论文总字数：21799字

摘 要

当静脉发生血栓时，血液在静脉中就不能正常凝集，甚至阻塞了血管。血栓是某些心血管疾病的致病源，也常发生于骨科手术后，尤其常见于下肢创伤性骨折术后并发症，在术后引起人非正常死亡的案例中，静脉血栓或肺栓塞的情况占了很大的比例。所以，为了防止血栓的发生，抗凝治疗是十分有效的手段。

长久以来，人们时刻关注着抗凝药物的发展。临床上使用的肝素、低分子肝素、华法林等是比较传统的抗凝药物，而且这些药物由于各种原因使其在临床使用过程中受到了限制。所以新型抗凝血药物是临床上迫切需要的。

本文以4-(4-氨基苯基)-3-吗啉酮为起始原料，经过四步反应制得利伐沙班，其中反应中所需的中间体5-氯噻吩-2-甲酰氯由另一步反应制得。

本文对反应溶剂、原料投料比等进行实验，确定了最佳反应条件，优化了利伐沙班的工艺合成路线，切实提高了利伐沙班的合成产率。以2-苯胺基乙醇计，收率为43.8%。终产物纯度为：99.81%，e.e. %为：99.6%。

与此同时，本反应反应条件温和，实验步骤较少，成本较低，对环境污染小，实验重复性好，为工业化生产提供了一条合理的工艺路线。

关键词：利伐沙班 抗凝药物 合成路线

Abstract

Vascular occlusion which caused by abnormal blood coagulation in vein is the main feature of VTE(venous thrombus embolism).Thrombus is etiology of some CVD(cardiovascular disease).It often occurs after the orthopedic surgery; especially the lower limb traumatic fracture surgery. For example leading DVT(deep vein thrombus)or pulmonary embolism. Both cases can kill human.Therefore;anticoagulation therapy is the main therapeutic method to prevent and treat the thrombosis.

The development of anti-clotting drugs is concerned all the time.However, these traditional drugs, such as heparin; low molecular weight heparin and warfarin, have some drawbacks, which limit their use in the clinical setting.So new anti-clotting drugs is required urgently.

In this paper; the 4- (4-aminophenyl) -3-morpholinone is treated as starting material in the test. Obtaining rivaroxaban after 4 steps reaction and the 5-chloro-thiophene-2-carbonyl chloride(intermediate) which is needed in the reaction can obtain by another step in the reaction.

In order to make sure the best reaction condition; I count the rate of material and solvent. It is proved that we can obtain rivaroxaban better and faster. The statistics treats 2-anilino-ethanol as standard; the yield is 43.8%; the final product purity is 99.81%; e% is 99.6%.

At the same time this reaction has lots of advantage; such as mild reaction conditions; less steps; less cost; less pollution and easy to repeat. Offering a reasonable technical route for industrialized production.

Key Words: Rivaroxaban; Anticoagulants; Synthetic route

目 录

摘要······························································Ⅰ

ABSTRACT······················································Ⅱ

第一章 文献综述··················································1

1.1血栓性疾病······················································1

1.1.1 血栓的概念················································1

1.1.2 血栓的分类················································1

1.1.3 血栓的形成················································2

1.1.3.1 血管璧功能异常······································2

1.1.3.2 血小管功能异常······································2

1.1.3.3 红细胞因素··········································2

1.1.3.4 凝血因子的作用······································2

1.1.3.5 抗凝作用············································3

1.1.4 血栓的后果················································3

1.1.5 血栓的治疗················································3

1.1.5.1 抗凝血药············································3

1.1.5.2 抗血小板聚集药······································4

1.1.5.3 溶栓药··············································4

1.2 凝血酶因子Xa(FXa)的介绍········································5

1.3 关于利伐沙班的介绍·············································5

1.3.1 利伐沙班简介··············································5

1.3.2 利伐沙班的特点及性质······································5

第二章 利伐沙班的合成···········································6

2.1 文献报道中的利伐沙班的合成路线······························6

2.2 利伐沙班合成工艺的改进······································7

2.3 本文所用的利伐沙班合成路线··································7

2.4 利伐沙班的应用··············································8

2.5 利伐沙班的发展前景··········································9

第三章 实验过程·················································10

3.1 实验仪器和实验试剂·········································10

3.1.1 实验仪器··············································10

3.1.2 实验试剂··············································10

3.2 实验步骤···················································11

3.2.1 2-((2R)-2-羟基-3-{[4-(3-氧代-4-吗啉基)苯基]氨基}丙基)-1H-异吲哚-1,3(2H)-二酮(6)的合成·············································12

3.2.2 2-({(5S)-2-氧代-3-[4-(3-氧代-4-吗啉基)苯基]-1,3-恶唑烷-5-基}甲基)-1H-异吲哚-1,3(2H)-二酮(5)的合成··································12

3.3.3 4-{4-[(5S)-5-氨基甲基]-2-氧代-1,3-恶唑烷-3-基]苯基}吗啉-3-酮盐酸盐(2)的合成······················································13

3.3.4 5-氯-N-({(5S)-2-氧代-3-[4-(3-氧代-4-吗啉基)苯基]1,3-恶唑烷-5-基}-甲基)-2-噻吩甲酰胺(1)的合成······································13

总 结····························································15

展 望····························································16

参考文献·························································17

附图······························································21

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