阿那格雷三氯衍生物的合成
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摘要
以3,4,5-三氯苯胺为起始物料,经过桑德迈尔反应,氧化开环,还原反应,烷基化反应,环合反应得到阿那格雷三氯衍生物。桑德迈尔反应中,反应温度控制在70～80℃范围内,4,5,6-三氯靛红收率为79.7%;氧化开环中,反应温度保持50℃,在6 mol/L氢氧化钠水溶液中滴加过氧化氢,6-氨基-2,3,4-三氯苯甲酸收率64.4%;环合反应时,用氯甲脒盐酸盐替代溴化氰作为环合剂,避免剧毒物对人体的伤害。所得到化合物及中间体经过质谱、核磁共振氢谱等分析手段进行了表征,波谱数据与化合物结构吻合。合成阿那格雷三氯衍生物的方法步骤少、收率高,具有良好的应用前景。
Starting from 3,4,5-trichloroaniline,an anagrelide trichloroderivative was synthesized via 5 sequential reaction steps including Sandmeyer reaction,oxidative ring-opening,reduction,alkylation,and cyclization reactions. The reaction temperature was adjusted in the range of 70-80 ℃ in the Sandmeyer reaction,and the yield of 4,5,6-trichloroindigo reached 79.7%. In the oxidative ring-opening process,concentrated H2 O2 solution was added drop by drop into a 6 mol/L NaOH aqueous solution at a constant temperature of 50 ℃,and the yield of 6-amino-2,3,4-trichloro-benzoic acid was 64.4%. In the cyclization reaction,chloroformamidinehydrochloride was employed as the cyclizing agent instead of the highly toxic cyanogen bromide. The overall products and intermediates in each reaction step were characterized using mass spectroscopy and1 HNMR spectroscopy,and the results are in good agreement with the corresponding molecular structures. This study provides a novel method to synthesize an anagrelide trichloroderivative with relatively less steps and high yield,thus showing a good prospect for industrial application.
Starting from 3,4,5-trichloroaniline,an anagrelide trichloroderivative was synthesized via 5 sequential reaction steps including Sandmeyer reaction,oxidative ring-opening,reduction,alkylation,and cyclization reactions. The reaction temperature was adjusted in the range of 70-80 ℃ in the Sandmeyer reaction,and the yield of 4,5,6-trichloroindigo reached 79.7%. In the oxidative ring-opening process,concentrated H2 O2 solution was added drop by drop into a 6 mol/L NaOH aqueous solution at a constant temperature of 50 ℃,and the yield of 6-amino-2,3,4-trichloro-benzoic acid was 64.4%. In the cyclization reaction,chloroformamidinehydrochloride was employed as the cyclizing agent instead of the highly toxic cyanogen bromide. The overall products and intermediates in each reaction step were characterized using mass spectroscopy and1 HNMR spectroscopy,and the results are in good agreement with the corresponding molecular structures. This study provides a novel method to synthesize an anagrelide trichloroderivative with relatively less steps and high yield,thus showing a good prospect for industrial application.
引文
[1]康影,王瑞,孙铁民.血小板凝聚抑制剂阿那格雷的合成[J].中国医药工业杂志,2001,32(2):51-52.
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[3]SARMA A,MCLORNAN D P,HARRISON C N.Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia[J].Orphanet Journal of Rare Diseases,2017(7):11-23.
[4]JENKS T A,BEVERUNG W N,PARTYKA R A.Preparation of 6,7-dichloro-1,5-dihydroimidazo(2,1-b)-quinazolin-2(3H)-one:CA,1137474A[P].1982-12-14.
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[6]伯纳德·戈尔丁.阿那格雷和类似物的制备方法:中国,102256981A[P].2011-11-23.
[7]保罗·麦基.用于制备阿那格雷及其类似物的方法:中国,103180323A[P].2013-06-26.
[8]STEPHEN E W,TED M B,JOHN A,et al.Design of thymidylate synthase inhibitorsusing protein crystal structures:the synthesis and biological evaluation of a novel classof 5-substituted quinazolinones[J].Journal of Medicinal Chemistry,1993,36(6):733-746.
[9]宁树一,魏凯,张华.一种用于工业化放大生产盐酸阿那格雷原料药的制备方法:中国,102757434A[P].2012-10-31.
[10]SUI X C,JOHN F W,ECKARD W.Glycine receptor antagonist pharmacophore:US,5597922A[P].1997-01-28.
[11]SADLER P W,REGINALD L W.Synthesis and absorption spectra of the symmetricalchloroindigos[J].Journal of the American Chemical Society,1956,78(6):1251-1255.
[12]YOSHIHIRO I,AYAKA M,TORU N,et al.Synthesis of quinolinomorphinaderivatives as highlyselectiveδopioid receptor ligands[J].Bioorganic&Medicinal Chemistry,2012,20(19):5810-5831.
[13]ANTONI T S,JOSEP M,ADRIANA P,et al.Synthesis of new benzoxazinonederivativesas neuropeptide Y5antagonists for the treatment of obesity[J].Journal of Medicinal Chemistry,2005,48(6):2080-2092.
[14]PHILIP C L,TOMS R.2-amino-5,6-dichloro-3,4-dihydroquinazoline,its method of making and using and pharmaceutical compositions thereof:US,6194420B1[P].2001-02-27.
[15]THOMAS A J,LIVERPOOL N Y,WARREN N B,et al.Alkyl5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydrohalides:US,4146718A[P].1979-03-27.
[16]GIELING R G,LINDEN J B,VERKERK P R,et al.Process for making anagrelide:WO,2014139572A1[P].2014-09-18.
[2]倪洪斌.血小板凝聚抑制剂阿那格雷的合成研究[D].吉林:吉林大学,2006.
[3]SARMA A,MCLORNAN D P,HARRISON C N.Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia[J].Orphanet Journal of Rare Diseases,2017(7):11-23.
[4]JENKS T A,BEVERUNG W N,PARTYKA R A.Preparation of 6,7-dichloro-1,5-dihydroimidazo(2,1-b)-quinazolin-2(3H)-one:CA,1137474A[P].1982-12-14.
[5]LANG P C,SPENCER R P,YEH W L,et al.Method for the manufacture of anagrelide:WO,200208228A2[P].2002-01-31.
[6]伯纳德·戈尔丁.阿那格雷和类似物的制备方法:中国,102256981A[P].2011-11-23.
[7]保罗·麦基.用于制备阿那格雷及其类似物的方法:中国,103180323A[P].2013-06-26.
[8]STEPHEN E W,TED M B,JOHN A,et al.Design of thymidylate synthase inhibitorsusing protein crystal structures:the synthesis and biological evaluation of a novel classof 5-substituted quinazolinones[J].Journal of Medicinal Chemistry,1993,36(6):733-746.
[9]宁树一,魏凯,张华.一种用于工业化放大生产盐酸阿那格雷原料药的制备方法:中国,102757434A[P].2012-10-31.
[10]SUI X C,JOHN F W,ECKARD W.Glycine receptor antagonist pharmacophore:US,5597922A[P].1997-01-28.
[11]SADLER P W,REGINALD L W.Synthesis and absorption spectra of the symmetricalchloroindigos[J].Journal of the American Chemical Society,1956,78(6):1251-1255.
[12]YOSHIHIRO I,AYAKA M,TORU N,et al.Synthesis of quinolinomorphinaderivatives as highlyselectiveδopioid receptor ligands[J].Bioorganic&Medicinal Chemistry,2012,20(19):5810-5831.
[13]ANTONI T S,JOSEP M,ADRIANA P,et al.Synthesis of new benzoxazinonederivativesas neuropeptide Y5antagonists for the treatment of obesity[J].Journal of Medicinal Chemistry,2005,48(6):2080-2092.
[14]PHILIP C L,TOMS R.2-amino-5,6-dichloro-3,4-dihydroquinazoline,its method of making and using and pharmaceutical compositions thereof:US,6194420B1[P].2001-02-27.
[15]THOMAS A J,LIVERPOOL N Y,WARREN N B,et al.Alkyl5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydrohalides:US,4146718A[P].1979-03-27.
[16]GIELING R G,LINDEN J B,VERKERK P R,et al.Process for making anagrelide:WO,2014139572A1[P].2014-09-18.
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