抗抑郁药盐酸舍曲林合成工艺研究与改进
摘要
盐酸舍曲林是一种长效、副作用少的抗抑郁剂。国内关于盐酸舍曲林的完整合成暂未见报道。本文以1-萘酚、邻二氯苯为原料，无水三氯化铝作催化剂，经过一步Friedel-Crafts烷基化反应生成中间体4-(3，4-二氯苯基)-1-萘满酮，随后与甲胺发生还原胺化反应生成外消旋体盐酸舍曲林，经过旋光拆分后得到所需的右旋顺式盐酸舍曲林。
在合成中间体4-(3，4-二氯苯基)-1-萘满酮过程中，采用乙酸乙酯代替邻二氯苯作萃取溶剂，大大降低了减压蒸馏真空度的要求，简化了操作。同时本文系统地考察了合成中的各种影响因素，找到了适宜的工艺条件，产率达72.48％。与文献值相比，产率提高11.48％，而反应时间缩短一半。在此基础上，对该步合成机理与动力学进行了研究，得出反应是分步进行的一级反应，反应速度是与温度及1-萘酚有关的变量。
在对中间体4-(3，4-二氯苯基)-1-萘满酮与甲胺发生的还原胺化反应进行优化时，首次采用甲胺的甲醇溶液作胺化剂，这样就不需要使用TiCl_4，常温下即可发生反应生成盐酸舍曲林。系统研究合成中各种影响因素后，找到了最优的工艺条件，合成产率36.4％。为进一步提高该步反应的总产率，我们创造性地采用叔丁醇钠作碱平衡剂，将反式的盐酸舍曲林转化为顺式产品，转化率44.56％。
因此，以1-萘酚为参比，合成总产率为15.6％。采用熔点、HPLC、旋光分析、元素分析、IR、H-NMR等手段对产物结构进行了确认。
Sertraline hydrochloride is an antidepressant with permanence of effect and less side-effect. There is no paper on the total synthesis of it in China. In this paper, the intermediate 4-(3,4-dichlorophenyl)-l-tetralone was synthesized by one step Friedel-Crafts alkylation with alpha-naphthol and orthodichlorobenzene as raw materials and anhydrous aluminium as catalyzer. Then racemize sertraline hydrochloride was synthesized with the intermediate and methyl amine by reductive animation. After resolution of racemate, dextro-cis- sertraline hydrochloride was obtained.
Orthodichlorobenzene was usually used as extraction reagent to synthesize the intermediate 4-(3,4-dichlorophenyl)-l-tetralone, which made operation difficult. After ethyl acetate acted as the substitute of orthodichlorobenzene, vacuum degree in decompression distillation was not strict. The system factors affecting the reaction were investigated and the optimal reaction conditions were obtained. The yield of synthesizing 4-(3,4-dichlorophenyl)-l-tetralone from alpha-naphthol and orthodichlorobenzene was 72.48%. Comparing with paper, the yield was improved by 11.48% and the half of the reaction time was saved. On the basis of the experiment, the mechanism and the reaction kinetic model were studied and conclusions were drawed that the reaction was a first-degree and reaction speed was a variable which was related with temperature and the concentration of alpha-naphthol.
When the reductive amination between the intermediate 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was optimized, methanol solution of methyl amine was used as aminating agent for the first time. So, TiCl4 was not needed, and the reaction can run at room temperature. The factors affecting the reaction were investigated in the round, and the optimal reaction conditions were obtained. The yield of synthesizing racemize sertraline hydrochloride from 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was 36.4%. To get
ABSTRACT
higher total yield of this step, trans- isomeric was innovatively converted to cis-isomeric by catalyzing of basic equilibration agent sodium tert.-butoxide. The converting yield was 44.56%.
In conclusions, compared with alpha-naphthol, the total synthesis yield was 15.6%. The structure of the product was confirmed by melting-point, HPLC, optical activity analysis, element analysis, IR, H-NMR and et al.
在合成中间体4-(3，4-二氯苯基)-1-萘满酮过程中，采用乙酸乙酯代替邻二氯苯作萃取溶剂，大大降低了减压蒸馏真空度的要求，简化了操作。同时本文系统地考察了合成中的各种影响因素，找到了适宜的工艺条件，产率达72.48％。与文献值相比，产率提高11.48％，而反应时间缩短一半。在此基础上，对该步合成机理与动力学进行了研究，得出反应是分步进行的一级反应，反应速度是与温度及1-萘酚有关的变量。
在对中间体4-(3，4-二氯苯基)-1-萘满酮与甲胺发生的还原胺化反应进行优化时，首次采用甲胺的甲醇溶液作胺化剂，这样就不需要使用TiCl_4，常温下即可发生反应生成盐酸舍曲林。系统研究合成中各种影响因素后，找到了最优的工艺条件，合成产率36.4％。为进一步提高该步反应的总产率，我们创造性地采用叔丁醇钠作碱平衡剂，将反式的盐酸舍曲林转化为顺式产品，转化率44.56％。
因此，以1-萘酚为参比，合成总产率为15.6％。采用熔点、HPLC、旋光分析、元素分析、IR、H-NMR等手段对产物结构进行了确认。
Sertraline hydrochloride is an antidepressant with permanence of effect and less side-effect. There is no paper on the total synthesis of it in China. In this paper, the intermediate 4-(3,4-dichlorophenyl)-l-tetralone was synthesized by one step Friedel-Crafts alkylation with alpha-naphthol and orthodichlorobenzene as raw materials and anhydrous aluminium as catalyzer. Then racemize sertraline hydrochloride was synthesized with the intermediate and methyl amine by reductive animation. After resolution of racemate, dextro-cis- sertraline hydrochloride was obtained.
Orthodichlorobenzene was usually used as extraction reagent to synthesize the intermediate 4-(3,4-dichlorophenyl)-l-tetralone, which made operation difficult. After ethyl acetate acted as the substitute of orthodichlorobenzene, vacuum degree in decompression distillation was not strict. The system factors affecting the reaction were investigated and the optimal reaction conditions were obtained. The yield of synthesizing 4-(3,4-dichlorophenyl)-l-tetralone from alpha-naphthol and orthodichlorobenzene was 72.48%. Comparing with paper, the yield was improved by 11.48% and the half of the reaction time was saved. On the basis of the experiment, the mechanism and the reaction kinetic model were studied and conclusions were drawed that the reaction was a first-degree and reaction speed was a variable which was related with temperature and the concentration of alpha-naphthol.
When the reductive amination between the intermediate 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was optimized, methanol solution of methyl amine was used as aminating agent for the first time. So, TiCl4 was not needed, and the reaction can run at room temperature. The factors affecting the reaction were investigated in the round, and the optimal reaction conditions were obtained. The yield of synthesizing racemize sertraline hydrochloride from 4-(3,4-dichlorophenyl)-l-tetralone and methyl amine was 36.4%. To get
ABSTRACT
higher total yield of this step, trans- isomeric was innovatively converted to cis-isomeric by catalyzing of basic equilibration agent sodium tert.-butoxide. The converting yield was 44.56%.
In conclusions, compared with alpha-naphthol, the total synthesis yield was 15.6%. The structure of the product was confirmed by melting-point, HPLC, optical activity analysis, element analysis, IR, H-NMR and et al.
引文
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[3]Pascual M., Gloria S., Rosa B., et al. Effects of antidepressants in adrenergic neurotransmission of human vas deferens. Urology, 1995, 55, 4: 592～597
[4]胡亚云．关于抑郁症的社会学思考．信阳师范学院学报(哲学社会科学版)，2001，21(4)：44～47
[5]叶维菲．认识抑郁症．健康促进，2002，2：28～29
[6]章新奇，张金芳．认识抑郁症．癌症康复，2002(4)：30～31
[7]杜占文．解读抑郁症．国外科技动态，2000，10：14～15
[8]周志宽．中国抗抑郁药中药研究前景广阔．健康报，2001
[9]刘效巍，许晶．5-羟色胺受体与抑郁症．临床精神医学杂志，2002，12(6)：375～376
[10]陈钰，张心保，翟书涛．生长抑素与抑郁症．国外医学精神病学分册，1999，26：134～137
[11]高桂林．舍曲林在强迫症、抑郁症治疗中的应用．中国临床康复，2002，6：736
[12]邹海宁．SPECT研究抑郁症的新进展．山东精神医学，1999，12：66～67
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[14]R.A. Lawrenson MB, BS, MD, et al. Treatment of depression in UK general practice: selective serotonin reuptake inhibitors and tricycles antidepressants compared. Journal of affective disorders, 2000, 59: 149～157
[15]Bill Deakin. Dose optimization in antidepressant drug development. International Congress Series, 2001, 1220: 223～245
[16]T.G.Dinan. Adjunctive therapy in severe depression. European Neuropsychopharmacology, 1996, 6: S4/4
[17]Bruce M. Johnson, Pei-Tei L. Chang. Sertraline hydrochloride. Analylitical Profiles of Drug Subatances and Excipients, 1992, 24: 443～486
[18]徐积恩．抗抑郁药盐酸舍曲林．国外医药：合成药．生化药．制剂分册，1992，13(2)：109～110
[19]Preskorn S.H.. Pharmacokinetics of antidepressants: why and how they are relevant. Journal of clinic psychiatry, 1993, 54 (suppl): 14
[20]Goodnick P.J.. Pharmacokinetic aptimisation of therapy with newer antidepressants. Clinic pharmacokinet, 1994, 27: 307
[21]高桂林．舍曲林在强迫症、抑郁症治疗中的应用．中国临床康复，2002，6(5)：736
[22]刘鑫荣，曾思群．抗抑郁新药—舍曲林．上海医药，1994，2(2)：32～33
[23]杜文华，易祖芹．舍曲林的临床应用进展．医药导报，2000，19(5)：479～480
[24]杨云宁．新抗抑郁药—舍曲林．上海精神医学，1994，6(2)：114～115
[25]甘景梨．舍曲林的药理学及临床研究进展．实用医学杂志，1998，11(4)：63～65
[26]Fabre LF, Abuzzahab FS, Amin M, et al. Sertraline safety and efficacy in major depression: a double-blind fixed-dose comparison with placebo. Biol Psychiatry, 1995, 38: 592
[27]Bennie E, Mullin JM, Martindale JJ. A double-blind multi-center trial comparing sertraline and fluoxetine in outpatients with major depression. J Clin Psychiatry, 1995, 56: 229
[28]Mertenc C, Bartholome F, Cosyns P, et al. A controlled comparison of sertraline and fluoxetine in acute and continuation treatment of major depression. Presented at 148th American Psychiatric Association, Miami, USA, 1995: 20～25
[29]N.J.Johnson, R.Lane. Sertraline: an assessment of clinical benefit and cost in UK. European Neuropsychopharmacology, 1995, 5(3): 314～315
[30]Lauten.M, Rovis.T. General strategy toward the tetrahydronaphthalene skeleton, an expedient total synthesis of sertraline. Journal of Organic Chemistry, 1997, 62: 5246～5247
[31]Lauten.M, Rovis.T. Selective functionalization 1,2-dihydronaphthalenonls leads to a concise,stereoselective synthesis of sertraline. Tetrahedron, 1999, 55: 8967～8976
[32]Lauten.M, Rovis.T. Selective functionalization 1,2-dihydronaphthalenonls leads to a concise,stereoselective synthesis of sertraline. Tetrahedron, 1999, 55: 8967～8976
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