柱前衍生化HPLC法测定1种酰氯类化合物

目的：建立高效液相色谱法测定1种酰氯类化合物5-氯噻吩-2-甲酰氯。方法：采用Ameritech Accurasil C₈（250 mm×4.6 mm，5μm）色谱柱，以0.01 mol·L^-1磷酸水溶液为流动相A，乙腈为流动相B进行梯度洗脱，流速1.0 mL·min^-1，柱温35℃，检测波长274 nm；以无水甲醇为衍生化试剂，三乙胺为缚酸剂，经衍生后进样测定。结果：5-氯噻吩-2-甲酰氯含量检测方法的专属性好；在1.012~2.040 mg·mL^-1浓度范围内线性良好r=0.998 2，n=5；精密度、溶液稳定性好，RSD分别为0.040%（n=6）和1.2%（n=7）；平均回收率（n=9）为99.0%，RSD为0.80%；色谱条件发生微小变化时，方法耐用性好；5-氯噻吩-2-甲酸的定量下限和检测下限分别为1.871 μg·mL^-1和0.623 7 μg·mL^-1，5-氯噻吩-2-甲酰氯的定量下限和检测下限分别为1.562 μg·mL^-1和0.468 6 μg·mL^-1；3批供试品中特定杂质和最大单一未知杂质含量均小于1.0%，主成分含量分别为98.5%、98.4%、98.4%。结论：本方法适用于5-氯噻吩-2-甲酰氯的测定，对于其他酰氯类化合物的测定也有重要的参考价值。

Objective: To establish an HPLC method for the determination of an acyl chloride compound 5-chlorothiophene-2-carbonyl chloride.Methods: HPLC was performed on an Ameritech Accurasil C₈ column (250 mm×4.6 mm, 5 μm) with a gradient elution system of 0.01 mol·L^-1 phosphoric acid solution-acetonitrile.The flow rate was 1.0 mL·min^-1, and the column temperature was maintained at 35℃, the detection wavelength was 274 nm. Triethylamine and anhydrous methanol were added into the drug solution sequentially as acid binding and derivatization reagents, respectively.Results: The method had good specificity and it showed an excellent linearity within the range of 1.012-2.040 mg·mL^-1 (r²=0.998 2, n=5).The precision and solution stability were satisfactory, with the RSDs of 0.040% (n=6) and 1.2% (n=7), respectively.The average recovery was 99.0%, with the RSD of 0.80% (n=9).The method had good durability when chromatographic conditions changed slightly.The limit of quantitation of 5-chloro-2-thiophenecarboxylic acid and 5-chlorothiophene-2-carbonyl chloride were 1.871 μg·mL^-1 and 1.562 μg·mL^-1, respectively.The limit of detection of 5-chloro-2-thiophenecarboxylic acid and 5-chlorothiophene-2-carbonyl chloride were 0.623 7 μg·mL^-1 and 0.468 6 μg·mL^-1, respectively.The determination results of the three batches of samples showed that the contents of the specified impurity and the maximum single unknown impurity were less than 1.0%, and the contents of 5-chlorothiophene-2-carbonyl chloride were 98.5%, 98.4% and 98.4%, respectively.Conclusion: The method is suitable for the determination of and it also has important reference value for the determination of other acyl chloride compounds.

[1] 喻名强,刘广义,尹兴荣,等.酰氯的合成方法及其应用新进展[J].精细化工中间体,2011,41(4):1 YU MQ,LIU GY,YIN XR,et al.Recent advancement of synthesis and application of acyl chloride[J].Fine Chem Intermed,2011,41(4):1
[2] 徐兆瑜.一些重要酰氯化合物的合成和应用[J].精细化工原料及中间体,2009(3):26 XU ZY.Synthesis and its application of acid-chloride compounds[J].Fine Chem Ind Raw Mater Intermed,2009(3):26
[3] 徐兆瑜.一些重要酰氯化合物的合成和应用[J].精细化工原料及中间体,2009(4):25 XU ZY.Synthesis and its application of acid-chloride compounds[J].Fine Chem Ind Raw Mater Intermed,2009(4):25
[4] 陈诚,潘振涛,罗文俊,等.利伐沙班的合成工艺研究[J].精细化工中间体,2015,45(1):53 CHEN C,PAN ZT,LUO WJ,et al.Study on the synthesis of rivaroxaban[J].Fine Chem Intermed,2015,45(1):53
[5] 杨银萍,王红波,马庆文.利伐沙班的合成工艺改进[J].中国药物化学杂志,2013,23(1):26 YANG YP,WANG HB,MA QW.Improvement of synthesis process of rivaroxaban[J].Chin J Med Chem,2013,23(1):26
[6] 陈鑫,陈识峰,王晨竹,等.盐酸头孢替安酰氯法合成工艺专有杂质的研究[J].中国抗生素杂志,2017,42(1):33 CHEN X,CHEN SF,WANG CZ,et al.Study of proprietary impurities introduced by acyl chloride method for cefotiam dihydrochloride[J].Chin J Antibiot,2017,42(1):33
[7] 曹卫凯.头孢呋辛酯的合成研究[J].合成技术及应用,2016,31(2):4 CAO WK.Optimization of synthesis technology of cefuroxime axetil[J].Synth Technol Appl,2016,31(2):4
[8] 贺书泽.七氟菊酯合成方法改进[J].现代农药,2015,14(2):28 HE SZ.Improved synthesis of tefluthrin[J].Mod Agrochem,2015,14(2):28
[9] 刘安昌,冯佳丽,贺晓露,等.新型杀线虫剂Tioxazafen的合成[J].农药,2014,53(8):561 LIU AC,FENG JL,HE XL,et al.Study of synthetic process of novel pesticides tioxazafen[J].Chin J Pestic,2014,53(8):561
[10] 张辉,张晨杰,徐敏敏,等.HPLC与SERS联用技术及其在有机反应现场监测的应用[J].光谱学与光谱分析,2018,38(10):213 ZHANG H,ZHANG CJ,XU MM,et al.On-line monitoring of organic reactions based on high performance liquid chromatography and surface enhanced raman spectroscopy[J].Spectrosc Spectral Anal,2018,38(10):213
[11] 郑秀萍,乔文强,王植源,等.基于3种荧光化合物检测草酰氯气体的化学发光试纸法[J].应用化学,2016,33(10):1203 ZHENG XP,QIAO WQ,WANG ZY,et al.Test paper method of chemiluminescence based on three fluorescent compounds for the detection of oxalyl chloride vapor[J].Chin J Appl Chem,2016,33(10):1203
[12] 吴暎,林萍.分步滴定法测定草酰氯的含量[J].理化检验-化学分册,2014,50(10):1307 WU Y,LIN P.Determination of oxaloyl chloride by stepwise titration[J].Phys Test Chem Anal Part B:Chem Anal,2014,50(10):1307
[13] 楼姝含,王栋,顾晓彤,等.柱前衍生化HPLC法测定盐酸美金刚的含量[J].中国新药杂志,2016,25(19):2268 LOU SH,WANG D,GU XT,et al.Determination of memantine hydrochloride with pre-column derivatization HPLC[J].Chin J New Drugs,2016,25(19):2268
[14] 王丽,邢旭,秦青,等.柱前衍生化HPLC法测定加巴喷丁胶囊中主药的含量[J].药学进展,2013,37(1):38 WANG L,XING X,QIN Q,et al.Determination of gabapentin in gabapentin capsules by pre-column derivation HPLC method[J].Prog Pharm Sci,2013,37(1):38
[15] 黄滔敏,陈念祖,王东蕾,等.柱前衍生化HPLC法测定注射用氨磷汀的含量[J].复旦学报(医学版),2013,40(1):60 HUANG TM,CHEN NZ,WANG DL,et al.HPLC method using pre-column derivatization for determinating the content of amifostine[J].J Fudan Univ Med Sci,2013,40(1):60
[16] 阮晓玲,郑项元,徐洁,等.药物中基因毒性杂质分析方法的研究进展[J].中国药科大学学报,2016,47(3):267 RUAN XL,ZHENG XY,XU J,et al.Advances in analytical techniques for the determination of genotoxic impurities in pharmaceuticals[J].J China Pharm Univ,2016,47(3):267
[17] FU M,LU Q,HEWITT E,et al.Ultra high performance liquid chromatography coupled with high resolution quantitation mass spectrometry method development and validation for determining genotoxic 2,5-dichlorobenzoyl chloride in MLN9708 drug substance[J].J Pharm Biomed Anal,2014,89(4):233
[18] RAMAN NV,PRASAD AV,REDDY KR,et al.Sensitive derivatization methods for the determination of genotoxic impurities in drug substances using hyphenated techniques[J].J Pharm Biomed Anal,2014,89:276