碱性紫5、盐酸兰地洛尔、三卤异氰尿酸的合成以及拉米夫定的工艺设计
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摘要
本文由以下四个部分组成:
Ⅰ碱性紫5的合成;
Ⅱ盐酸兰地洛尔的合成;
Ⅲ三卤异氰尿酸的合成;
Ⅳ拉米夫定的工艺设计。
第一部分:碱性紫5,其化学名称为3-氨基-7-(N,N-二甲基)-5-苯基吩嗪盐酸盐,早期主要用于棉花、丝绸、皮革的染色,现在被广泛作为电镀光亮剂。关于碱性紫5的合成,我们自行设计了一条新的合成路线,选择N,N-二甲基对苯二胺盐酸盐和苯胺为原料,以重铬酸钾和浓盐酸为氧化剂,采用“一锅法”制备得到碱性紫5。该工艺较简单,产率较高,适合于工业化生产。产品结构经过IR验证。
第二部分:盐酸兰地洛尔,其化学名称为4-(2-羟基-3-((2-((4-吗啉)甲酰胺基)乙基)胺基)丙氧基)苯丙酸(2,2-二甲基-1,3-二氧戊环-4-基)甲酯(S-(R*,R*))一盐酸盐,是一种新型超短效、高选择性的肾上腺素β_1受体(β_1受体)阻断药,主要用于治疗手术时心动过速性心律失常(心房纤维性颤动、心房扑动及窦性和室上性心动过速)。关于盐酸兰地洛尔的合成,我们自行设计了一条新的合成路线,首先选择以吗啉和三光气为原料经傅克酰基化、氨解反应得到中间体4-(N-β氨基乙基胺甲酰)吗啉,与文献相比,工艺操作简单,反应时间较短;然后以(2S)-(+)-缩水甘油基对甲苯磺酸酯和对羟基苯丙酸乙酯为原料,经开环、氨解、水解、酯交换反应后得到最终产品。使用该合成路线后整个反应过程无需氩气保护,适合于工业化生产。
第三部分:三卤异氰尿酸主要包括三氯异氰尿酸,三溴异氰尿酸和三碘异氰尿酸。三卤异氰尿酸是一种高效的卤化剂,由于三卤异氰尿酸能将X~+离子转移到反应底物中,这样在有机化学反应中就不需要使用有毒性、腐蚀性的卤素,它们符合绿色化学和原子经济学的要求。本文选择以氰尿酸钠盐通卤素法来合成三卤异氰尿酸,确定了较佳的工艺条件,适合于工业化生产。产品结构经过IR验证。
第四部分:拉米夫定,其化学名为(2R-顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊-5-基)-1H-嘧啶-2-酮,是第一个正式进入临床治疗慢性乙型肝炎病毒(HBV)感染的口服核苷类药物。本设计遵循技术上先进、工艺上可靠、经济上合理、系统上最优的原则,针对现有拉米夫定生成工艺进行了改进,通过实验室小试确定了工艺流程中的各影响因素(物料配比、反应温度、反应时间)的较佳条件。
This paper is made up of the synthesis of basic Violet5, landiololhydrochloride,trihaloisocyanuric acids,and the process design of lamivudine.
The first part is on the synthesis of Basic Violet 5,whose chemical name is 3-amino-7-dimethylamino-5-phenylphenazinium chloride.It mainly used for the dyeing cotton,silk,leather in early days,now drives extensive conduct and actions on electroplating.Considering the synthesis method of Basic Violet 5,we designed a simple and new one,which employed N,N-dimethyl-p-phenylenediamin dihydrochloride and aniline as raw materials,potassium dichromate and hydrochloric acid as oxidizing agent and afforded a higher yield. The craft is favorable for industrialization.The structure of the product was characterized by IR.
The second part is on the synthesis of landiololhydrochloride,whose chemical name is benzenepropanoic acid,4-(2-hydroxy-3-((2-((4-morpholinylcarbonyl)amino)ethyl)amino)propoxy)-, (2,2-dimethyl-1,3-dioxolan-4-y1)methyl ester,(S-(R~*,R~*))-hydrochloride. Landiolol is a newly developed blockage for ultra-short-acting,high cardioselective adrenergicβ_1 antagonists(β_1 antagonists).It is mainly used to treat intra-operative tachyarrhythmias(atrial fibrillation,flutter or supraventricular tachycardia).We firstly design a new way which employed morpholine and bis(trichloromethyl)carbonate as raw materials,through Friedel-Crafts reaction, ammonolysis reaction to synthesize 4-[N-(2-Amino ethyl)carbamoyl]morpholine. Compared with literature,there were many merits in our method,such as simple craft,easy operation and high yield.In addition,we designed a new one,which employed(2S)-(+)-Glycidyl tosylate and 3-(4-Hydroxyphenyl)propionic acid ethyl ester as raw materials,through ring-opening reaction,ammonolysis,hydrolyzation, transesterification reaction to synthesize landiololhydrochloride,which needn't under an atmosphere of argon.The craft is favorable for industrialization.
The third part is on the synthesis of trihaloisocyanuric acids,which comprise trichloroisocyanuric acid,tribromoisocyanuric acid and triiodoisocyanuric acid. Trihaloisocyanuric acids are efficient halogenating agents,due to their capability of halenium('X+')atoms transfer to unsaturated substrates.These trihaloisocyanuric acids are also very interesting from the green chemistry point of view,as they can introduce halogen atoms in organic compounds without using toxic and corrosive X_2 and also present good atom economy.In the thesis,we make sure a better craft condition,which employed cyanuric acid and halogen to synthesis trihaloisocyanuric acids.The craft is favorable for industrialization.The structures of the products were characterized by IR.
The forth part is on the process design of lamivudine,whose chemical name is 2-deoxy-3-thiacytidine(2R-cis)-4-Amino- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidinone.Lamivudine is a synthetic nucleoside analogue for oral administration,which first form ally come to use for the clinical treatment of HBV.In this thesis,following the fundament of advanced technology, reliable craft,rational economy and optimal system,the design aimed at the resolution of the problem of production technology.The optimal condition of the influencing factors(material mixture ratio,reaction temperature and reaction time)in technological process was determined according to the experiment data in laboratory.
Ⅰ碱性紫5的合成;
Ⅱ盐酸兰地洛尔的合成;
Ⅲ三卤异氰尿酸的合成;
Ⅳ拉米夫定的工艺设计。
第一部分:碱性紫5,其化学名称为3-氨基-7-(N,N-二甲基)-5-苯基吩嗪盐酸盐,早期主要用于棉花、丝绸、皮革的染色,现在被广泛作为电镀光亮剂。关于碱性紫5的合成,我们自行设计了一条新的合成路线,选择N,N-二甲基对苯二胺盐酸盐和苯胺为原料,以重铬酸钾和浓盐酸为氧化剂,采用“一锅法”制备得到碱性紫5。该工艺较简单,产率较高,适合于工业化生产。产品结构经过IR验证。
第二部分:盐酸兰地洛尔,其化学名称为4-(2-羟基-3-((2-((4-吗啉)甲酰胺基)乙基)胺基)丙氧基)苯丙酸(2,2-二甲基-1,3-二氧戊环-4-基)甲酯(S-(R*,R*))一盐酸盐,是一种新型超短效、高选择性的肾上腺素β_1受体(β_1受体)阻断药,主要用于治疗手术时心动过速性心律失常(心房纤维性颤动、心房扑动及窦性和室上性心动过速)。关于盐酸兰地洛尔的合成,我们自行设计了一条新的合成路线,首先选择以吗啉和三光气为原料经傅克酰基化、氨解反应得到中间体4-(N-β氨基乙基胺甲酰)吗啉,与文献相比,工艺操作简单,反应时间较短;然后以(2S)-(+)-缩水甘油基对甲苯磺酸酯和对羟基苯丙酸乙酯为原料,经开环、氨解、水解、酯交换反应后得到最终产品。使用该合成路线后整个反应过程无需氩气保护,适合于工业化生产。
第三部分:三卤异氰尿酸主要包括三氯异氰尿酸,三溴异氰尿酸和三碘异氰尿酸。三卤异氰尿酸是一种高效的卤化剂,由于三卤异氰尿酸能将X~+离子转移到反应底物中,这样在有机化学反应中就不需要使用有毒性、腐蚀性的卤素,它们符合绿色化学和原子经济学的要求。本文选择以氰尿酸钠盐通卤素法来合成三卤异氰尿酸,确定了较佳的工艺条件,适合于工业化生产。产品结构经过IR验证。
第四部分:拉米夫定,其化学名为(2R-顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊-5-基)-1H-嘧啶-2-酮,是第一个正式进入临床治疗慢性乙型肝炎病毒(HBV)感染的口服核苷类药物。本设计遵循技术上先进、工艺上可靠、经济上合理、系统上最优的原则,针对现有拉米夫定生成工艺进行了改进,通过实验室小试确定了工艺流程中的各影响因素(物料配比、反应温度、反应时间)的较佳条件。
This paper is made up of the synthesis of basic Violet5, landiololhydrochloride,trihaloisocyanuric acids,and the process design of lamivudine.
The first part is on the synthesis of Basic Violet 5,whose chemical name is 3-amino-7-dimethylamino-5-phenylphenazinium chloride.It mainly used for the dyeing cotton,silk,leather in early days,now drives extensive conduct and actions on electroplating.Considering the synthesis method of Basic Violet 5,we designed a simple and new one,which employed N,N-dimethyl-p-phenylenediamin dihydrochloride and aniline as raw materials,potassium dichromate and hydrochloric acid as oxidizing agent and afforded a higher yield. The craft is favorable for industrialization.The structure of the product was characterized by IR.
The second part is on the synthesis of landiololhydrochloride,whose chemical name is benzenepropanoic acid,4-(2-hydroxy-3-((2-((4-morpholinylcarbonyl)amino)ethyl)amino)propoxy)-, (2,2-dimethyl-1,3-dioxolan-4-y1)methyl ester,(S-(R~*,R~*))-hydrochloride. Landiolol is a newly developed blockage for ultra-short-acting,high cardioselective adrenergicβ_1 antagonists(β_1 antagonists).It is mainly used to treat intra-operative tachyarrhythmias(atrial fibrillation,flutter or supraventricular tachycardia).We firstly design a new way which employed morpholine and bis(trichloromethyl)carbonate as raw materials,through Friedel-Crafts reaction, ammonolysis reaction to synthesize 4-[N-(2-Amino ethyl)carbamoyl]morpholine. Compared with literature,there were many merits in our method,such as simple craft,easy operation and high yield.In addition,we designed a new one,which employed(2S)-(+)-Glycidyl tosylate and 3-(4-Hydroxyphenyl)propionic acid ethyl ester as raw materials,through ring-opening reaction,ammonolysis,hydrolyzation, transesterification reaction to synthesize landiololhydrochloride,which needn't under an atmosphere of argon.The craft is favorable for industrialization.
The third part is on the synthesis of trihaloisocyanuric acids,which comprise trichloroisocyanuric acid,tribromoisocyanuric acid and triiodoisocyanuric acid. Trihaloisocyanuric acids are efficient halogenating agents,due to their capability of halenium('X+')atoms transfer to unsaturated substrates.These trihaloisocyanuric acids are also very interesting from the green chemistry point of view,as they can introduce halogen atoms in organic compounds without using toxic and corrosive X_2 and also present good atom economy.In the thesis,we make sure a better craft condition,which employed cyanuric acid and halogen to synthesis trihaloisocyanuric acids.The craft is favorable for industrialization.The structures of the products were characterized by IR.
The forth part is on the process design of lamivudine,whose chemical name is 2-deoxy-3-thiacytidine(2R-cis)-4-Amino- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidinone.Lamivudine is a synthetic nucleoside analogue for oral administration,which first form ally come to use for the clinical treatment of HBV.In this thesis,following the fundament of advanced technology, reliable craft,rational economy and optimal system,the design aimed at the resolution of the problem of production technology.The optimal condition of the influencing factors(material mixture ratio,reaction temperature and reaction time)in technological process was determined according to the experiment data in laboratory.
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