CN104876929B - Synthesis and Application of one kind of 1,2,3,4-tetrahydro-naphthyridine compounds - Google Patents

Synthesis and Application of one kind of 1,2,3,4-tetrahydro-naphthyridine compounds Download PDF

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CN104876929B
CN104876929B CN201510253313.2A CN201510253313A CN104876929B CN 104876929 B CN104876929 B CN 104876929B CN 201510253313 A CN201510253313 A CN 201510253313A CN 104876929 B CN104876929 B CN 104876929B
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张珉
熊彪
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华南理工大学
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Abstract

本发明属于医药化工合成技术领域,具体涉及一种1,2,3,4‑四氢萘啶类化合物的合成方法及应用。 The present invention belongs to the chemical synthesis field of medical technology, and particularly relates to a method for synthesizing 1,2,3,4-tetrahydro Application of a naphthyridine compounds. 所述合成方法为:在反应器中,加入具有相邻甲醇和氨基取代基的化合物、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150℃下搅拌反应1~48小时后经分离提纯得到。 The synthetic method is: in a reactor, methanol and addition of the compound adjacent to an amino group having a substituent, an alcohol, a metal catalyst, a ligand and a solvent, added base is accelerator into an inert gas, at 40 ~ 150 ℃ after the reaction stirred for 1 to 48 hours to obtain purified isolated. 该方法操作安全简单,原料成本低,有利于工业化生产。 The method is simple and safe, low raw material costs, in favor of industrial production. 本发明的1,2,3,4‑四氢萘啶类化合物可用于合成1‑(2‑甲巯基)‑嘧啶‑4‑基)‑7‑苯基‑1,2,3,4‑四氢‑1,8‑萘啶,并进一步制备了药物活性成分N‑苯乙基‑4‑(‑7‑苯基‑3,4‑二氢‑1,8‑萘啶‑1(2H)‑基‑2‑胺。 1,2,3,4-tetrahydro-naphthyridine compounds of the invention are useful for the synthesis of 1- (2-mercapto-yl) - pyrimidin-4-yl) -7-phenyl-1,2,3,4- 1,8-naphthyridine hydrogen, and the pharmaceutically active ingredient is further prepared N- phenethyl-4 - (- 7-phenyl-3,4-dihydro-1,8-naphthyridin--1 (2H) - yl-amine.

Description

一种1 ,2,3,4-四氢萘啶类化合物的合成方法及应用 One kind of 1, 2,3,4-tetrahydro Synthesis and Application of naphthyridine compounds

技术领域 FIELD

[0001] 本发明属于医药化工合成技术领域,具体涉及一种1,2,3,4_四氢萘啶类化合物的合成方法及应用。 [0001] The present invention belongs to the chemical synthesis field of medical technology, and particularly relates to a method for synthesizing Application of a 1,2,3,4_ tetrahydronaphthyridine compounds.

背景技术 Background technique

[0002] 1,2,3,4_四氢萘啶类化合物质是一类具有生物和药物活性的含氮化合物,是某些天然产物和药物的重要结构骨架。 [0002] 1,2,3,4_ tetrahydronaphthyridine compounds substance is a nitrogen compound having biological and pharmacological activity, some of the structural framework is an important natural products and drugs. 此类化合物对非肽蛋白、玻连蛋白和整合蛋白受体有很强的拮抗作用,能够用作脂质膜和低密度脂蛋白的抗氧化剂,在对抗炎症,消除疼痛,治疗糖尿病方面有重大用途。 Such compounds are non-peptide proteins, and vitronectin integrin receptor, and has a strong antagonistic action, and can be used as LDL lipid membrane antioxidants, significant in combating inflammation, eliminate pain, the treatment of diabetes use. 此外,1,2,3,4_四氢萘啶类化合物也是一类重要的原料、中间体, 在有机合成中具有重要的用途。 Further, 1,2,3,4_ tetrahydronaphthyridine compounds are an important class of raw materials, intermediates, has an important use in organic synthesis. 因此,1,2,3,4_四氢萘啶的合成一直得到广泛的关注。 Thus, 1,2,3,4_ tetrahydronaphthyridine synthesis has been widespread concern.

[0003] 传统的1,2,3,4_四氢萘啶类化合物的合成方法是以2-氨基吡啶、丙烯酸酯为原料,通过分子间加成,多聚磷酸脱水和硼烷的还原作用等多步反应来构建目标化合物。 [0003] The traditional method of synthesis 1,2,3,4_ tetrahydronaphthyridine compounds are 2-aminopyridine, acrylate as a raw material, intermolecular addition, polyphosphoric acid dehydrating and borane reduction and other multi-step reaction to construct the target compound. 由于丙烯酸酯或多聚磷酸类物质高毒易腐蚀性,且硼烷的使用条件要求苛刻,整个合成过程步骤繁琐,容易引起环境污染、严重威胁人的生产和生活安全,所以在工业应用中受到极大限ffjij (M. ffi jtmans, Angew. Chem. Int. Ed. 2003,42,4370-4373 ;M. ffi jtmans, J. Org. Chem. 2004, 69,9215-9223)。 Since the acrylate or polyphosphate species susceptibility to corrosion of highly toxic, and boranes conditions demanding, complicated step of the overall synthesis process, readily cause environmental pollution, a serious threat to human life and safety of production, it is subjected to in industrial applications greatly limit ffjij (M. ffi jtmans, Angew Chem Int Ed 2003,42,4370-4373;....... M ffi jtmans, J. Org Chem 2004, 69,9215-9223).

[0004] 近些年,一些其它的合成1,2,3,4-四氢萘啶的方法也陆续被报道,主要有:(1)2-氨基-3-甲基吡啶和邻苯二甲酸酐的氨解反应,再经过NBS溴化作用以及苯乙酮的缩合,最后用钯碳在高压氢气下催化还原(SRNagarajan,US Pat .0092538,2004 ;H.Kroth,PCT Int.045383,2011;HNNguyen,ZJWang,Tetrahedron Lett,2007,48,7460-7463; K.LeonarcUBioorg.Med.Chem.Lett .2005,15,2679-2684); (2)以氨基吡啶甲醛和芳香酮的弗里德兰德反应制备萘啶,然后经过钯碳在高压氢气下催化还原(T. -G. Nam, NA Porter, J.Am. Chem. Soc. 2007,129,10211-10219; SRNagarajan,US .Pat .0092538,2004),但以上技术仍然存在合成步骤复杂及条件难以控制的缺点。 [0004] In recent years, a number of other synthetic methods naphthyridine 1,2,3,4-tetrahydro have gradually been reported are: (1) 2-Amino-3-methylpyridine and phthaloyl anhydride ammonia decomposition reaction, and then after NBS bromination and condensation of acetophenone, and finally with palladium on carbon catalyst (SRNagarajan, US Pat .0092538,2004 reduced under high-pressure hydrogen; H.Kroth, PCT Int.045383,2011; HNNguyen, ZJWang, Tetrahedron Lett, 2007,48,7460-7463; K.LeonarcUBioorg.Med.Chem.Lett .2005,15,2679-2684); (2) in pyridine carbaldehyde and amino aromatic ketones Friedlander the reaction naphthyridine was prepared and then subjected to catalytic reduction palladium on carbon (T. -G under high pressure hydrogen Nam, NA Porter, J.Am. Chem Soc 2007,129,10211-10219;... SRNagarajan, US .Pat .0092538, 2004), but these technologies are still complex synthetic steps and conditions difficult to control shortcomings.

发明内容 SUMMARY

[0005] 为了解决以上现有技术的缺点和不足之处,本发明的首要目的在于提供一种1,2, 3,4-四氢萘啶类化合物的合成方法。 [0005] In order to solve the above prior art drawbacks and shortcomings, the primary object of the present invention is to provide a 1,2, 3,4-tetrahydro synthesis of naphthyridine compounds.

[0006] 本发明的另一目的在于提供一种1,2,3,4-四氢萘啶类化合物在Buchwald-Hartwig偶联反应(布赫瓦尔德-哈特维希反应)中的应用。 [0006] Another object of the present invention is to provide a 1,2,3,4-tetrahydro-naphthyridine compounds in the Buchwald-Hartwig amination - Application (Buchwald Hartwig reaction) was added.

[0007] 本发明目的通过以下技术方案实现: [0007] The object of the present invention is achieved by the following technical scheme:

[0008] -种1,2,3,4_四氢萘啶类化合物的合成方法,包括以下步骤: [0008] - synthesis species 1,2,3,4_ tetrahydronaphthyridine compounds, comprising the steps of:

[0009]在反应器中,加入化合物1、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150 °C下搅拌反应1~48小时,反应结束后冷却至室温,稀释反应液,过滤, 减压蒸除溶剂得粗产物,经柱层析提纯得到1,2,3,4-四氢萘啶类化合物; [0009] In the reaction vessel, Compound 1, alcohols, metal catalyst, a ligand and a solvent, added base is accelerator into an inert gas, reaction was stirred for 1 to 48 hours at 40 ~ 150 ° C, the reaction after cooling to room temperature, the reaction solution was diluted, filtered, and the solvent was evaporated under reduced pressure to give the crude product is purified by column chromatography to give 1,2,3,4-tetrahydro-naphthyridine compound;

[0010]所述的化合物1是指具有相邻甲醇和氨基取代基的氮杂环化合物,包括具有式(1) 结构的化合物、3-氨基-2-羟甲基吡啶、4-氨基-3-羟甲基吡啶或2-氨基-3-羟甲基哌嗪;所述的醇是指具有式(2)结构的醇、环己醇,吡啶乙醇,1,2,3,4_四氢-1-萘酚或5,6,7,8_四氢-8-羟基喹啉; [0010] The compound 1 refers to methanol and nitrogen heterocyclic compounds having adjacent amino substituent, comprising the compound (1) having the structure of formula 3-amino-2-hydroxymethyl-pyridine, 4-amino-3 - pyridine or 2-amino-hydroxymethyl-3-hydroxymethyl-piperazine; refers to alcohol having the formula (2) structure of the alcohol, cyclohexanol, ethanol, pyridine, tetrahydro 1,2,3,4_ 5,6,7,8_ 1-naphthol or tetrahydro-8-hydroxyquinoline;

Figure CN104876929BD00041

[0012] 其中,R1和R2为相同或者不相同的苯基、甲基、乙基、甲氧基、卤素取代基或氢;R3和R 4为相同或者不相同的氢、甲基、乙基、丙基、苯基、苄基、4-氯苯基或4-三氟甲基苯基。 [0012] wherein, R1, and R2 are the same or different from phenyl, methyl, ethyl, methoxy, hydrogen or halogen substituent; R3 and R 4 are the same or different hydrogen, methyl, ethyl, , propyl, phenyl, benzyl, 4-chlorophenyl or 4-trifluoromethylphenyl.

[0013] 上述合成方法所涉及的部分反应方程式如下: [0013] portion of the reaction involved in the above synthesis method follows the equation:

Figure CN104876929BD00042

[0015] 所述的反应器优选schlenk管(史兰克管);所述的惰性气体为氮气或者氩气。 [0015] The reactor is preferably schlenk tube (Shi Lanke tube); the inert gas is nitrogen or argon.

[0016] 所述化合物1与醇的摩尔比为1: (1~20);优选1:1。 The [0016] Compound 1 and the molar ratio of alcohol is 1: (1 to 20); preferably 1: 1.

[0017]所述的金属催化剂为醋酸铜、硫酸铜、氯化铁、醋酸钯、双三苯基膦二氯化钯、环辛二烯氯化铱、三氯化铱、十二羰基三钌、二氯双(4-甲基异丙基苯基)钌和双三苯基膦-1H-茚氯化钌中的一种或两种以上的混合;所述的配体为三苯基膦、邻菲罗啉、1,4_双(二苯基膦) 丁烧、2-苯基R比啶和4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)中的一种或两种以上的混合。 [0017] The metal catalyst is copper acetate, copper sulfate, ferric chloride, palladium acetate, palladium dichloride bis triphenylphosphine, cyclooctadiene iridium chloride, iridium trichloride, dodecyl triruthenium mixing dichlorobis (4-isopropylphenyl) ruthenium and bis (triphenylphosphine) ruthenium chloride -1H- indene one or two or more; the ligand is triphenylphosphine , phenanthroline, 1,4_-bis (diphenylphosphino) butane burning, R ratio of 2-phenyl-piperidine and xantphos (Xantphos ) above in one or both of mixing.

[0018] 所述的溶剂为乙腈、四氢呋喃、N,N_二甲基甲酰胺、二甲基亚砜、甲苯、甲醇、叔戊醇和水中的一种或两种以上的混合。 [0018] The solvent is one kind of tetrahydrofuran, acetonitrile, N, N_-dimethylformamide, dimethyl sulfoxide, toluene, methanol, t-amyl alcohol, water or a mixture of two or more.

[0019] 所述碱为碳酸钠、碳酸钾、碳酸铯、甲醇钠、叔丁醇钾、叔丁醇钠、叔丁醇锂、四甲基乙二胺和三乙胺中的一种或两种以上的混合;碱的加入量与化合物1的摩尔比为(0.5~5): 1;优选0.5:1。 [0019] the base is sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, tert-butoxide A tetramethylethylenediamine and triethylamine or two above admixture; amount of base added 1 molar ratio of the compound (0.5-5): 1; preferably 0.5: 1.

[0020] 所述的柱层析提纯所用的洗脱液为石油醚:乙酸乙酯的体积比为(0.5~50): 1的混合溶剂。 [0020] the column chromatography used as the eluent petroleum ether: ethyl acetate in a volume ratio of (0.5 to 50): 1 mixed solvent.

[0021 ] 上述1,2,3,4-四氢萘啶类化合物在Buchwald-Hartwig偶联反应中的应用。 Applications [0021] The 1,2,3,4-tetrahydro-naphthyridine compounds in the Buchwald-Hartwig amination of.

[0022] 所述应用包括以下应用步骤: [0022] The applying step comprising the following:

[0023] (1)在反应器中加入1,2,3,4-四氢-7-苯基-1,8-萘啶、4-氯-2-(甲巯基)嘧啶、金属催化剂、配体、碱和溶剂,充入N2保护,在100 °C搅拌反应10小时后,停止加热及搅拌,冷却至室温,降温到0 °c,用饱和氯化铵溶液淬灭,反应液依次经洗涤、萃取、过滤和减压旋蒸去除溶剂,再通过柱层析分离纯化,得到中间产物1-(2-甲巯基)-嘧啶-4-基)-7_苯基_1,2,3, 4-四氛-1,8_蔡啶; [0023] (1) was added in a reactor, 1,2,3,4-tetrahydro-1,8-naphthyridine-7-phenyl, 4-chloro-2- (methylmercapto) pyrimidine, a metal catalyst, with body, a base and a solvent, the charged N2 protection, was stirred at 100 ° C for 10 hours, heating was stopped and stirring, and cooled to room temperature, cooled to 0 ° c, quenched with saturated ammonium chloride solution, the reaction solution was washed successively , extraction, filtration, and solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to obtain an intermediate product 1- (2-mercapto-yl) - pyrimidin-4-yl) phenyl _1,2,3 -7_, 4- four atmosphere -1,8_ CAI piperidine;

[0024] (2)将步骤(1)的中间产物加入到二氯甲烷中,降温至0°C,加入间氯过氧苯甲酸进行反应,反应结束后加入饱和碳酸氢钠溶液淬灭,反应液依次经萃取、洗涤、干燥和真空旋蒸去除溶剂,得到粗亚砜产物;将粗亚砜产物加入到溶解了苯乙胺的N-甲基吡咯烷酮溶液中,冲入N2保护,在100°C搅拌反应10小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到N-苯乙基-4-(-7-苯基_3,4_二氢-1, 萘啶(2H)-基_2_ 胺。 [0024] (2) The step (1) was added to the intermediate product in dichloromethane, was cooled to 0 ° C, the reaction between m-chloroperbenzoic acid was added, quenched with saturated sodium bicarbonate solution was added after the completion of the reaction, the reaction was washed successively extracted, washed, dried and the solvent was removed by rotary evaporation in vacuo to give the crude product sulfoxide; the crude sulfoxide was added to dissolve the product N- methylpyrrolidone solution of phenethylamine, into the N2 protection, at 100 ° C after stirring for 10 hours, heating was stopped and stirring, and cooled to room temperature, the reaction solution was diluted, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give N- phenethyl-4 - (--7- dihydro-1-phenyl-_3,4_, naphthyridine (2H) - yl _2_ amine.

[0025]所述的金属催化剂为醋酸铜、硫酸铜、氯化铁、醋酸钯、双三苯基膦二氯化钯、环辛二烯氯化铱、三氯化铱、十二羰基三钌、二氯双(4-甲基异丙基苯基)钌和双三苯基膦-1H-茚氯化钌中的一种或两种以上的混合;所述的配体为三苯基膦、邻菲罗啉、1,4_双(二苯基膦) 丁烧、2-苯基R比啶和4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)中的一种或两种以上的混合。 [0025] The metal catalyst is copper acetate, copper sulfate, ferric chloride, palladium acetate, palladium dichloride bis triphenylphosphine, cyclooctadiene iridium chloride, iridium trichloride, dodecyl triruthenium mixing dichlorobis (4-isopropylphenyl) ruthenium and bis (triphenylphosphine) ruthenium chloride -1H- indene one or two or more; the ligand is triphenylphosphine , phenanthroline, 1,4_-bis (diphenylphosphino) butane burning, R ratio of 2-phenyl-piperidine and xantphos (Xantphos ) above in one or both of mixing.

[0026] 本发明的制备方法及所得到的产物具有如下优点及有益效果: [0026] The production method of the present invention and the resulting product has the following advantages and beneficial effects:

[0027] 本发明以醇为原料一步合成1,2,3,4_四氢萘啶类化合物,具有合成步骤简单、操作安全(无需使用高压氢气)、原料无毒且价廉易得、合成方法对功能团兼容性好、原子经济性高的优点。 [0027] In the present invention, a raw material one-step synthesis 1,2,3,4_ alcohol tetrahydronaphthyridine compounds, synthetic step simple, safe operation (without the use of high-pressure hydrogen), non-toxic and readily available and inexpensive starting material, synthesis the method of compatibility of functional groups, the advantage of high atom economy.

附图说明 BRIEF DESCRIPTION

[0028] 图1和图2分别为实施例1所得产物的氢谱图和碳谱图; [0028] Figures 1 and 2 respectively, the product of Example 1 obtained spectra hydrogen and carbon spectra;

[0029]图3和图4分别为实施例2所得产物的氢谱图和碳谱图; [0029] Figures 3 and 4 are embodiments of hydrogen and carbon spectra of the spectra of the resulting product 2;

[0030]图5和图6分别为实施例3所得产物的氢谱图和碳谱图; [0030] Figures 5 and 6 are embodiments of hydrogen and carbon spectra spectra obtained in Example 3 product;

[0031]图7和图8分别为实施例4所得产物的氢谱图和碳谱图; [0031] Figures 7 and 8 are embodiments of hydrogen and carbon spectra of the spectra of the resulting product 4;

[0032]图9和图10分别为实施例5所得产物的氢谱图和碳谱图; [0032] FIGS. 9 and 10 are embodiments of hydrogen and carbon spectra of the spectra of the product obtained in Example 5;

[0033]图11和图12分别为实施例6所得产物的氢谱图和碳谱图; [0033] FIGS. 11 and 12 are each a hydrogen and carbon spectra spectrum of the product obtained in Example 6 of the embodiment;

[0034]图13和图14分别为实施例7所得产物的氢谱图和碳谱图; [0034] FIGS. 13 and 14 obtained in Example 7 are spectra of hydrogen and carbon spectra of the product;

[0035]图15和图16分别为实施例8所得中间产物的氢谱图和碳谱图; [0035] Figures 15 and 16 are embodiments of hydrogen and carbon spectra of eight spectra resulting intermediate product;

[0036]图17和图18分别为实施例8所得目的产物的氢谱图和碳谱图。 [0036] Figures 17 and 18 are embodiments of hydrogen and carbon spectra of eight spectra obtained the desired product.

具体实施方式 Detailed ways

[0037] 下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。 [0037] and the following description in conjunction with the accompanying drawings of the embodiments of the present invention will be further detailed embodiment, the embodiment of the present invention is not limited thereto.

[0038] 实施例1 [0038] Example 1

[0039] 在schlenk管中加入0.5毫摩尔2-氨基-3-羟甲基吡啶、0.5毫摩尔1_(对甲苯基)乙醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9_ 二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130 °C搅拌反应5小时后,停止加热及搅拌, 冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率90%。 [0039] In schlenk tube was added 0.5 mmol of 2-amino-3-hydroxymethyl-pyridine, 0.5 mmol 1_ (p-tolyl) ethanol, 0.25 mmole of potassium t-butoxide, 0.005 mmol twelve triruthenium, 0.015 mmol 4,5-bis diphenylphosphino -9,9_ dimethyl-xanthene, 1.2 ml tert-amyl alcohol, after filling with N2 protection, and the reaction was stirred at 130 ° C 5 hours, the heating and stirring, cooled to rt, diluted reaction solution was filtered, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate a mixed solvent, 90% yield.

[0040] 所得产物的氢谱图及碳谱图分别如图1和图2所示,结构表征数据如下: Hydrogen and carbon spectra spectra [0040] The resulting product are shown in Figure 1 and 2, characterized by the following data structure:

[0041] 咕NMR(400MHz,CDCl3):S = 7.78(d,J = 8.0Hz,2H),7.18-7.23(m,3H),6.91(d,J = 7.2Hz,lH),5.01(brs,lH),3.42(s,2H),2.75(t,J=6.0Hz,2H),2.38(s,3H),1.90-1,95(m, 2H)〇 [0041] cushions NMR (400MHz, CDCl3): S = 7.78 (d, J = 8.0Hz, 2H), 7.18-7.23 (m, 3H), 6.91 (d, J = 7.2Hz, lH), 5.01 (brs, lH), 3.42 (s, 2H), 2.75 (t, J = 6.0Hz, 2H), 2.38 (s, 3H), 1.90-1,95 (m, 2H) square

[0042] 13C 匪R(100MHz,CDC13) :S=155.78,153.40,138.24,137.18,136.39,129.21, 126 • 68,115 • 01,109 • 37,41 • 51,26 • 46,21 • 30,21 • 24。 [0042] 13C bandit R (100MHz, CDC13): S = 155.78,153.40,138.24,137.18,136.39,129.21, 126 • 68,115 • 01,109 • 37,41 • 51,26 • 46,21 • 30, 21 • 24.

[0043] IR(KBr):3235,3054,2923,2851,1602,1564,1531,1455,1281,1179,1117,792cm _ Lm-、 [0043] IR (KBr): 3235,3054,2923,2851,1602,1564,1531,1455,1281,1179,1117,792cm _ Lm-,

[0044] MS(EI,m/z):224.[M] +。 [0044] MS (EI, m / z): 224 [M] +..

[0045] HRMS(ESI): Calcd• for C15H16N2[M+H] +: 225 • 1386;found: 225 • 1390。 [0045] HRMS (ESI): Calcd • for C15H16N2 [M + H] +: 225 • 1386; found: 225 • 1390.

[0046] 根据以上数据推断所得产物的结构如下式所示: [0046] The data shown in the above estimation of the resulting product the following structure formula:

Figure CN104876929BD00061

[0048] 实施例2 [0048] Example 2

[0049] 在schlenk管中加入0.5毫摩尔2-氨基-3-羟甲基吡啶、0.5毫摩尔环己醇、0.25毫摩尔叔丁醇钾,〇. 005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130°C搅拌反应10小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率61%。 [0049] 0.5 mmol of 2-amino-3-hydroxymethyl-pyridine, 0.5 mmol of cyclohexanol, 0.25 mmole of potassium t-butoxide, in a schlenk tube square. 005 mmol twelve triruthenium, 0.015 mmol molar xantphos, 1.2 ml tert-amyl alcohol, after filling with N2 protection, was stirred at 130 ° C for 10 hours, heating was stopped and stirring was cooled to at room temperature, the reaction solution was diluted, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate mixture solvent, yield 61%.

[0050] 所得产物的氢谱图及碳谱图分别如图3和图4所示,结构表征数据如下: [0050] Hydrogen and carbon spectra spectrum of the resulting product are shown in FIGS. 3 and 4, characterized by the following data structure:

[0051] 4 NMR(400MHz,CDC13):S6.86(s,1H),4.73(brs,lH),3.37(s,2H),2.66(m,4H), 2.56(t,J = 6.0Hz,2H),1.89(m,2H),1.80(m,2H),1.73(m,2H)。 [0051] 4 NMR (400MHz, CDC13): S6.86 (s, 1H), 4.73 (brs, lH), 3.37 (s, 2H), 2.66 (m, 4H), 2.56 (t, J = 6.0Hz, 2H), 1.89 (m, 2H), 1.80 (m, 2H), 1.73 (m, 2H).

[0052] 13C 匪R(101MHz,CDC13):8153.94,152.38,137.59,141.95,120.51,113.81, 41•74,31•93,27•82,26•33,23•41,23•25,21•83。 [0052] 13C bandit R (101MHz, CDC13): 8153.94,152.38,137.59,141.95,120.51,113.81, 41 • 74,31 • 93,27 • 82,26 • 33,23 • 41,23 • 25,21 • 83.

[0053] IR(KBr):3253,3101,2928,2845,1617,1532,1400,1273,1125,757cm _1〇 [0053] IR (KBr): 3253,3101,2928,2845,1617,1532,1400,1273,1125,757cm _1〇

[0054] MS(EI,m/z):188[M]+〇 [0054] MS (EI, m / z): 188 [M] + square

[0055] HRMS(ESI): Calcd• for C12H16N2[M+H] +: 189 • 1386;found: 189 • 1388。 [0055] HRMS (ESI): Calcd • for C12H16N2 [M + H] +: 189 • 1386; found: 189 • 1388.

[0056]根据以上数据推断所得产物得结构如下式所示: [0056] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00062

[0058] 实施例3 [0058] Example 3

[0059] 在schlenk管中加入0.5毫摩尔2-氨基-3-羟甲基吡啶、0.5毫摩尔正戊醇、0.25毫摩尔叔丁醇钾,〇. 005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130°C搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率58%。 [0059] In schlenk tube was added 0.5 mmol of 2-amino-3-hydroxymethyl-pyridine, 0.5 mmol of n-pentanol, 0.25 mmol of potassium t-butoxide, square. 005 mmol twelve triruthenium, 0.015 mmol molar xantphos, 1.2 ml tert-amyl alcohol, after filling with N2 protection, the reaction was stirred at 130 ° C 12 hours, the heating and stirring, was cooled to at room temperature, the reaction solution was diluted, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate mixture solvent, yield 58%.

[0060] 所得产物的氢谱图及碳谱图分别如图5和图6所示,结构表征数据如下: [0060] Hydrogen and carbon spectra are spectra of the resulting product as shown in FIGS. 5 and 6, characterized by the following data structure:

[0061] 4 NMR(400MHz,CDC13):S7.67(s,1H),6.98(s,lH),4.81(brs,lH),3.38(s,2H), 2.70(t,J = 6.0Hz,2H) ,2.39(t,J = 7.2Hz 2H), 1.90 (m, 2H), 1.55(m, 2H), 0.91 (t, J = 7.2Hz,3H)〇 [0061] 4 NMR (400MHz, CDC13): S7.67 (s, 1H), 6.98 (s, lH), 4.81 (brs, lH), 3.38 (s, 2H), 2.70 (t, J = 6.0Hz, 2H), 2.39 (t, J = 7.2Hz 2H), 1.90 (m, 2H), 1.55 (m, 2H), 0.91 (t, J = 7.2Hz, 3H) square

[0062] 13C NMR( 101MHz,CDCh): S154 • 65,145 • 20,136 • 75,126 • 44,115 • 75,41 • 68,34• 25, 26.65,24.70,21.56,13.67〇 [0062] 13C NMR (101MHz, CDCh): S154 • 65,145 • 20,136 • 75,126 • 44,115 • 75,41 • 68,34 • 25, 26.65,24.70,21.56,13.67〇

[0063] IR(KBr):3246,3005,2957,2854,1617,1538,1401,1266,1104,762,724cm _1〇 [0063] IR (KBr): 3246,3005,2957,2854,1617,1538,1401,1266,1104,762,724cm _1〇

[0064] MS(EI,m/z):176[M] +。 [0064] MS (EI, m / z): 176 [M] +.

[0065] HRMS(ESI): Calcd• for C11H16N2[M+H] +: 177 • 1386;found: 177 • 1387。 [0065] HRMS (ESI): Calcd • for C11H16N2 [M + H] +: 177 • 1386; found: 177 • 1387.

[0066] 根据以上数据推断所得产物得结构如下式所示: [0066] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00071

[0068] 实施例4 [0068] Example 4

[0069] 在schlenk管中加入0.5毫摩尔6-甲基-2-氨基-3-羟甲基吡啶、0.5毫摩尔1_(对氯苯基)乙醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N 2保护,在130 °C搅拌反应16小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率43%。 [0069] 0.5 mmol of methyl-2-amino-3-hydroxymethyl-pyridine schlenk tube, 0.5 mmol 1_ (p-chlorophenyl) ethanol, 0.25 mmole of potassium t-butoxide, 0.005 mmol of twelve triruthenium, 0.015 mmol xantphos, 1.2 ml tert-amyl alcohol, charged into the N 2 protection, the reaction was stirred at 130 ° C 16 hours after stirring and heating was stopped, cooled to room temperature, the reaction solution was diluted, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate mixed solvent, yield 43%.

[0070] 所得产物的氢谱图及碳谱图分别如图7和图8所示,结构表征数据如下: [0070] Hydrogen and carbon spectra spectrum of the resulting product are shown in Figures 7 and 8, characterized by the following data structure:

[0071] 咕NMR(400MHz,CDCl3):S7.84(d,J = 7.6Hz,2H),7.36(d,J = 8.4Hz,2H),7.22(d,J = 7.6Hz,lH),6.91(d ,J = 7.6Hz,lH) ,4.86(brs, 1H), 3.58(s, 1H), 2.58-2.80(m, 2H), 1.96 (m,lH),1.53-1.64(m,lH),1.26(d ,J = 6.4Hz,3H)〇 [0071] cushions NMR (400MHz, CDCl3): S7.84 (d, J = 7.6Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.22 (d, J = 7.6Hz, lH), 6.91 (d, J = 7.6Hz, lH), 4.86 (brs, 1H), 3.58 (s, 1H), 2.58-2.80 (m, 2H), 1.96 (m, lH), 1.53-1.64 (m, lH), 1.26 (d, J = 6.4Hz, 3H) square

[0072] 13C 匪R(101MHz,CDC13):S155.96,152.57,138.35,136.78,134.08,128.59, 127.81,114.95,109.41,47.24,29.41,25.69,22.46。 [0072] 13C bandit R (101MHz, CDC13): S155.96,152.57,138.35,136.78,134.08,128.59, 127.81,114.95,109.41,47.24,29.41,25.69,22.46.

[0073] IR(KBr):3420,2922,2843,1593,1462,1341,1273,1084,801,755cm _1〇 [0073] IR (KBr): 3420,2922,2843,1593,1462,1341,1273,1084,801,755cm _1〇

[0074] MS(EI,m/z):258[M]+〇 [0074] MS (EI, m / z): 258 [M] + square

[0075] HRMS(ESI): Calcd• for C15H15CIN2[M+H] +: 259 • 0997;found: 259 • 1002。 [0075] HRMS (ESI): Calcd • for C15H15CIN2 [M + H] +: 259 • 0997; found: 259 • 1002.

[0076] 根据以上数据推断所得产物得结构如下式所示: [0076] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00072

[0078] 实施例5 [0078] Example 5

[0079] 在schlenk管中加入0.5毫摩尔3-氨基-2-羟甲基吡啶、0.5毫摩尔苯乙醇、0.5毫摩尔叔丁醇钾,〇. 005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130°C搅拌反应10小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率46%。 [0079] In schlenk tube was added 0.5 mmol of 3-amino-2-hydroxymethyl-pyridine, 0.5 mmol of phenethyl alcohol, 0.5 mmole of potassium t-butoxide, square. 005 mmol twelve triruthenium, 0.015 mmoles xantphos, 1.2 ml tert-amyl alcohol, after filling with N2 protection, was stirred at 130 ° C for 10 hours, heating was stopped and stirring was cooled to room temperature diluted reaction solution was filtered, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate mixed solvent yield 46%.

[0080] 所得产物的氢谱图及碳谱图分别如图9和图10所示,结构表征数据如下: [0080] Hydrogen and carbon spectra spectrum of the resulting product are shown in FIGS. 9 and 10, characterized by the following data structure:

[0081] 4 NMR(400MHz,CDC13):S8.09(s,1H),7.52(d,J = 7.2Hz,2H),7.43(t,J = 7.6Hz, 2H) ,7.35(t,J = 7.2Hz,lH) ,6.91(s,lH) ,3.91(brs,lH) ,3.34(s,2H),2.97(t,J = 6.0Hz, 2H),2.06(m,2H)〇 [0081] 4 NMR (400MHz, CDC13): S8.09 (s, 1H), 7.52 (d, J = 7.2Hz, 2H), 7.43 (t, J = 7.6Hz, 2H), 7.35 (t, J = 7.2Hz, lH), 6.91 (s, lH), 3.91 (brs, lH), 3.34 (s, 2H), 2.97 (t, J = 6.0Hz, 2H), 2.06 (m, 2H) square

[0082] 13C 匪R(101MHz,CDC13):S141.80,140.77,138.52,136.51,135.26,128.85, 127.59,126.98,118.55,41.60,30.08,21.86 〇 [0082] 13C bandit R (101MHz, CDC13): S141.80,140.77,138.52,136.51,135.26,128.85, 127.59,126.98,118.55,41.60,30.08,21.86 square

[0083] IR(KBr):3249,3019,2929,2849,1601,1532,1458,1399,1260,1188,1013,874, 758,695cm-1。 [0083] IR (KBr): 3249,3019,2929,2849,1601,1532,1458,1399,1260,1188,1013,874, 758,695cm-1.

[0084] MS(EI,m/z):210[M] +。 [0084] MS (EI, m / z): 210 [M] +.

[0085] HRMS(ESI): Calcd• for C14H14N2[M+H] +: 211 • 1230;found: 211 • 1233。 [0085] HRMS (ESI): Calcd • for C14H14N2 [M + H] +: 211 • 1230; found: 211 • 1233.

[0086] 根据以上数据推断所得产物得结构如下式所示: [0086] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00081

[0088] 实施例6 [0088] Example 6

[0089] 在schlenk管中加入0.5毫摩尔2-氨基-3-羟甲基哌嗪、0.5毫摩尔1-苯乙醇、0.25 毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N 2保护,在130 °C搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率63%。 [0089] 0.5 mmol of 2-amino-3-hydroxymethyl-piperazine, 0.5 mmol phenethanol, 0.25 mmole of potassium t-butoxide, 0.005 mmol twelve triruthenium in schlenk tube, 0.015 mmol after mol xantphos, 1.2 ml tert-amyl alcohol, charged into the N 2 protection, the reaction was stirred at 130 ° C 12 hours, the heating and stirring, cooled to rt, diluted reaction solution was filtered, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether: ethyl acetate a mixed solvent, 63% yield.

[0090] 所得产物的氢谱图及碳谱图分别如图11和图12所示,结构表征数据如下: Hydrogen and carbon spectra spectra [0090] The resulting product are shown in FIGS. 11 and 12, characterized by the following data structure:

[0091] 4 NMR(400MHz,CDC13):S7.83(d,J = 7.6Hz,2H),7.37(t,J = 7.2Hz,2H),7.25(s, 1H) ,6.91(d,J = 7.6Hz,lH) ,6.68(d,J = 7.6Hz,lH) ,5.09(brs,lH) ,3.49(s,2H) ,3.38(s, 2H)〇 [0091] 4 NMR (400MHz, CDC13): S7.83 (d, J = 7.6Hz, 2H), 7.37 (t, J = 7.2Hz, 2H), 7.25 (s, 1H), 6.91 (d, J = 7.6Hz, lH), 6.68 (d, J = 7.6Hz, lH), 5.09 (brs, lH), 3.49 (s, 2H), 3.38 (s, 2H) square

[0092] 13C 匪R(101MHz,CDC13):S146.77,145.28,139.99,128.43,128.16,127.13, 125.90,119.32,110.94,40.78,40.52〇 [0092] 13C bandit R (101MHz, CDC13): S146.77,145.28,139.99,128.43,128.16,127.13, 125.90,119.32,110.94,40.78,40.52〇

[0093] IR(KBr):3405,3236,2921,2853,1603,1530,1505,1354,1277,1223,1127,1022, 816,778,752,697cm- 1。 [0093] IR (KBr): 3405,3236,2921,2853,1603,1530,1505,1354,1277,1223,1127,1022, 816,778,752,697cm- 1.

[0094] MS(EI,m/z):211[M]+〇 [0094] MS (EI, m / z): 211 [M] + square

[0095] HRMS(ESI):Calcd.for Ci3Hi3N3[M+H] + :212.1182;found:212.1187。 [0095] HRMS (ESI): Calcd.for Ci3Hi3N3 [M + H] +: 212.1182; found: 212.1187.

[0096] 根据以上数据推断所得产物得结构如下式所示: [0096] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00082

[0098] 实施例7 [0098] Example 7

[0099] 在schlenk管中加入0.5毫摩尔2-氨基-3-羟甲基-4,6-二苯基吡啶、1.5毫摩尔乙醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N 2保护,在130 °C搅拌反应12小时后,停止加热及搅拌, 冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率72%。 [0099] 0.5 mmol of the 2-amino-3-hydroxymethyl-4,6-diphenyl schlenk tube pyridine, 1.5 mmol of ethanol, 0.25 mmole of potassium t-butoxide, 0.005 mmol triruthenium dodecacarbonyl after ruthenium, 0.015 mmol xantphos, 1.2 ml tert-amyl alcohol, charged into the N 2 protection, the reaction was stirred at 130 ° C 12 h heating was stopped stirring and cooled to room temperature, the reaction solution was diluted, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 12: 1 petroleum ether : a mixed solvent of ethyl acetate, yield 72%.

[0100] 所得产物的氢谱图及碳谱图分别如图13和图14所示,结构表征数据如下: [0100] Hydrogen and carbon spectra spectrum of the resulting product are shown in FIGS. 14 and 13, characterized by the following data structure:

[0101] NMR(400MHz,CDC13):S7.90-7.94(m,2H),7.30-7.46(m,8H),6.92(s,lH),5.32 (brs,lH),3.37(s,2H),2.66(t,J = 6.0Hz,2H),1.83(m,2H)。 [0101] NMR (400MHz, CDC13): S7.90-7.94 (m, 2H), 7.30-7.46 (m, 8H), 6.92 (s, lH), 5.32 (brs, lH), 3.37 (s, 2H) , 2.66 (t, J = 6.0Hz, 2H), 1.83 (m, 2H).

[0102] 13C 匪R(101MHz,CDC13):5156.29,153.61,149.72,140.00,139.94,128.63, 128.48,128.27,128.20,127.63,126.69,112.04,111.34,41.59,25.06,21.70〇 [0102] 13C bandit R (101MHz, CDC13): 5156.29,153.61,149.72,140.00,139.94,128.63, 128.48,128.27,128.20,127.63,126.69,112.04,111.34,41.59,25.06,21.70〇

[0103] IR(KBr):3265,3021,2836,1576,1493,1450,1401,1314,1267,1191,1068,837, 765,695cm- 1。 [0103] IR (KBr): 3265,3021,2836,1576,1493,1450,1401,1314,1267,1191,1068,837, 765,695cm- 1.

[0104] MS(EI,m/z):286[M] + 〇 [0104] MS (EI, m / z): 286 [M] + square

[0105] HRMS(ESI): Calcd • for C20H18N2[M+H] +: 287 • 1543; found: 287 • 1546。 [0105] HRMS (ESI): Calcd • for C20H18N2 [M + H] +: 287 • 1543; found: 287 • 1546.

[0106] 根据以上数据推断所得产物得结构如下式所示: [0106] The data shown in the above product to give the resulting structure to infer the formula:

Figure CN104876929BD00091

[0108] 实施例8 [0108] Example 8

[0109] (1)在schlenk管中加入1.0毫摩尔1,2,3,4_四氢-7-苯基-1,8-萘啶(按实施例6的方法制备,将原料2-氨基-3-羟甲基哌嗪替换为2-氨基-3-羟甲基吡啶)、1.5毫摩尔4-氯-2-(甲巯基)嘧啶、〇. 05毫摩尔醋酸钯,0.05毫摩尔Xantphos,2.0毫摩尔甲醇钠和2.0毫升甲苯,充入N2保护,在100°C搅拌反应10小时后,停止加热及搅拌,冷却至室温,降温到0°C,用饱和氯化铵溶液淬灭,洗涤萃取过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到中间产物,所用的柱层析洗脱液为体积比为8:1的石油醚:乙酸乙酯混合溶剂,产率71%。 [0109] (1) was added 1.0 mmol of 1,2,3,4_ tetrahydro-7-phenyl-1,8-naphthyridine prepared (as described in Example 6 in schlenk tubes, the raw material 2-amino -3-hydroxymethyl-piperazine was replaced amino-3-hydroxymethylpyridine), 1.5 mmol of 4-chloro-2- (methylmercapto) pyrimidine, square 05 mmol palladium acetate, 0.05 mmol Xantphos, 2.0 mmol of sodium methoxide and 2.0 ml of toluene, after filling with N2 protection, was stirred at 100 ° C for 10 hours, heating was stopped and stirring, and cooled to room temperature, cooled to 0 ° C, quenched with saturated ammonium chloride solution, washed extract was filtered, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the intermediate product by column chromatography eluent used was a volume ratio of 8: 1 petroleum ether: ethyl acetate mixed solvent, yield 71 %.

[0110] 所得中间产物的氢谱图及碳谱图分别如图15和图16所示,结构表征数据如下: [0110] Hydrogen and carbon spectra of the resulting intermediate spectra are shown in Figures 15 and 16, characterized by the following data structure:

[0111] 4 MMR(400MHz,CDC13):S8.18(d,J = 5.6Hz,lH),7.97(d,J = 7.2Hz,2H),7.82(d, J = 6.0Hz,lH) ,7.35-7.54(m,5H),4.21 (t,J = 4.8Hz,2H),2.85(d,J = 6.0Hz,2H),2.57(s, 3H),2.04(m,2H)〇 [0111] 4 MMR (400MHz, CDC13): S8.18 (d, J = 5.6Hz, lH), 7.97 (d, J = 7.2Hz, 2H), 7.82 (d, J = 6.0Hz, lH), 7.35 -7.54 (m, 5H), 4.21 (t, J = 4.8Hz, 2H), 2.85 (d, J = 6.0Hz, 2H), 2.57 (s, 3H), 2.04 (m, 2H) square

[0112] 13C 匪R(101MHz,CDC13):5179.84,160.00,155.16,152.84,151.90,138.75, 138.31,128.88,128.78,126.41,122.25,114.64,106.37,44.91,26.95,22.62,14.13〇 [0112] 13C bandit R (101MHz, CDC13): 5179.84,160.00,155.16,152.84,151.90,138.75, 138.31,128.88,128.78,126.41,122.25,114.64,106.37,44.91,26.95,22.62,14.13〇

[0113] IR(KBr):3050,3013,2924,1600,1561,1530,1467,1436,1345,1316,1232,1203, 1174,976,900,811,772,745,694cm _1〇 [0113] IR (KBr): 3050,3013,2924,1600,1561,1530,1467,1436,1345,1316,1232,1203, 1174,976,900,811,772,745,694cm _1〇

[0114] MS(EI,m/z):334[M]+〇 [0114] MS (EI, m / z): 334 [M] + square

[0115] HRMS(ESI): Calcd• for Ci9HisN4S[M+H] +: 335 • 1325;found: 335 • 1319。 [0115] HRMS (ESI): Calcd • for Ci9HisN4S [M + H] +: 335 • 1325; found: 335 • 1319.

[0116]根据以上数据推断所得中间产物的结构如下式所示: [0116] The data shown in the above structural estimation resultant intermediate of the formula:

Figure CN104876929BD00092

[0118] (2)在25毫升圆底烧瓶中加入0.5毫摩尔步骤(1)得到的1 -(2-甲巯基)-嘧啶-4- 基)-7_苯基_1,2,3,4_四氢-1,8-萘啶、5毫升二氯甲烷、降温至lj0°C,加入0.75毫摩尔间氯过氧苯甲酸,保持低温反应30分钟;待反应结束后,加入饱和碳酸氢钠溶液淬灭。 [0118] (2) step was added 0.5 mmoles in 25 ml round bottom flask (1) to give 1 - (2-mercapto-yl) - pyrimidin-4-yl) phenyl _1,2,3 -7_, 4_ tetrahydro-1,8-naphthyridine, 5 ml of dichloromethane, cooled to lj0 ° C, was added 0.75 mmol of m-chloroperbenzoic acid, to maintain a low temperature for 30 minutes; after completion of the reaction, saturated bicarbonate quenched with a solution of sodium. 收集有机层, 并用二氯甲烷多次萃取水层,合并有机层并用lmol/L的氢氧化钠溶液洗涤。 The organic layers were combined organic layers were collected, and the aqueous layer was extracted several times with methylene chloride, and washed with lmol / L sodium hydroxide solution. 分液,得到有机层,并用无水硫酸钠干燥,用真空旋转蒸发仪移除溶剂得到粗亚砜产物。 Liquid separation to obtain an organic layer and dried over anhydrous sodium sulfate, and removing the solvent by a rotary evaporator in vacuo to give a crude product sulfoxide. 将亚砜粗品加入到1.5mL的溶解了2.5毫摩尔苯乙胺的N-甲基吡咯烷酮溶液当中,冲入氮气,将混合液置于100 °C条件下反应10小时,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚: 乙酸乙酯混合溶剂,产率91 %。 The crude sulfoxide was dissolved in 1.5mL was added to N- methylpyrrolidone solution of 2.5 mmol of phenethylamine among charged with nitrogen, the reaction mixture was placed in 100 ° C for for 10 hours, the heating and stirring, cooled to rt, diluted reaction solution was filtered, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to give the desired product by column chromatography, the eluent used was a volume ratio of 5: 1 petroleum ether: ethyl acetate a mixed solvent, 91% yield.

[0119] 所得目标产物的氢谱图及碳谱图分别如图17和图18所示,结构表征数据如下: [0119] Hydrogen and carbon spectra of the resulting spectrum of the target product are shown in FIGS. 17 and 18, characterized by the following data structure:

[0120] 4 NMR(400MHz,CDC13):S8.00(t,J = 6.4Hz,3H),7.18-7.50(m,llH),5.10(brs, 1H) ,4.15(s,2H),3.69(q,J = 6.4Hz,2H) ,2.94(t,J = 6.4Hz,2H) ,2.81(t,J = 6.0Hz,2H), 2.00(m,2H)〇 [0120] 4 NMR (400MHz, CDC13): S8.00 (t, J = 6.4Hz, 3H), 7.18-7.50 (m, llH), 5.10 (brs, 1H), 4.15 (s, 2H), 3.69 ( q, J = 6.4Hz, 2H), 2.94 (t, J = 6.4Hz, 2H), 2.81 (t, J = 6.0Hz, 2H), 2.00 (m, 2H) square

[0121] 13C 匪R(101MHz,CDC13):5162.12,161.31,156.17,152.80,152.48,139.74, 139.01,138.09,128.93,128.74,128.56,126.48,126.28,122.09,114.03,101.16,44.75, 42.96,36.17,27.09,22.74。 [0121] 13C bandit R (101MHz, CDC13): 5162.12,161.31,156.17,152.80,152.48,139.74, 139.01,138.09,128.93,128.74,128.56,126.48,126.28,122.09,114.03,101.16,44.75, 42.96,36.17, 27.09,22.74.

[0122] IR(KBr):3256,3026,2928,2851,1606,1558,1517,1467,1409,1312,1265,1237, 1182,1127,1073,1020,913,817,748,694,641cm _1〇 [0122] IR (KBr): 3256,3026,2928,2851,1606,1558,1517,1467,1409,1312,1265,1237, 1182,1127,1073,1020,913,817,748,694,641cm _1〇

[0123] MS(EI,m/z):407[M]+〇 [0123] MS (EI, m / z): 407 [M] + square

[0124] HRMS(ESI): Calcd• for C26H25N5[M+H] +: 408 • 2183;found: 408 • 2192。 [0124] HRMS (ESI): Calcd • for C26H25N5 [M + H] +: 408 • 2183; found: 408 • 2192.

[0125] 枏抿以h教抿椎断所得日标产物得结构加下忒所示: [0125] In nan sip sip h teach vertebral off to give the resulting product to adding the superscript shown at Intuit:

Figure CN104876929BD00101

[0127]本实施例所涉及的反应方程式如下: [0127] The present embodiment relates to a reaction formula as follows:

Figure CN104876929BD00102

[0129]上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化, 均应为等效的置换方式,都包含在本发明的保护范围之内。 [0129] The preferred embodiment of the present invention embodiment, but the embodiment of the present invention is not limited to the above embodiments, changes made to any other without departing from the spirit and principle of the present invention, modifications, substitutions , combined, simplified, should be equivalent replacement method, it is included within the scope of the present invention.

Claims (6)

1. 一种I,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:包括W下合成步骤: 在反应器中,加入化合物1、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150°C下揽拌反应1~48小时,反应结束后冷却至室溫,稀释反应液,过滤,减压蒸除溶剂得粗产物,经柱层析提纯得到1,2,3,4-四氨糞晚类化合物; 所述的化合物1是指具有式(1)结构的化合物、3-氨基-2-径甲基化晚、4-氨基-3-径甲基化晚或2-氨基-3-径甲基赃嗦;所述的醇是指具有式(2)结构的醇、环己醇、化晚乙醇、1, 2,3,4-四氨-1-糞酪或5,6,7,8-四氨-8-径基哇嘟; An I, synthesis of 2,3,4-tetraamine manure Night compounds, wherein: W is synthesized comprising the steps of: in a reaction vessel, Compound 1, alcohols, metal catalyst, a ligand and a solvent , base is added accelerator into an inert gas, embrace the reaction stirred at 40 ~ 150 ° C 1 ~ 48 hours after the reaction was cooled to rt, diluted reaction solution was filtered, the solvent was evaporated under reduced pressure to give the crude product , purified by column chromatography to give 1,2,3,4-amino compound through fecal night; the compound 1 means a compound of formula (1) having the structure, methyl 3-amino-diameter of late, amino-3-methyl diameter of nights or stolen methyl 2-amino-winded path; refers to alcohol having the formula (2) structure of the alcohol, cyclohexanol, ethanol lATE, 1, 2 , 3,4-tetraamine -1- feces or 5,6,7,8-casein amino group wow beep -8- diameter;
Figure CN104876929BC00021
其中,Ri和R2为相同或者不相同的苯基、甲基、乙基、甲氧基、面素取代基或氨;R3和R 4为相同或者不相同的氨、甲基、乙基、丙基、苯基、苄基、4-氯苯基或4-立氣甲基苯基; 所述的金属催化剂为醋酸铜、硫酸铜、氯化铁、醋酸钮、双=苯基麟二氯化钮、环辛二締氯化银、S氯化银、十二幾基S钉、二氯双(4-甲基异丙基苯基)钉和双S苯基麟-IH-巧氯化钉中的一种或两种W上的混合;所述的配体为=苯基麟、邻菲罗嘟、1,4-双(二苯基麟)下烧、2-苯基化晚和4,5-双二苯基麟-9,9-二甲基氧杂蔥中的一种或两种W上的混合。 Wherein, Ri of and R2 are the same or different from phenyl, methyl, ethyl, methoxy, or amino group substituted prime surface; R3 and R 4 are the same or different amino, methyl, ethyl, propyl group, phenyl, benzyl, 4-chlorophenyl or 4-methylphenyl standing gas; said metal catalyst is copper acetate, copper sulfate, ferric chloride, acetate button, lin = phenyl dichloride bis button, two associated cyclooctadiene silver chloride, silver chloride S, dodecyl group several staples S, dichloro-bis (4-isopropylphenyl) phenyl staple S and bis Qiao-lin -IH- staple chloride a hybrid on two or W; the ligand is lin = phenyl, phenanthroline beep, calcined at 1,4-bis (diphenylphosphino Lin), and 2-phenyl-4 lATE , 5-bis-9,9-diphenyl-lin methyl oxa mixed on one or both of onion W.
2. 根据权利要求1所述的一种1,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:所述的反应器是指SChlenk管;所述的惰性气体为氮气或者氣气。 The synthesis method of claim 1. A night manure 1,2,3,4-amino compound as claimed in claim, wherein: said reactor means SChlenk tube; said inert gas is nitrogen gas or air.
3. 根据权利要求1所述的一种1,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:所述的化合物1与醇的摩尔比为1: (1~20)。 The synthesis method of claim 1. A night manure 1,2,3,4-amino compound as claimed in claim, wherein: the molar ratio of the compound of claim 1 with an alcohol of 1: (1 to 20 ).
4. 根据权利要求1所述的一种1,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:所述的溶剂为乙腊、四氨巧喃、N,N-二甲基甲酯胺、二甲基亚讽、甲苯、甲醇、叔戊醇和水中的一种或两种W上的混合。 The synthesis method of claim 1. A night manure 1,2,3,4-amino compound as claimed in claim, wherein: said solvent is acetic December, tetraamine clever furans, N, N- dimethyl ester amines, mixed on dimethylmethylene Bitterness, toluene, methanol, water, tertiary amyl alcohol and one or both of W.
5. 根据权利要求1所述的一种1,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:所述碱为碳酸钢、碳酸钟、碳酸飽、甲醇钢、叔下醇钟、叔下醇钢、叔下醇裡、四甲基乙二胺和= 乙胺中的一种或两种W上的混合;碱的加入量与化合物1的摩尔比为(0.5~5) :1。 The synthesis method of claim 1. A night manure 1,2,3,4-amino compound as claimed in claim, wherein: said steel base is carbonate, carbonate clock, carbonation, methanol steel, t Zhong an alcohol, a tertiary alcohol steel, the tertiary alcohol, the ethylamine mixed on one or both of W and tetramethylethylenediamine =; amount of base added 1 molar ratio of the compound (0.5 5): 1.
6. 根据权利要求1所述的一种1,2,3,4-四氨糞晚类化合物的合成方法,其特征在于:所述的柱层析提纯所用的洗脱液为石油酸:乙酸乙醋的体积比为(0.5~50):1的混合溶剂。 The synthesis method of claim 1. A night manure 1,2,3,4-amino compound as claimed in claim, wherein: said column chromatography is used eluent petroleum acids: acetic acid the volume ratio of ethyl ester (0.5 to 50): 1 mixed solvent.
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