恩诺沙星-d_5的合成
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摘要
以乙醇-d6为原料,与碘反应得到碘乙烷-d_5,进一步与1-Boc-哌嗪经过两步反应得到中间体1-乙基哌嗪-d_5,然后与1-环丙基-7-氯-6-氟-1,4-二氢-4-氧代喹啉-3-羧酸乙酯发生Buchwald-Hartwig偶联反应得到1-环丙基-6-氟-1,4-二氢-4-氧-7-(4-乙基-1-哌嗪基)-3-喹啉羧酸乙酯-d_5,最后经碱水解后得到标题化合物,5步总收率为52%,其结构经1HNMR、13CNMR、IR与ESI-MS表征,化学纯度为99. 5%,同位素丰度为99. 3%,可作为食品安全领域检测用稳定同位素内标试剂。
The synthesis of enrofloxacin-d_5 has been achieved in five steps as follows: iodination of CD_3CD_2OD with I_2 to yield CD_3CD_2I,which was used to ethylation of 1-Boc-piperazine in 2 steps provided 1-ethylpiperazine-d_5.The key ethyl 1-cyclopropyl-7-( 4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate-d_5 was constructed from 1-ethylpiperazine-d_5 and ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate via a Buchwald-Hartwig coupling reaction. The final step was a hydrolyzation by alkaline.The total yield was 52%,and the structure was confirmed by1 HNMR,13 CNMR,IR and ESI-MS.The purity was 99. 5% and isotopic enrichment of D was 99. 3%.It could be used as an internal standard in the field of food safety detection.
The synthesis of enrofloxacin-d_5 has been achieved in five steps as follows: iodination of CD_3CD_2OD with I_2 to yield CD_3CD_2I,which was used to ethylation of 1-Boc-piperazine in 2 steps provided 1-ethylpiperazine-d_5.The key ethyl 1-cyclopropyl-7-( 4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate-d_5 was constructed from 1-ethylpiperazine-d_5 and ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate via a Buchwald-Hartwig coupling reaction. The final step was a hydrolyzation by alkaline.The total yield was 52%,and the structure was confirmed by1 HNMR,13 CNMR,IR and ESI-MS.The purity was 99. 5% and isotopic enrichment of D was 99. 3%.It could be used as an internal standard in the field of food safety detection.
引文
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[13]岳振峰,谢丽琪,陈小霞,等.牛奶中16种喹诺酮类药物残留量的高效液相色谱-串联质谱法测定[J].分析测试学报,2008,27(3):240-243.
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[15]TAYLOR R R R,TWIN H C,WEN W W,et al.Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates:synthesis and biological activity of a ciprofloxacin analogue[J].Tetrahedron,2010,66(18):3 370-3 377.
[16]OLD D W,WOLFE J P,BUCHWALD S L,et al.A highly active catalyst for palladium-catalyzed cross-coupling reactions:room-temperature suzuki couplings and amination of unactivated aryl chlorides[J]. J. Am. Chem. Soc.,1998,120(37):9 722-9 723.
[17]雷雯,候捷,杜晓宁,等.气相色谱-质谱联用测定氘标记卤代苯及其衍生物的同位素丰度[J].化学试剂,2015,37(10):903-907.
[2]应翔宇,李冬郊.恩诺沙星在健康及巴氏杆菌感染鸡体内的药物代谢动力学研究[J].中国兽药杂志,2002,36(1):3-6.
[3]刘开永,汪开毓.恩诺沙星在水产中的应用与研究[J].中国兽药杂志,2004,38(10):32-34.
[4]中华人民共和国农业农村部.2018年度动物及动物产品兽药残留监控计划[N].中国畜牧兽医报,2018-01-22.
[5]农业部畜牧兽医局.动物性食品中恩诺沙星和环丙沙星残留检测方法-高效液相色谱法[J].中国兽药杂志,2003,37(8):11-13.
[6]龚云飞,邹晓楠,张露露,等.化学发光免疫法检测食品中恩诺沙星残留的研究[J].食品工业科技,2014,35(4):66-69.
[7]魏东.氟喹诺酮类药物残留免疫学检测方法的研究[D].长春:吉林大学,2007.
[8]汤轶伟,李译,兰建兴,等.分子印迹技术在恩诺沙星检测中的应用[J].食品工业科技,2014,35(12):368-372.
[9]赵伟.毛细管电泳法分析食品和体液中氟喹诺酮类药物残留[D].保定:河北大学,2008.
[10]邵黎.鸡肉中恩诺沙星的MISPE-HPCE检测方法的研究[D].合肥:安徽农业大学,2009.
[11]李小玲,黄向荣,万译文,等.高效液相色谱-串联质谱法同时测定水产品中诺氟沙星、环丙沙星和恩诺沙星[J].中国渔业质量与标准,2013,3(4):25-30.
[12]魏博娟,吴成业,钱卓真.液质联用法测定水产品中喹诺酮类药物残留量的不确定度评定[J].南方水产科学,2012,8(3):59-64.
[13]岳振峰,谢丽琪,陈小霞,等.牛奶中16种喹诺酮类药物残留量的高效液相色谱-串联质谱法测定[J].分析测试学报,2008,27(3):240-243.
[14]徐仲杰,卢伟京,卢浩.稳定同位素标记恩诺沙星-D5的合成[J].精细化工,2012,29(11):1 050-1 052.
[15]TAYLOR R R R,TWIN H C,WEN W W,et al.Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates:synthesis and biological activity of a ciprofloxacin analogue[J].Tetrahedron,2010,66(18):3 370-3 377.
[16]OLD D W,WOLFE J P,BUCHWALD S L,et al.A highly active catalyst for palladium-catalyzed cross-coupling reactions:room-temperature suzuki couplings and amination of unactivated aryl chlorides[J]. J. Am. Chem. Soc.,1998,120(37):9 722-9 723.
[17]雷雯,候捷,杜晓宁,等.气相色谱-质谱联用测定氘标记卤代苯及其衍生物的同位素丰度[J].化学试剂,2015,37(10):903-907.