2-氯-5-三氟甲基吡啶的合成研究
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摘要
2-氯-5-三氟甲基吡啶是合成农药及医药的重要有机化工中间体。本文在探讨合成2-氯-5-三氟甲基吡啶的关键中间体2-氯-5-三氯甲基吡啶合成路线的基础上,确定了以3-甲基吡啶为原料的四步法合成工艺,即:N-氧化、吡啶环氯化、侧链氯化、氟化四步反应,分别得到中间体N-氧-3-甲基吡啶、2-氯-5-甲基吡啶、2-氯-5-三氯甲基吡啶和终产物2-氯-5-三氟甲基吡啶,通过对各步反应影响因素的考察,得到了较佳的小试合成工艺条件,以起始原料3-甲基吡啶计,反应的总收率为30.5%。该合成路线具有原料便宜易得、反应条件较为温和、反应过程易于控制等优点。各步合成反应条件为:
1. N-氧-3-甲基吡啶合成:用30%过氧化氢为氧化剂,以冰乙酸为溶剂,在酸性下反应,3-甲基吡啶与30%过氧化氢的摩尔比为1:1.5,反应温度70℃,反应时间为24小时,粗产品中N-氧-3-甲基吡啶的含量为93.9%,收率为84.8%;
2. 2-氯-5-甲基吡啶合成:用苯甲酰氯为氯化剂,以二氯甲烷作溶剂,三乙胺作吸酸剂,N-氧-3-甲基吡啶与苯甲酰氯的摩尔比为1:1.4,电动搅拌,微回流状态下反应3小时,粗产品中2-氯-5-甲基吡啶的含量为81.5%,收率为54.4%;
3. 2-氯-5-三氯甲基吡啶合成:用氯气作氯化剂,偶氮二异丁腈作引发剂,邻二氯苯作溶剂,偶氮二异丁腈加入量为2-氯-5-甲基吡啶质量的5%,温度140℃,电动搅拌下反应20小时,粗产品中2-氯-5-三氯甲基吡啶的含量为78.3%,经硅胶柱分离后得到纯品,收率为82.7%;
4. 2-氯-5-三氟甲基吡啶合成:用无水氟化钾作氟化剂,十六烷基三甲基溴化铵(CTAB)作相转移催化剂,二甲基亚砜作溶剂,2-氯-5-三氯甲基吡啶与无水氟化钾的摩尔比为1:2,CTAB的加入量为2-氯-5-三氯甲基吡啶质量的8%,电动搅拌,微回流状态下反应6小时,2-氯-5-三氟甲基吡啶含量达99%以上,收率为80.0%。
各步反应的中间体及最终产物均用GC-MS和1H NMR表征了其结构。
2-chloro-5-trifluromethylpyridine (CTFP) is a key intermediate for agrochemical and pharmaceutical synthesis. In this thesis, a novel method of CTFP synthesis derived from 3-methylpyridine was developed in 4 steps, i.e., N-oxidation, chlorination with benzoyl chloride, chlorination with the chlorine, and fluorination with KF, which involved in three intermediates as N-oxide-3-methylpyridine(NOMP), 2-chloro-5-methylpyridine(CMP), and 2-chloro-5-trichloromethylpyridine (CTP) respectively. All the four synthetic processes were optimized by an overall yield of 30.5% CTFP, which show the benefit of cheap materials, mild reaction conditions and controllable operation. Each step of the reactions is described as follows:
1. Synthesis of N-oxide-3-methylpyridine(NOMP)
3-Methylpyridine was treated with 30% H2O2 in an acetic acid solution under 70℃for 24 hours, where the molar ratio of 3-methylpyridine to 30% H2O2 is 1:1.5 and 84.8% yield of NOMP with 93.9% content in the crude product was obtained;
2. Synthesis of 2-chloro-5-methylpyridine(CMP) CMP was prepared by the treatment of NOMP with benzoyl chloride in dichloromethane in the presence of triethylamine as the acid scavenger, where the molar ratio of N-oxide-3-methylpyridine to benzoyl chloride is 1:1.4, and 54.4% yield of CMP was obtained with 81.5% content in the crude product after reluxing for 3 hours with agitating;
3. Synthesis of 2-chloro-5-trichloromethylpyridine(CTP)
CMP was dealed with chlorine as chlorination reagent and azodiisobutyronitrile(AIBN) as activator in 1,2-dichlorobenzene solvent. 5% AIBN to CMP dosage was introduced and a mixture containing 78.3% CTP was obtained under 140℃for 20 hours. Pure CTP was achieved by silica column separation in 82.7% yield;
4. Synthesis of 2-chloro-5-trifluromethylpyridine(CTFP)
Fluorination was realized by the treatment of CTP with anhydrous KF as the fluorination reagent and hexadecyl trimethyl ammonium bromide (CTAB) as the phase transfer catalyst in DMSO. 80.0% yield of CTFP was obtained at 99% content in product with a molar ratio of CTP to KF 1:2 and 8% CTBA to CTP dosage after refluxing for 6 hours.
NOMP, CMP, CTP, and CTFP were characterized by GC-MS and 1H NMR spectra.
1. N-氧-3-甲基吡啶合成:用30%过氧化氢为氧化剂,以冰乙酸为溶剂,在酸性下反应,3-甲基吡啶与30%过氧化氢的摩尔比为1:1.5,反应温度70℃,反应时间为24小时,粗产品中N-氧-3-甲基吡啶的含量为93.9%,收率为84.8%;
2. 2-氯-5-甲基吡啶合成:用苯甲酰氯为氯化剂,以二氯甲烷作溶剂,三乙胺作吸酸剂,N-氧-3-甲基吡啶与苯甲酰氯的摩尔比为1:1.4,电动搅拌,微回流状态下反应3小时,粗产品中2-氯-5-甲基吡啶的含量为81.5%,收率为54.4%;
3. 2-氯-5-三氯甲基吡啶合成:用氯气作氯化剂,偶氮二异丁腈作引发剂,邻二氯苯作溶剂,偶氮二异丁腈加入量为2-氯-5-甲基吡啶质量的5%,温度140℃,电动搅拌下反应20小时,粗产品中2-氯-5-三氯甲基吡啶的含量为78.3%,经硅胶柱分离后得到纯品,收率为82.7%;
4. 2-氯-5-三氟甲基吡啶合成:用无水氟化钾作氟化剂,十六烷基三甲基溴化铵(CTAB)作相转移催化剂,二甲基亚砜作溶剂,2-氯-5-三氯甲基吡啶与无水氟化钾的摩尔比为1:2,CTAB的加入量为2-氯-5-三氯甲基吡啶质量的8%,电动搅拌,微回流状态下反应6小时,2-氯-5-三氟甲基吡啶含量达99%以上,收率为80.0%。
各步反应的中间体及最终产物均用GC-MS和1H NMR表征了其结构。
2-chloro-5-trifluromethylpyridine (CTFP) is a key intermediate for agrochemical and pharmaceutical synthesis. In this thesis, a novel method of CTFP synthesis derived from 3-methylpyridine was developed in 4 steps, i.e., N-oxidation, chlorination with benzoyl chloride, chlorination with the chlorine, and fluorination with KF, which involved in three intermediates as N-oxide-3-methylpyridine(NOMP), 2-chloro-5-methylpyridine(CMP), and 2-chloro-5-trichloromethylpyridine (CTP) respectively. All the four synthetic processes were optimized by an overall yield of 30.5% CTFP, which show the benefit of cheap materials, mild reaction conditions and controllable operation. Each step of the reactions is described as follows:
1. Synthesis of N-oxide-3-methylpyridine(NOMP)
3-Methylpyridine was treated with 30% H2O2 in an acetic acid solution under 70℃for 24 hours, where the molar ratio of 3-methylpyridine to 30% H2O2 is 1:1.5 and 84.8% yield of NOMP with 93.9% content in the crude product was obtained;
2. Synthesis of 2-chloro-5-methylpyridine(CMP) CMP was prepared by the treatment of NOMP with benzoyl chloride in dichloromethane in the presence of triethylamine as the acid scavenger, where the molar ratio of N-oxide-3-methylpyridine to benzoyl chloride is 1:1.4, and 54.4% yield of CMP was obtained with 81.5% content in the crude product after reluxing for 3 hours with agitating;
3. Synthesis of 2-chloro-5-trichloromethylpyridine(CTP)
CMP was dealed with chlorine as chlorination reagent and azodiisobutyronitrile(AIBN) as activator in 1,2-dichlorobenzene solvent. 5% AIBN to CMP dosage was introduced and a mixture containing 78.3% CTP was obtained under 140℃for 20 hours. Pure CTP was achieved by silica column separation in 82.7% yield;
4. Synthesis of 2-chloro-5-trifluromethylpyridine(CTFP)
Fluorination was realized by the treatment of CTP with anhydrous KF as the fluorination reagent and hexadecyl trimethyl ammonium bromide (CTAB) as the phase transfer catalyst in DMSO. 80.0% yield of CTFP was obtained at 99% content in product with a molar ratio of CTP to KF 1:2 and 8% CTBA to CTP dosage after refluxing for 6 hours.
NOMP, CMP, CTP, and CTFP were characterized by GC-MS and 1H NMR spectra.
引文
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[3]赵卫光,王建国,袁德凯等.吡啶类农药研究趋势及发现的含吡啶环的天然活性物质[J].农药,2002,41(7):8-11
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[8] Singh M,Mack R E.Recommendable routes to trifluromethyl-substituted Pyridine- and Quinolinecarbpxylic acids[J].European Journal of Organic Chemistry,2003,2003(8):1559-1568
[9] Yoshiro K, Istumaro K, Akio O,et al.Studies on the organic fluorine compounds XXIV : Photochemical trifluoromethylation of aromatic compounds[J].Chem.Pharm.Bull,1978,16 (4):1247～1249
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[12] Howarit M S , Watson D J , Scovell E G . Process for the preparation of fluoromethylpyridines[P].US:4745193,1988-05-17
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[14] Yonosuke A, Heikichi S.Production of halogeno-trifluoromethyl pyridine[P].JP:62-2012758,1987-01-22
[15] Ryuzo N , Kanichi F , Takahiro H , et al . 2-Subsituted-5-trifluoromethyl pyridine[P].JP:54-061183,1979-05-17
[16] Beckers H , Burger H , Bursch P , et al . Synthesis and properties of (trifluoromethyl)trichlorosilane, a versatile precursor for CF3Si compounds [J].Journal of Organometallic Chemistry,1986,316(1-2):41-50
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[19] Fung A P . Liquid phase halogen exchange of (trichloromethyl) pyridines to (trifluromethyl)pyridines[P].US:4567273,1986-01-28
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[21]苏莉.2-氯-5-三氯甲基吡啶的定向合成与结构测定[J].农药,2007,46(5):310-311
[22] Ryuzo N,Kanichi F,Yokomichi Isao, et al.Preparation of chloro-β-trifluoro-methyl pyridine[P].JP:56-120667,1981-09-22
[23] Wilhelm L B , Joerg J , Andreas M . Method for producing substituted halopyridines[P].US:20080214825,2008-09-04
[24] Ryuzo N , Kanichi F , Yokomichi Isao , et al . Pyridine derivaltives with trifluoromethyl groups in theβ-position[P].DE:3008081,1980-09-11
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[26] Ishihara Sangyo Kaisha Co.Ltd.Chloro-3-trifluoromethyl pyridine[P].JP:55-122762,1980-09-20
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[28] Klaus J.Process for the preparation of 2-chloro-5-chloromethyl pyridine[P].US:4990622, 1991-02-05.
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[33]崔咪芬,乔旭,赵培新等.邻、对氯甲苯侧链光氯化的研究[J].南京工业大学学报,2007,29(1):54-59
[34]李丽娟,高华,丁同富等.2,4-二氯甲苯光氯化反应动力学[J].化学工程,2006,34(7):31-33
[35]陆阳,陶京朝,张志荣.吡虫啉的合成方法研究[J].化学技术与开发,2008,37(11):20-22
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[37]徐宝财,王关兴,辛秀兰等.2,3-二甲基-N-氧化吡啶的合成[J].精细化工,2007,24(7):681-683
[38]孙春霞,彭盘英,崔世海等.2-氯-5-甲基吡啶结晶母液的分离[J].南京师范大学学报(工程技术版),2003,3(2):12-14
[39]宣日成,李祖光,吕亚萍.2-氯-5-甲基吡啶的合成及其新的提纯方法[J].浙江工业大学学报,2003,31(2):208-211
[40]乔萍,闻建平.2-氯-5-甲基吡啶合成的研究进展[J].现代化工,2001,21(12):23-26
[41]康秀卿.制备吡虫啉中间体2-氯-5-甲基吡啶的研究[D].北京:北京化工大学,2003-12
[42]陆一匡,周新龙,王小平等.以3-甲基吡啶为原料制备2-氯-5-甲基吡啶中氯化剂的选择[J].江苏农药,2000,4:16-17
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[2]刘常林.含吡啶杂环农药的开发研究值得重视[J].精细与专用化学品,1999,8:15
[3]赵卫光,王建国,袁德凯等.吡啶类农药研究趋势及发现的含吡啶环的天然活性物质[J].农药,2002,41(7):8-11
[4] Jeannin P.Insecticidal combination to control mammal fleas,in particular fleas on cats and dogs[P].US:6685954,2004-02-03
[5] Singh M , Mack R E . Effect of organosilicone-based adjuvants on herbicide efficacy[J].Pesticide Science,2006,38(2-3):219-225
[6]王晓岚.新杀菌剂氟啶胺的生物活性[J].农药译丛,1996,18(1):43-48
[7] Ryuzo N,Kanichi F,Takahiro H,et al.5-Trifluoromethyl pyridine derivatives substituted in the 2-position[P].BE:865137,1979-09-21
[8] Singh M,Mack R E.Recommendable routes to trifluromethyl-substituted Pyridine- and Quinolinecarbpxylic acids[J].European Journal of Organic Chemistry,2003,2003(8):1559-1568
[9] Yoshiro K, Istumaro K, Akio O,et al.Studies on the organic fluorine compounds XXIV : Photochemical trifluoromethylation of aromatic compounds[J].Chem.Pharm.Bull,1978,16 (4):1247～1249
[10] Yasuo M. Fluoroalkylpyridines[P]. JP: 542079283, 1979-06-25
[11] Gatlin J E,Vandort M A,Volkmann C L.Preparation of (trifluoromethyl)pyridines[P].US:4547577,1985-10-15
[12] Howarit M S , Watson D J , Scovell E G . Process for the preparation of fluoromethylpyridines[P].US:4745193,1988-05-17
[13] Ryuzo N,Kanichi F,Takahiro H,et al.2-Chloro-5-trifluoromethyl pyridine and its preparation[P].JP:55-022617,1980-02-18
[14] Yonosuke A, Heikichi S.Production of halogeno-trifluoromethyl pyridine[P].JP:62-2012758,1987-01-22
[15] Ryuzo N , Kanichi F , Takahiro H , et al . 2-Subsituted-5-trifluoromethyl pyridine[P].JP:54-061183,1979-05-17
[16] Beckers H , Burger H , Bursch P , et al . Synthesis and properties of (trifluoromethyl)trichlorosilane, a versatile precursor for CF3Si compounds [J].Journal of Organometallic Chemistry,1986,316(1-2):41-50
[17] Ryuzo N,Kanichi F,Isao Y,et al.Chloro-β-trifluoromethyl pyridines[P].DE:3009695,1980-10-02
[18] Dakin Kogyo Co.Ltd.2-Chloro-5-trifluoromethyl pyridine or 2-Fluoro-5-trifluoro-methyl pyridine[P].JP:56-029573, 1981-05-24
[19] Fung A P . Liquid phase halogen exchange of (trichloromethyl) pyridines to (trifluromethyl)pyridines[P].US:4567273,1986-01-28
[20]关槐,楚士晋.合成2-氯-5-三氯甲基吡啶的新方法[J].现代农药,2004,3(5):8-10
[21]苏莉.2-氯-5-三氯甲基吡啶的定向合成与结构测定[J].农药,2007,46(5):310-311
[22] Ryuzo N,Kanichi F,Yokomichi Isao, et al.Preparation of chloro-β-trifluoro-methyl pyridine[P].JP:56-120667,1981-09-22
[23] Wilhelm L B , Joerg J , Andreas M . Method for producing substituted halopyridines[P].US:20080214825,2008-09-04
[24] Ryuzo N , Kanichi F , Yokomichi Isao , et al . Pyridine derivaltives with trifluoromethyl groups in theβ-position[P].DE:3008081,1980-09-11
[25] Graham W, Leyland R N,O'Brin Anne.2-Chloro-5-trifluoromethyl pyridine or 2-Chloro-5-perchlorofluoromethyl pyridine[P].Braz. Pedido PI:79 07971,1980-07-08
[26] Ishihara Sangyo Kaisha Co.Ltd.Chloro-3-trifluoromethyl pyridine[P].JP:55-122762,1980-09-20
[27] Ryuzo N, Kanichi F,Yokomichi Isao,et al.Trifluoromethyl-2-pyridinone or pyridinthione compounds and process for the preparation of the same[P].US:4546191,1985-10-8
[28] Klaus J.Process for the preparation of 2-chloro-5-chloromethyl pyridine[P].US:4990622, 1991-02-05.
[29]张伟,徐杰.一种合成2-氯-5-三氟甲基吡啶的方法[P].CN:1202082C,2005-05-18
[30]沈彪,司玉贵,姜标等.氯甲基吡啶类化合物的液相氟化法[P].CN:1316423A, 2001-10-10
[31]陈娇领,江正平.2-氯-5-三氟甲基吡啶的合成[J].浙江化工,2005,36(6):19-20
[32]江正平.2-氯-5-三氟甲基吡啶的合成[D].浙江:浙江大学,2004-12
[33]崔咪芬,乔旭,赵培新等.邻、对氯甲苯侧链光氯化的研究[J].南京工业大学学报,2007,29(1):54-59
[34]李丽娟,高华,丁同富等.2,4-二氯甲苯光氯化反应动力学[J].化学工程,2006,34(7):31-33
[35]陆阳,陶京朝,张志荣.吡虫啉的合成方法研究[J].化学技术与开发,2008,37(11):20-22
[36]王大威,赵宝祥,左华.2-氯-5-甲基吡啶的合成研究[J].山东医药工业,2003,22(5):1
[37]徐宝财,王关兴,辛秀兰等.2,3-二甲基-N-氧化吡啶的合成[J].精细化工,2007,24(7):681-683
[38]孙春霞,彭盘英,崔世海等.2-氯-5-甲基吡啶结晶母液的分离[J].南京师范大学学报(工程技术版),2003,3(2):12-14
[39]宣日成,李祖光,吕亚萍.2-氯-5-甲基吡啶的合成及其新的提纯方法[J].浙江工业大学学报,2003,31(2):208-211
[40]乔萍,闻建平.2-氯-5-甲基吡啶合成的研究进展[J].现代化工,2001,21(12):23-26
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