CN111233849A - Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof - Google Patents

Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof Download PDF

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CN111233849A
CN111233849A CN201811469505.7A CN201811469505A CN111233849A CN 111233849 A CN111233849 A CN 111233849A CN 201811469505 A CN201811469505 A CN 201811469505A CN 111233849 A CN111233849 A CN 111233849A
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isoquinoline
oxazoline
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李圣坤
李伟
王国通
来继星
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Nanjing Agricultural University
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Abstract

本发明涉及一类新型异喹啉‑噁唑啉手性配体及其制备和应用,该类化合物的化学结构式如下式所示,

Figure DSA0000175108410000011
通式中取代基R1和R2连接的碳原子的立体构型为R或者S;本发明涉及的异喹啉‑噁唑啉手性配体是一种用途十分广泛的化合物,可作为配体与金属形成络合物或者组合物用于不对称催化,特别是本发明的异喹啉‑噁唑啉配体与金属钯组合可以有效的催化硼酸与硝基烯烃的不对称迈克尔加成,具有优异的立体选择性。The present invention relates to a class of novel isoquinoline-oxazoline chiral ligands and their preparation and application. The chemical structural formula of the compound is shown in the following formula:
Figure DSA0000175108410000011
In the general formula, the stereoconfiguration of the carbon atom to which the substituents R 1 and R 2 are connected is R or S; the isoquinoline-oxazoline chiral ligand involved in the present invention is a compound with a wide range of uses, which can be used as a ligand. The compound or composition is used for asymmetric catalysis, especially the combination of the isoquinoline-oxazoline ligand and metal palladium of the present invention can effectively catalyze the asymmetric Michael addition of boronic acid and nitroalkene, Has excellent stereoselectivity.

Description

新型异喹啉-噁唑啉类手性配体及其制备和应用Novel isoquinoline-oxazoline chiral ligands and their preparation and application

技术领域technical field

本发明涉及一类新型异喹啉-噁唑啉手性配体及其制备和应用,属于催化不对称有机合成领域。The invention relates to a novel isoquinoline-oxazoline chiral ligand and its preparation and application, and belongs to the field of catalytic asymmetric organic synthesis.

背景技术Background technique

催化不对称有机合成一直是有机合成化学研究领域的热点,其中利用金属复合物进行的不对称催化由于具有高效性、良好的原子经济性和较低的环境影响,一直以来被认为是制备纯净对映体的有效方式(Vogel,P.,et al.,Springer Berlin Heidelberg:Berlin,Heidelberg,2003;pp 3-44.)。自从发现有机配体可以影响金属催化剂的空间效应和电子效应以来,新颖高效的手性配体的研发一直处于不对称催化的核心地位(Desimoni,G.,et ai.,Chemical Reviews 2006,106(9),3561-3651.),手性配体存在下金属催化的有机反应通过降低温度、减少副产物的生成来提高反应活性、区域选择性和对映选择性。1986年,Brunner小组发现了第一个含噁唑啉的配体-吡啶噁唑啉配体(PyoX)(Brunner,H.,etal.,Journal of Organometallic Chemistry 1987,328(1),71-80.)。自此开创性的工作以来,许多吡啶噁唑啉配体被开发出来并且在许多类型反应中表现出优良的催化性能。在不对称合成化学中原料的易得性、稳定性是一个重要因素(Xi,T.,et al.,OrganicLetters 2015,17(24),5939-5941.),噁唑啉配体可以通过易得的氨基醇以较短的步骤,较高的产率合成(Hargaden,G.C.,et al.,Chemical Reviews 2009,109(6),2505-2550.)。因此吡啶-噁唑啉型手性配体在不对称催化,尤其是一些新颖高效的不对称方法学中迅速流行起来。最近研究发现吡啶-噁唑啉型配体可以催化一些极具挑战性的经典不对称反应例如:Asymmetric Heck-type reactions、Asymmetric(aza)-Wacker-type,这表明了其作为配体的特性和用于开发新的催化方法学的应用潜力(Yang,G.,et al.,Chemical SocietyReviews 2018,47(5),1783-1810)。本发明设计合成了一类新型异喹啉-噁唑啉手性配体,并发现其可以用于催化不对称合成中,在迈克尔加成反应中以较高的产率和ee值得到了加成产物。Catalytic asymmetric organic synthesis has always been a hotspot in the field of synthetic organic chemistry, in which asymmetric catalysis using metal complexes has long been considered to be a promising candidate for the preparation of pure compounds due to its high efficiency, good atom economy and low environmental impact. An efficient way of enantiomers (Vogel, P., et al., Springer Berlin Heidelberg: Berlin, Heidelberg, 2003; pp 3-44.). Since the discovery that organic ligands can affect the steric and electronic effects of metal catalysts, the development of novel and efficient chiral ligands has been at the heart of asymmetric catalysis (Desimoni, G., et ai., Chemical Reviews 2006, 106( 9), 3561-3651.), Metal-catalyzed organic reactions in the presence of chiral ligands improve reactivity, regioselectivity and enantioselectivity by lowering the temperature and reducing the generation of by-products. In 1986, Brunner's group discovered the first oxazoline-containing ligand - pyridineoxazoline ligand (PyoX) (Brunner, H., et al., Journal of Organometallic Chemistry 1987, 328(1), 71-80 .).) Since this pioneering work, many pyridineoxazoline ligands have been developed and exhibit excellent catalytic performance in many types of reactions. The availability and stability of starting materials are an important factor in asymmetric synthetic chemistry (Xi, T., et al., Organic Letters 2015, 17(24), 5939-5941.), oxazoline ligands can be easily The resulting aminoalcohols were synthesized in shorter steps and in higher yields (Hargaden, G.C., et al., Chemical Reviews 2009, 109(6), 2505-2550.). Therefore, pyridine-oxazoline-type chiral ligands have rapidly become popular in asymmetric catalysis, especially some novel and efficient asymmetric methodologies. Recent studies have found that pyridine-oxazoline-type ligands can catalyze some very challenging classical asymmetric reactions such as: Asymmetric Heck-type reactions, Asymmetric(aza)-Wacker-type, which shows its properties as ligands and Application potential for developing new catalytic methodologies (Yang, G., et al., Chemical Society Reviews 2018, 47(5), 1783-1810). The present invention designs and synthesizes a new type of isoquinoline-oxazoline chiral ligand, and finds that it can be used in catalytic asymmetric synthesis, and is added with high yield and ee value in Michael addition reaction product.

发明内容SUMMARY OF THE INVENTION

本发明提供了一种新型异喹啉-噁唑啉手性配体及其制备和应用,通过异喹啉-3-羧酸与手性氨基醇缩合,环化合成异喹啉-噁唑啉手性配体,并将其用于迈克尔加成反应,获得了较高的催化活性和立体选择性。The invention provides a novel isoquinoline-oxazoline chiral ligand and its preparation and application. The isoquinoline-oxazoline is synthesized by cyclization through the condensation of isoquinoline-3-carboxylic acid and a chiral amino alcohol. Chiral ligands were used in the Michael addition reaction, and high catalytic activity and stereoselectivity were obtained.

本发明所述的新型异喹啉-噁唑啉手性配体,其通式如下:The novel isoquinoline-oxazoline chiral ligand of the present invention has the following general formula:

Figure BSA0000175108430000011
Figure BSA0000175108430000011

通式中与取代基R1和R2连接的碳原子的立体构型为R或者S;In the general formula, the stereo configuration of the carbon atom connected to the substituents R 1 and R 2 is R or S;

其中取代基R1代表:C1~C8的烃基,苯基,取代的苯基(苯基上取代基为C1~C6的烃基,烃氧基以及卤代烃基,取代基的数量为1~5),苄基,取代的苄基(苯基上取代基为C1~C6的烃基,烃氧基以及卤代烃基,取代基的数量为1~5),羟亚甲基,羧酸,羧酸烃基酯(C1~C6),C1~C6烃基羰基,苯基羰基,取代的苯基羰基(苯基上取代基为C1~C6的烃基,烃氧基以及卤代烃基,取代基的数量为1~5),取代的羟甲基(羟基的邻位被C1~C6的烃基,苯基,和取代的苯基取代),Wherein the substituent R 1 represents: a C 1 -C 8 hydrocarbon group, a phenyl group, a substituted phenyl group (the substituent on the phenyl group is a C 1 -C 6 hydrocarbon group, a hydrocarbon oxy group and a halogenated hydrocarbon group, and the number of the substituents is 1~5), benzyl, substituted benzyl (the substituents on the phenyl group are C 1 ~C 6 hydrocarbyl, hydrocarbyloxy and halogenated hydrocarbyl, the number of substituents is 1~5), hydroxymethylene, Carboxylic acid, carboxylic acid hydrocarbyl ester (C 1 -C 6 ), C 1 -C 6 hydrocarbyl carbonyl, phenyl carbonyl, substituted phenyl carbonyl (the substituent on the phenyl group is C 1 -C 6 hydrocarbyl, hydrocarbyloxy and halogenated hydrocarbon groups, the number of substituents is 1 to 5), substituted hydroxymethyl (the ortho position of the hydroxyl group is substituted by a C 1 to C 6 hydrocarbon group, a phenyl group, and a substituted phenyl group),

取代基R2分别代表:甲基、乙基、异丙基、仲丁基、异丁基、羟亚甲基、羧酸烃基酯(1-6碳)、芳香基和芳香基亚甲基;Substituents R 2 respectively represent: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, carboxylate hydrocarbyl ester (1-6 carbons), aryl and arylmethylene;

以及

Figure BSA0000175108430000021
as well as
Figure BSA0000175108430000021

本发明涉及的化合物可以根据如下合成路线来进行化学合成,包括以下四步反应:The compounds involved in the present invention can be chemically synthesized according to the following synthetic routes, including the following four-step reactions:

Figure BSA0000175108430000022
Figure BSA0000175108430000022

步骤1,反应体系中加入L-苯丙氨酸、37%甲醛和浓盐酸加热至95℃搅拌5小时,冷却至室温后过滤得四氢异喹啉-3-羧酸。In step 1, L-phenylalanine, 37% formaldehyde and concentrated hydrochloric acid were added to the reaction system, heated to 95° C. and stirred for 5 hours, cooled to room temperature, and filtered to obtain tetrahydroisoquinoline-3-carboxylic acid.

步骤2,四氢异喹啉-3-羧酸溶于N,N-二甲基甲酰胺(DMF),冰浴条件下,加入高锰酸钾(0.5倍量),室温下搅拌72小时,TLC跟踪监测,反应完全后,过滤,滤液减压浓缩,所得固体用蒸馏水洗涤三次,得异喹啉-3-羧酸。Step 2, tetrahydroisoquinoline-3-carboxylic acid was dissolved in N,N-dimethylformamide (DMF), potassium permanganate (0.5 times the amount) was added under ice bath conditions, and stirred at room temperature for 72 hours, TLC tracking monitoring, after the reaction is complete, filter, the filtrate is concentrated under reduced pressure, and the obtained solid is washed three times with distilled water to obtain isoquinoline-3-carboxylic acid.

步骤3,异喹啉-3-羧酸(1倍量)和氨基醇类化合物(1倍量)溶于二氯甲烷,冰浴条件下加入1-羟基苯并三唑(1.3倍量),随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.3倍量),室温下搅拌反应,TLC跟踪监测,反应完全后,分别用水,饱和碳酸氢钠溶液,饱和氯化钠溶液洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析,得异喹啉酰胺醇。Step 3, isoquinoline-3-carboxylic acid (1 times the amount) and amino alcohol compounds (1 times the amount) were dissolved in dichloromethane, and 1-hydroxybenzotriazole (1.3 times the amount) was added under ice bath conditions, Subsequently, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 times the amount) was added, and the reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, water and saturated hydrogen carbonate were used respectively. Sodium solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and chromatographed on silica gel column to obtain isoquinoline amide alcohol.

步骤4,异喹啉酰胺醇溶于二氯甲烷,冰浴下滴加氯化亚砜(3倍量),室温搅拌反应5小时,减压浓缩,随后加入乙腈溶解,滴加三乙胺(2倍量),加热至95℃搅拌反应TLC跟踪监测,反应完全后,减压蒸除溶剂,二氯甲烷溶解,分别用水,饱和碳酸氢钠溶液,饱和氯化钠溶液洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析,得白色固体L。Step 4, isoquinoline amide alcohol is dissolved in dichloromethane, thionyl chloride (3 times the amount) is added dropwise under an ice bath, the reaction is stirred at room temperature for 5 hours, concentrated under reduced pressure, then acetonitrile is added to dissolve, and triethylamine ( 2 times the amount), heated to 95 ° C with stirring and reaction TLC tracking monitoring, after the reaction was complete, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and anhydrous sulfuric acid. Dry over sodium, evaporate the solvent under reduced pressure, and perform silica gel column chromatography to obtain L as a white solid.

本发明所提供的异喹啉-噁唑啉手性配体的合成具有原料廉价易得、易于操作等特点。The synthesis of the isoquinoline-oxazoline chiral ligand provided by the invention has the characteristics of cheap and easy-to-obtain raw materials, easy operation and the like.

本发明所涉及的异喹啉噁唑啉手性配体,优选如下化合物:The isoquinoline oxazoline chiral ligands involved in the present invention are preferably the following compounds:

Figure BSA0000175108430000033
Figure BSA0000175108430000033

具体实施方法Specific implementation method

下面对本发明的实施作详细说明:本实施例在以本发明技术方案为前提下进行实施,给出了具体的操作过程,但本发明的保护范围不仅限于以下反应实例。The implementation of the present invention is described in detail below: the present embodiment is implemented on the premise of the technical solution of the present invention, and a specific operation process is provided, but the protection scope of the present invention is not limited to the following reaction examples.

实施例一Example 1

向反应体系中加入L-苯丙氨酸(10g,60mmol)、37%甲醛33mL和浓盐酸87mL加热至95℃搅拌5小时,冷却至室温后过滤得白色固体I 8.3g,收率83%。L-phenylalanine (10 g, 60 mmol), 33 mL of 37% formaldehyde and 87 mL of concentrated hydrochloric acid were added to the reaction system, heated to 95° C. and stirred for 5 hours, cooled to room temperature, and filtered to obtain 8.3 g of white solid I with a yield of 83%.

反应体系中加入中间体四氢异喹啉-3-羧酸I(5.3g,30mmol),80mLN,N-二甲基甲酰胺(DMF),冰浴条件下,加入高锰酸钾(2.5g,16mmol),室温下搅拌72小时,过滤,滤液减压浓缩,所得固体用蒸馏水洗涤三次,得黄色固体异喹啉-3-羧酸II 3.1g,收率62%。The intermediate tetrahydroisoquinoline-3-carboxylic acid I (5.3g, 30mmol), 80mL of N,N-dimethylformamide (DMF) were added to the reaction system, and potassium permanganate (2.5g) was added under ice bath conditions. , 16 mmol), stirred at room temperature for 72 hours, filtered, the filtrate was concentrated under reduced pressure, and the obtained solid was washed three times with distilled water to obtain 3.1 g of yellow solid isoquinoline-3-carboxylic acid II with a yield of 62%.

Figure BSA0000175108430000032
Figure BSA0000175108430000032

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-2-氨基丙醇(75mg,1mmol),溶于20ml二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-1,收率76%。The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-2-aminopropanol (75mg, 1mmol), dissolved in 20ml of dichloromethane, HOBt (175mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2) respectively. , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate =4:1, 5% triethylamine), the product was obtained as a white solid III- 1. The yield is 76%.

反应体系中加入中间体酰胺醇III-1(115mg,0.5mmol)溶于10mL二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10mL乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应4小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得白色固体L1,收率90%。The intermediate amido alcohol III-1 (115 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain a white solid L1 with a yield of 90%.

Figure BSA0000175108430000041
Figure BSA0000175108430000041

化合物L1的结构鉴定数据如下:The structural identification data of compound L1 are as follows:

1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.42(s,1H),8.02(d,J=8.44Hz,1H),7.90(d,J=8.19Hz,1H),7.78-7.65(m,2H),4.62-4.68(m,1H),4.44-4.54(m,1H),4.08(td,J1=1.23Hz,J2=8.06Hz,1H),1.43(d,J1=1.08Hz,J2=6.62Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.42 (s, 1H), 8.02 (d, J=8.44 Hz, 1H), 7.90 (d, J=8.19 Hz, 1H), 7.78 -7.65(m, 2H), 4.62-4.68(m, 1H), 4.44-4.54(m, 1H), 4.08(td, J1 = 1.23Hz, J2= 8.06Hz , 1H), 1.43(d, J 1 = 1.08 Hz, J 2 = 6.62 Hz, 3H).

13C NMR(100MHz,CDCl3)δ163.05,152.68,140.30,135.57,130.95,129.30,128.77,127.70,127.51,121.58,74.65,62.34,21.41. 13 C NMR (100 MHz, CDCl 3 ) δ 163.05, 152.68, 140.30, 135.57, 130.95, 129.30, 128.77, 127.70, 127.51, 121.58, 74.65, 62.34, 21.41.

ESI-HRMS,calcd for C13H13N2O[M+H]+213.0950,found 213.1098.ESI-HRMS, calcd for C 13 H 13 N 2 O[M+H] + 213.0950, found 213.1098.

实施例二Embodiment 2

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-2-氨基丁醇(89mg,1mmol),溶于20ml二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得白色固体III-2,收率68%。Intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), S-2-aminobutanol (89 mg, 1 mmol) were added to the reaction system, dissolved in 20 ml of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2) respectively. , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate =4:1, 5% triethylamine), white solid III-2 was obtained, Yield 68%.

反应体系中加入中间体酰胺醇III-2(122mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10ml乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应4小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L2,收率87%。The intermediate amide alcohol III-2 (122 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L2 with a yield of 87%.

Figure BSA0000175108430000042
Figure BSA0000175108430000042

化合物L2的结构鉴定数据如下:The structural identification data of compound L2 are as follows:

1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.42(s,1H),8.02(d,J=8.51Hz,1H),7.90(d,J=8.33Hz,1H),7.64-7.78(m,2H),4.62(dd,J1=8.21Hz,J2=9.58Hz,1H),4.31-4.40(m,1H),4.17(t,J=8.13Hz,1H),1.87(m,1H),1.64-1.74(m,1H),1.05(t,J=7.40Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.42 (s, 1H), 8.02 (d, J=8.51 Hz, 1H), 7.90 (d, J=8.33 Hz, 1H), 7.64 -7.78(m, 2H), 4.62(dd, J1 = 8.21Hz, J2= 9.58Hz , 1H), 4.31-4.40(m, 1H), 4.17(t, J=8.13Hz, 1H), 1.87( m, 1H), 1.64-1.74 (m, 1H), 1.05 (t, J=7.40Hz, 3H).

13C NMR(100MHz,CDCl3)δ164.34,152.70,142.03,140.13,135.58,131.05,129.44,128.95,128.77,127.73,127.68,127.59,126.88,122.14,75.31,70.40. 13 C NMR (100 MHz, CDCl 3 ) δ 164.34, 152.70, 142.03, 140.13, 135.58, 131.05, 129.44, 128.95, 128.77, 127.73, 127.68, 127.59, 126.88, 122.14, 75.31, 70.4

ESI-HRMS,calcd for C14H15N2O[M+H]+227.1106,found 227.1264.ESI-HRMS, calcd for C 14 H 15 N 2 O[M+H] + 227.1106, found 227.1264.

实施例三Embodiment 3

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、R-2-氨基丁醇(89mg,1mmol),溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得白色固体III-3,收率68%。The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), R-2-aminobutanol (89 mg, 1 mmol), dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3mmol), EDCi (250mg, 1.3mmol), stirred overnight at room temperature, the reaction system was washed with water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated sodium chloride solution (10ml×2) respectively , dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate =4:1, 5% triethylamine), white solid III-3 was obtained, Yield 68%.

反应体系中加入中间体酰胺醇III-3(122mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10ml乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应4小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L3,收率87%。The intermediate amido alcohol III-3 (122 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L3 with a yield of 87%.

Figure BSA0000175108430000051
Figure BSA0000175108430000051

化合物L3的结构鉴定数据如下:The structural identification data of compound L3 are as follows:

1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.41(s,1H),8.01(d,J=8.62Hz,1H),7.89(d,J=8.05Hz,1H),7.70(m,2H),4.60(dd,J1=8.12Hz,J2=9.57Hz,1H),4.34(m,1H),4.16(t,J=8.19Hz,1H),1.85(m,1H),1.67(m,1H),1.04(t,J=7.50Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.30 (s, 1H), 8.41 (s, 1H), 8.01 (d, J=8.62 Hz, 1H), 7.89 (d, J=8.05 Hz, 1H), 7.70 (m, 2H), 4.60 (dd, J1 = 8.12Hz, J2= 9.57Hz , 1H), 4.34 (m, 1H), 4.16 (t, J=8.19Hz, 1H), 1.85 (m, 1H) , 1.67(m, 1H), 1.04(t, J=7.50Hz, 3H).

13C NMR(100MHz,CDCl3)δ163.08,152.69,140.30,135.57,130.96,129.28,128.77,127.71,127.52,121.61,72.75,68.40,28.61,10.23. 13 C NMR (100 MHz, CDCl 3 ) δ 163.08, 152.69, 140.30, 135.57, 130.96, 129.28, 128.77, 127.71, 127.52, 121.61, 72.75, 68.40, 28.61, 10.23.

ESI-HRMS,calcd for C14H15N2O[M+H]+227.1106,found 227.1264.ESI-HRMS, calcd for C 14 H 15 N 2 O[M+H] + 227.1106, found 227.1264.

实施例四Embodiment 4

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-缬氨醇溶于20ml二氯甲烷,冰浴条件下加入HoBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-4,收率73%。In the reaction system, add intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-valinol was dissolved in 20ml of dichloromethane, HoBt (175mg, 1.3mmol), EDCi (250mg, 1.3 mmol), stirred at room temperature overnight, the reaction system was washed with water (10 ml × 2), saturated sodium bicarbonate solution (10 ml × 2), and saturated sodium chloride solution (10 ml × 2), dried over anhydrous sodium sulfate, reduced The solvent was evaporated under pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), the product was obtained as white solid III-4 with a yield of 73%.

反应体系中加入中间体酰胺醇III-4(129mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10ml乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应4小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L4,收率85%。The intermediate amido alcohol III-4 (129 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L4 with a yield of 85%.

Figure BSA0000175108430000061
Figure BSA0000175108430000061

化合物L4的结构鉴定数据如下:The structural identification data of compound L4 are as follows:

1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.44(s,1H),8.02(d,J=7.85Hz,1H),7.91(d,J=8.19Hz,1H),7.71(m,2H),4.55(td,J1=1.20Hz,J2=7.40Hz,1H),4.16-4.30(m,2H),1.95(m,1H),1.09(d,J=6.70Hz,3H),0.97(d,J=6.71Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 1H), 8.44 (s, 1H), 8.02 (d, J=7.85 Hz, 1H), 7.91 (d, J=8.19 Hz, 1H), 7.71 (m, 2H), 4.55 (td, J1 = 1.20Hz, J2= 7.40Hz , 1H), 4.16-4.30 (m, 2H), 1.95 (m, 1H), 1.09 (d, J=6.70Hz, 3H), 0.97 (d, J=6.71Hz, 3H).

13C NMR(100MHz,CDCl3)δ163.61,152.71,140.23,137.95,135.57,131.00,129.35,129.24,128.85,128.62,127.73,127.56,126.55,121.74,72.51,68.20,41.79. 13 C NMR (100 MHz, CDCl 3 ) δ 163.61, 152.71, 140.23, 137.95, 135.57, 131.00, 129.35, 129.24, 128.85, 128.62, 127.73, 127.56, 126.55, 121.74, 41.79.51, 68.20

ESI-HRMS,calcd for C15H17N2O[M+H]+241.1263,found 241.1427.ESI-HRMS, calcd for C 15 H 17 N 2 O[M+H] + 241.1263, found 241.1427.

实施例五Embodiment 5

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-苯甘氨醇(137mg,1mmol),溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-5,收率72%。The intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol) and S-phenylglycinol (137 mg, 1 mmol) were added to the reaction system, dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2), respectively, It was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), the product was obtained as white solid III-5 , the yield is 72%.

反应体系中加入中间体酰胺醇III-5(146mg,0.5mmol)溶于10mL二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10ml乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应6小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L5,收率89%。The intermediate amido alcohol III-5 (146 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L5 with a yield of 89%.

Figure BSA0000175108430000071
Figure BSA0000175108430000071

化合物L5的结构鉴定数据如下:The structural identification data of compound L5 are as follows:

1H NMR(400MHz,CDCl3)δ9.35(s,1H),8.57(s,1H),8.04(d,J=8.05Hz,1H),7.92(d,J=8.17Hz,1H),7.67-7.80(m,2H),7.28-7.42(m,5H),5.51(dd,J=8.54Hz,J=10.33Hz,1H),4.95(dd,J1=8.55,J2=10.30Hz,1H),4.44(t,J=8.55Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 8.57 (s, 1H), 8.04 (d, J=8.05 Hz, 1H), 7.92 (d, J=8.17 Hz, 1H), 7.67 -7.80 (m, 2H), 7.28-7.42 (m, 5H), 5.51 (dd, J=8.54Hz, J= 10.33Hz , 1H), 4.95 (dd, J1 = 8.55, J2=10.30Hz, 1H ), 4.44(t, J=8.55Hz, 1H).

13C NMR(100MHz,CDCl3)δ163.05,152.68,140.30,135.57,130.95,129.30,128.77,127.70,127.51,121.58,74.65,62.34,21.41. 13 C NMR (100 MHz, CDCl 3 ) δ 163.05, 152.68, 140.30, 135.57, 130.95, 129.30, 128.77, 127.70, 127.51, 121.58, 74.65, 62.34, 21.41.

ESI-HRMS,calcd for C18H15N2O[M+H]+275.1106,found 275.1270.ESI-HRMS, calcd for C 18 H 15 N 2 O[M+H] + 275.1106, found 275.1270.

实施例六Embodiment 6

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-苯丙氨醇(151mg,1mmol),溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-6,收率73%。The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), S-phenylalaninol (151 mg, 1 mmol), dissolved in 20 mL of dichloromethane, and HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride solution (10 mL×2), respectively, It was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), the product was obtained as white solid III-6 , the yield is 73%.

反应体系中加入中间体酰胺醇III-6(153mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10mL乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应6小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L6,收率85%。The intermediate amido alcohol III-6 (153 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product as a white solid L6 in a yield of 85%.

Figure BSA0000175108430000072
Figure BSA0000175108430000072

化合物L6的结构鉴定数据如下:The structural identification data of compound L6 are as follows:

1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.43(s,1H),8.03(d,J=8.14Hz,1H),7.92(d,J=8.03Hz,1H),7.72(m,2H),7.19-7.38(m,5H),4.71(m,1H),4.48(t,J=9.01Hz,1H),4.27(t,J=8.17Hz,1H),3.38(dd,J1=4.91Hz,J2=13.83Hz,1H),2.80(dd,J1=9.30Hz,J2=13.91Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 1H), 8.43 (s, 1H), 8.03 (d, J=8.14 Hz, 1H), 7.92 (d, J=8.03 Hz, 1H), 7.72 (m, 2H), 7.19-7.38 (m, 5H), 4.71 (m, 1H), 4.48 (t, J=9.01Hz, 1H), 4.27 (t, J=8.17Hz, 1H), 3.38 (dd, J 1 =4.91Hz, J 2 =13.83Hz, 1H), 2.80 (dd, J 1 =9.30Hz, J 2 =13.91Hz, 1H).

13C NMR(100MHz,CDCl3)δ163.01,152.67,140.37,135.60,130.94,129.30,128.74,127.70,127.52,121.64,73.05,70.69,32.79,19.20,18.19. 13 C NMR (100 MHz, CDCl 3 ) δ 163.01, 152.67, 140.37, 135.60, 130.94, 129.30, 128.74, 127.70, 127.52, 121.64, 73.05, 70.69, 32.79, 19.20, 18.19.

ESI-HRMS,calcd for C19H17N2O[M+H]+289.1263,found 289.1439.ESI-HRMS, calcd for C 19 H 17 N 2 O[M+H] + 289.1263, found 289.1439.

实施例七Embodiment 7

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol),S-叔亮氨醇溶于20ml二氯甲烷,冰浴条件下加入HoBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-7,收率76%。Intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) was added to the reaction system, S-tert-leucinol was dissolved in 20ml of dichloromethane, HoBt (175mg, 1.3mmol), EDCi (250mg) were added under ice bath conditions , 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 ml × 2), saturated sodium bicarbonate solution (10 ml × 2), saturated sodium chloride solution (10 ml × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), the product was obtained as white solid III-7 with a yield of 76%.

反应体系中加入中间体酰胺醇III-7(136mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10ml乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应4小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10ml×2),饱和碳酸氢钠溶液(10ml×2),饱和氯化钠溶液(10ml×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L7,收率81%。Intermediate amido alcohol III-7 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 ml of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir to react for 4 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10ml×2), saturated sodium bicarbonate solution (10ml×2), saturated chlorine After washing with sodium chloride solution (10ml×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product L7 as a white solid with a yield of 81%.

Figure BSA0000175108430000081
Figure BSA0000175108430000081

化合物L7的结构鉴定数据如下:The structural identification data of compound L7 are as follows:

1H NMR(400MHz,CDCl3)δ9.34(s,1H),8.48(s,1H),8.04(d,J=8.04Hz,1H),7.94(d,J=8.15Hz,1H),7.68-7.79(m,2H),4.50(dd,J1=8.60Hz,J2=10.21Hz,1H),4.37(t,J=8.51Hz,1H),4.19(dd,J1=8.24Hz,J2=10.09Hz,1H),1.03(s,9H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.34 (s, 1H), 8.48 (s, 1H), 8.04 (d, J=8.04 Hz, 1H), 7.94 (d, J=8.15 Hz, 1H), 7.68 -7.79(m, 2H), 4.50(dd, J1 = 8.60Hz, J2= 10.21Hz , 1H), 4.37(t, J=8.51Hz, 1H), 4.19(dd, J1 = 8.24Hz, J 2 = 10.09Hz, 1H), 1.03(s, 9H).

13C NMR(100MHz,CDCl3)δ163.08,152.69,140.36,135.59,130.95,129.30,128.75,127.71,127.52,121.60,72.75,68.42,28.61,10.21. 13 C NMR (100 MHz, CDCl 3 ) δ 163.08, 152.69, 140.36, 135.59, 130.95, 129.30, 128.75, 127.71, 127.52, 121.60, 72.75, 68.42, 28.61, 10.21.

ESI-HRMS,calcd for C16H19N2O[M+H]+254.1419,found 255.1585.ESI-HRMS, calcd for C 16 H 19 N 2 O[M+H] + 254.1419, found 255.1585.

实施例八Embodiment 8

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol),S-异亮氨醇溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得产物得白色固体III-8,收率74%。Intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) was added to the reaction system, S-isoleucinol was dissolved in 20mL of dichloromethane, HOBt (175mg, 1.3mmol), EDCi (250mg) were added under ice bath conditions , 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated sodium chloride solution (10 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), the product was obtained as white solid III-8 with a yield of 74%.

反应体系中加入中间体酰胺醇III-8(136mg,0.5mmol)溶于10mL二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10mL乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应6小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L8,收率83%。The intermediate amido alcohol III-8 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 mL of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then 10 mL of acetonitrile was added. Dissolve, add 277 μL of triethylamine dropwise, heat to 95°C and stir for 6 hours, evaporate the solvent under reduced pressure, dissolve in dichloromethane, use water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated chlorine After washing with sodium chloride solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 2:1, 5% triethyl acetate amine) to obtain the product L8 as a white solid with a yield of 83%.

Figure BSA0000175108430000091
Figure BSA0000175108430000091

化合物L8的结构鉴定数据如下:The structural identification data of compound L8 are as follows:

1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.44(s,1H),8.02(d,J=8.11Hz,1H),7.91(d,J=8.08Hz,1H),7.72(m,2H),4.53(dd,J1=7.91Hz,J2=9.48Hz,1H),4.29-4.39(m,1H),4.26(d,J=8.25Hz,1H),1.77-1.87(m,1H),1.66-1.74(m,1H),1.23-1.36(m,1H),0.98(t,J=7.43Hz,3H),0.92(d,J=6.84Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 1H), 8.44 (s, 1H), 8.02 (d, J=8.11 Hz, 1H), 7.91 (d, J=8.08 Hz, 1H), 7.72 (m, 2H), 4.53 (dd, J1 = 7.91Hz, J2= 9.48Hz , 1H), 4.29-4.39 (m, 1H), 4.26 (d, J=8.25Hz, 1H), 1.77-1.87 ( m, 1H), 1.66-1.74 (m, 1H), 1.23-1.36 (m, 1H), 0.98 (t, J=7.43Hz, 3H), 0.92 (d, J=6.84Hz, 3H).

13C NMR(100MHz,CDCl3)δ161.78,152.63,140.14,135.59,130.92,129.29,128.73,127.71,127.52,121.60,72.60,71.03,38.86,26.45,12.89,11.66. 13 C NMR (100 MHz, CDCl 3 ) δ 161.78, 152.63, 140.14, 135.59, 130.92, 129.29, 128.73, 127.71, 127.52, 121.60, 72.60, 71.03, 38.86, 26.45, 12.89, 11.66.

ESI-HRMS,calcd for C16H19N2O[M+H]+255.1419,found 255.1585.ESI-HRMS, calcd for C 16 H 19 N 2 O[M+H] + 255.1419, found 255.1585.

实施例九Embodiment 9

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、S-亮氨醇溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得白色固体III-9,收率72%。The reaction system was added with intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), S-leucinol was dissolved in 20mL of dichloromethane, HOBt (175mg, 1.3mmol), EDCi (250mg, 1.3 mmol), stirred overnight at room temperature, the reaction system was washed with water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, and then reduced The solvent was evaporated under pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine), white solid III-9 was obtained with a yield of 72%.

反应体系中加入中间体III-9(136mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应5小时,减压浓缩,随后加10mL乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应6小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L9,收率82%。Intermediate III-9 (136 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, and then dissolved by adding 10 mL of acetonitrile, 277 μL of triethylamine was added dropwise, heated to 95°C and stirred for 6 hours, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride were added dropwise. The solution (10 mL×2) was washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and subjected to silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate =2:1, 5% triethylamine) , the product was white solid L9, the yield was 82%.

Figure BSA0000175108430000092
Figure BSA0000175108430000092

化合物L9的结构鉴定数据如下:The structural identification data of compound L9 are as follows:

1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.41(s,1H),8.01(d,J=8.09Hz,1H),7.90(d,J=8.18Hz,1H),7.65-7.80(m,2H),4.64(dd,J1=8.08Hz,J2=9.36Hz,1H),4.44(m,1H),4.10(t,J=8.28Hz,1H),1.87-1.95(m,1H),1.79-1.86(m,1H),1.43(dt,J1=7.72Hz,J2=13.38Hz,1H),0.99(dd,J1=6.53Hz,J2=8.97Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.41 (s, 1H), 8.01 (d, J=8.09 Hz, 1H), 7.90 (d, J=8.18 Hz, 1H), 7.65 -7.80(m, 2H), 4.64(dd, J1 = 8.08Hz, J2= 9.36Hz , 1H), 4.44(m, 1H), 4.10(t, J=8.28Hz, 1H), 1.87-1.95( m, 1H), 1.79-1.86 (m, 1H), 1.43 (dt, J1 = 7.72Hz, J2= 13.38Hz , 1H), 0.99 (dd, J1 = 6.53Hz, J2= 8.97Hz , 6H ).

13C NMR(100MHz,CDCl3)δ162.92,152.68,140.40,135.59,130.94,129.28,128.74,127.71,127.52,121.59,73.71,65.46,45.56,25.45,22.80,22.76. 13 C NMR (100 MHz, CDCl 3 ) δ 162.92, 152.68, 140.40, 135.59, 130.94, 129.28, 128.74, 127.71, 127.52, 121.59, 73.71, 65.46, 45.56, 25.45, 22.80, 22.76.

ESI-HRMS,calcdfor C16H19N2O[M+H]+255.1419,found 255.1580.ESI-HRMS, calcd for C 16 H 19 N 2 O[M+H] + 255.1419, found 255.1580.

实施例十Embodiment ten

反应体系中加入中间体异喹啉-3-羧酸II(173mg,1mmol)、(1S,2R)-(-)-1-2-茚醇(150mg,1mmol),溶于20mL二氯甲烷,冰浴条件下加入HOBt(175mg,1.3mmol),EDCi(250mg,1.3mmol),室温下搅拌过夜,反应体系分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=4∶1,5%三乙胺),得白色固体III-10,收率72%。Intermediate isoquinoline-3-carboxylic acid II (173 mg, 1 mmol), (1S, 2R)-(-)-1-2-indanol (150 mg, 1 mmol) were added to the reaction system, dissolved in 20 mL of dichloromethane, HOBt (175 mg, 1.3 mmol), EDCi (250 mg, 1.3 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature overnight. After washing with sodium solution (10 mL×2), drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate = 4:1, 5% triethylamine ) to obtain white solid III-10 with a yield of 72%.

反应体系中加入中间体III-10(152mg,0.5mmol)溶于10ml二氯甲烷,滴加110μL(1.5mmol)二氯亚砜,室温搅拌反应6小时,减压浓缩,随后加10mL乙腈溶解,滴加277μL三乙胺,加热至95℃搅拌反应6小时,减压蒸除溶剂,二氯甲烷溶解,分别用水(10mL×2),饱和碳酸氢钠溶液(10mL×2),饱和氯化钠溶液(10mL×2)洗涤后,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析后(洗脱剂:V石油醚/V乙酸乙酯=2∶1,5%三乙胺),得产物白色固体L10,收率82%。Intermediate III-10 (152 mg, 0.5 mmol) was added to the reaction system, dissolved in 10 ml of dichloromethane, 110 μL (1.5 mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 6 hours, concentrated under reduced pressure, and then dissolved by adding 10 mL of acetonitrile, 277 μL of triethylamine was added dropwise, heated to 95°C and stirred for 6 hours, the solvent was evaporated under reduced pressure, dissolved in dichloromethane, water (10 mL×2), saturated sodium bicarbonate solution (10 mL×2), and saturated sodium chloride were added dropwise. The solution (10 mL×2) was washed, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and subjected to silica gel column chromatography (eluent: V petroleum ether /V ethyl acetate =2:1, 5% triethylamine) , the product was white solid L10, the yield was 82%.

Figure BSA0000175108430000101
Figure BSA0000175108430000101

化合物L9的结构鉴定数据如下:The structural identification data of compound L9 are as follows:

1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.43(s,1H),8.00(d,J=8.15Hz,1H),7.89(d,J=8.03Hz,1H),7.60-7.77(m,3H),7.26-7.29(m,3H),5.86(d,J=7.76Hz,1H),5.66-5.57(m,1H),3.53(dd,J1=4.03Hz,J2=10.00Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.29 (s, 1H), 8.43 (s, 1H), 8.00 (d, J=8.15 Hz, 1H), 7.89 (d, J=8.03 Hz, 1H), 7.60 -7.77 (m, 3H), 7.26-7.29 (m, 3H), 5.86 (d, J=7.76Hz, 1H), 5.66-5.57 (m, 1H), 3.53 (dd, J1 = 4.03Hz , J2 =10.00Hz, 2H).

13C NMR(100MHz,CDCl3)δ163.64,152.62,141.76,140.34,139.82,135.51,130.96,129.28,128.81,128.56,127.69,127.51,125.84,125.32,121.90,83.93,39.83. 13 C NMR (100 MHz, CDCl 3 ) δ 163.64, 152.62, 141.76, 140.34, 139.82, 135.51, 130.96, 129.28, 128.81, 128.56, 127.69, 127.51, 125.84, 125.93, 12.3.90, 83

ESI-HRMS,calcd for C19H15N2O[M+H]+287.1184,found 287.1290.ESI-HRMS, calcd for C 19 H 15 N 2 O[M+H] + 287.1184, found 287.1290.

实施例十一Embodiment 11

不对称迈克尔加成反应Asymmetric Michael addition reaction

在10mL反应瓶中加入Pd(TFA)2(3.4mg,0.01mmol)、L7(3.8mg,0.015mmol),2mL甲醇,40℃搅拌半小时。随后加入硝基苯乙烯(38mg,0.25mmol),对甲氧基苯硼酸(76mg,0.5mmol)。TLC跟踪监测反应完成,减压浓缩,柱层析(V石油醚∶V乙酸乙酯=30∶1)。加成产物ee值为93%。Pd(TFA) 2 (3.4 mg, 0.01 mmol), L7 (3.8 mg, 0.015 mmol), 2 mL of methanol were added to a 10 mL reaction flask, and the mixture was stirred at 40° C. for half an hour. Nitrostyrene (38 mg, 0.25 mmol), p-methoxyphenylboronic acid (76 mg, 0.5 mmol) were then added. The completion of the reaction was monitored by TLC tracking, concentrated under reduced pressure, and subjected to column chromatography (V petroleum ether :V ethyl acetate =30:1). The ee of the addition product was 93%.

Figure BSA0000175108430000111
Figure BSA0000175108430000111

结构鉴定数据如下:The structural identification data are as follows:

1H NMR(400MHz,CDCl3)δ7.32(m,1H),7.23(m,2H),7.15(m,1H),6.85(m,1H),4.96(d,J=2.43Hz,1H),4.94(s,1H),4.86(t,J=8.05Hz,1H),3.78(s,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 (m, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 6.85 (m, 1H), 4.96 (d, J=2.43Hz, 1H) , 4.94(s, 1H), 4.86(t, J=8.05Hz, 1H), 3.78(s, 1H).

13C NMR(100MHz,CDCl3)δ158.92,139.65,131.27,129.04,128.71,127.62,127.52,114.40,79.55,55.36,48.35. 13 C NMR (100MHz, CDCl3) δ 158.92, 139.65, 131.27, 129.04, 128.71, 127.62, 127.52, 114.40, 79.55, 55.36, 48.35.

Claims (6)

1. a novel isoquinoline-oxazoline chiral ligand, characterized by having the following structural formula:
Figure FSA0000175108420000011
wherein the substituent R1Represents: c1~C8A phenyl group, a substituted phenyl group (the substituent on the phenyl group is C)1~C6The number of the substituent groups is 1-5), benzyl, substituted alkyl, alkoxy and halogenated alkylBenzyl (substituent on phenyl is C1~C6The number of the substituents is 1 to 5), hydroxymethylene, carboxylic acid, and carboxylic acid alkyl ester (C)1~C6),C1~C6Hydrocarbyl carbonyl, phenylcarbonyl, substituted phenylcarbonyl (substituent on phenyl is C)1~C6The number of the substituent is 1-5), and substituted hydroxymethyl (the ortho position of the hydroxyl is substituted by C)1~C6Phenyl, and substituted phenyl substitution),
the substituents R2 represent respectively: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, hydrocarbyl carboxylate (1-6 carbons), aryl and arylmethylene;
and
Figure FSA0000175108420000012
substituent R in the general formula1And R2The steric configuration of the attached carbon atom is R or S.
2. The compound of formula (I) according to claim 1, characterized in that it is selected from the following compounds:
Figure FSA0000175108420000013
3. the method for synthesizing the chiral isoquinoline oxazoline ligand of claim 1, which is derived from phenylalanine through the following four-step reaction:
Figure FSA0000175108420000021
and (3) preparing an isoquinoline oxazoline chiral ligand.
4. The method for synthesizing isoquinoline-oxazoline chiral ligand according to claim 1, wherein phenylalanine is used as a starting material, tetrahydroisoquinoline-3-carboxylic acid is obtained through Pictet-Spengler reaction, isoquinoline-3-carboxylic acid is obtained through oxidative dehydrogenation, chiral amidol is obtained through condensation with chiral β -amino alcohol, and finally the isoquinoline-oxazoline ligand is obtained through cyclization of the chiral amidol.
5. The metal complex of isoquinoline-oxazoline chiral ligand of claim 1 with metallic palladium (Pd), copper (Cu) and nickel (Ni).
6. The isoquinoline-oxazoline chiral ligand of claim 1 and the metal complex of claim 5 for use in asymmetric catalytic reactions, including Michael addition reactions, [2+3] cycloaddition reactions of imines and olefins, and asymmetric oxidation reactions.
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Publication number Priority date Publication date Assignee Title
CN111925356A (en) * 2020-08-17 2020-11-13 华东理工大学 Synthesis and application of chiral quinoline-imidazoline ligands
CN111925356B (en) * 2020-08-17 2023-04-28 华东理工大学 Synthesis method and application of chiral quinoline-imidazoline ligand
CN115232115A (en) * 2022-08-10 2022-10-25 贵州大学 A kind of dichloroquinoline-oxazoline chiral ligand and its preparation method and application
CN115232115B (en) * 2022-08-10 2024-04-16 贵州大学 A dichloroquinoline-oxazoline chiral ligand and its preparation method and application
CN115368350A (en) * 2022-09-19 2022-11-22 兰州大学 PyrOX ligand containing electron-rich group at 5-position of pyridine

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