论文总字数：25520字

摘 要

甲状腺分泌的甲状腺激素主要成分为T3和T4，其含量低于正常水平会导致甲减的产生。L-甲状腺素钠(Levothynoxtine Na)为治疗甲减的首选药物，它是人工合成的L-甲状腺素钠盐。

本文从甲状腺出发，简略地介绍了甲状腺认识历程和功能，详细介绍了甲状腺功能减退症的分类，临床症状以及致病机理。同时，对比了几种治疗甲减的药物，从中可知为何L-甲状腺素钠为替代治疗的首选药物。之后再详细介绍了L-甲状腺素钠的相关情况。

查阅文献对比七条合成路线的优缺点，我们选择采用以下路线进行实验：以3,5-二碘-L-酪氨酸为原料，与硫酸铜络合，再与二苯甲醚基碘鎓碘盐进行偶联，经酸水解，再碘代得到L-甲状腺素，最后成钠盐。

在该路线中，通过控制单一变量对每个步骤产率的影响因素进行考察，确定了最佳反应条件。论文工作如下：

1）中间体M-1 3,5-二碘-L-酪氨酸铜络合物的合成和优化

3,5-二碘-L-酪氨酸在NaOH溶液中与CuSO₄反应得到中间体M-1。最佳反应条件为：3,5-二碘-L-酪氨酸、硫酸铜与氢氧化钠的摩尔比为1:1:1.8，收率为94.5%。

2）中间体M-2 O-(4-甲氧苯基)-3,5-二碘-L-酪氨酸的合成和优化

M-1在二异丙胺中与二苯甲醚基碘鎓碘盐得到中间体M-2。最佳反应条件为：M-1、二苯甲醚基碘鎓碘盐与二异丙胺的摩尔比为1:2:2，在90 ℃反应3 h，收率为45.0%。

3）中间体M-3 3,5-二碘-L-甲状腺原氨酸的合成和优化

M-2在HAc中与HI进行酸水解反应得到中间体M-3。最佳反应条件为：M-2与氢碘酸的质量体积比为1:6，100 ℃反应5 h，收率为78.9%。

4）中间体M-4 L-甲状腺素的合成和优化

M-3在NaOH溶液中与I₂反应得到中间体M-4。最佳反应条件：M-3、NaOH和I₂的摩尔比为1:5:4，0 ℃反应3 h，收率为84.8%。

5）终产物L-甲状腺素钠的合成和优化

M-4与碳酸钠成盐得到L-甲状腺素钠。最佳反应条件为：溶剂水与中间体M-4的体积质量比为30:1，中间体M-4与碳酸钠的摩尔比为1:3，加热至沸腾后冷却析晶，收率为82.0%。

关键词：甲状腺激素 左甲状腺素钠 甲状腺功能减退症 合成工艺

SYNTHETIC PROCESS OF LEVOTHYROXINE SODIUM

ABSTRACT

The main components of thyroid hormone secreted by the thyroid gland are T3 and T4, and its content below normal levels will cause hypothyroidism. L-thyroxine sodium (Levothyroxtine Na) is the drug of choice for the treatment of hypothyroidism. It is a synthetic sodium salt of L-thyroxine.

Starting from the thyroid, this article briefly introduces the history and function of thyroid recognition, and details the classification, clinical symptoms and pathogenic mechanism of hypothyroidism. At the same time, several drugs for hypothyroidism are compared, from which we can see why L-thyroxine sodium is the first choice for replacement therapy. After that, the relevant situation of L-thyroxine sodium was introduced in detail.

Consult the literature to compare the advantages and disadvantages of the seven synthetic routes. We chose to use the following route for the experiment:using 3,5-diiodo-L-tyrosine as the raw material, complexing with copper sulfate, and then diphenyl ether iodonium iodide The salt is coupled, hydrolyzed by acid, and then iodinated to obtain L-thyroxine, and finally into sodium salt.

In this route, the optimal reaction conditions were determined by examining the factors that influence the yield of each step by controlling a single variable. The thesis work is as follows:

1) Synthesis and optimization of intermediate M-1 3,5-diiodo-L-tyrosine copper complex

3,5-Diiodo-L-tyrosine reacts with CuSO₄ in NaOH solution to obtain intermediate M-1. The optimal reaction conditions are: the molar ratio of 3,5-diiodo-L-tyrosine, copper sulfate and sodium hydroxide is 1:1:1.8, and the yield is 94.5%.

2) Synthesis and optimization of intermediate M-2 O-(4-methoxyphenyl) -3,5-diiodo-L-tyrosine

M-1 and diphenyl ether iodonium iodide salt in diisopropylamine to give intermediate M-2. The optimal reaction conditions are:M-1, the molar ratio of diphenyl ether iodonium iodide salt and diisopropylamine is 1:2:2, the reaction is carried out at 90 ℃ for 3 h, the yield is 45.0%.

3) Synthesis and optimization of intermediate M-3 3,5-diiodo-L-thyronine

M-2 undergoes acid hydrolysis reaction with HI in HAc to obtain intermediate M-3. The optimal reaction conditions are: the mass-to-volume ratio of M-2 and hydroiodic acid is 1:6, and the reaction at 100 ℃ for 5 h, the yield is 78.9%.

4) Synthesis and optimization of intermediate M-4 L-thyroxine

M-3 reacts with I₂ in NaOH solution to obtain intermediate M-4. The optimal reaction conditions: the molar ratio of M-3, NaOH and I2 is 1:5:4, the reaction is carried out at 0 ℃ for 3 h, and the yield is 84.8%.

5) Synthesis and optimization of the final product L-thyroxine sodium

M-4 forms a salt with sodium carbonate to obtain sodium L-thyroxine. The optimal reaction conditions are: the volume ratio of solvent water to intermediate M-4 is 30:1, the molar ratio of intermediate M-4 to sodium carbonate is 1:3, heated to boiling and cooled to crystallize, the yield is 82.0%.

KEYWORDS: Hypothyroidism; Levothyroxine sodium; Synthesis; Process

目 录

摘 要 I

ABSTRACT III

第一章 文献综述 1

1.1 甲状腺相关简介 1

1.1.1 历史 1

1.1.2 甲状腺功能 1

1.1.3 甲状腺疾病 1

1.2 甲状腺功能减退症 2

1.2.1 分类 2

1.2.2 临床表现 2

1.2.3 甲状腺功能减退症原因 2

1.3 治疗甲状腺功能减退症的药物 3

1.3.1 甲状腺素提取物 3

1.3.2 甲状腺片 4

1.3.3 碘塞罗宁钠 4

1.3.4 L-甲状腺素钠 4

1.4 L-甲状腺素钠的概况 5

1.4.1 L-甲状腺素钠的基本信息 5

1.4.2 物理化学性质 5

1.4.3 L-甲状腺素钠的药理作用 6

1.4.4 L-甲状腺素钠的药代动力学 6

1.4.5 临床治疗 6

1.4.6 L-甲状腺素钠的不良反应 6

1.5 L-甲状腺素钠的合成 6

1.5.1 L-甲状腺素钠的合成路线一 6

1.5.2 L-甲状腺素钠的合成路线二 7

1.5.3 L-甲状腺素钠的合成路线三 7

1.5.4 L-甲状腺素钠的合成路线四 8

1.5.5 L-甲状腺素钠的合成路线五 8

1.5.6 L-甲状腺素钠的合成路线六 8

1.5.7 L-甲状腺素钠的合成路线七 9

1.6 本课题的目的和思路 9

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