):251-252.
[14]Huang Peng(黄鹏),Ni Shoudong(倪受东),Feng Chuanping(冯传平).Study on improvement of synthetic process for bambuterol hydrochloride[J].Anhui Med Pharm J(安徽医药),2004,8(3):168-169.
[15]PASTO D J,LEPESKA B.The measurement and interpretation of hydrogen-tritium kinetic isotope effects in borane and borohydride reductions of ketones.Implications on steric approach control vs.product development control[J].J Am Chem Soc,1976,98(5):1091-1095.
[16]Jiang Darong(蒋达荣).The chemical equations of reduction of ketones and aldehydes by lithium aluminium hydride or sodium borohydride[J].University Chemistry(大学化学),1997,12(4):53-54.
[17]LO C-T F,KARAN K,DADIS B R.Kinetic studies of reaction between sodium borohydride and methanol,water,and their mixtures[J].Ind Eng Chem Res,2007,46(17):5478-5484.
[18]Xu Yaohui(徐耀辉),Du Hongguang(杜红光),Gu Min(顾民).Efects of acid binding agents on synthesis of N,N'-bis-(cyclohexyl)-terephthalamide[J].Petrochemical Technology(石油化工),2013,42(10):1148-1153.
[19]Shi Hongxin(史鸿鑫),Qiu Xiaoli(邱小丽),Wu Hongke(武宏科),et al.Synthesis and properties of ammonium salts of perfluorohexylsulfonamides[J].Fine Chemicals(精细化工),2012,29(5):438-442.
[20]Zhang Laiguo,Luo Shineng,Liu Xiaoya,et al.The synthesis of N,N'-bismethyl-N,N'-bis-(2,3,4,5,6-pentahydroxyhexyl)-2,3,5,6-tetraiodoterephthalamide[J].Chemical Reagents(化学试剂),2006,28(7):423-425.
[21]Yu Tingting(喻婷婷),Wu Tingting(武婷婷),Zeng Runsheng(曾润生),et al.Study on the cycle reaction between l-benzoyl-5-phernyl-2-thiobiuret and 2-bromo-l-phenylethanone[J].Journal of Suzhou University(苏州大学学报),2005,21(2):70-72.
[22]Xu Lubin(徐鲁斌).Studies on the reaetion of bromoallenes with l,3-diearbonyl compounds and Ti(Ⅲ)-mediated intramolecular radieal cyelization of epoxy Allene[D].Hangzhou(杭州):Zhejiang University(浙江大学),2006.
[23]TU Y,ZHONG J,WANG H,et al.Synthesis of stable isotope labeled D9-mabuterol,D9-bambuterol,and D9-cimbuterol[J].J Labelled Comp Radiopharm,2016,59(13):546-551.
[24]Wang Yucheng(王玉成),Wang Suhui(王苏惠),Cai Peijun(蔡佩君),et al.Improved synthesis of bambuterol[J].Chin J Pharm(中国医药工业杂志),1999,30(8):337-338.
[25]de la HOZ A,DIAZ-ORTIZ A,MORENO A.Microwaves in organic synthesis.Thermal and non-thermal microwave effects[J].Chem Soc Rev,2005,34(2):164-178.
[26]Feng Gang(冯刚).Study on microwave assisted organic synthesis and the nonthermal microwave effect in chemical reactions[D].Chongqing(重庆):Chongqing University(重庆大学),2009.
[27]Xu Zhongjie(徐仲杰),Lu Weijing(卢伟京),Lu Hao(卢浩).The synthesis of D-Xylose-U-C5[J].Journal of Isotopes(同位素),2012,25(4):209-213.