Ⅰ.乙胺丁醇的合成工艺研究 Ⅱ.地尔硫卓手性中间体的拆分工艺研究Ⅲ.头孢吡肟的合成工艺研究
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说明：
摘要：本报告由三部分组成：Ⅰ.乙胺丁醇的合成工艺研究；Ⅱ.地尔硫卓手性中间体的拆分工艺研究；Ⅲ.头孢吡肟的合成工艺研究。
Ⅰ. 乙胺丁醇的合成工艺研究
报告对乙胺丁醇及其关键中间体2-氨基丁醇的国内外的生产及研究状况做了比较全面地总结，并且详细地分析、比较了各条合成路线的优劣及其实用性。在文献调研的基础上，结合企业生产实际及目前的实验室条件选择dl-2-氨基丁醇的合成方法中的路线4，6，7作为工艺研究的重点并对其进行了工艺考查，得出了确切的结论，为企业进行品种决策提供了依据。对dl-2-氨基丁醇的拆分工艺进行了详细的研究， 比较了甲醇、无水乙醇、甲醇-异丙醇和甲醇-丙酮四种拆分溶剂对拆分结果的影响，结果表明以甲醇为拆分溶剂比较理想。选择冰醋酸—(+)-酒石酸（1:1）的混合酸为拆分剂，经过工艺考查发现：选用混合酸为拆分剂基本可以达到单独使用(+)-酒石酸为拆分剂的拆分效果，可以节省1/2量的(+)-酒石酸。对“可逆拆分”这种新的拆分方法进行了研究，分别选用了（±）扁桃酸和（±）酒石酸为拆分剂，实验结果表明这一拆分方法有一定的理论意义和实用价值，但目前用于工业化规模生产还需进一步优化工艺条件。l-2-氨基丁醇的消旋化工艺研究，分别选用钯碳和Raney Ni作催化剂，甲苯、乙醇、异丙醇等为溶剂，在一定压力下反应，实验结果表明选择Raney Ni为催化剂，乙醇为溶剂可以获得较满意的消旋化结果。
Ⅱ. 地尔硫卓手性中间体的拆分工艺研究
报告对钙拮抗剂类心血管药物地尔硫卓的药理学及药代动力学特征进行了概述；对有关地尔硫卓手性中间体拆分工艺的国内外研究状况做了比较全面的总结，并且详细地分析、比较了各种拆分方法的优劣及其实用性。在文献调研的基础上，对中间体dl-3-(4-甲氧基苯基)-2,3-环氧丙酸甲酯(3)和 dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸甲酯(4)的拆分工艺进行了研究，得出了确切的结论。分别选用D-α-苯乙胺和L-赖氨酸为拆分剂，对中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(5)的拆分工艺过程进行了详细的考察,拆分收率由原来的34%提高到48.3%。另外，对拆分剂的回收及拆分中的副产物l-cis-3- (4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(甲酯)的消旋化工艺已做了详细的工艺研究，使拆分剂的回收率达到80%以上，l-cis-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(甲酯)的回收率达到42%，减少了资源浪费，降低了生产成本。
Ⅲ. 头孢吡肟的合成工艺研究
报告简要介绍了第四代头孢菌素盐酸头孢吡肟的药理学特征与临床应用，对有关盐酸头孢吡肟合成工艺的国内外研究状况做了比较全面的总结。通过实验考查，确定了合成路线；以降低成本，简化操作，提高收率，节能环保为目标，对合成工艺进行研究。以7-ACA为起始原料，经硅烷化保护氨基和羧基、碘代、置换、脱保护、成盐、缩合、成盐等六步反应，合成了目标化合物，总收率为21％（以7-ACA计）。产品结构经1H-NMR、MS确证。
选择以环己烷为溶剂，一锅法制备了关键中间体7-氨基-3-[1-(1-甲基四氢吡咯烷)甲基]头孢烷酸盐酸盐，并对其合成工艺进行优化，优化后的工艺具有操作方便、条件温和、安全环保等特点。选择丙酮-水作为缩合反应的溶剂，通过对反应条件的考查，得出了最佳反应条件，产品收率高，色泽浅，纯度高。
自行设计了一条盐酸头孢吡肟的合成路线并进行了详细工艺考察，得到的头孢吡肟盐酸盐，收率较高，但是产品颜色较深，工艺还有待改进。
对盐酸头孢吡肟△3异构体的产生机理以及影响因素进行了初步研究，发现通过控制反应的温度和时间，能够大大避免该异构体的产生。对产品的二级质谱学特征进行了分析、讨论。
关键词：乙胺丁醇，地尔硫卓，头孢吡肟，中间体，拆分，合成工艺
ABSTRACT
This report consists of three sections, which includes: Ⅰ. Study on the synthetic technology of Ethambutol, Ⅱ. Sstudy on the resolution methods of the key intermediates for Diltiazem synthesis, Ⅲ. Study on the synthetic technology of Cefepiem.
Ⅰ. Study on the synthetic technology of Ethambutol
In this section, the research and production status of Ethambutol and its key intermediates have been described roundly, the disadvantages and practicability of the synthetic routes for Ethambutol synthesis had also been analyzed and compared in detail. After reference the literature methods, combining with the production feasibility and our lab conditions, take the synthetic route 4,6 and 7 as our focus for the synthesis of dl-2-aminobutol, the reaction conditions had also been optimized. The research results provided corporations with a base of decision-making. The resolution procedure of dl-2-aminobutol was investigated. The influence of resolution solvents (methanol, ethanol, methanol-isopropanol and methanol-acetone) on resolution results had also been compared, and it was conclude that methanol would be the best resolution solvent in this process. After investigation, the mixture of glycial acetic acid and tartaric acid can replace tartaric acid as the resolution reagent in this procedure, but the consumption of tartaric acid can be economized half quantity than that before. The “reversible resolution process” with racemic mandelic acid and racemic tartaric acid had also been investigated, the research result showed that although this resolution process would have certain theoretic meaning and practicality, but need to optimize the resolution procedure further. The racemizing process for l-2-aminobutol have been researched by taking Pd-C or Raney nickel as catalyst in ethanol or isopropanol under certain pressure. It had been conclude that this racemizing process can be conducted by catalyzing Raney nickel in ethanol.
Ⅱ. Study on the resolution methods of the key intermidiates for Diltiazem synthesis
In this section, the pharmacological and pharmacodynamics characters of Diltiazem, the calcium channel blocker, was introduced briefly. The resaerch status of technological process for Diltiazem resolution had also been summarized. The disadvantages and practicability of each method had also been analyzed and compared in detail. After reference the literature methods, resolution process of methyl dl-3- (4-methoxyphenyl) -glycidate and methyl dl-3- (4- methoxyphenyl)- 3-(2-aminothiophenyl) -2-hydroxy -propionate have been investigated. The resolution process of dl-3-(4-methoxyphenyl)-3- (2-aminothiophenyl)-2-hydroxy-propionic acid had been examined by kaking D-α-phenylethylamine and L- lysine as the resolution reagent, the yield of this resolution process was raised to 48.3% form 34%. In addition, the recycle of resolution reagents and racemizing process of the by-product, l-3-(4-methoxy -phenyl)- 3- (2-aminothiophenyl) -2-hydroxy-propionic acid (or its methyl ester), had also been investigated detailedly, the recycle ratio of resolution reagents was more than 80%, the recycle ratio of l-3-(4-methoxyphenyl)- 3- (2-aminothio- phenyl)-2-hydroxy-propionic acid was 42%, so that the production cost would be cutted.
Ⅲ. Study on the synthetic technology of Cefepime
In this section, the Cefepime dihydrochloride, one of the fourth-generation cephalosporins, was introduced briefly, including its antibiotic mechanism, pharmacological properties and clinical effects. The resaerch status of technological process for Cefepime synthesis had also been summarized in detail. After investigation of a series of synthetic routes of Cefepime, we determined the best route and researched each step of the synthetic process for the goal of cost-cut, simplifying operation procedure and improving yield.
The cyclohexane was taken as the solvent of one-pot procedure of preparing 7- amino -3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride which was the key intermediate of Cefepime in an overall yield of 21% scarcely with undesirable byproduct △3isomer. This procedure was simple, mild, environment-friendly, and suitable for scale-up production.
A new procedure for the synthesis of Cefepime dihydrochloride had been designed and obtained crude product in good yield. But it was dark-colored and the process need to be further optimized.
The mechanism of byproduct △3 isomer produced had also been preliminary speculated that the △3 isomer could be seriously reduced by controlling proper reaction time and temperature. The MS characteristic of the product was analyzed and discussed in detail.
Keywords：Ethambutol, Diltiazem , Cefepime, intermediates, resolution, synthetic technology
一、前言
1.1抗结核药乙胺丁醇简介
通用名: 乙胺丁醇
化学名：（+）2,2’-（1,2-乙二基二亚氨基）-双-l-丁醇二盐酸盐
英文名：Ethambutol Hydrochloride
化学结构式：
目录：
内容摘要……………………………………………………………………………………1
ABSTRACT………………………………………………………………………………3
Ⅰ.乙胺丁醇的合成工艺研究……………………………………………………………6
一、前言…………………………………………………………………………………7
1.1 抗结核药乙胺丁醇简介…………………………………………………………7
1.2 结核病的国内外发展趋势………………………………………………………8
1.3 抗结核病药乙胺丁醇国内外生产情况…………………………………………8
二、乙胺丁醇的合成工艺总结…………………………………………………………9
2.1 乙胺丁醇的合成路线……………………………………………………………9
2.2 d-2-氨基丁醇的合成路线………………………………………………………10
2.3 dl-2-氨基丁醇的拆分……………………………………………………………14
2.4 工艺研究的工作重点…………………………………………………………15
三、结果与讨论…………………………………………………………………………15
3.1 合成路线4的工艺研究…………………………………………………………15
3.2 合成路线6的工艺研究…………………………………………………………16
3.3 合成路线7的工艺研究…………………………………………………………16
3.3 dl-2-氨基丁醇的拆分工艺研究………………………………………………17
3.3 l-2-氨基丁醇的消旋化工艺研究………………………………………………19
四、实验部分……………………………………………………………………………20
4.1 合成路线4的工艺研究…………………………………………………………20
4.2 合成路线7的工艺研究…………………………………………………………21
4.3 dl-2-氨基丁醇的拆分工艺研究………………………………………………22
4.4 l-2-氨基丁醇的消旋化…………………………………………………………24
五、小结………………………………………………………………………………25
参考文献………………………………………………………………………………26
Ⅱ.地尔硫卓手性中间体的拆分工艺研究………………………………………………28
一、前言………………………………………………………………………………29
1.1 地尔硫卓的简介………………………………………………………………29
1.2 药理学特征……………………………………………………………………29
1.3 地尔硫卓的药代动力学………………………………………………………30
二、地尔硫卓手性中间体的拆分工艺总结…………………………………………30
2.1 地尔硫卓的合成工艺…………………………………………………………30
2.2 中间体拆分方法的选择………………………………………………………31
2.3 工艺的研究重点………………………………………………………………36
三、结果与讨论…………………………………………………………………………36
3.1 中间体dl-3-(4-甲氧基苯基)-2,3-环氧丙酸甲酯(3)的拆分工艺研究…………36
3.2 中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸甲酯(4)的拆分工艺研究………………………………………………………………………………………36
3.3 中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(5)的拆分工艺研究…………………………………………………………………………………………37
3.4 消旋化路线的工艺研究………………………………………………………40
四、实验部分……………………………………………………………………………41
4.1 dl-3-（4-甲氧基苯基）-3-（2-氨基苯硫基）-2-羟基丙酸甲酯（4）的拆分…41
4.2 dl-3-（4-甲氧基苯基）-2,3-环氧丙酸甲酯（3）的拆分………………………42
4.3（2R,3R）-2-羟基-3-（2-氨基苯硫基）-3-（4-甲氧苯基）-丙酸（甲酯）的消旋化………………………………………………………………………………43
4.4 dl-3-（4-甲氧基苯基）-3-（2-氨基苯硫基）¬¬-2-羟基丙酸（5）的拆分……44
4.5 地尔硫卓的制备………………………………………………………………46
五、小结………………………………………………………………………………47
参考文献………………………………………………………………………………48
Ⅲ. 盐酸头孢吡肟的合成工艺研究……………………………………………………61
一、 前言………………………………………………………………………………62
1.1 盐酸头孢吡肟的简介…………………………………………………………62
1.2 头孢吡肟药理学特征…………………………………………………………62
1.3 头孢吡肟药代动力学特点……………………………………………………63
1.4 立题依据………………………………………………………………………63
二、头孢吡肟的合成路线选择……………………………………………………63
2.1 文献报道的头孢吡肟的合成路线……………………………………………63
2.2 自行设计的头孢吡肟合成路线………………………………………………69
2.3 工艺研究的重点………………………………………………………………69
三、盐酸头孢吡肟合成工艺的研究……………………………………………………70
3.1自行设计的合成路线的工艺考察………………………………………………70
3.2 合成路线五的合成工艺考察…………………………………………………71
3.3 盐酸头孢吡肟异构体形成机理的解释………………………………………78
四、实验部分…………………………………………………………………………82
4.1 仪器与试剂……………………………………………………………………82
4. 2 自行设计的合成路线六………………………………………………………82
4.3 7-氨基-3-[1-（1-甲基吡咯烷）基]头孢烷酸盐酸盐（4）的制备…………83
4.4 盐酸头孢吡肟（6）的制备……………………………………………………83
五、结论………………………………………………………………………………85
参考文献………………………………………………………………………………86
致谢………………………………………………………………………………………88
博士生期间发表的学术论文，专著……………………………………………………89
个人简历…………………………………………………………………………………90
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5.肖和平，结核病流行的近期特点，中国临床医生[J]，2004; 32（7）:2-4
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9.白国义，陈立功，刑鹏等，乙胺丁醇的合成，精细化工[J]，2004；21（12）:943-949
10.Satoshi Kambe et al, Bull Chem Soc , 1968;41:1444-47
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19.Hiroyuki N, Method of optical resolution of （.+-.）-2-amino-1-butanol and/or （.+-.）-mandelic acid[P], US: 4340751, 1982-07-20
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作者点评：
本报告由三部分组成：Ⅰ.乙胺丁醇的合成工艺研究；Ⅱ.地尔硫卓手性中间体的拆分工艺研究；Ⅲ.头孢吡肟的合成工艺研究
1.本文对乙胺丁醇及其关键中间体2-氨基丁醇的国内外的生产及研究状况做了比较全面地文献调研和归纳、总结；并且详细地分析、比较了各条合成路线的优劣及其实用性。
2.在文献调研的基础上，结合企业生产实际及目前的实验室条件选择了dl-2-氨基丁醇的合成方法中的路线4，6，7作为工艺研究的重点并对其进行了工艺考查，得出了确切的结论，为企业进行品种决策提供了依据。
3.对现有的拆分工艺进行了详细的研究，包括：
a)拆分溶剂的选择：比较了甲醇、无水乙醇、甲醇-异丙醇和甲醇-丙酮四种拆分溶剂对拆分结果的影响，结果表明以甲醇拆分溶剂比较理想。
b)以冰醋酸--（+）-酒石酸（1:1）的混合酸为拆分剂，经过工艺考查认为：选用混合酸为拆分剂基本可以达到单独使用（+）-酒石酸为拆分剂的拆分效果，可以节省一半量的（+）-酒石酸。
c)对“可逆拆分”这种新的拆分方法进行了研究，分别选用了（±）扁桃酸和（±）酒石酸为拆分剂，实验结果表明这一拆分方法有一定的理论意义和使用价值，但如果用于工业化规模生产还需进一步优化工艺条件。
4. l-2-氨基丁醇的消旋化工艺研究，分别选用钯碳和Raney Ni作催化剂，甲苯、乙醇、异丙醇等为溶剂，在一定压力下反应，实验结果表明选择Raney Ni为催化剂，乙醇为溶剂可以获得较满意的消旋化结果。
资料包括： 论文(22页10632字)
说明：
摘要：本报告由三部分组成：Ⅰ.乙胺丁醇的合成工艺研究；Ⅱ.地尔硫卓手性中间体的拆分工艺研究；Ⅲ.头孢吡肟的合成工艺研究。
Ⅰ. 乙胺丁醇的合成工艺研究
报告对乙胺丁醇及其关键中间体2-氨基丁醇的国内外的生产及研究状况做了比较全面地总结，并且详细地分析、比较了各条合成路线的优劣及其实用性。在文献调研的基础上，结合企业生产实际及目前的实验室条件选择dl-2-氨基丁醇的合成方法中的路线4，6，7作为工艺研究的重点并对其进行了工艺考查，得出了确切的结论，为企业进行品种决策提供了依据。对dl-2-氨基丁醇的拆分工艺进行了详细的研究， 比较了甲醇、无水乙醇、甲醇-异丙醇和甲醇-丙酮四种拆分溶剂对拆分结果的影响，结果表明以甲醇为拆分溶剂比较理想。选择冰醋酸—(+)-酒石酸（1:1）的混合酸为拆分剂，经过工艺考查发现：选用混合酸为拆分剂基本可以达到单独使用(+)-酒石酸为拆分剂的拆分效果，可以节省1/2量的(+)-酒石酸。对“可逆拆分”这种新的拆分方法进行了研究，分别选用了（±）扁桃酸和（±）酒石酸为拆分剂，实验结果表明这一拆分方法有一定的理论意义和实用价值，但目前用于工业化规模生产还需进一步优化工艺条件。l-2-氨基丁醇的消旋化工艺研究，分别选用钯碳和Raney Ni作催化剂，甲苯、乙醇、异丙醇等为溶剂，在一定压力下反应，实验结果表明选择Raney Ni为催化剂，乙醇为溶剂可以获得较满意的消旋化结果。
Ⅱ. 地尔硫卓手性中间体的拆分工艺研究
报告对钙拮抗剂类心血管药物地尔硫卓的药理学及药代动力学特征进行了概述；对有关地尔硫卓手性中间体拆分工艺的国内外研究状况做了比较全面的总结，并且详细地分析、比较了各种拆分方法的优劣及其实用性。在文献调研的基础上，对中间体dl-3-(4-甲氧基苯基)-2,3-环氧丙酸甲酯(3)和 dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸甲酯(4)的拆分工艺进行了研究，得出了确切的结论。分别选用D-α-苯乙胺和L-赖氨酸为拆分剂，对中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(5)的拆分工艺过程进行了详细的考察,拆分收率由原来的34%提高到48.3%。另外，对拆分剂的回收及拆分中的副产物l-cis-3- (4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(甲酯)的消旋化工艺已做了详细的工艺研究，使拆分剂的回收率达到80%以上，l-cis-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(甲酯)的回收率达到42%，减少了资源浪费，降低了生产成本。
Ⅲ. 头孢吡肟的合成工艺研究
报告简要介绍了第四代头孢菌素盐酸头孢吡肟的药理学特征与临床应用，对有关盐酸头孢吡肟合成工艺的国内外研究状况做了比较全面的总结。通过实验考查，确定了合成路线；以降低成本，简化操作，提高收率，节能环保为目标，对合成工艺进行研究。以7-ACA为起始原料，经硅烷化保护氨基和羧基、碘代、置换、脱保护、成盐、缩合、成盐等六步反应，合成了目标化合物，总收率为21％（以7-ACA计）。产品结构经1H-NMR、MS确证。
选择以环己烷为溶剂，一锅法制备了关键中间体7-氨基-3-[1-(1-甲基四氢吡咯烷)甲基]头孢烷酸盐酸盐，并对其合成工艺进行优化，优化后的工艺具有操作方便、条件温和、安全环保等特点。选择丙酮-水作为缩合反应的溶剂，通过对反应条件的考查，得出了最佳反应条件，产品收率高，色泽浅，纯度高。
自行设计了一条盐酸头孢吡肟的合成路线并进行了详细工艺考察，得到的头孢吡肟盐酸盐，收率较高，但是产品颜色较深，工艺还有待改进。
对盐酸头孢吡肟△3异构体的产生机理以及影响因素进行了初步研究，发现通过控制反应的温度和时间，能够大大避免该异构体的产生。对产品的二级质谱学特征进行了分析、讨论。
关键词：乙胺丁醇，地尔硫卓，头孢吡肟，中间体，拆分，合成工艺
ABSTRACT
This report consists of three sections, which includes: Ⅰ. Study on the synthetic technology of Ethambutol, Ⅱ. Sstudy on the resolution methods of the key intermediates for Diltiazem synthesis, Ⅲ. Study on the synthetic technology of Cefepiem.
Ⅰ. Study on the synthetic technology of Ethambutol
In this section, the research and production status of Ethambutol and its key intermediates have been described roundly, the disadvantages and practicability of the synthetic routes for Ethambutol synthesis had also been analyzed and compared in detail. After reference the literature methods, combining with the production feasibility and our lab conditions, take the synthetic route 4,6 and 7 as our focus for the synthesis of dl-2-aminobutol, the reaction conditions had also been optimized. The research results provided corporations with a base of decision-making. The resolution procedure of dl-2-aminobutol was investigated. The influence of resolution solvents (methanol, ethanol, methanol-isopropanol and methanol-acetone) on resolution results had also been compared, and it was conclude that methanol would be the best resolution solvent in this process. After investigation, the mixture of glycial acetic acid and tartaric acid can replace tartaric acid as the resolution reagent in this procedure, but the consumption of tartaric acid can be economized half quantity than that before. The “reversible resolution process” with racemic mandelic acid and racemic tartaric acid had also been investigated, the research result showed that although this resolution process would have certain theoretic meaning and practicality, but need to optimize the resolution procedure further. The racemizing process for l-2-aminobutol have been researched by taking Pd-C or Raney nickel as catalyst in ethanol or isopropanol under certain pressure. It had been conclude that this racemizing process can be conducted by catalyzing Raney nickel in ethanol.
Ⅱ. Study on the resolution methods of the key intermidiates for Diltiazem synthesis
In this section, the pharmacological and pharmacodynamics characters of Diltiazem, the calcium channel blocker, was introduced briefly. The resaerch status of technological process for Diltiazem resolution had also been summarized. The disadvantages and practicability of each method had also been analyzed and compared in detail. After reference the literature methods, resolution process of methyl dl-3- (4-methoxyphenyl) -glycidate and methyl dl-3- (4- methoxyphenyl)- 3-(2-aminothiophenyl) -2-hydroxy -propionate have been investigated. The resolution process of dl-3-(4-methoxyphenyl)-3- (2-aminothiophenyl)-2-hydroxy-propionic acid had been examined by kaking D-α-phenylethylamine and L- lysine as the resolution reagent, the yield of this resolution process was raised to 48.3% form 34%. In addition, the recycle of resolution reagents and racemizing process of the by-product, l-3-(4-methoxy -phenyl)- 3- (2-aminothiophenyl) -2-hydroxy-propionic acid (or its methyl ester), had also been investigated detailedly, the recycle ratio of resolution reagents was more than 80%, the recycle ratio of l-3-(4-methoxyphenyl)- 3- (2-aminothio- phenyl)-2-hydroxy-propionic acid was 42%, so that the production cost would be cutted.
Ⅲ. Study on the synthetic technology of Cefepime
In this section, the Cefepime dihydrochloride, one of the fourth-generation cephalosporins, was introduced briefly, including its antibiotic mechanism, pharmacological properties and clinical effects. The resaerch status of technological process for Cefepime synthesis had also been summarized in detail. After investigation of a series of synthetic routes of Cefepime, we determined the best route and researched each step of the synthetic process for the goal of cost-cut, simplifying operation procedure and improving yield.
The cyclohexane was taken as the solvent of one-pot procedure of preparing 7- amino -3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride which was the key intermediate of Cefepime in an overall yield of 21% scarcely with undesirable byproduct △3isomer. This procedure was simple, mild, environment-friendly, and suitable for scale-up production.
A new procedure for the synthesis of Cefepime dihydrochloride had been designed and obtained crude product in good yield. But it was dark-colored and the process need to be further optimized.
The mechanism of byproduct △3 isomer produced had also been preliminary speculated that the △3 isomer could be seriously reduced by controlling proper reaction time and temperature. The MS characteristic of the product was analyzed and discussed in detail.
Keywords：Ethambutol, Diltiazem , Cefepime, intermediates, resolution, synthetic technology
一、前言
1.1抗结核药乙胺丁醇简介
通用名: 乙胺丁醇
化学名：（+）2,2’-（1,2-乙二基二亚氨基）-双-l-丁醇二盐酸盐
英文名：Ethambutol Hydrochloride
化学结构式：
目录：
内容摘要……………………………………………………………………………………1
ABSTRACT………………………………………………………………………………3
Ⅰ.乙胺丁醇的合成工艺研究……………………………………………………………6
一、前言…………………………………………………………………………………7
1.1 抗结核药乙胺丁醇简介…………………………………………………………7
1.2 结核病的国内外发展趋势………………………………………………………8
1.3 抗结核病药乙胺丁醇国内外生产情况…………………………………………8
二、乙胺丁醇的合成工艺总结…………………………………………………………9
2.1 乙胺丁醇的合成路线……………………………………………………………9
2.2 d-2-氨基丁醇的合成路线………………………………………………………10
2.3 dl-2-氨基丁醇的拆分……………………………………………………………14
2.4 工艺研究的工作重点…………………………………………………………15
三、结果与讨论…………………………………………………………………………15
3.1 合成路线4的工艺研究…………………………………………………………15
3.2 合成路线6的工艺研究…………………………………………………………16
3.3 合成路线7的工艺研究…………………………………………………………16
3.3 dl-2-氨基丁醇的拆分工艺研究………………………………………………17
3.3 l-2-氨基丁醇的消旋化工艺研究………………………………………………19
四、实验部分……………………………………………………………………………20
4.1 合成路线4的工艺研究…………………………………………………………20
4.2 合成路线7的工艺研究…………………………………………………………21
4.3 dl-2-氨基丁醇的拆分工艺研究………………………………………………22
4.4 l-2-氨基丁醇的消旋化…………………………………………………………24
五、小结………………………………………………………………………………25
参考文献………………………………………………………………………………26
Ⅱ.地尔硫卓手性中间体的拆分工艺研究………………………………………………28
一、前言………………………………………………………………………………29
1.1 地尔硫卓的简介………………………………………………………………29
1.2 药理学特征……………………………………………………………………29
1.3 地尔硫卓的药代动力学………………………………………………………30
二、地尔硫卓手性中间体的拆分工艺总结…………………………………………30
2.1 地尔硫卓的合成工艺…………………………………………………………30
2.2 中间体拆分方法的选择………………………………………………………31
2.3 工艺的研究重点………………………………………………………………36
三、结果与讨论…………………………………………………………………………36
3.1 中间体dl-3-(4-甲氧基苯基)-2,3-环氧丙酸甲酯(3)的拆分工艺研究…………36
3.2 中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸甲酯(4)的拆分工艺研究………………………………………………………………………………………36
3.3 中间体dl-3-(4-甲氧基苯基)-3-(2-氨基苯硫基)¬¬-2-羟基丙酸(5)的拆分工艺研究…………………………………………………………………………………………37
3.4 消旋化路线的工艺研究………………………………………………………40
四、实验部分……………………………………………………………………………41
4.1 dl-3-（4-甲氧基苯基）-3-（2-氨基苯硫基）-2-羟基丙酸甲酯（4）的拆分…41
4.2 dl-3-（4-甲氧基苯基）-2,3-环氧丙酸甲酯（3）的拆分………………………42
4.3（2R,3R）-2-羟基-3-（2-氨基苯硫基）-3-（4-甲氧苯基）-丙酸（甲酯）的消旋化………………………………………………………………………………43
4.4 dl-3-（4-甲氧基苯基）-3-（2-氨基苯硫基）¬¬-2-羟基丙酸（5）的拆分……44
4.5 地尔硫卓的制备………………………………………………………………46
五、小结………………………………………………………………………………47
参考文献………………………………………………………………………………48
Ⅲ. 盐酸头孢吡肟的合成工艺研究……………………………………………………61
一、 前言………………………………………………………………………………62
1.1 盐酸头孢吡肟的简介…………………………………………………………62
1.2 头孢吡肟药理学特征…………………………………………………………62
1.3 头孢吡肟药代动力学特点……………………………………………………63
1.4 立题依据………………………………………………………………………63
二、头孢吡肟的合成路线选择……………………………………………………63
2.1 文献报道的头孢吡肟的合成路线……………………………………………63
2.2 自行设计的头孢吡肟合成路线………………………………………………69
2.3 工艺研究的重点………………………………………………………………69
三、盐酸头孢吡肟合成工艺的研究……………………………………………………70
3.1自行设计的合成路线的工艺考察………………………………………………70
3.2 合成路线五的合成工艺考察…………………………………………………71
3.3 盐酸头孢吡肟异构体形成机理的解释………………………………………78
四、实验部分…………………………………………………………………………82
4.1 仪器与试剂……………………………………………………………………82
4. 2 自行设计的合成路线六………………………………………………………82
4.3 7-氨基-3-[1-（1-甲基吡咯烷）基]头孢烷酸盐酸盐（4）的制备…………83
4.4 盐酸头孢吡肟（6）的制备……………………………………………………83
五、结论………………………………………………………………………………85
参考文献………………………………………………………………………………86
致谢………………………………………………………………………………………88
博士生期间发表的学术论文，专著……………………………………………………89
个人简历…………………………………………………………………………………90
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作者点评：
本报告由三部分组成：Ⅰ.乙胺丁醇的合成工艺研究；Ⅱ.地尔硫卓手性中间体的拆分工艺研究；Ⅲ.头孢吡肟的合成工艺研究
1.本文对乙胺丁醇及其关键中间体2-氨基丁醇的国内外的生产及研究状况做了比较全面地文献调研和归纳、总结；并且详细地分析、比较了各条合成路线的优劣及其实用性。
2.在文献调研的基础上，结合企业生产实际及目前的实验室条件选择了dl-2-氨基丁醇的合成方法中的路线4，6，7作为工艺研究的重点并对其进行了工艺考查，得出了确切的结论，为企业进行品种决策提供了依据。
3.对现有的拆分工艺进行了详细的研究，包括：
a)拆分溶剂的选择：比较了甲醇、无水乙醇、甲醇-异丙醇和甲醇-丙酮四种拆分溶剂对拆分结果的影响，结果表明以甲醇拆分溶剂比较理想。
b)以冰醋酸--（+）-酒石酸（1:1）的混合酸为拆分剂，经过工艺考查认为：选用混合酸为拆分剂基本可以达到单独使用（+）-酒石酸为拆分剂的拆分效果，可以节省一半量的（+）-酒石酸。
c)对“可逆拆分”这种新的拆分方法进行了研究，分别选用了（±）扁桃酸和（±）酒石酸为拆分剂，实验结果表明这一拆分方法有一定的理论意义和使用价值，但如果用于工业化规模生产还需进一步优化工艺条件。
4. l-2-氨基丁醇的消旋化工艺研究，分别选用钯碳和Raney Ni作催化剂，甲苯、乙醇、异丙醇等为溶剂，在一定压力下反应，实验结果表明选择Raney Ni为催化剂，乙醇为溶剂可以获得较满意的消旋化结果。