论文总字数：18880字

摘 要

在食品医药及化工行业中,手性甘油醛缩丙酮是用来合成一些手性药物和具有光学活性的天然产物的重要前体，其中(S)-丙酮缩甘油醛可以用来合成很多手性物质,它是合成一系列洛尔类手性药物的重要中间体,同时它也是抗艾滋病药地瑞那韦(Darunavir)的关键中间体——(3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮的合成原料。地瑞那韦是一种新的用于艾滋病治疗的非肽类抗逆转病毒蛋白酶抑制剂，由强生制药冰岛分公司Tibotec首次研发成功，是目前6种蛋白酶抑制剂(沙奎那韦，利托那韦，茚地那韦，萘非那韦，安瑞那韦及ABT378/r)中生物利用度最高的，它通过阻断从受感染的宿主细胞表面释放新的、成熟的病毒粒子的形成过程，抑制病毒的蛋白酶而起作用，能有效地控制艾滋病的恶化。目前，地瑞那韦已成为市场销量最大、副作用较小的治疗艾滋病的药物，有很大的发展前景。

本课题实验分为两部分，第一部分以L-抗坏血酸为合成原料，先用2,2-二甲氧基丙烷保护原料的羟基得到L-抗坏血酸缩丙酮，然后用双氧水对L-抗坏血酸缩丙酮进行氧化开环得到2-(2,2 -二甲基-1,3-二氧戊环-4-基)-2-羟基乙酸钙，最后用次氯酸钙将其氧化脱羧得到(S)-丙酮缩甘油醛，所得产率有待优化提高。第二部分以(R)-丙酮缩甘油醛代替昂贵的(S)-丙酮缩甘油醛为原料合成(3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮，先与磷酸三甲酯发生Wittig-Horner反应，再与硝基甲烷发生Michael加成反应，最后在强酸性环境下发生酯交换反应得到(3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮。其中Wittig-Horner反应是合成中涉及到的重点反应，是整个反应的关键步骤，决定着反应产物的空间构型和最终产物的药效。经过反复优化，将第一步反应产物进行分离提纯，第二步反应则以较纯的原料进行投料，因此产率得以提高，已由原先的4%提高到10%。经过反复实验，已得到产物。将产物提纯并通过核磁共振对产物进行表征，初步确定合成产物即目标产物。

关键词：丙酮缩甘油醛 Wittig-Horner反应 地瑞那韦(Darunavir) (3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮 中间体

Research and application about chiral acetone condensation glyceraldehyde

Abstract

Chiral glyceraldehyde acetonide is important precursors to synthesize some chiral drugs and some natural products with optical activity in food and medicine and chemical industry. The case (S)- acetone condensation glyceraldehyde can be used to synthesize many chiral material and it is a important intermediates to synthesize a series of chiral drugs, like Loar and meanwhile it is the source to synthesize (3aR,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one, which is the important intermediates of anti-HIV drugs named Darunavir. Darunavir is a new non-peptide antiretroviral protease inhibitors applied to AIDS treatment and it was first researched successfully by Tibotec. Currently Darunavir has been the highest bioavailability of six protease inhibitor. It suppresses the virus protease and work by interdict the virion’s forming process. The new and ripe virion was released from surface of the infected host cells so that Darunavir can effectively control the deterioration of AIDS.

This topic experiment is divided into two parts. The first part is started with L-ascorbic acid. First, 2, 2 - dimethoxy propane is added into the action to protect the reactant’hydroxy. Then hydrogen peroxide is added to oxidize L-ascorbic acid acetonide so that L-ascorbic acid acetonide is reduced to be 2-(2,2-dimethyl-1,3- dioxolan-4-yl)-2- hydroxy calcium acetate. At last, calcium hypochlorite is added to oxidize 2-(2,2-dimethyl-1,3- dioxolan-4-yl)-2- hydroxy calcium acetate so that it can decarboxylate to be (S)- acetone condensation glyceraldehyde. The yield is to be increased. In the second part, the expensive (S)- acetone condensation glyceraldehyde was replaced by (R)- acetone condensation glyceraldehyde to synthesize (3aR,4S,6aR) -4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one. First, it occurs Wittig-Horner

reaction with trimethyl phosphate added into the action. Then it occurs Michael addition reaction with nitromethane added into the action. At last, it occurs transesterification reaction and gives (3aR,4S,6aR) -4-methoxy - tetrahydro - furo [3,4-b]furan-2(3H)-one with the acidic environment. Wittig-Horner reaction is the key reaction and the key step which decides the steric configuration of the reaction product and the pesticide effect of Darunavir. After repeated optimization, by separating and purifing the product of step one, that means the step two is input with pure material, the productive rate has been increased from 4% to 10%. By repeating experiment, the aim product has been synthesized successfully. The product has been confirmed tentatively as the target product by NMR of the product.

Keywords: Acetone Condensation Glyceraldehyde; Wittig-Horner Reaction; Darunavir;(3aR,4S,6aR)-4-methoxy-tetrahydro-furo[3,4-b]furan-2(3H)-one;Intermediate

目 录

摘 要 I

Abstract II

第一章 文献综述 1

1.1 前言 1

1.2 (R)-丙酮缩甘油醛 1

1.2.1 (R)-丙酮缩甘油醛的制备 2

1.2.2 (R)-丙酮缩甘油醛的发展现状与前景 2

1.3 (S)-丙酮缩甘油醛 2

1.3.1 (S)-丙酮缩甘油醛的制备 3

1.3.2 (S)-丙酮缩甘油醛的发展现状与前景 3

1.4 反应机理简介 4

1.4.1 Wittig反应简介与反应机理 4

1.4.2 Wittig- Horner反应简介与反应机理 6

1.4.3 Michael加成反应简介与反应机理 8

1.5（3aS，4S，6aR）-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2（3H）-酮 9

1.5.1 应用 10

1.6 本课题研究的主要内容和意义 10

第二章 (S)-丙酮缩甘油醛的合成 12

2.1前言 12

2.2 实验部分 12

2.2.1实验仪器 12

2.2.2实验试剂 13

2.2.3 实验方法 13

第三章（3aS，4S，6aR）-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2（3H）-酮的合成 16

3.1 前言 16

3.2 实验部分 16

3.2.1实验仪器 16

3.2.2实验试剂 17

3.2.3 实验方法 17

第四章 结果与讨论 20

4.2 (R，E)-甲基3 -(2,2-二甲基-1,3 -二氧戊环-4-基)丙烯酸乙酯 VI的核磁表征 21

4.3 (3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮 VIII的核磁表征 22

4.4 (3aS，4S，6aR)-4-甲氧基-四氢呋喃并[3,4-b]呋喃-2(3H)-酮 VIII的红外表征 23

第五章 结论与展望 24

5.1结论 24

5.2展望 24

参考文献 26

致 谢 28

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