环丙胺的合成
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摘要
本论文介绍了环丙胺和环丙烷甲酸的用途、应用前景、研究现状及主要工艺路线，并对各路线的优缺点作了简洁的分析。针对合成环丙胺及环丙烷甲酸的特点，确定了六步合成环丙胺的工艺路线，依次合成出了γ-氯代丁酸异丙酯、环丙烷甲酸异丙酯、环丙烷甲酸、环丙烷甲酰氯、环丙烷甲酰胺、环丙胺。研究了以γ-丁内酯、异丙醇和亚硫酰氯为原料，在常温常压下，不分离出中间体γ-氯代丁酰氯或γ-氯代丁酸，一步合成γ-氯代丁酸异丙酯的改进方法，经过对影响该步反应的各种因素进行分析和实验，得到了较好的结论，γ-氯代丁酸异丙酯的产率超过93％。以γ-氯代丁酸异丙酯和氢氧化钠为原料，经固-液相转移催化反应，并采用溶剂苯与水形成共沸物，用分水器除去水的方法合成了环丙烷甲酸异丙酯，经过对工艺条件的优化，使该步产率达到了73％。以环丙烷甲酸异丙酯和氢氧化钠为原料，经液-液相转移催化反应合成了环丙烷甲酸，通过优化工艺条件，使水解得率达到了84.2％。让环丙烷甲酸与亚硫酰氯反应，合成了环丙烷甲酰氯，经过对反应条件的优化，该步得率达到了97.2％。以乙酸乙酯作溶剂，在冰水浴中向环丙烷甲酰氯中通入氨气，合成出了环丙烷甲酰胺，经索式提取器提取该步得率达到了95.6％。环丙烷甲酰胺在次溴酸钠碱液中经Hoffmann降解生成了环丙胺，经过对工艺条件的优化，该步得率达到了97.5％。本文利用各中间产物及目标产物环丙胺的物理性质(比如熔点、沸点、折射率)以及化学性质(比如酰胺的水解反应)，采用经典的滴定方法并结合现代的分析方法(比如红外、气相色谱、气质联用)对合成出的各物质进行了定性和定量分析。
This paper introduced the usage . research background and main routes of synthesizing cyclopropylamine and cyclopropanecarboxylic acid. The paper analyzed the advantages and the disadvantages of every synthesizing route briefly. According to the character of cyclopropylamine and cyclopropanecarboxylic acid, the author decided to synthesize cyclopropylamine by six steps. Iso-propyl- γ chlorobutyrate. cyclopropanecarboxylic acid isopropy cyclopropanecarboxylic acid . cyclopropanecarbonyl chloride cyclopropanecarboxamide and cyclopropylamine were synthesized in order. The improvement of synthesizing iso-propyl- γ chlorobutyrate from γ -butyrolactone . sulfur oxychloride and iso-propyl alcohol at normal atmospheric temperature and atmosphere at one step was investigated, unseperating the intermediate- γ -chlorobutyryl chloride or γ -chlorobutyric acid. A series of experiments were proceeded through analyzing all kinds of factors which affect the reaction and the author got a good conclusion. The yield of iso-propyl- γ -chlorobutyrate was beyond of 93%,based on γ -butyrolactone. Cyclopropanecarboxylic acid isopropyl was synthesized from iso-propyl- γ chlorobutyrate and sodium hydroxide. This reaction was catalyzed by phase transfer catalyst(PTC). Benzene and water could form azeotropic mixture and the water produced during the reaction was discharged azeotropically. A series of experiments were proceeded through analyzing all kinds of factors which affect the reaction.The yield was beyond of 73%, based on iso-propyl- γ chlorobutyrate. Cyclopropanecarboxylic acid was synthesized from cyclopropanecarboxylic acid isopropyl by liquid-liquid phase transfer catalysis. By optimizing the factors which affect the reaction, the hydrolytic yield was 84.2%, based on cyclopropanecarboxylic acid isopropyl. Cyclopropanecarbonyl chloride was synthesized by reaction of cycolpropanecarboxylic acid and sulfur oxychloride. By optimizing the factors which affect the reaction, the yield was 97.2%, based on cycolpropanecarboxylic acid. Ethyl acetate acted as solvate and the temperature was 0℃. On this condition we let cyclopropanecarbonyl chloride react with ammonia and got cyclopropanecarboxamide. The yield was 95.6%, based on cyclopropanecarbonyl chloride. Cyclopropylamine was preparated by Hofmann degradation of cyclopropanecarboxamide. The yield was %. According to the physical character and chemical character of all intermediates and cyclopropylamine,.these synthetics were qualitatively analysized and quantitatively analysized by using traditional titration and modern analytical methods (IR, GC, GC-MS) .
This paper introduced the usage . research background and main routes of synthesizing cyclopropylamine and cyclopropanecarboxylic acid. The paper analyzed the advantages and the disadvantages of every synthesizing route briefly. According to the character of cyclopropylamine and cyclopropanecarboxylic acid, the author decided to synthesize cyclopropylamine by six steps. Iso-propyl- γ chlorobutyrate. cyclopropanecarboxylic acid isopropy cyclopropanecarboxylic acid . cyclopropanecarbonyl chloride cyclopropanecarboxamide and cyclopropylamine were synthesized in order. The improvement of synthesizing iso-propyl- γ chlorobutyrate from γ -butyrolactone . sulfur oxychloride and iso-propyl alcohol at normal atmospheric temperature and atmosphere at one step was investigated, unseperating the intermediate- γ -chlorobutyryl chloride or γ -chlorobutyric acid. A series of experiments were proceeded through analyzing all kinds of factors which affect the reaction and the author got a good conclusion. The yield of iso-propyl- γ -chlorobutyrate was beyond of 93%,based on γ -butyrolactone. Cyclopropanecarboxylic acid isopropyl was synthesized from iso-propyl- γ chlorobutyrate and sodium hydroxide. This reaction was catalyzed by phase transfer catalyst(PTC). Benzene and water could form azeotropic mixture and the water produced during the reaction was discharged azeotropically. A series of experiments were proceeded through analyzing all kinds of factors which affect the reaction.The yield was beyond of 73%, based on iso-propyl- γ chlorobutyrate. Cyclopropanecarboxylic acid was synthesized from cyclopropanecarboxylic acid isopropyl by liquid-liquid phase transfer catalysis. By optimizing the factors which affect the reaction, the hydrolytic yield was 84.2%, based on cyclopropanecarboxylic acid isopropyl. Cyclopropanecarbonyl chloride was synthesized by reaction of cycolpropanecarboxylic acid and sulfur oxychloride. By optimizing the factors which affect the reaction, the yield was 97.2%, based on cycolpropanecarboxylic acid. Ethyl acetate acted as solvate and the temperature was 0℃. On this condition we let cyclopropanecarbonyl chloride react with ammonia and got cyclopropanecarboxamide. The yield was 95.6%, based on cyclopropanecarbonyl chloride. Cyclopropylamine was preparated by Hofmann degradation of cyclopropanecarboxamide. The yield was %. According to the physical character and chemical character of all intermediates and cyclopropylamine,.these synthetics were qualitatively analysized and quantitatively analysized by using traditional titration and modern analytical methods (IR, GC, GC-MS) .
引文
1 郭惠元．我国喹诺酸类抗菌药物研究开发概况．中国医药工业杂志．1989，20(9)：421-424
2 周伟澄，张秀平．氟喹诺酮类药物研究的新进展．中国医药工业杂志．1997， 28(2)：75-80
3 李安良．药物化学．第1版．北京：高等教育出版社，1999
4 张为民．环丙胺的制备方法．陕西化工．1993(4)：23-24
5 黄光斗．环丙胺的生产开发及应用．化工时刊．1998，12(8)：31-33
6 梁诚．环丙胺生产与市场．江苏化工．2001(29)：93-94
7 北京化学试剂公司．化学试剂·精细化学品手册．第1版．北京：化学工业出版社，2002
8 环丙烷甲酸的合成及其在药物中的应用．南京化工大学硕士学位论文
9 程国侯，王震涛．环丙胺的合成．中国医药工业杂志．1995，26(10)：466-467
10 杨阿喜，葛纪龙．从废四氢呋喃制备环丙基甲酸．化工时刊．2002(3)：37-38
11 刘元金，张元忠．环丙烷甲酸及其衍生物的制备方法[专利]．1997．CN1167480
12 许关煜．医药中间体手册．33，35
13 Kleemiss Wolfgang. Process for the preparation of cyclopropanamine [P] .US: 5, 728, 873,1998-03-17
14 赵学清．张虞安．环丙胺的合成．中国医药工业杂志．1994，25(5)：225-226
15 司永利．王双，孟颢适．环丙胺的合成．沈阳化工学院学报．1995，9(1)：74-77
16 廖国礼．杨勇．环丙胺的合成．湘潭大学自然科学学报．1998(4)：76-77
17 徐克勋．精细有机化工原料及中间体手册．第1版．北京：化学工业出版社，1998
18 金旭虎．环丙胺的工业生产方法[专利]．1996，CN1125715A
19 周龙虎，史达清，戴桂元．γ-氯代丁酸酯的合成研究．化学通报．1994．(10)：27-28
20 刘鸿，张翠娥，吕晓平．环丙胺的合成．中国医药工业杂志．1997，28(10)：467-468
21 李和平，葛虹，张福强等．环丙胺合成新工艺研究．化学世界．1997，358-360
22 任宇，边军，朱崇泉等．环丙胺的合成．江苏化工．1995，23(1)：22-23
23 吴跃东，赵山川、陈主峰．环丙胺的合成．辽宁化工．2001，30(2)：79-80
24 易健民．唐阔文．黄良．环丙胺合成的新方法．精细化工．2000，17(9) 552-555
25 吴信亮．檀杰，吴新民．环丙胺的合成研究．安徽科技．2000，(6)：38-39
26 高原，周龙虎．史达清等．环丙烷甲酸的改进合成．中国医药工业杂志．1996，27(9)：418
27 叶蓓蓉．环丙胺的合成及开发前景．安徽化工．2000，103(1)：20
28 王京平．环丙胺的生产及开发前景．石家庄化工．1998，4：18
29 王树良，戴桂元，冯友健．环丙胺的合成．中国医药工业杂志．1993，24(11)：514-516
30 李眉，郭惠元．环丙胺合成路线图解．中国医药工业杂志．1992，23(3)：141
31 周惠，范莉萍，李建等．环丙烷甲酸的合成．四川化工．1990(1)：12-13
32 Kleemiss Wolfgang.Process for the preparation of cyclopropylamine [P] .US: 6, 107, 522,2000-08-22
33 袁淑军，吕春绪，朱红军．合成环丙烷甲酸的工艺改进．精细石油化工．2001(6)：39-41
34 樊能廷，任建南，孙福生．英汉精细化学品辞典．第1版．北京：北京理工大学出版社，1994
35 魏义德．有机化工原料大全．第2版．北京：化学工业出版社，1999
36 陈士能．中国化工产品大全．第2版．北京：化学工业出版社．1998
37 孙履厚．精细化工新材料与技术．第1版．北京：中国石化出版社．1998
38 姚蒙正，程侣柏，王家儒．精细化工产品合成原理．第2版．北京：中国石化出版社，2000
39 杨锦宗．工业有机合成基础．第1版．北京：中国石化出版社，1998
40 Kleemis Wolfgang、Kalz, Thomas.Continuous preparation of cyclopropylamine via the Hoffmann degradation of cyclopropylcarboxamide (CA: 126: 143916j)
41 Kaufhold, Manfred、Kleemiss, Wolfgang、Feld, Marcel. Multi-step process for the preparation of the cyclopropylamine from γ-butyrolactone (CA: 132: 63995t)
2 周伟澄，张秀平．氟喹诺酮类药物研究的新进展．中国医药工业杂志．1997， 28(2)：75-80
3 李安良．药物化学．第1版．北京：高等教育出版社，1999
4 张为民．环丙胺的制备方法．陕西化工．1993(4)：23-24
5 黄光斗．环丙胺的生产开发及应用．化工时刊．1998，12(8)：31-33
6 梁诚．环丙胺生产与市场．江苏化工．2001(29)：93-94
7 北京化学试剂公司．化学试剂·精细化学品手册．第1版．北京：化学工业出版社，2002
8 环丙烷甲酸的合成及其在药物中的应用．南京化工大学硕士学位论文
9 程国侯，王震涛．环丙胺的合成．中国医药工业杂志．1995，26(10)：466-467
10 杨阿喜，葛纪龙．从废四氢呋喃制备环丙基甲酸．化工时刊．2002(3)：37-38
11 刘元金，张元忠．环丙烷甲酸及其衍生物的制备方法[专利]．1997．CN1167480
12 许关煜．医药中间体手册．33，35
13 Kleemiss Wolfgang. Process for the preparation of cyclopropanamine [P] .US: 5, 728, 873,1998-03-17
14 赵学清．张虞安．环丙胺的合成．中国医药工业杂志．1994，25(5)：225-226
15 司永利．王双，孟颢适．环丙胺的合成．沈阳化工学院学报．1995，9(1)：74-77
16 廖国礼．杨勇．环丙胺的合成．湘潭大学自然科学学报．1998(4)：76-77
17 徐克勋．精细有机化工原料及中间体手册．第1版．北京：化学工业出版社，1998
18 金旭虎．环丙胺的工业生产方法[专利]．1996，CN1125715A
19 周龙虎，史达清，戴桂元．γ-氯代丁酸酯的合成研究．化学通报．1994．(10)：27-28
20 刘鸿，张翠娥，吕晓平．环丙胺的合成．中国医药工业杂志．1997，28(10)：467-468
21 李和平，葛虹，张福强等．环丙胺合成新工艺研究．化学世界．1997，358-360
22 任宇，边军，朱崇泉等．环丙胺的合成．江苏化工．1995，23(1)：22-23
23 吴跃东，赵山川、陈主峰．环丙胺的合成．辽宁化工．2001，30(2)：79-80
24 易健民．唐阔文．黄良．环丙胺合成的新方法．精细化工．2000，17(9) 552-555
25 吴信亮．檀杰，吴新民．环丙胺的合成研究．安徽科技．2000，(6)：38-39
26 高原，周龙虎．史达清等．环丙烷甲酸的改进合成．中国医药工业杂志．1996，27(9)：418
27 叶蓓蓉．环丙胺的合成及开发前景．安徽化工．2000，103(1)：20
28 王京平．环丙胺的生产及开发前景．石家庄化工．1998，4：18
29 王树良，戴桂元，冯友健．环丙胺的合成．中国医药工业杂志．1993，24(11)：514-516
30 李眉，郭惠元．环丙胺合成路线图解．中国医药工业杂志．1992，23(3)：141
31 周惠，范莉萍，李建等．环丙烷甲酸的合成．四川化工．1990(1)：12-13
32 Kleemiss Wolfgang.Process for the preparation of cyclopropylamine [P] .US: 6, 107, 522,2000-08-22
33 袁淑军，吕春绪，朱红军．合成环丙烷甲酸的工艺改进．精细石油化工．2001(6)：39-41
34 樊能廷，任建南，孙福生．英汉精细化学品辞典．第1版．北京：北京理工大学出版社，1994
35 魏义德．有机化工原料大全．第2版．北京：化学工业出版社，1999
36 陈士能．中国化工产品大全．第2版．北京：化学工业出版社．1998
37 孙履厚．精细化工新材料与技术．第1版．北京：中国石化出版社．1998
38 姚蒙正，程侣柏，王家儒．精细化工产品合成原理．第2版．北京：中国石化出版社，2000
39 杨锦宗．工业有机合成基础．第1版．北京：中国石化出版社，1998
40 Kleemis Wolfgang、Kalz, Thomas.Continuous preparation of cyclopropylamine via the Hoffmann degradation of cyclopropylcarboxamide (CA: 126: 143916j)
41 Kaufhold, Manfred、Kleemiss, Wolfgang、Feld, Marcel. Multi-step process for the preparation of the cyclopropylamine from γ-butyrolactone (CA: 132: 63995t)