论文总字数：20283字

摘 要

便秘是临床常见的一种疾病，然而，传统药物治疗通常不能令人满意，特别是病人的生活质量。普卡必利是全球第一个高选择性和高亲和力的5-HT₄受体激动剂，CAS号：179474-85-2,英文名称prucalopride,主要作用是刺激结肠动力，这也解释了它为什么能治疗应用其他治疗方案无效的便秘患者。

普卡必利的上市,是便秘治疗领域的一个全新突破。普卡必利的药物作用机制与目前广泛使用的便秘药物稍有不同：普卡必利只对5-HT₄受体有高度的亲和力，从而只促进结肠蠕动,不影响胃排空和小肠传输，同时不阻断钾离子通道,所以避免了诸如心律失常等心血管副作用,这是它和其他促动力药相比相当明显的一大优势。

普卡必利安全性较高,长期使用机体对药物的反应性也无明显下降趋势,每日只需要服药1 次,就可以有效缓解便秘,可成为便秘患者的一种新选择。

本文主要介绍了普卡必利的药理作用、药物代谢动力学特点和临床药效，在参考大量国内外文献和专利资料的基础上,摸索出了较为合适的合成路线：首先，以对乙酰氨基水杨酸甲酯为起始原料,通过氯代、溴化、醚合、成环和水解等步骤,合成中间体4-氨基-5-氯-2,3-二氢苯并呋喃-7-羧酸,再以4-哌啶酮为起始原料,通过N-甲氧丙基化、肟化和还原获得另一中间体1-(3-甲氧基丙基)-4-哌啶胺。最后将上述两个中间体缩合获得目标产品普卡必利。整条合成工艺路线操作简单,安全性高、收率较高。

关键词： 普卡必利 慢性便秘 合成

The Synthesis of Prucalopride

Abstract

Constipation is a common clinical disease, however, traditional medical treatment is usually not satisfactory, especially in the quality of life of patients. Prucalopride is the world's first high 5-HT₄ receptor agonist which has high selectivity and affinity, the chemical name 4-amino-5-chloro-2,3-2H-N-[1-(3- methoxy-propyl-4-piperidinyl] -7-benzofuran,the English name prucalopride,abbreviations PKBL,CAS number: 179474-85-2. It stimulates colonic motility which also explains why it can be applied to patients with chronic constipation that other treatments find ineffective.

The launch of prucalopride is a breakthrough in constipation therapeutic area. Prucalopride’s mechanism has a little difference with the constipation drugs which are now widely used: Prucalopride only plays a role on the 5-HT4 receptor,so,it only promote colon motility and do not affect gastric emptying and intestinal transmission at all.Meanwhile,it has no interaction with the hERG potassium pathway, so it reduces many unnecessary cardiovascular side effects, such as arrhythmia.It is a quite obvious advantage compared to other prokinetics.

Prucalopride has good safety、tolerance and appears adverse reactions rarely.Just take the medicine once a day,then you can increase the number of bowel movements weekly and effectively relieve the symptoms of constipation, it is a new effective drug for chronic constipation patients to choose.

This article will give a more comprehensive discussion about the pharmacological effects of prucalopride, and pharmacokinetics characteristics and synthetic routes, on the base of referring to a number of domestic and foreign patent documents and materials basis, 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid was synthesized from acetaminophen methyl salicylate by chlorination, bromination , esterification,cyclization and hydrolysis, Meanwhile,another intermediate 1- (3-methoxypropyl) -4-piperidinamine was synthesized from 4-piperidyl by N- methoxypropyl, oximation and reduction. Finally, we get the target product prucalopride through a condensation reaction of the two intermediates.The entire synthetic route is simple, safe, and has high yield.

Key words：prucalopride;chronic constipation;synthesis

目 录

摘 要 I

ABSTRACT II

第一章 文献综述 1

1.1便秘及其药物的研究进展 1

1.2 普卡必利 2

1.2.1普卡必利简介 2

1.2.2普卡必利的药理作用 2

1.2.3普卡必利的药代动力学性质 3

1.2.4 普卡必利的临床疗效对比 4

第二章 普卡必利的合成路线 7

2.1普卡必利的合成路线 7

第三章 实验部分 9

3.1实验试剂及仪器 9

3.1.1实验试剂 9

3.1.2实验仪器 10

3.2详细实验步骤 11

3.2.1中间体6的合成 11

3.2.2 中间体11的合成 12

3.2.3终产物的合成 14

3.2.4 讨论 15

3.3反应监控 17

3.4三废处理方案 17

第四章 总结与展望 19

4.1 结论 19

4.2 展望 19

参考文献 20

致 谢 22

第一章 文献综述

1.1便秘及其药物的研究进展

便秘是一种常见的、通常是慢性的胃肠蠕动失调症，特点是症状的多样性，包括腹胀，使劲，腹痛，块状或硬便，不完全排空的感觉，和偶发排便（每周少于三次排便）^[1]。在临床实践中是通过不频繁，难以或不能令人满意的肠道排空的症状来诊断的。不少患者没有明显的饮食、全身或局部结构性原因导致自己的症状，即特发性或功能性便秘。

慢性便秘全球患病率约为14％，大多数便秘患者属于慢传输型便秘（结肠传输的速率降低），多见于妇女和老人，极少数人症状特别严重，可以显著影响患者的生活健康质量 (HRQoL)，并降低工作效率。慢性便秘患者生活健康质量差已被证明是医疗保健利用率增加的预测因子。

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