阿加曲班杂质合成研究
|
摘要
目的探讨阿加曲班起始原料3-甲基-8-喹啉磺酰氯中的异构体杂质来源与合成方法,为阿加曲班的质量控制提供依据和杂质对照品。方法杂质A以5-溴-3-甲基喹啉为起始物,依次进行Buchwald、脱保护基、与亚硝酸盐重氮化及Sandermeyer等反应制得;杂质B以5-溴-2-硝基苯甲醛为起始物,经铁粉还原、关环,再经Buchwald、脱保护基、重氮化及Sandermeyer等反应制得。结果该试验所合成的2个异构体杂质经液相色谱-质谱联用(LC-MS)及氢谱核磁共振(1H-NMR)进行结构确证,与目标化合物结构相符。结论该合成方法简单易行,合成的2个异构体杂质可作为杂质对照品,用于阿加曲班原料药的质量控制。
Objective To investigate the source and synthesis method of isomer impurities in 3-methyl-8-quinoline sulfonyl chloride,the starting material of argatroban anhydrous,and to provide a basis and impurity reference materials for quality control of argatrobananhydrous. Methods The impurity A was prepared from 5-bromo-3-methylquinoline by reaction with Buchwald, off-protectinggroup,diazotization and Sandermeyer. The impurity B was prepared from 5-bromo-2-nitrobenzaldehyde by the reduction with iron powderand closure of the ring, and reaction of Buchwald, off-protecting group, azotization and Sandermeyer. Results The structures of thetwo isomers were confirmed by LC-MS and1 H-NMR, which were consistent with the target compounds. Conclusion The syntheticmethod is simple and feasible. The two synthesized isomer impurities can be used as impurity reference substances for the qualitycontrol of argatroban anhydrous.
Objective To investigate the source and synthesis method of isomer impurities in 3-methyl-8-quinoline sulfonyl chloride,the starting material of argatroban anhydrous,and to provide a basis and impurity reference materials for quality control of argatrobananhydrous. Methods The impurity A was prepared from 5-bromo-3-methylquinoline by reaction with Buchwald, off-protectinggroup,diazotization and Sandermeyer. The impurity B was prepared from 5-bromo-2-nitrobenzaldehyde by the reduction with iron powderand closure of the ring, and reaction of Buchwald, off-protecting group, azotization and Sandermeyer. Results The structures of thetwo isomers were confirmed by LC-MS and1 H-NMR, which were consistent with the target compounds. Conclusion The syntheticmethod is simple and feasible. The two synthesized isomer impurities can be used as impurity reference substances for the qualitycontrol of argatroban anhydrous.
引文
[1]汪燕.新型抗凝药物研究进展[J].中国新药杂志,2011,20(6):514-517.
[2]袁莉娟,刘爱民,刘蕾.新型凝血酶抑制剂阿加曲班[J].中国新药杂志,2005,14(2):230-234.
[3]王鑫鑫,钱远宇,孟庆义.小分子直接凝血酶抑制剂阿加曲班在急性冠脉综合征中的应用[J].中国医药导刊,2009,11(1):42-43.
[4]王秀菊.阿加曲班治疗进展性脑梗死的临床研究[J].吉林医学,2013,34(9):1655.
[5]张淑峰,李海霞,邓巍巍.阿加曲班治疗脑梗死及对血流动力学影响的临床研究[J].中国医药导报,2009,6(12):69-70.
[6] BRUCE ET,RICHARD ML,CYNTHIA LF. Aminoguanidnes andAlkoxyguanidines as Protease Inhibitors:US,2001/6235778B1[P].2001-05-22.
[7] MCCASLAND GE. The Preparation of 8-QuinolinesulfonicAcid[J]. J Org Chem,1946,11:277-280.
[8] OLGA G,KAROLA RB,DMITRI G. Trans-Spanned PalladiumCatalyst for Mild and Efficient Amination of Aryl Halides withBenzophenone Imine[J]. Synthesis,2008,4:537-542.
[9] TITCOMB LR,CADDICK S,CLOKE FGN,et al. Unexpected reac-tivity of two-coordinate palladium-carbine complexes; syntheticand catalytic implications[J]. Chemical Communications,2001,15:1388-1389.
[10] YUE HF,GUO L,LIU XQ,et al. Nickel-Catalyzed Synthesis ofPrimary Aryl and Heteroaryl Amines via C-O Bond Cleavage[J].Organic Letters,2017,19(7):1788-1791.
[11] POKHODYLO NT,MATIYCHUK VS,OBUSHAK MD,et al.(Arylsulfonyl)acetones and Acetonitr-iles:New ActivatedMethylenic Building Blocks for Synthesis of 1,2,3-Triazoles[J].Synthesis,2009,14:2321-2323.
[12] HOFFMAN RV. m-Trifluoromethylbenzenesulfonyl Chloride[J].Organic Syntheses,1981,60:121.
[13] MERCK SHARP,DOHME CORP. Purine Inhibitors of HumanPhosphatidylinositol 3-Kinase Delta:WO,2017/166104A1[P].2017-10-05.
[14]吕伟.一种医药中间体N-芳基喹唑啉-2-胺化合物的制备方法:中国,105669566A[P]. 2016-06-15.
[15] TERUHISA,TOKUNAGA,WILLIAN,et al. Pyrrole derivatives:US,2003/0181496 A1[P]. 2003-09-25.
[16] Glaxosmithkline Intellectual Property(NO. 2)Limited. Fatty AcidSynthase Inhibitors:WO,2014/108858A1[P]. 2014-07-17.
[17] KIUMARS B,MOHAMMAD MK,MEHDI S. Direct Conversion ofThiols to Sulfonyl Chlorides and Sulfonamides[J]. J Org Chem,2009,74(24):9287-9291.
[2]袁莉娟,刘爱民,刘蕾.新型凝血酶抑制剂阿加曲班[J].中国新药杂志,2005,14(2):230-234.
[3]王鑫鑫,钱远宇,孟庆义.小分子直接凝血酶抑制剂阿加曲班在急性冠脉综合征中的应用[J].中国医药导刊,2009,11(1):42-43.
[4]王秀菊.阿加曲班治疗进展性脑梗死的临床研究[J].吉林医学,2013,34(9):1655.
[5]张淑峰,李海霞,邓巍巍.阿加曲班治疗脑梗死及对血流动力学影响的临床研究[J].中国医药导报,2009,6(12):69-70.
[6] BRUCE ET,RICHARD ML,CYNTHIA LF. Aminoguanidnes andAlkoxyguanidines as Protease Inhibitors:US,2001/6235778B1[P].2001-05-22.
[7] MCCASLAND GE. The Preparation of 8-QuinolinesulfonicAcid[J]. J Org Chem,1946,11:277-280.
[8] OLGA G,KAROLA RB,DMITRI G. Trans-Spanned PalladiumCatalyst for Mild and Efficient Amination of Aryl Halides withBenzophenone Imine[J]. Synthesis,2008,4:537-542.
[9] TITCOMB LR,CADDICK S,CLOKE FGN,et al. Unexpected reac-tivity of two-coordinate palladium-carbine complexes; syntheticand catalytic implications[J]. Chemical Communications,2001,15:1388-1389.
[10] YUE HF,GUO L,LIU XQ,et al. Nickel-Catalyzed Synthesis ofPrimary Aryl and Heteroaryl Amines via C-O Bond Cleavage[J].Organic Letters,2017,19(7):1788-1791.
[11] POKHODYLO NT,MATIYCHUK VS,OBUSHAK MD,et al.(Arylsulfonyl)acetones and Acetonitr-iles:New ActivatedMethylenic Building Blocks for Synthesis of 1,2,3-Triazoles[J].Synthesis,2009,14:2321-2323.
[12] HOFFMAN RV. m-Trifluoromethylbenzenesulfonyl Chloride[J].Organic Syntheses,1981,60:121.
[13] MERCK SHARP,DOHME CORP. Purine Inhibitors of HumanPhosphatidylinositol 3-Kinase Delta:WO,2017/166104A1[P].2017-10-05.
[14]吕伟.一种医药中间体N-芳基喹唑啉-2-胺化合物的制备方法:中国,105669566A[P]. 2016-06-15.
[15] TERUHISA,TOKUNAGA,WILLIAN,et al. Pyrrole derivatives:US,2003/0181496 A1[P]. 2003-09-25.
[16] Glaxosmithkline Intellectual Property(NO. 2)Limited. Fatty AcidSynthase Inhibitors:WO,2014/108858A1[P]. 2014-07-17.
[17] KIUMARS B,MOHAMMAD MK,MEHDI S. Direct Conversion ofThiols to Sulfonyl Chlorides and Sulfonamides[J]. J Org Chem,2009,74(24):9287-9291.