CN116410136A - Quinoline derivative and preparation method thereof - Google Patents

Quinoline derivative and preparation method thereof Download PDF

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CN116410136A
CN116410136A CN202310195220.3A CN202310195220A CN116410136A CN 116410136 A CN116410136 A CN 116410136A CN 202310195220 A CN202310195220 A CN 202310195220A CN 116410136 A CN116410136 A CN 116410136A
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quinoline
quinoline derivative
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马爱军
郑景云
罗颖
冯娜
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Wuyi University Fujian
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20Spiro-condensed ring systems
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

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Abstract

本发明公开了一种喹啉衍生物及其制备方法,属于有机合成技术领域;本发明提供的一种喹啉衍生物的制备方法为以式Ⅰ所示化合物为原料,在惰性气体及有机酸的作用下,于有机溶剂中发生脱氢关环反应,得式Ⅱ所示喹啉衍生物;本发明提供的制备方法中,无需原料的1,2位的碳碳双键,直接在本发明提供的有机酸作用下即可脱氢进而关环,从而适用的底物范围更广,实际利用价值更高。另外,本发明提供的制备方法操作简单、设备要求低、收率高,利于实际应用,具体的,得到的产品的收率可达90%;

Figure DDA0004106912190000011
The invention discloses a quinoline derivative and a preparation method thereof, which belong to the technical field of organic synthesis; the preparation method of a quinoline derivative provided by the invention is to use the compound shown in formula I as a raw material, in an inert gas and an organic acid Under the action of the dehydrogenation ring-closing reaction in an organic solvent, the quinoline derivative shown in formula II is obtained; in the preparation method provided by the invention, the carbon-carbon double bond at the 1,2 position of the raw material is not needed, and the Under the action of the provided organic acid, it can dehydrogenate and then close the ring, so that the scope of applicable substrates is wider and the actual utilization value is higher. In addition, the preparation method provided by the present invention is simple in operation, low in equipment requirements, and high in yield, which is beneficial to practical application. Specifically, the yield of the obtained product can reach 90%;
Figure DDA0004106912190000011

Description

一种喹啉衍生物及其制备方法A kind of quinoline derivative and preparation method thereof

技术领域technical field

本发明属于有机合成技术领域,尤其涉及一种喹啉衍生物及其制备方法。The invention belongs to the technical field of organic synthesis, and in particular relates to a quinoline derivative and a preparation method thereof.

背景技术Background technique

喹啉的结构(式A)是由苯环并吡咯环的一类分子,其衍生物(式B和式C)大部分具有生物活性。喹啉类化合物广泛应用于医药、染料、感光材料、橡胶、溶剂和化学试剂等。喹啉在医药上主要用于制造烟酸系、8-羟基喹啉系和奎宁系三大类药物。烟酸系药物有烟酸胺、强心剂、兴奋剂和治绦虫病药;8-羟基喹啉系可用于制造医治阿米巴虫病用药和创伤消毒剂,以及防霉剂和纺织助剂等;伯氨奎宁、氯化奎宁和羟氨奎宁则是合成的治疟疾特效药。甲基喹啉可用于制造彩色胶片增感剂和染料,还可作为溶剂、浸渍剂、腐蚀抑制剂、奎宁系药物和杀虫剂等。The structure of quinoline (formula A) is a class of molecules composed of benzopyrrole rings, most of its derivatives (formula B and formula C) have biological activity. Quinoline compounds are widely used in medicine, dyes, photosensitive materials, rubber, solvents and chemical reagents. Quinoline is mainly used in the manufacture of three major categories of drugs, niacin, 8-hydroxyquinoline and quinine. Niacin-based drugs include nicotinamide, cardiotonic agents, stimulants and taeniasis drugs; 8-hydroxyquinolines can be used to manufacture medicines for treating amoebiasis and wound disinfectants, as well as antifungal agents and textile auxiliaries, etc.; Primine, chloroquine, and hydroxyquine are synthetic antimalarial drugs. Methylquinoline can be used to make color film sensitizers and dyes, and can also be used as solvents, impregnating agents, corrosion inhibitors, quinine-based drugs and insecticides, etc.

据现有文献报道,目前关于喹啉及喹啉衍生物的合成,广泛运用的途径都是苯胺或苯胺的衍生物为起始原料通过以下4种方法形成吡啶环得到喹啉或喹啉衍生物:(1)周环反应(Aza D-A Reaction);(2)Aldol Reaction关环反应,如Camps quinoline Synthesis、

Figure BDA0004106912180000011
Reaction、Pfitinger Reaction、Niementowski quinoline Synthesis;(3)在苯胺N的γ位,构建一个亲电中心,通过SEAr反应关环,如Combes Reaction、SkraupReaction、Gould-Jacobs Reaction、Doebner-Miller Reaction、Doebner Reaction、KnorrReaction、Conrad-Limpach Reaction;(4)利用N的亲和性,通过SNAr反应构建喹啉类化合物,如构建沙星类药物母核(喹诺酮)。According to existing literature reports, the widely used approach for the synthesis of quinoline and quinoline derivatives is that aniline or aniline derivatives are used as starting materials to form a pyridine ring through the following four methods to obtain quinoline or quinoline derivatives : (1) Pericyclic reaction (Aza DA Reaction); (2) Aldol Reaction ring-closing reaction, such as Camps quinoline Synthesis,
Figure BDA0004106912180000011
Reaction, Pfitinger Reaction, Niementowski quinoline Synthesis; (3) At the γ-position of aniline N, construct an electrophilic center, and close the ring through SEAr reaction, such as Combes Reaction, SkraupReaction, Gould-Jacobs Reaction, Doebner-Miller Reaction, Doebner Reaction, KnorrReaction, Conrad-Limpach Reaction; (4) Utilize the affinity of N to construct quinoline compounds through SNAr reaction, such as constructing the mother core (quinolone) of floxacin drugs.

在这些策略中,合成喹啉及喹啉衍生物使用的方法或要使用昂贵的试剂,或者要使用到较大量的催化剂等。有部分反应需要用到昂贵的配体和金属氧化剂等,不符合绿色化学的发展。过去的喹啉及喹啉衍生物的合成大多都是以苯胺或苯胺的衍生物通过分子间的反应完成喹啉骨架的构筑,很少有分子内的反应,通过分子内的反应构筑喹啉骨架。另外,目前合成的喹啉衍生物都是在喹啉的1、2、3、4位衍生化,仍未有一步反应构筑喹啉的同时在苯环上衍生的喹啉衍生物。由于取代基有吸电子和给电子导致的定位效应,因此,在喹啉的苯环上带有基团很多时候不利于后续反应的进行,所以目前在苯环上衍生化尤其在6位碳上的直接衍生化未查询到有报道过,过去的方法都是在原料上直接带有的;Among these strategies, the methods used for the synthesis of quinoline and quinoline derivatives either use expensive reagents or use relatively large amounts of catalysts. Some reactions require the use of expensive ligands and metal oxidants, which do not conform to the development of green chemistry. In the past, the synthesis of quinoline and quinoline derivatives mostly used aniline or aniline derivatives to complete the construction of the quinoline skeleton through intermolecular reactions. There were few intramolecular reactions, and the quinoline skeleton was constructed through intramolecular reactions. . In addition, the currently synthesized quinoline derivatives are all derivatized at the 1, 2, 3, and 4 positions of quinoline, and there is no one-step reaction to construct quinoline while derivatizing on the benzene ring. Because the substituent has the positioning effect caused by electron-withdrawing and electron-donating, therefore, the group on the benzene ring of quinoline is often not conducive to the subsequent reaction, so the current derivatization on the benzene ring is especially at the 6-position carbon. No direct derivatization has been found and reported, and the past methods were all directly carried on the raw material;

Figure BDA0004106912180000021
Figure BDA0004106912180000021

发明内容Contents of the invention

本发明的目的在于克服上述现有技术的不足之处而提供一种能够在分子内一步高效构筑喹啉骨架,同时在喹啉的苯环碳上进行衍生化的喹啉衍生物及其制备方法。The purpose of the present invention is to overcome the shortcomings of the above-mentioned prior art and provide a quinoline derivative that can efficiently construct a quinoline skeleton in one step in the molecule, and simultaneously derivatize the benzene ring carbon of quinoline and its preparation method .

为实现上述目的,本发明采取的技术方案为:一种喹啉衍生物的制备方法,所述制备方法包括以下步骤:以式Ⅰ所示化合物为原料,在惰性气体及有机酸的作用下,于有机溶剂中发生脱氢关环反应,得式Ⅱ所示喹啉衍生物,In order to achieve the above object, the technical solution adopted by the present invention is: a preparation method of quinoline derivatives, the preparation method comprising the following steps: using the compound shown in formula I as a raw material, under the action of an inert gas and an organic acid, A dehydrogenation ring-closing reaction occurs in an organic solvent to obtain a quinoline derivative shown in formula II,

Figure BDA0004106912180000022
Figure BDA0004106912180000022

其中,R1选自氢、烷基、酰基、烷氧基、酯基、羰基中的任意一种;Wherein, R is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester, and carbonyl;

R2选自氢、烷基、酰基、烷氧基、酯基、羰基中的任意一种; R is selected from any one of hydrogen, alkyl, acyl, alkoxy, ester, and carbonyl;

R3选自烷基、烷氧基、酯基中的任意一种; R is selected from any one of alkyl, alkoxy and ester groups;

R’选自-OMs、-OTf、-NTf2中的任意一种。R' is selected from any one of -OMs, -OTf, -NTf 2 .

本发明提供的一种喹啉衍生物的制备方法中通过以式Ⅰ所示化合物(苯基叠氮酮类衍生物)为底物,在有机酸作用下进行分子内的脱氢关环反应,形成喹啉环结构化合物;同时本发明提供的分子内脱氢关环反应过程中,无需原料的1,2位的碳碳双键,直接在本发明提供的有机酸作用下即可脱氢进而关环,从而适用的底物范围更广,实际利用价值更高。In the preparation method of a quinoline derivative provided by the present invention, by using the compound shown in formula I (phenyl azide ketone derivative) as a substrate, the intramolecular dehydrogenation ring-closing reaction is carried out under the action of an organic acid, Form quinoline ring structure compound; Simultaneously in the intramolecular dehydrogenation ring-closing reaction process provided by the present invention, do not need the 1,2 carbon-carbon double bond of raw material, can dehydrogenate directly under the action of the organic acid provided by the present invention and then Close the ring, so that the scope of applicable substrates is wider, and the actual utilization value is higher.

作为本发明所述制备方法的优选实施方式,R1选自氢、C1-C6烷基、C1-C6酰基、C1-C6烷氧基、C1-C6酯基、C1-C6羰基中的任意一种;R2选自氢、C1-C6烷基、C1-C6酰基、C1-C6烷氧基、C1-C6酯基、C1-C6羰基中的任意一种;R3选自C1-C6烷基、C1-C6烷氧基、C1-C6酯基中的任意一种。As a preferred embodiment of the preparation method of the present invention, R is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester, and C1-C6 carbonyl R2 is selected from any one of hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester, C1-C6 carbonyl; R3 is selected from C1-C6 alkane Any one of C1-C6 alkoxy group, C1-C6 ester group.

优选地,R1选自氢、甲基、乙基、丙基、异丙基、甲酰基、乙酰基、丙酰基、甲氧基、乙氧基、丙氧基、甲酸乙酯基、乙酸甲酯基、乙酸乙酯基、甲酮基、环戊酮基中的任意一种;R2选自氢、甲基、乙基、丙基、异丙基、甲酰基、乙酰基、丙酰基、甲氧基、乙氧基、丙氧基、甲酸乙酯基、乙酸甲酯基、乙酸乙酯基、甲酮基、环戊酮基中的任意一种;R3选自甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、甲酸乙酯基、乙酸甲酯基、乙酸乙酯基中的任意一种。Preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate Any one of ester group, ethyl acetate group, ketone group, cyclopentanone group; R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, Any one of methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate, ketone, cyclopentanone; R3 is selected from methyl, ethyl , propyl, isopropyl, methoxy, ethoxy, propoxy, ethyl formate, methyl acetate, ethyl acetate.

作为本发明所述制备方法的优选实施方式,所述有机酸为三氟甲磺酸、甲基磺酸、双三氟甲烷磺酰亚胺中的任意一种。As a preferred embodiment of the preparation method of the present invention, the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, and bistrifluoromethanesulfonimide.

优选地,所述有机酸为三氟甲磺酸、甲基磺酸中的任意一种;进一步优选地,所述有机酸为三氟甲磺酸。Preferably, the organic acid is any one of trifluoromethanesulfonic acid and methanesulfonic acid; more preferably, the organic acid is trifluoromethanesulfonic acid.

发明人研究发现,三氟甲磺酸、甲基磺酸、双三氟甲烷磺酰亚胺为强的质子酸,通过加入强的质子酸能够高效的发生脱氢反应,从而有利于后续关环形成喹啉环;进一步优选为三氟甲磺酸、甲基磺酸,是由于考虑到合成的喹啉类衍生物为中间体,后续需要进一步反应以合成相应的活性物质,而三氟甲磺酸酯和甲基磺酸酯是一类非常活泼的反应基团,容易离去,进而发生取代、水解等化学反应形成喹啉类活性物。The inventors have found that trifluoromethanesulfonic acid, methanesulfonic acid, and bistrifluoromethanesulfonimide are strong protonic acids, and by adding strong protonic acids, dehydrogenation reactions can occur efficiently, thereby facilitating subsequent ring closure Form a quinoline ring; further preferably trifluoromethanesulfonic acid, methanesulfonic acid, because considering that the synthetic quinoline derivatives are intermediates, subsequent reactions need to be further reacted to synthesize corresponding active substances, while trifluoromethanesulfonic acid Ester and methanesulfonate are a kind of very active reactive groups, which are easy to leave, and then undergo chemical reactions such as substitution and hydrolysis to form quinoline active substances.

作为本发明所述制备方法的优选实施方式,所述有机酸和式Ⅰ所示化合物的摩尔比为有机酸:式Ⅰ所示化合物=(1-8):1。As a preferred embodiment of the preparation method of the present invention, the molar ratio of the organic acid to the compound represented by formula I is organic acid:compound represented by formula I=(1-8):1.

优选地,当选择的有机酸为三氟甲磺酸时,所述有机酸和式Ⅰ所示化合物的摩尔比为有机酸:式Ⅰ所示化合物=3:1;当选择的有机酸为甲基磺酸时,所述有机酸和式Ⅰ所示化合物的摩尔比为有机酸:式Ⅰ所示化合物=(5-8):1。Preferably, when the selected organic acid is trifluoromethanesulfonic acid, the molar ratio of the organic acid to the compound shown in formula I is organic acid:compound shown in formula I=3:1; when the selected organic acid is formic acid When sulfonic acid is used, the molar ratio of the organic acid to the compound shown in formula I is organic acid:compound shown in formula I=(5-8):1.

发明人研究发现,当进一步根据有机酸的选择控制有机酸和式Ⅰ所示化合物的摩尔比在上述点值或小范围值时,得到的产品的收率更好,在60%以上,甚至可以达到90%。The inventors have found that when the molar ratio of the organic acid to the compound shown in Formula I is further controlled at the above-mentioned point value or a small range of values according to the selection of the organic acid, the yield of the product obtained is better, more than 60%, and can even be up to 90%.

作为本发明所述制备方法的优选实施方式,所述有机溶剂为甲苯、乙腈、氯仿、二氯甲烷、二氯乙烷中的至少一种。As a preferred embodiment of the preparation method of the present invention, the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane.

作为本发明所述制备方法的优选实施方式,所述式Ⅰ所示化合物与有机溶剂的质量体积比为(0.01~0.1)g:1mL。As a preferred embodiment of the preparation method of the present invention, the mass volume ratio of the compound represented by formula I to the organic solvent is (0.01-0.1) g: 1 mL.

作为本发明所述制备方法的优选实施方式,所述脱氢关环反应的温度为(-40)~25℃。As a preferred embodiment of the preparation method of the present invention, the temperature of the dehydrogenation and ring-closing reaction is (-40) to 25°C.

优选地,所述脱氢关环反应的温度为(-20)~25℃。Preferably, the temperature of the dehydrogenation ring-closing reaction is (-20)-25°C.

发明人研究发现,当进一步优选温度为(-20)~25℃时,得到的产品的收率更高且反应条件相对简单,对设备要求低。The inventors have found that when the temperature is further preferably (-20) to 25°C, the yield of the product obtained is higher, the reaction conditions are relatively simple, and the requirements for equipment are low.

作为本发明所述制备方法的优选实施方式,所述脱氢关环反应的时间为6-18h;在实际的实验中,通过TLC点板来确定反应的终点。As a preferred embodiment of the preparation method of the present invention, the time for the dehydrogenation and ring-closing reaction is 6-18 hours; in actual experiments, the end point of the reaction is determined by TLC spotting.

作为本发明所述制备方法的优选实施方式,所述惰性气体为氮气或稀有气体中的任意一种。As a preferred embodiment of the preparation method of the present invention, the inert gas is any one of nitrogen or rare gas.

作为本发明所述制备方法的优选实施方式,在反应结束后还包括后处理步骤,所述后处理步骤包括加入饱和碳酸氢钠水溶液淬灭后用乙酸乙酯萃取、洗涤后收集有机相,接着浓缩有机相后柱层析。As a preferred embodiment of the preparation method of the present invention, after the reaction is completed, a post-processing step is also included, and the post-processing step includes adding a saturated aqueous sodium bicarbonate solution to quench, extracting with ethyl acetate, and collecting the organic phase after washing, then Concentrate the organic phase and perform column chromatography.

优选地,所述洗涤为依次采用水、饱和食盐水洗涤。Preferably, the washing is sequentially washing with water and saturated brine.

优选地,所述柱层析使用的硅胶目数为200-300目,洗脱剂为石油醚和乙酸乙酯,且每100mL洗脱剂中加入2mL的三乙胺。Preferably, the silica gel mesh used in the column chromatography is 200-300 mesh, the eluent is petroleum ether and ethyl acetate, and 2 mL of triethylamine is added to every 100 mL of the eluent.

另外,本发明还提供了一种喹啉衍生物,采用本发明所述的制备方法制备而成。In addition, the present invention also provides a quinoline derivative prepared by the preparation method described in the present invention.

本发明提供的一种喹啉衍生物可用于合成多种喹啉类活性化合物或含本发明喹啉类衍生物的天然产物,比如拓扑替康(Topotecan,式C)、RORgt modulator(式B)等;A quinoline derivative provided by the invention can be used to synthesize various quinoline active compounds or natural products containing the quinoline derivative of the present invention, such as topotecan (Topotecan, formula C), RORgt modulator (formula B) wait;

Figure BDA0004106912180000041
Figure BDA0004106912180000041

与现有技术相比,本发明的有益效果为:Compared with prior art, the beneficial effect of the present invention is:

本发明提供的一种喹啉衍生物的制备方法中通过以式Ⅰ所示化合物(苯基叠氮酮类衍生物)为底物,在有机酸作用下进行分子内的脱氢关环反应,形成喹啉环结构化合物;同时本发明提供的分子内脱氢关环反应过程中,无需原料的1,2位的碳碳双键,直接在本发明提供的有机酸作用下即可脱氢进而关环,从而适用的底物范围更广,实际利用价值更高。另外,本发明提供的制备方法操作简单、设备要求低、收率高,利于实际应用,具体的,得到的产品的收率可达90%、纯度也在95%以上。In the preparation method of a quinoline derivative provided by the present invention, by using the compound shown in formula I (phenyl azide ketone derivative) as a substrate, the intramolecular dehydrogenation ring-closing reaction is carried out under the action of an organic acid, Form quinoline ring structure compound; Simultaneously in the intramolecular dehydrogenation ring-closing reaction process provided by the present invention, do not need the 1,2 carbon-carbon double bond of raw material, can dehydrogenate directly under the action of the organic acid provided by the present invention and then Close the ring, so that the scope of applicable substrates is wider, and the actual utilization value is higher. In addition, the preparation method provided by the invention is simple in operation, low in equipment requirements, and high in yield, which is beneficial to practical application. Specifically, the yield of the obtained product can reach 90%, and the purity is also above 95%.

具体实施方式Detailed ways

为更好的说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific examples.

本发明所采用的试剂、方法和设备,如无特殊说明,均为本领域常规试剂、方法和设备。The reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art unless otherwise specified.

实施例1Example 1

本发明实施例提供一种喹啉衍生物T-1,其结构如式T-1所示,The embodiment of the present invention provides a quinoline derivative T-1, the structure of which is shown in formula T-1,

Figure BDA0004106912180000051
Figure BDA0004106912180000051

所述喹啉衍生物T-1的制备方法包括如下步骤:The preparation method of described quinoline derivative T-1 comprises the steps:

合成路线如下:The synthetic route is as follows:

Figure BDA0004106912180000052
Figure BDA0004106912180000052

具体地,specifically,

(1)S-2的合成(1) Synthesis of S-2

在100mL干燥圆底烧瓶中加入S-1(3.278g,21.98mmol),在氮气氛围下加入65mL二氯甲烷搅拌溶解,在冰浴下缓慢滴入二氯亚砜(2.4mL,32.97mmol)搅拌反应6h,TLC检测原料反应完全。减压蒸馏除去多余的二氯亚砜和溶剂,得到黄色油状液体。用60mL丙酮溶解后加入碘化钠(6.600g,44.00mmol),搅拌反应10h。加入60mL水搅拌,有大量固体析出,过滤出固体即可得到产物S-2(3.80g,14.67mmol),两步反应的总产率为67%;Add S-1 (3.278g, 21.98mmol) into a dry 100mL round-bottom flask, add 65mL dichloromethane under nitrogen atmosphere and stir to dissolve, slowly add thionyl chloride (2.4mL, 32.97mmol) dropwise under ice bath and stir After 6 hours of reaction, TLC detected that the reaction of the raw materials was complete. Excess thionyl chloride and solvent were distilled off under reduced pressure to obtain a yellow oily liquid. After dissolving with 60 mL of acetone, sodium iodide (6.600 g, 44.00 mmol) was added, and the reaction was stirred for 10 h. After adding 60 mL of water and stirring, a large amount of solids precipitated, and the solids were filtered to obtain the product S-2 (3.80 g, 14.67 mmol). The total yield of the two-step reaction was 67%;

S-2的表征:1H NMR(500MHz,Chloroform-d)δ7.55(dd,J=8.0,1.3Hz,1H),7.46(dd,J=7.6,1.7Hz,1H),7.28(td,J=7.5,1.2Hz,1H),7.14(td,J=7.7,1.7Hz,1H),4.57(s,2H);Characterization of S-2: 1H NMR (500MHz, Chloroform-d) δ7.55 (dd, J = 8.0, 1.3Hz, 1H), 7.46 (dd, J = 7.6, 1.7Hz, 1H), 7.28 (td, J =7.5,1.2Hz,1H),7.14(td,J=7.7,1.7Hz,1H),4.57(s,2H);

13C NMR(126MHz,Chloroform-d)δ138.2,130.7,130.3,129.5,125.1,118.7,0.3。13C NMR (126 MHz, Chloroform-d) δ 138.2, 130.7, 130.3, 129.5, 125.1, 118.7, 0.3.

(2)S-6的合成(2) Synthesis of S-6

在100mL干燥圆底烧瓶中依次加入S-5(1.261g,10.00mmol),S-2(2.590g,10.00mmol),碳酸钾(2.764g,20.00mmol)和50mL四氢呋喃搅拌反应8小时。TLC检测反应完全,50mL水淬灭反应。乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤有机相1次,合并有机相,无水硫酸钠干燥有机相。减压蒸馏浓缩,经过柱层析(200-300目硅胶,石油醚和乙酸乙酯作为洗脱剂)纯化得到化合物S-6,黄色油状液体,2.187g,产率为85%。S-5 (1.261g, 10.00mmol), S-2 (2.590g, 10.00mmol), potassium carbonate (2.764g, 20.00mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, purified by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain compound S-6, yellow oily liquid, 2.187 g, yield 85%.

S-5的表征:1H NMR(500MHz,Chloroform-d)δ7.33-7.25(m,1H),7.14(ddd,J=8.0,2.5,1.2Hz,1H),7.10-7.00(m,2H),3.26(dd,J=14.1,2.1Hz,1H),3.12(dd,J=14.1,2.5Hz,1H),2.53(ddt,J=11.7,5.7,1.8Hz,1H),2.37-2.26(m,4H),2.15-2.04(m,1H),1.83-1.64(m,3H);Characterization of S-5: 1H NMR (500MHz, Chloroform-d) δ7.33-7.25 (m, 1H), 7.14 (ddd, J=8.0, 2.5, 1.2Hz, 1H), 7.10-7.00 (m, 2H) ,3.26(dd,J=14.1,2.1Hz,1H),3.12(dd,J=14.1,2.5Hz,1H),2.53(ddt,J=11.7,5.7,1.8Hz,1H),2.37-2.26(m ,4H),2.15-2.04(m,1H),1.83-1.64(m,3H);

13C NMR(126MHz,Chloroform-d)δ216.11,204.12,138.90,131.37,128.47,128.23,124.88,118.15,77.05,69.47,38.57,33.91,30.12,26.39,19.42。13C NMR (126MHz, Chloroform-d) δ216.11, 204.12, 138.90, 131.37, 128.47, 128.23, 124.88, 118.15, 77.05, 69.47, 38.57, 33.91, 30.12, 26.39, 19.42.

(3)T-1的合成(3) Synthesis of T-1

在15mL干燥的反应管中加入化合物S-6(0.257g,1.00mmol),在N2氛围下加入5mLDCM(二氯甲烷),将反应体系降温至0℃,缓慢滴入甲基磺酸(0.577g,6.00mmol),在0℃下继续搅拌30分钟。反应6h后,TLC监测原料反应完全,0℃加入5mL饱和碳酸氢钠水溶液搅拌10分钟淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-1,收率为68%,化合物在空气中的颜色为紫黑色。Add compound S-6 (0.257g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM (dichloromethane) under N 2 atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 30 minutes. After reacting for 6 hours, TLC monitored the completion of the reaction of the raw materials, and quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-1 with a yield of 68%, and the color of the compound in air was purple-black.

T-1的表征:1H NMR(500MHz,Chloroform-d)δ7.35(d,J=8.4Hz,1H),7.16(ddd,J=8.5,2.7,1.0Hz,1H),7.09(dd,J=2.9,1.2Hz,1H),3.16(s,3H),2.98(dd,J=16.1,1.2Hz,1H),2.59(d,J=16.1Hz,1H),2.53-2.41(m,2H),2.12(s,3H),2.08-2.05(m,1H),2.01-1.89(m,2H),1.90-1.77(m,1H);Characterization of T-1: 1H NMR (500MHz, Chloroform-d) δ7.35 (d, J = 8.4Hz, 1H), 7.16 (ddd, J = 8.5, 2.7, 1.0Hz, 1H), 7.09 (dd, J =2.9,1.2Hz,1H),3.16(s,3H),2.98(dd,J=16.1,1.2Hz,1H),2.59(d,J=16.1Hz,1H),2.53-2.41(m,2H) ,2.12(s,3H),2.08-2.05(m,1H),2.01-1.89(m,2H),1.90-1.77(m,1H);

13C NMR(126MHz,Chloroform-d)δ171.20,170.20,147.23,141.96,127.43,126.75,121.71,121.07,53.22,39.19,37.45,32.51,30.99,23.65,19.18,19.31。13C NMR (126MHz, Chloroform-d) δ171.20, 170.20, 147.23, 141.96, 127.43, 126.75, 121.71, 121.07, 53.22, 39.19, 37.45, 32.51, 30.99, 23.65, 19.18, 19.3 1.

实施例2Example 2

本发明实施例提供一种喹啉衍生物T-2,The embodiment of the present invention provides a quinoline derivative T-2,

Figure BDA0004106912180000071
Figure BDA0004106912180000071

其与实施例1的唯一差别在于步骤(3)的合成中,本实施例T-2的合成步骤(3)为:在15mL干燥的反应管中加入化合物S-6(0.257g,1.00mmol),在N2氛围下加入5mL DCM(二氯甲烷),将反应体系降温至0℃,缓慢滴入三氟甲磺酸(0.300g,2.00mmol),在0℃下继续搅拌30分钟。反应8h后,TLC监测原料反应完全,0℃加入5mL饱和碳酸氢钠水溶液搅拌10分钟淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-1,收率为70%。The only difference between it and Example 1 is that in the synthesis of step (3), the synthesis step (3) of T-2 in this example is: add compound S-6 (0.257g, 1.00mmol) to a 15mL dry reaction tube , added 5 mL of DCM (dichloromethane) under N 2 atmosphere, cooled the reaction system to 0°C, slowly added trifluoromethanesulfonic acid (0.300g, 2.00mmol) dropwise, and continued to stir at 0°C for 30 minutes. After reacting for 8 hours, TLC monitored the complete reaction of the raw materials, and then quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-1 with a yield of 70%.

实施例3Example 3

本发明实施例在实施例1-2的基础上探究反应过程中的原料的摩尔比、反应温度、有机溶剂的选择对以S-6为原料合成喹啉类衍生物的影响;In the embodiment of the present invention, on the basis of Example 1-2, the molar ratio of raw materials in the reaction process, the reaction temperature, and the selection of organic solvents have an impact on the synthesis of quinoline derivatives using S-6 as a raw material;

1、在实施例1的基础上进行探究,除表1中的给出的条件的差异外,其余与实施例1中步骤(3)完全一致;1. Explore on the basis of Example 1, except for the difference in the conditions given in Table 1, all the other are completely consistent with step (3) in Example 1;

表1Table 1

Figure BDA0004106912180000072
Figure BDA0004106912180000072

Figure BDA0004106912180000081
Figure BDA0004106912180000081

2、在实施例2的基础上进行探究,除表2中的给出的条件的差异外,其余与实施例2中步骤(3)完全一致;2, explore on the basis of embodiment 2, except the difference of the condition that provides in table 2, all the other are completely consistent with step (3) in embodiment 2;

表2Table 2

Figure BDA0004106912180000082
Figure BDA0004106912180000082

从表1-2中序号5和序号18、序号8与序号21、序号9与序号22中可以看出,即使是反应过程中的反应温度、有机溶剂和反应物摩尔比都一样时,有机酸的差异也会对产品的收率带来明显影响;另外,分别从表1和表2中可以看出,当有机酸固定时,反应过程中的反应温度、有机溶剂和反应物摩尔比也会对收率带来明显影响;当以甲基磺酸为有机酸时,随着甲基磺酸与S-6的摩尔比逐渐增加,收率先增加后几乎维持不变,当两者的摩尔比为(2-8):1时,得到的收率在44-69%之间;当以三氟甲磺酸为有机酸时,随着三氟甲磺酸与S-6的摩尔比逐渐增加,收率先增加后显著降低,当优选两者的摩尔比为(2-3):1时,得到的收率在70-86%之间,另外,随着反应温度的逐渐增加,收率也呈现出现增加后降低的趋势,进一步优选为反应温度为(-20)~25℃时,得到的收率在75-90%之间。From No. 5 and No. 18 in Table 1-2, No. 8 and No. 21, No. 9 and No. 22, it can be seen that even if the reaction temperature, organic solvent and reactant molar ratio in the reaction process are the same, the organic acid The difference will also have a significant impact on the yield of the product; in addition, as can be seen from Table 1 and Table 2, when the organic acid is fixed, the reaction temperature, organic solvent and reactant molar ratio in the reaction process will also Bring obvious influence to yield; When using methanesulfonic acid as organic acid, along with the mol ratio of methanesulfonic acid and S-6 increases gradually, yield increases first and then almost remains unchanged, when the molar ratio of the two When being (2-8): 1, the yield that obtains is between 44-69%; When using trifluoromethanesulfonic acid as organic acid, along with the mol ratio of trifluoromethanesulfonic acid and S-6 increases gradually , the yield first increases and then significantly decreases. When the preferred molar ratio of the two is (2-3): 1, the yield obtained is between 70-86%. In addition, as the reaction temperature increases gradually, the yield also increases. It shows a trend of increasing and then decreasing, and it is more preferable that the yield is between 75-90% when the reaction temperature is (-20)-25°C.

实施例4Example 4

本发明实施例提供一种喹啉衍生物T-3,其结构如式T-3所示,The embodiment of the present invention provides a quinoline derivative T-3, the structure of which is shown in formula T-3,

Figure BDA0004106912180000091
Figure BDA0004106912180000091

所述喹啉衍生物T-3的制备方法包括如下步骤:The preparation method of described quinoline derivative T-3 comprises the steps:

合成路线如下:The synthetic route is as follows:

Figure BDA0004106912180000092
Figure BDA0004106912180000092

具体地,specifically,

(1)S-2的合成同实施例1中一致(1) The synthesis of S-2 is consistent with that in Example 1

(2)S-4的合成(2) Synthesis of S-4

在100mL干燥圆底烧瓶中依次加入S-2(3.80g,14.67mmol),S3(2.06g,14.67mmol),碳酸钾(4.055g,29.34mmol)和50mL四氢呋喃搅拌反应8小时。TLC检测反应完全,50mL水淬灭反应。乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤有机相1次,合并有机相,无水硫酸钠干燥有机相。减压蒸馏浓缩,经过柱层析(200-300目硅胶,石油醚和乙酸乙酯作为洗脱剂)纯化得到化合物S-4 2.963g。S-2 (3.80g, 14.67mmol), S3 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. It was concentrated by distillation under reduced pressure, and purified by column chromatography (200-300 mesh silica gel, petroleum ether and ethyl acetate as eluent) to obtain 2.963 g of compound S-4.

S-4的表征:1H NMR(500MHz,Chloroform-d)δ7.40–7.25(m,1H),7.16(dd,J=8.1,1.2Hz,1H),7.13(dd,J=7.6,1.6Hz,1H),7.04(td,J=7.5,1.2Hz,1H),3.08(s,2H),2.88(p,J=6.5Hz,1H),2.37(ddd,J=18.8,8.7,6.3Hz,2H),2.16(ddd,J=18.8,9.3,7.0Hz,2H),2.05(ddt,J=13.5,9.3,6.7Hz,2H),1.85–1.57(m,2H);Characterization of S-4: 1H NMR (500MHz, Chloroform-d) δ7.40–7.25 (m, 1H), 7.16 (dd, J = 8.1, 1.2Hz, 1H), 7.13 (dd, J = 7.6, 1.6Hz ,1H),7.04(td,J=7.5,1.2Hz,1H),3.08(s,2H),2.88(p,J=6.5Hz,1H),2.37(ddd,J=18.8,8.7,6.3Hz, 2H), 2.16(ddd, J=18.8, 9.3, 7.0Hz, 2H), 2.05(ddt, J=13.5, 9.3, 6.7Hz, 2H), 1.85–1.57(m, 2H);

13C NMR(126MHz,Chloroform-d)δ211.9,138.7,131.9,128.6,128.2,125.1,118.0,70.8,42.6,37.3,33.2,24.6。13C NMR (126MHz, Chloroform-d) δ 211.9, 138.7, 131.9, 128.6, 128.2, 125.1, 118.0, 70.8, 42.6, 37.3, 33.2, 24.6.

(3)T-3的合成(3) Synthesis of T-3

在15mL干燥的反应管中加入化合物S-4(0.085g,1.00mmol),在N2氛围下加入2mLDCM(二氯甲烷),将反应体系降温至0℃,缓慢滴入甲基磺酸(0.577g,6.00mmol),在0℃下继续搅拌15分钟。反应6h后,TLC监测原料反应完全,0℃加入5mL饱和碳酸氢钠水溶液搅拌10分钟淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-3,收率为55%,化合物在空气中的颜色为紫黑色。Add compound S-4 (0.085g, 1.00mmol) into a 15mL dry reaction tube, add 2mL DCM (dichloromethane) under N 2 atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 15 minutes. After reacting for 6 hours, TLC monitored the completion of the reaction of the raw materials, and quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-3 with a yield of 55%, and the color of the compound in air was purple-black.

T-3的表征:1H NMR(500MHz,Chloroform-d)δ7.38(d,J=8.4Hz,1H),7.15(dd,J=2.7,0.9Hz,0H),7.04(d,1H),3.14(s,3H),2.94(t,2H),2.78-2.60(m,3H),2.60-2.51(m,1H),2.49-2.37(m,1H),2.04-1.95(m,1H),1.71-1.53(m,1H)。Characterization of T-3: 1H NMR (500MHz, Chloroform-d) δ7.38(d, J=8.4Hz, 1H), 7.15(dd, J=2.7, 0.9Hz, 0H), 7.04(d, 1H), 3.14(s,3H),2.94(t,2H),2.78-2.60(m,3H),2.60-2.51(m,1H),2.49-2.37(m,1H),2.04-1.95(m,1H), 1.71-1.53 (m, 1H).

实施例5Example 5

本发明实施例提供一种喹啉衍生物T-4,其结构如式T-4所示,The embodiment of the present invention provides a quinoline derivative T-4, the structure of which is shown in formula T-4,

Figure BDA0004106912180000101
Figure BDA0004106912180000101

所述喹啉衍生物T-4的制备方法包括如下步骤:The preparation method of described quinoline derivative T-4 comprises the steps:

合成路线如下:The synthetic route is as follows:

Figure BDA0004106912180000102
Figure BDA0004106912180000102

具体地,specifically,

(1)S-2的合成同实施例1中一致(1) The synthesis of S-2 is consistent with that in Example 1

(2)S-8的合成(2) Synthesis of S-8

在100mL干燥圆底烧瓶中依次加入S-7(1.141g,10mmol),S-2(2.590g,10mmol),碳酸钾(2.764g,15mmol)和50mL四氢呋喃搅拌反应8小时。TLC检测反应完全,50mL水淬灭反应。乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤有机相1次,合并有机相,无水硫酸钠干燥有机相。减压蒸馏浓缩,经过柱层析纯化得到化合物S-8 1.594g,产率为65%。S-7 (1.141g, 10mmol), S-2 (2.590g, 10mmol), potassium carbonate (2.764g, 15mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 1.594 g of compound S-8 with a yield of 65%.

S-8的表征:1H NMR(500MHz,Chloroform-d)δ7.28(ddd,J=9.4,4.9,2.1Hz,1H),7.13(dt,J=8.0,1.7Hz,1H),7.06(dtt,J=16.6,7.4,1.9Hz,2H),3.34-3.12(m,2H),2.18(p,J=3.9,3.0Hz,6H),1.34-1.18(m,3H);Characterization of S-8: 1H NMR (500MHz, Chloroform-d) δ7.28 (ddd, J = 9.4, 4.9, 2.1Hz, 1H), 7.13 (dt, J = 8.0, 1.7Hz, 1H), 7.06 (dtt ,J=16.6,7.4,1.9Hz,2H),3.34-3.12(m,2H),2.18(p,J=3.9,3.0Hz,6H),1.34-1.18(m,3H);

13C NMR(126MHz,Chloroform-d)δ207.02,207.00,138.91,132.12,128.37,128.27,124.68,118.17,67.19,67.17,33.70,27.11,17.70。13C NMR (126MHz, Chloroform-d) δ207.02, 207.00, 138.91, 132.12, 128.37, 128.27, 124.68, 118.17, 67.19, 67.17, 33.70, 27.11, 17.70.

(3)T-4的合成(3) Synthesis of T-4

在15mL干燥的反应管中加入化合物S-8(0.245g,1.00mmol),在N2氛围下加入5mLDCM(二氯甲烷),将反应体系降温至0℃,缓慢滴入甲基磺酸(0.577g,6.00mmol),在0℃下继续搅拌15分钟。反应8h后,TLC监测原料反应完全,0℃加入5mL饱和碳酸氢钠水溶液搅拌10分钟淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-4,收率为23%,化合物在空气中的颜色为紫黑色。Add compound S-8 (0.245g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM (dichloromethane) under N 2 atmosphere, cool the reaction system to 0°C, slowly add methanesulfonic acid (0.577 g, 6.00 mmol), stirring was continued at 0°C for 15 minutes. After reacting for 8 hours, TLC monitored the complete reaction of the raw materials, and then quenched the reaction by adding 5 mL of saturated aqueous sodium bicarbonate solution at 0°C and stirring for 10 minutes. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) and purified to obtain compound T-4 with a yield of 23%, and the color of the compound in air was purple-black.

T-4的表征:1H NMR(500MHz,Chloroform-d)δ6.83(d,J=8.0Hz,1H),6.15(dd,J=8.1,2.4Hz,1H),6.01(d,J=2.5Hz,1H),3.11(d,J=7.5Hz,2H),2.19(s,2H),1.17(s,3H),1.09(s,3H),1.05(s,3H)。Characterization of T-4: 1H NMR (500MHz, Chloroform-d) δ6.83(d, J=8.0Hz, 1H), 6.15(dd, J=8.1, 2.4Hz, 1H), 6.01(d, J=2.5 Hz, 1H), 3.11(d, J=7.5Hz, 2H), 2.19(s, 2H), 1.17(s, 3H), 1.09(s, 3H), 1.05(s, 3H).

实施例6Example 6

本发明实施例提供一种喹啉衍生物T-5,其结构如式T-5所示,The embodiment of the present invention provides a quinoline derivative T-5, the structure of which is shown in the formula T-5,

Figure BDA0004106912180000121
Figure BDA0004106912180000121

所述喹啉衍生物T-5的制备方法包括如下步骤:The preparation method of described quinoline derivative T-5 comprises the steps:

合成路线如下:The synthetic route is as follows:

Figure BDA0004106912180000122
Figure BDA0004106912180000122

具体地,specifically,

(1)S-2的合成同实施例1中一致(1) The synthesis of S-2 is consistent with that in Example 1

(2)S-10的合成(2) Synthesis of S-10

在100mL干燥圆底烧瓶中依次加入S-2(3.80g,14.67mmol),S9(2.06g,14.67mmol),碳酸钾(4.055g,29.34mmol)和50mL四氢呋喃搅拌反应8小时。TLC检测反应完全,50mL水淬灭反应。乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤有机相1次,合并有机相,无水硫酸钠干燥有机相。减压蒸馏浓缩,经过柱层析纯化得到化合物S-1012.625g,产率为69%。S-2 (3.80g, 14.67mmol), S9 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 2.625 g of compound S-1010, with a yield of 69%.

S-10的表征:1H NMR(500MHz,Chloroform-d)δ7.32-7.23(m,1H),7.12(ddd,J=8.3,7.3,1.5Hz,2H),7.03(tt,J=7.5,1.2Hz,1H),4.09(t,J=7.3Hz,1H),3.08(dd,J=7.4,1.3Hz,2H),2.64-2.42(m,2H),2.43-2.27(m,2H),0.98(td,J=7.2,1.2Hz,5H);Characterization of S-10: 1H NMR (500MHz, Chloroform-d) δ7.32-7.23 (m, 1H), 7.12 (ddd, J = 8.3, 7.3, 1.5Hz, 2H), 7.03 (tt, J = 7.5, 1.2Hz, 1H), 4.09(t, J=7.3Hz, 1H), 3.08(dd, J=7.4, 1.3Hz, 2H), 2.64-2.42(m, 2H), 2.43-2.27(m, 2H), 0.98(td,J=7.2,1.2Hz,5H);

13C NMR(126MHz,Chloroform-d)δ206.2,138.0,131.5,129.5,128.3,118.1,65.9,36.2,30.2,7.5。13C NMR (126 MHz, Chloroform-d) δ 206.2, 138.0, 131.5, 129.5, 128.3, 118.1, 65.9, 36.2, 30.2, 7.5.

(3)T-5的合成(3) Synthesis of T-5

在15mL干燥的反应管中加入S-10(0.259g,1.00mmol),在N2氛围下加入5mL DCM,降温至0℃,缓慢滴入TfOH(0.450g,3.00mmol),在0℃继续搅拌15min。反应10h后,TLC监测反应完全,加入5mL饱和碳酸氢钠淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-5 0.184g,产率为51%。Add S-10 (0.259g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under N2 atmosphere, cool down to 0°C, slowly drop TfOH (0.450g, 3.00mmol), and continue stirring at 0°C 15min. After 10 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.184 g of compound T-5 with a yield of 51%.

T-5的表征:1H NMR(500MHz,Chloroform-d)δ8.36(s,1H),8.18(d,J=9.2Hz,1H),7.80(d,J=2.7Hz,1H),7.67(dd,J=9.2,2.8Hz,1H),3.19(q,J=7.5Hz,2H),3.06(q,J=7.2Hz,2H),1.37(t,J=7.5Hz,3H),1.30(t,J=7.2Hz,3H);Characterization of T-5: 1H NMR (500MHz, Chloroform-d) δ8.36(s, 1H), 8.18(d, J=9.2Hz, 1H), 7.80(d, J=2.7Hz, 1H), 7.67( dd, J=9.2, 2.8Hz, 1H), 3.19(q, J=7.5Hz, 2H), 3.06(q, J=7.2Hz, 2H), 1.37(t, J=7.5Hz, 3H), 1.30( t,J=7.2Hz,3H);

13C NMR(126MHz,Chloroform-d)δ203.7,163.3,147.0,146.8,135.9,133.5,131.7,125.6,124.6,120.0,119.5,117.5,35.5,30.5,21.6,13.7,8.3;13C NMR (126MHz, Chloroform-d) δ203.7, 163.3, 147.0, 146.8, 135.9, 133.5, 131.7, 125.6, 124.6, 120.0, 119.5, 117.5, 35.5, 30.5, 21.6, 13.7, 8.3;

19F NMR(471MHz,Chloroform-d)δ-72.61。19F NMR (471 MHz, Chloroform-d) δ-72.61.

实施例7Example 7

本发明实施例提供一种喹啉衍生物T-6,其结构如式T-6所示,The embodiment of the present invention provides a quinoline derivative T-6, the structure of which is shown in formula T-6,

Figure BDA0004106912180000131
Figure BDA0004106912180000131

所述喹啉衍生物T-6的制备方法和实施例6的唯一差别在于步骤(3)的不同,本发明实施例步骤(3)为T-6的合成:The only difference between the preparation method of the quinoline derivative T-6 and Example 6 is the difference in step (3), the step (3) of the embodiment of the present invention is the synthesis of T-6:

在15mL干燥的反应管中加入化合物S-10(0.259g,1.00mmol),在N2氛围下加入5mLDCM,降温至0℃,缓慢滴入MsOH(0.577g,6.00mmol),在0℃继续搅拌15min。反应10h后,TLC监测反应完全,加入5mL饱和碳酸氢钠淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-6 0.080g,产率为26%。Add compound S-10 (0.259g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under N2 atmosphere, cool down to 0°C, slowly drop MsOH (0.577g, 6.00mmol), and continue stirring at 0°C 15min. After 10 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added to every 100 mL of eluent) to obtain 0.080 g of compound T-6 with a yield of 26%.

T-6的表征:1H NMR(500MHz,Chloroform-d)δ8.35(s,1H),8.15(d,J=9.1Hz,1H),7.82(d,J=2.7Hz,1H),7.68(dd,J=9.1,2.6Hz,1H),3.25(s,3H),3.19(q,J=7.5Hz,3H),3.06(q,J=7.2Hz,3H),1.37(t,J=7.5Hz,3H),1.29(t,J=7.3Hz,3H)。Characterization of T-6: 1H NMR (500MHz, Chloroform-d) δ8.35(s, 1H), 8.15(d, J=9.1Hz, 1H), 7.82(d, J=2.7Hz, 1H), 7.68( dd, J=9.1, 2.6Hz, 1H), 3.25(s, 3H), 3.19(q, J=7.5Hz, 3H), 3.06(q, J=7.2Hz, 3H), 1.37(t, J=7.5 Hz, 3H), 1.29 (t, J = 7.3Hz, 3H).

实施例8Example 8

本发明实施例提供一种喹啉衍生物T-7,其结构如式T-7所示,The embodiment of the present invention provides a quinoline derivative T-7, the structure of which is shown in the formula T-7,

Figure BDA0004106912180000141
Figure BDA0004106912180000141

所述喹啉衍生物T-7的制备方法包括如下步骤:The preparation method of described quinoline derivative T-7 comprises the steps:

合成路线如下:The synthetic route is as follows:

Figure BDA0004106912180000142
Figure BDA0004106912180000142

具体地,specifically,

(1)S-2的合成同实施例1中一致(1) The synthesis of S-2 is consistent with that in Example 1

(2)S-12的合成(2) Synthesis of S-12

在100mL干燥圆底烧瓶中依次加入S-2(3.80g,14.67mmol),S-11(2.06g,14.67mmol),碳酸钾(4.055g,29.34mmol)和50mL四氢呋喃搅拌反应8小时。TLC检测反应完全,50mL水淬灭反应。乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤有机相1次,合并有机相,无水硫酸钠干燥有机相。减压蒸馏浓缩,经过柱层析纯化得到化合物S-122.951g,产率为77%。S-2 (3.80g, 14.67mmol), S-11 (2.06g, 14.67mmol), potassium carbonate (4.055g, 29.34mmol) and 50mL tetrahydrofuran were successively added into a 100mL dry round bottom flask and stirred for 8 hours. TLC detected that the reaction was complete, and 50 mL of water quenched the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 2.951 g of compound S-12 with a yield of 77%.

(3)T-7的合成(3) Synthesis of T-7

在15mL干燥的反应管中加入化合物S-12(0.261g,1.00mmol),在N2氛围下加入5.0mL DCM,降温至0℃,缓慢滴入TfOH(0.450g,3.00mmol),在0℃继续搅拌15min。反应12h后,TLC监测反应完全,加入5mL饱和碳酸氢钠淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-7 0.185g,产率为51%。Compound S-12 (0.261g, 1.00mmol) was added to a 15mL dry reaction tube, 5.0mL DCM was added under N2 atmosphere, the temperature was lowered to 0°C, TfOH (0.450g, 3.00mmol) was slowly added dropwise, and at 0°C Stirring was continued for 15 min. After 12 h of reaction, TLC monitored the completion of the reaction, and 5 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.185 g of compound T-7 with a yield of 51%.

T-7的表征:1H NMR(500MHz,Chloroform-d)δ8.80(s,1H),8.29-8.11(m,1H),7.84(d,J=2.7Hz,1H),7.69(dd,J=9.3,2.7Hz,1H),4.49(d,J=7.1Hz,2H),3.05(s,3H),1.49(s,1H);Characterization of T-7: 1H NMR (500MHz, Chloroform-d) δ8.80(s, 1H), 8.29-8.11(m, 1H), 7.84(d, J=2.7Hz, 1H), 7.69(dd, J =9.3,2.7Hz,1H),4.49(d,J=7.1Hz,2H),3.05(s,3H),1.49(s,1H);

19F NMR(471MHz,Chloroform-d)δ-72.80。19F NMR (471 MHz, Chloroform-d) δ-72.80.

实施例9Example 9

本发明实施例提供一种喹啉衍生物T-8,其结构如式T-8所示,The embodiment of the present invention provides a quinoline derivative T-8, the structure of which is shown in formula T-8,

Figure BDA0004106912180000151
Figure BDA0004106912180000151

所述喹啉衍生物T-8的制备方法和实施例8的唯一差别在于步骤(3)的不同,本发明实施例步骤(3)为T-8的合成:The only difference between the preparation method of the quinoline derivative T-8 and Example 8 is the difference in step (3), the step (3) of the embodiment of the present invention is the synthesis of T-8:

在15mL干燥的反应管中加入化合物S-12(0.261g,1.00mmol),在N2氛围下加入5mLDCM,降温至0℃,缓慢滴入MsOH(0.577g,6.00mmol),在0℃继续搅拌15min。反应14h后,TLC监测反应完全,加入1mL饱和碳酸氢钠淬灭反应。用乙酸乙酯萃取混合体系,用水洗涤有机相2次,饱和食盐水洗涤1次。合并有机相,用无水硫酸钠干燥有机相,经过减压蒸馏、柱层析(固定相为三乙胺预处理过的200-300目硅胶,洗脱剂为石油醚和乙酸乙酯。且每100mL洗脱剂中加入2mL的三乙胺)纯化得到化合物T-8 0.109g,产率为35%。Add compound S-12 (0.261g, 1.00mmol) into a 15mL dry reaction tube, add 5mL DCM under N2 atmosphere, cool down to 0°C, slowly drop MsOH (0.577g, 6.00mmol), and continue stirring at 0°C 15min. After 14 h of reaction, TLC monitored the completion of the reaction, and 1 mL of saturated sodium bicarbonate was added to quench the reaction. The mixed system was extracted with ethyl acetate, the organic phase was washed twice with water and once with saturated brine. The organic phases were combined, dried with anhydrous sodium sulfate, subjected to vacuum distillation, and column chromatography (the stationary phase was 200-300 mesh silica gel pretreated with triethylamine, and the eluent was petroleum ether and ethyl acetate. 2 mL of triethylamine was added per 100 mL of eluent) to obtain 0.109 g of compound T-8 with a yield of 35%.

T-8的表征:1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.16(d,J=9.2Hz,1H),7.85(d,J=2.7Hz,1H),7.70(dd,J=9.1,2.7Hz,1H),4.47(q,J=7.1Hz,2H),3.26(s,3H),3.03(s,3H),1.48(t,J=7.2Hz,3H)。Characterization of T-8: 1H NMR (500MHz, Chloroform-d) δ8.78(s, 1H), 8.16(d, J=9.2Hz, 1H), 7.85(d, J=2.7Hz, 1H), 7.70( dd, J=9.1, 2.7Hz, 1H), 4.47(q, J=7.1Hz, 2H), 3.26(s, 3H), 3.03(s, 3H), 1.48(t, J=7.2Hz, 3H).

实施例10Example 10

本发明实施例提供一种喹啉衍生物T-2的应用转化,由T-2转化为化合物2的转化路线为:The embodiment of the present invention provides a kind of application transformation of quinoline derivative T-2, the conversion route from T-2 to compound 2 is:

Figure BDA0004106912180000152
Figure BDA0004106912180000152

具体地,specifically,

称取喹啉衍生物T-2(0.181g,0.5mmol,1.0eq.)加入到干燥的圆底25mL烧瓶中,加入3mL的超干四氢呋喃溶解体系。冰浴下缓慢滴加四丁基氟化铵溶液(1.5mL,1.5mmol,3.0eq.,1M in THF),升温至40℃,在40℃下搅拌反应3小时。TLC监测原料反应完全,石油醚:乙酸乙酯=1:1,Rf=0.35),加入5mL饱和氯化铵溶液淬灭反应。乙酸乙酯萃取反应体系,用水和饱和食盐水洗涤有机相,合并有机相,无水硫酸钠干燥有机相,柱层析纯化得到黄色油状液体0.084g,产率为73%。Weigh quinoline derivative T-2 (0.181g, 0.5mmol, 1.0eq.) into a dry 25mL round bottom flask, and add 3mL of ultra-dry tetrahydrofuran to dissolve the system. Tetrabutylammonium fluoride solution (1.5mL, 1.5mmol, 3.0eq., 1M in THF) was slowly added dropwise under ice-cooling, the temperature was raised to 40°C, and the reaction was stirred at 40°C for 3 hours. The complete reaction of raw materials was monitored by TLC (petroleum ether:ethyl acetate=1:1, Rf=0.35), and 5 mL of saturated ammonium chloride solution was added to quench the reaction. The reaction system was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.084 g of a yellow oily liquid with a yield of 73%.

化合物2的表征:1H NMR(500MHz,Chloroform-d)δ7.15(d,J=9.1Hz,1H),6.71-6.59(m,2H),2.95(d,J=15.8Hz,1H),2.53(d,J=15.9Hz,1H),2.49-2.36(m,2H),2.12(s,3H),2.09-2.01(m,3H),2.00-1.89(m,1H),1.90-1.77(m,1H);Characterization of Compound 2: 1H NMR (500MHz, Chloroform-d) δ7.15(d, J=9.1Hz, 1H), 6.71-6.59(m, 2H), 2.95(d, J=15.8Hz, 1H), 2.53 (d,J=15.9Hz,1H),2.49-2.36(m,2H),2.12(s,3H),2.09-2.01(m,3H),2.00-1.89(m,1H),1.90-1.77(m ,1H);

13C NMR(126MHz,Chloroform-d)δ167.0,156.5,134.7,126.6,126.3,115.7,114.4,54.0,39.2,32.6,30.8,22.5,19.1。13C NMR (126MHz, Chloroform-d) δ167.0, 156.5, 134.7, 126.6, 126.3, 115.7, 114.4, 54.0, 39.2, 32.6, 30.8, 22.5, 19.1.

从实施例10中可看出,采用本发明的制备方法不仅能高效的在分子内一步构造喹啉骨架,同时得到的产物能够简便的转化为其他可反应的底物,进而形成喹啉类活性物。As can be seen from Example 10, the preparation method of the present invention can not only efficiently construct a quinoline skeleton in one step in the molecule, but also obtain products that can be easily converted into other reactive substrates, thereby forming quinoline-like active compounds. things.

最后应当说明的是,以上实施例以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。Finally, it should be noted that the above examples are to illustrate the technical solutions of the present invention rather than limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the present invention can be Modifications or equivalent replacements shall be made to the technical solutions without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

1. A process for the preparation of a quinoline derivative, comprising the steps of: using a compound shown as a formula I as a raw material, under the action of inert gas and organic acid, carrying out dehydrogenation ring-closure reaction in an organic solvent to obtain a quinoline derivative shown as a formula II,
Figure FDA0004106912170000011
wherein R is 1 Any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 2 any one selected from hydrogen, alkyl, acyl, alkoxy, ester and carbonyl;
R 3 any one selected from alkyl, alkoxy and ester groups;
r' is selected from-OMs, -OTf, -NTf 2 Any one of the following.
2. The process of claim 1, wherein R is 1 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 2 Any one selected from hydrogen, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy, C1-C6 ester group and C1-C6 carbonyl; r is R 3 Is selected from any one of C1-C6 alkyl, C1-C6 alkoxy and C1-C6 ester.
3. The method according to claim 1, wherein the organic acid is any one of trifluoromethanesulfonic acid, methanesulfonic acid, bistrifluoromethanesulfonimide.
4. The process according to claim 1, wherein the molar ratio of the organic acid to the compound of formula i is: compound of formula i= (1-8): 1.
5. the method according to claim 1, wherein the organic solvent is at least one of toluene, acetonitrile, chloroform, dichloromethane, and dichloroethane.
6. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound represented by the formula i to the organic solvent is (0.01 to 0.1) g:1mL.
7. The method according to claim 1, wherein the dehydrogenation-cyclization reaction temperature is (-40) to 25 ℃.
8. The method according to claim 1, wherein the dehydrogenation-cyclization reaction is performed for a period of 6 to 18 hours.
9. The production method according to claim 1, wherein the inert gas is any one of nitrogen gas and a rare gas.
10. A quinoline derivative prepared by the method according to any one of claims 1-9.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068751A1 (en) * 2000-07-17 2002-06-06 American Home Products Corporation Phenyl-oxo-tetrahydroquinolin-3-yl beta-3 adrenergic receptor agonists
CN101200450A (en) * 2002-04-30 2008-06-18 Ucb公司 2,6-Quinolinyl and 2,6-naphthyl derivatives, processes for their preparation and their use as VLA-4 inhibitors
CN113429344A (en) * 2021-06-21 2021-09-24 五邑大学 Preparation method of 2-ethyl-3, 4-dihydro-1 (2H) -isoquinolinone
CN115850175A (en) * 2022-11-14 2023-03-28 五邑大学 A kind of phenyl trifluoromethanesulfonate imine compound and its preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068751A1 (en) * 2000-07-17 2002-06-06 American Home Products Corporation Phenyl-oxo-tetrahydroquinolin-3-yl beta-3 adrenergic receptor agonists
CN101200450A (en) * 2002-04-30 2008-06-18 Ucb公司 2,6-Quinolinyl and 2,6-naphthyl derivatives, processes for their preparation and their use as VLA-4 inhibitors
CN113429344A (en) * 2021-06-21 2021-09-24 五邑大学 Preparation method of 2-ethyl-3, 4-dihydro-1 (2H) -isoquinolinone
CN115850175A (en) * 2022-11-14 2023-03-28 五邑大学 A kind of phenyl trifluoromethanesulfonate imine compound and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MUCHOWSKI, JOSEPH M.等: "Concerning the mechanism of the Friedlaender quinoline synthesis", 《CANADIAN JOURNAL OF CHEMISTRY》, vol. 82, no. 3, 31 December 2004 (2004-12-31), pages 461 - 478, XP009530560, DOI: 10.1139/v03-211 *
NACSA, ERIC D.等: "Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 140, no. 9, 31 December 2018 (2018-12-31), pages 3322 - 3330 *

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