苯甲酸阿格列汀合成工艺的改进
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摘要
以3-甲基-6-氯尿嘧啶、2-氰基溴苄为起始原料,在碱性条件下经亲核取代反应得到2-(6-氯-3-甲基-2,4-二氧代-3,4-二氢-2H-嘧啶-1-基甲基)-苄腈,再与(R)-3-氨基哌啶二盐酸盐取代得到(R)-2-[(6-(3-氨基哌啶-1-基)-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)甲基]苄腈,最后与苯甲酸成盐以69. 61%的总收率得到目标化合物,纯度>99. 57%。该合成工艺反应条件温和、成本低廉,适用于工业化生产。
Alogliptin was synthezied by reacting with( R)-3-aminopiperdine dihydrochloride and 2-( 6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2 H-pyrimidin-1-ylmethyl)-benzo-nitrile which was produced by the nucleophilic substitution reaction of 3-methyl-6-chloro-uracil and 2-bromomethyl-benzonitrile.Alogliptin was reacted with benzoic acid to yield the target compound in total yield of69. 61% as well as purity more than 99. 57%. The optimized synthetic conditions were mild,low cost,and suitable for industrial production.
Alogliptin was synthezied by reacting with( R)-3-aminopiperdine dihydrochloride and 2-( 6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2 H-pyrimidin-1-ylmethyl)-benzo-nitrile which was produced by the nucleophilic substitution reaction of 3-methyl-6-chloro-uracil and 2-bromomethyl-benzonitrile.Alogliptin was reacted with benzoic acid to yield the target compound in total yield of69. 61% as well as purity more than 99. 57%. The optimized synthetic conditions were mild,low cost,and suitable for industrial production.
引文
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[2]尤启冬.药物化学[M].北京:人民卫生出版社,2014.
[3]孟艳秋,刘文虎,刘凤鑫,等.抗2型糖尿病药物研究进展[J].现代药物与临床,2013,28(3):461-464.
[4]STEIN S A,LAMOS E M,DAVIS S N.A review of the efficacy and safety of oral antidiabetic drugs[J]. Expert.Opin.Drug Saf.,2013,12(2):153-175.
[5]郝晨伟,李正翔.钠-葡萄糖共转运蛋白2抑制剂治疗2型糖尿病的临床研究进展[J].药物评价研究,2014,37(5):463-471.
[6]陈文文,党和勤,耿涛,等.新型降糖药DPP-4抑制剂研究进展[J].中国医院药学杂志,2016,36(6):511-517.
[7]李瑞丰,欧阳雪宇,吕飞,等.DPP-Ⅳ抑制剂列汀类抗糖尿病药物专利分析和专利布局[J].中国新药杂志,2015,(1):8-17.
[8]SCOTT L J.Alogliptin:a review of its use in the management of type 2 diabetes mellitus[J]. Drugs,2010,70(18):2 051-2 072.
[9]NAUCK M A,VILSBLL T,GALLWITZ B,et al.Incretin-based therapies:viewpoints on the way to consensus[J].Diabetes Care,2009,32(S2):223.
[10]INAGAKI N,ONOUCHI H,SANO H,et al.SYR-472,A novel once-weekly dipeptidyl peptidase-4(DPP-4)inhibitor,in type 2 diabetes mellitus:a phase 2,randomised,double-blind,placebo-controlled trial[J]. Lancet.Diabetes.Endo.,2014,2(2):125-132.
[11]FENG Jun,GWALTNEY S L,STAFFORD J A,et al.Dipeptidyl peptidase inhibitor:EP 1 586 571A[P].2005-10-19.
[12]李明杰,刘新泉,李晓峰,等.苯甲酸阿格列汀的制备方法:103 193 762A[P].2013-07-10.
[13]申迪,王子建,胥翠,等.苯甲酸阿格列汀的合成及其初步质量研究[J].中南药学,2016,(8):813-816.
[14]BHATTN G,NAIK S,SHARMA A K,et al.Process for preparation of alogliptin:WO 2 014 188 334[P].2014-11-27.
[15]赵哲,丁怀伟,赵明明,等.苯甲酸阿格列汀的合成工艺研究[J].中国医药导论,2014,16(10):1 352-1 353.
[16]叶天健,陈鑫,叶继华,等.一种苯甲酸阿格列汀的新制备方法:103 819 450A[P].2014-05-28.
[17]ZHOU Yu-xia,ZHOU Wen-tao,SUN Li-li,et al.Characterization of process-related impurities including forced degradation products of alogliptin benzoate and the development of the corresponding reversed-phase high-performance liquid chromatography method[J]. J. Sep. Sci.,2014,37:1 248-1 255.
[18]崔翼,罗邻涛,周定康,等.一种苯甲酸阿格列汀的制备工艺:102 942 556A[P].2013-02-27.
[19]莫国宁.一种苯甲酸阿格列汀的合成方法:104 086527[P].2014-10-08.
[20]VADALL L R,DASARIS R,MANUKONDA S R,et al.Process for preparation of alogliptin:WO 2 015 092 739[P].2015-06-25.
[21]刘昭文,吴龙火,王恩龙.苯甲酸阿格列汀的合成[J].海峡药学,2011,23(9):214-215.