WO2020253152A1 - 含磺酰胺的4-(n-甲基)氨基哌啶杨梅素衍生物、制备方法及用途 - Google Patents

含磺酰胺的4-(n-甲基)氨基哌啶杨梅素衍生物、制备方法及用途 Download PDF

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WO2020253152A1
WO2020253152A1 PCT/CN2019/124090 CN2019124090W WO2020253152A1 WO 2020253152 A1 WO2020253152 A1 WO 2020253152A1 CN 2019124090 W CN2019124090 W CN 2019124090W WO 2020253152 A1 WO2020253152 A1 WO 2020253152A1
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methyl
dimethoxy
trimethoxyphenyl
chromen
preparation
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PCT/CN2019/124090
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French (fr)
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薛伟
蒋仕春
陈英
苏时军
贺军
陈梅
金梅梅
贺鸣
王俊
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贵州大学
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Priority to US17/043,521 priority Critical patent/US20230131193A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01PBIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00Disinfectants; Antimicrobial compounds or mixtures thereof
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the technical field of chemical engineering, in particular to a sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative, and the sulfonamide-containing 4-(N-methyl)aminopiper
  • Myricetin (3',4',5',3,5,7-hexahydroxyflavonol, Myricetin (Myr)), the synonym of myricetin and myricetone, is a polyhydroxy group isolated from the bark of bayberry Flavonoids, chemical formula C 15 H 10 O 8 , relative molecular weight 318.24, yellow needle-like or granular crystals, melting point 324-326°C, soluble in methanol, ethanol, acetone, insoluble in chloroform, petroleum ether.
  • Fagaceae leguminosae, primulaceae, vitaceae, compositae and other plants.
  • myricetin has a variety of pharmacological activities such as antibacterial, anti-allergic, anti-viral, hypoglycemic, anti-inflammatory, anti-oxidant, and nerve protection, showing abundant resource advantages and huge potential use value.
  • Liu et al. (Journal of Zhejiang Forestry College, 2009, 26, 95-99.) used the growth rate method to systematically determine the antibacterial effect of myricetin.
  • the experimental results showed that myricetin had an effect on rice sheath blight and rape bacteria.
  • Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, Apple rot pathogen, and cotton fusarium wilt have strong inhibitory activity.
  • the EC 50 is 0.32, 0.33, 1.09, 0.69, 0.34 and 2.09. g/L, and has high inhibitory activity against rice sheath blight, rape sclerotium and apple rot.
  • myricetin has certain biological activities in medicine and pesticides.
  • the previous research work has less modified myricetin, mainly to study the biological activity of myricetin itself. It is reported that the active group of 4-(N-methyl)aminopiperidine of amide was introduced into myricetin to synthesize 4-(N-methyl)aminopiperidine myricetin derivatives containing sulfonamide and tested for agricultural activity.
  • the object of the present invention overcomes the above shortcomings and provides a sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative which has a good control effect on inhibiting plant pathogens and can be used as an agricultural fungicide.
  • Another object of the present invention is to provide a method for preparing the sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative.
  • Another object of the present invention is to provide the application of the sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative in inhibiting citrus canker and rice bacterial blight.
  • a sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative of the present invention has the general structural formula as follows:
  • R is a substituted phenyl group or a substituted aromatic heterocyclic group
  • n is the number of carbons in the carbon chain, 2, 3, 4, and 5, respectively.
  • the above-mentioned sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative wherein: the substituted aromatic heterocyclic group is thienyl, furyl, pyrrolyl, pyridyl, etc., and the substituted aromatic heterocyclic group Substituents include C1-6 alkyl groups, C1-6 alkoxy groups, nitro groups, halogen atoms, and hydrogen atoms in the ortho, meta, and para positions.
  • the preparation method of the sulfonamide-containing 4-(N-methyl)aminopiperidine myricetin derivative of the present invention has the following synthetic route:
  • the present invention has obvious beneficial effects. From the above technical scheme, it is known that in the synthesis of intermediate a of the present invention, crystalline potassium carbonate is cheaper than anhydrous potassium carbonate, and the yield is improved.
  • the invention mainly uses the alkaloid structural unit piperidine as a bridge to actively splice the natural product myricetin and sulfonyl chloride, and the obtained compound has higher antibacterial activity.
  • step three 4-((3-(5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-benzopyran-3-yl )Oxy)propyl)(methyl)amino tert-butyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate c) Dissolve it in a 100mL single-neck round bottom flask with about 30mL methanol, and then add 10mL 6mol/L hydrochloric acid methanol solution, stirring at room temperature for about 2h. TLC followed the reaction. When the reaction was over, stop the reaction.
  • the difference is that naphthalene-2-sulfonyl chloride is used as the raw material, and the yield is 66.9%.
  • target compound I3 5,7-Dimethoxy-3-(3-(N-methyl(1-(4-fluorobenzenesulfonyl)piperidinyl))amino)propoxy)-2-(3,4,5 -Trimethoxyphenyl)-4H-chromen-4-one (target compound I3) is prepared as follows:
  • the difference is that 4-fluorobenzenesulfonyl chloride is used as the raw material, and the yield is 45.3%.
  • the difference is that thiophenesulfonyl chloride is used as the raw material, and the yield is 63.3%.
  • target compound I5 5,7-Dimethoxy-3-(3-(N-methyl(1-(4-methoxybenzenesulfonyl)piperidinyl))amino)propoxy)-2-(3,4 ,5-Trimethoxyphenyl)-4H-chromen-4-one (target compound I5) is prepared as follows:
  • step (5) of Example 1 the difference is that 4-methoxybenzenesulfonyl chloride is used as the raw material, and the yield is 62.4%.
  • the difference is that 4-nitrobenzenesulfonyl chloride is used as the raw material, and the yield is 95.8%.
  • the difference is that benzenesulfonyl chloride is used as the raw material, and the yield is 55.3%.
  • step (5) of Example 1 the difference is that pyridine-2-sulfonyl chloride is used as the raw material, and the yield is 47.6%.
  • target compound IX 5,7-Dimethoxy-3-(3-(N-methyl(1-(quinolin-7-ylsulfonyl)piperidinyl))amino)propoxy)-2-(3,4 ,5-Trimethoxyphenyl)-4H-chromen-4-one (target compound IX) is prepared as follows:
  • step (5) of Example 1 the difference is that quinoline-7-sulfonyl chloride is used as the raw material, and the yield is 44.7%.
  • step (5) of Example 1 the difference is that 2-nitrobenzenesulfonyl chloride is used as a raw material, and the yield is 45.5%.
  • step (2) of Example 1 As in step (2) of Example 1. The difference is that 1,4-dibromobutane is used as the raw material.
  • target compound I15 5,7-Dimethoxy-3-(4-(N-methyl(1-(4-methoxybenzenesulfonyl)piperidinyl))amino)butoxy)-2-(3,4 ,5-Trimethoxyphenyl)-4H-chromene-4-one (target compound I15) is prepared as follows:
  • the turbidity method was used to test the inhibitory activity of the target compounds against citrus canker (X.citri), tobacco bacterial wilt (R.sola Nacearum), and rice bacterial blight (X.oryzae).
  • the specific operation steps are as follows:
  • test tubes Wash and sterilize the test tubes and place them on the test tube rack. Use a pipette to pipette 4.0 mL of the solution in the first step (1) into each test tube and add a rubber stopper. Pack every 6 test tubes once. The bacteria pot is sterilized at 121°C for 20 minutes and then ready for use;
  • Corrected OD value OD value of bacteria-containing medium-OD value of sterile medium
  • the turbidimetric method was used to test the effects of the target compounds on Citrus canker, Tobacco wilt, and Pseudomonas solanacearum at the test concentration of 100,50 ⁇ g/mL with the commercial agents Thiabendone and Ecuazole as positive controls. Inhibitory activity (see Table 3). The test results show that all the compounds have a certain inhibitory rate on the tested plant bacteria.
  • the inhibitory rate of compounds I1-8, I14, I16-20 against citrus canker Both surpass thiaclodone (70.68%) and ecumazole (66.63%); the inhibitory rates of compounds I10 and I11 on tobacco bacterial wilt (Rs) are higher than thiaclodone (40.20%) and ecumazole (65.69%)
  • the inhibitory rates of compounds I1-2, I11-18, and I20 to Xoo (Xoo) are higher than those of thiaclodone (70.12%) and ecloconazole (60.50%).
  • the inhibitory rates of compounds I1-8 and I14-20 on citrus canker are higher than those of thiaclodone (44.97%) and ecuazole (50.60%); compound I10 is effective against tobacco bacterial wilt
  • the inhibition rate of (Rs) is close to that of ecuazole (57.63%); the inhibition rate of compounds I1-2, I10-15, I17-18, I20 to Xoo (Xoo) is higher than that of thiaclodone (58.92%) , Ecuazole (39.14%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Environmental Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Dentistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

本发明公开了一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物、制备方法及用途,其结构通式如下所示:其中,R为取代苯基、取代芳杂环基;n为碳链中碳的个数分别为2、3、4、5。取代苯基为苯环上邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子或氢原子。取代芳杂环基为噻吩基、呋喃基、吡咯基、吡啶基等,芳杂环上的取代基为邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子或氢原子。本发明对抑植物病菌有较好的防治效果,可作为农用杀菌剂。

Description

含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物、制备方法及用途 技术领域
本发明涉及化工技术领域,具体来说涉及一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,同时还该含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物的制备方法,及该含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物在抑植物病菌方面的应用。
背景技术
杨梅素(3',4',5',3,5,7-六羟基黄酮醇,Myricetin(Myr)),异名杨梅树皮素、杨梅酮,是从杨梅树皮中分离出来的多羟基黄酮类化合物,化学式C 15H 10O 8,相对分子量318.24,黄色针状或颗粒状结晶,熔点324-326℃,溶于甲醇、乙醇、丙酮,不溶于氯仿、石油醚。存在于壳斗科(Fagaceae)、豆科(leguminosae)、报春花科(primulaceae)、葡萄科(vitaceae)、菊科(compositae)等植物中。据现代药理活性研究显示杨梅素具有抑菌、抗过敏、抗病毒、降血糖、抗炎、抗氧化、保护神经等多种药理活性,显示出丰富的资源优势和巨大的潜在利用价值。
2007年,Naz等(食品科技杂志,2007,72,341-345.)研究了杨梅素对葡萄球菌属、棒杆菌属、链球菌属和枯草芽孢杆菌属4种菌属的体外抑菌活性,结果表明,杨梅素对上述4种菌属均有不同程度的抑菌作用。
2009年,刘等(浙江林学院学报,2009,26,95-99.)采用生长速 率法对杨梅素进行了系统的抑菌作用测定,实验结果表明杨梅素对水稻纹枯病菌、油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、苹果腐烂病菌、棉花枯萎病菌等6种植物病原茵均有较强的抑制活性,EC 50分别是:0.32,0.33,1.09,0.69,0.34和2.09g/L,并对水稻纹枯病茵、油菜菌核病菌和苹果腐烂病菌的抑制活性较高。
2012年,Yu等(生物有机化学与药物化学快报,2012,22,4049-4054.)通过进行荧光共振能量转移(FRET)的双链DNA解旋测定法或使用比色为基础水解试验法,研究了杨梅素对体外SARS病毒的抑制作用,研究发现:杨梅素潜在的抑制了SARS病毒解旋酶蛋白,影响了ATP酶的活性,但是没有解旋活性,且杨梅素对于正常的乳房上皮MCF10A细胞没有表现出细胞毒性。进而说明了杨梅素对体外SARS病毒有很好的抑制作用。
综上所述,杨梅素在医药和农药方面都具有一定的生物活性,之前的研究工作对杨梅素的修饰较少,主要是对杨梅素本身的生物活性进行研究,但还未有将含磺酰胺的4-(N-甲基)氨基哌啶的活性基团引入杨梅素中合成含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物并进行农用活性测试的报道。
发明内容
本发明的目的克服上述缺点而提供的一种对抑植物病菌有较好的防治效果,可作为农用杀菌剂的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物。
本发明的另一目的在于提供该含磺酰胺的4-(N-甲基)氨基哌啶 杨梅素衍生物的制备方法。
发明的再一目的提供该含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物在抑制柑橘溃疡病菌和水稻白叶枯病菌方面的应用。
本发明的一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其结构通式如下所示:
Figure PCTCN2019124090-appb-000001
其中,R为取代苯基、取代芳杂环基;n为碳链中碳的个数分别为2、3、4、5。
上述的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其中:取代苯基为苯环上邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子、氢原子。
上述的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其中:取代芳杂环基为噻吩基、呋喃基、吡咯基、吡啶基等,取代芳杂环基上的取代基为邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子、氢原子。
本发明的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物的制备方法,其合成路线如下:
(1)以杨梅苷和碘甲烷为原料,结晶碳酸钾为催化剂,酸性调节制备3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a):
Figure PCTCN2019124090-appb-000002
(2)以中间体a和不同链长的二溴烷烃为原料,用碳酸钾为催化剂,N,N-二甲基甲酰胺(DMF)为溶剂制备3-溴-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b),如下所示:
Figure PCTCN2019124090-appb-000003
(3)以中间体b和4-(N-甲基)氨基-N-Boc哌啶为原料,用碳酸钾为催化剂,乙腈为溶剂,80℃条件下回流搅拌制备3-(4-(N-甲基)氨基-N-Boc哌啶)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体c),如下所示:
Figure PCTCN2019124090-appb-000004
(4)以中间体c为原料,用HCl脱去Boc保护后得到3-(4-(N-甲基)氨基哌啶)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d),如下所示:
Figure PCTCN2019124090-appb-000005
(5)以中间体d和取代磺酰氯为原料,碳酸钾为催化剂,无水乙醇作溶剂制备含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物(目标化合物I),如下所示:
Figure PCTCN2019124090-appb-000006
本发明的一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物在抑制柑橘溃疡病菌和水稻白叶枯病菌方面的应用。
本发明与现有技术相比,具有明显的有益效果,从以上技术方案可知:本发明中间体a的合成中,结晶碳酸钾比无水碳酸钾廉价,且产率有所提高。本发明主要用生物碱结构单元哌啶作为桥梁,将天然产物杨梅素和磺酰氯进行活性拼接,得到的化合物具有较高的抑菌活性。
具体实施方式
实施例1
5,7-二甲氧基-3-(3-(N-甲基(1-(4-甲基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合 物Ⅰ1)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
在250mL圆底烧瓶中依次加入4.64g杨梅苷(10mmol)、22.09g结晶K 2CO 3(16mmol)和120mL DMF,常温下搅拌0.5~1h后,缓慢滴加7.50mL碘甲烷(120mmol),室温搅拌48h,TLC跟踪反应(甲醇:乙酸乙酯=1:4,V/V)。停止反应后,过滤沉淀,滤渣用二氯甲烷洗涤滤渣,合并滤液,用100mL水稀释,用二氯甲烷萃取三次,合并有机层,减压浓缩,然后将浓缩物溶于30mL无水乙醇中,升温至回流,待溶液澄清后,回流下加入10mL浓盐酸,随后有黄色固体析出,继续反应2h,冷却,过滤,得到粗产物3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a),产率:54.4%。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
在100mL的单口圆底烧瓶中依次加入1.17g(3mmol)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)、1.66g K 2CO 3(12mmol)和30mL DMF,常温搅拌0.5-1h后,加入2.42g 1,3-二溴丙烷(12mmol),在此温度下继续反应12h,TLC监测反应(乙酸乙酯)。反应停止后,反应液用50mL的水分散,乙酸乙酯萃取(3×25mL),得到的乙酸乙酯层依次用1mol/L的HCl,饱和NaHCO 3,饱和NaCl水溶液分别洗涤2次后,合并乙酸乙酯层,无水NaSO 4干燥、减压除去溶剂,减压柱层析分离提纯(石油醚:乙酸乙酯=2:1,V/V)得到白色固体(中间体b),产率:78.9%。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
在100mL的单口圆底烧瓶中加入0.38g(1.78mmol)4-(N-甲基)氨基-N-Boc哌啶、0.5g(3.57mmol)K 2CO 3和40mL乙腈,常温搅拌0.5-1h后加入1g(1.96mmol)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b),随后升温至80℃,在此温度下搅拌4-6h。TLC跟踪反应,当反应结束,停止反应,冷却至室温,抽滤除去碳酸钾及固体杂质,减压除去溶剂,得到酒红色油状粗产物(中间体c)备用,产率:91.7%。
(5)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
步骤三中4-((3-(5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)用约30mL甲醇将其溶于100mL的单口圆底烧瓶中,再加入10mL 6mol/L的盐酸甲醇溶液,常温搅拌约2h。TLC跟踪反应,当反应结束,停止反应,减压除去溶剂后加入少量甲醇溶解,再加入20mL乙酸乙酯,不断搅拌至有黄色固体析出,抽滤,再分别用乙酸乙酯,二氯甲烷洗涤,自然风干得到黄色固体(中间体d),产率:93.2%。
(6)5,7-二甲氧基-3-(3-(N-甲基(1-(4-甲基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目 标化合物Ⅰ1)的制备:
在50mL单口圆底烧瓶中加入0.5g(0.86mmol)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d),0.36g(2.59mmol)K 2CO 3,20mL无水乙醇,常温搅拌至有大量白色固体后加入0.16g(0.86mmol)对甲基苯磺酰氯继续搅拌约2h。TLC跟踪反应,当反应结束,停止反应。将混合物倒入100mL水中,用二氯甲烷萃取(3×20mL),合并有机层,用饱和食盐水洗涤(3×20mL)、无水硫酸钠干燥、减压除去溶剂,得粗产物,经柱层析(乙酸乙酯:甲醇=5:1~1:10,V/V)提纯得到目标化合物Ⅰ1,产率:48.2%。
实施例2
55,7-二甲氧基-3-(3-(N-甲基(1-(萘-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ2)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(萘-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ2)的制备:
如实施例1第(5)步,区别在于以萘-2-磺酰氯为原料,产率:66.9%。
实施例3
5,7-二甲氧基-3-(3-(N-甲基(1-(4-氟苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ3)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(4-氟苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ3)的制备:
如实施例1第(5)步,区别在于以4-氟苯磺酰氯为原料,产率:45.3%。
实施例4
5,7-二甲氧基-3-(3-(N-甲基(1-(噻吩-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ4)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2- (3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(噻吩-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ4)的制备:
如实施例1第(5)步,区别在于以噻吩磺酰氯为原料,产率:63.3%。
实施例5
5,7-二甲氧基-3-(3-(N-甲基(1-(4-甲氧基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ5)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(4-甲氧基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ5)的制备:
如实施例1第(5)步,区别在于4-甲氧基苯磺酰氯为原料,产率:62.4%。
实施例6
5,7-二甲氧基-3-(3-(N-甲基(1-(4-硝基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ6)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(4-硝基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ6)的制备:
如实施例1第(5)步,区别在于4-硝基苯磺酰氯为原料,产率:95.8%。
实施例7
5,7-二甲氧基-3-(3-(N-甲基(1-(苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ7)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(苯磺酰基)哌啶基)) 氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ7)的制备:
如实施例1第(5)步,区别在于苯磺酰氯为原料,产率:55.3%。
实施例8
5,7-二甲氧基-3-(3-(N-甲基(1-(吡啶-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ8)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(吡啶-2-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ8)的制备:
如实施例1第(5)步,区别在于吡啶-2-磺酰氯为原料,产率:47.6%。
实施例9
5,7-二甲氧基-3-(3-(N-甲基(1-(喹啉-7-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ9)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(喹啉-7-基磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ9)的制备:
如实施例1第(5)步,区别在于喹啉-7-磺酰氯为原料,产率: 44.7%。
实施例10
5,7-二甲氧基-3-(3-(N-甲基(1-(2-硝基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ10)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。
(3)4-((3-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丙基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(3-(甲基(哌啶-4-基)氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(3-(N-甲基(1-(2-硝基苯磺酰基)哌啶基))氨基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ10)的制备:
如实施例1第(5)步,区别在于2-硝基苯磺酰氯为原料,产率:45.5%。
实施例11
5,7-二甲氧基-3-(4-(N-甲基(1-(4-甲基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ11)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例1第(2)步。区别在于以1,4-二溴丁烷为原料。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(4-甲基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ11)的制备:
如实施例1第(5)步,产率:33.1%。
实施例12
5,7-二甲氧基-3-(4-(N-甲基(1-(萘-2-基磺酰基)哌啶基)) 氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ12)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(萘-2-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ12)的制备:
如实施例2第(5)步,产率:33.6%。
实施例13
5,7-二甲氧基-3-(4-(N-甲基(1-(3-氟苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ13)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(4-氟苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ13)的制备:
如实施例3第(5)步,产率:36.0%。
实施例14
5,7-二甲氧基-3-(4-(N-甲基(1-(噻吩-2-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ14)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(噻吩-2-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ14)的制备:
如实施例4第(5)步,产率:58.6%。
实施例15
5,7-二甲氧基-3-(4-(N-甲基(1-(4-甲氧基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ15)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(4-甲氧基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ15)的制备:
如实施例5第(5)步,产率:61.2%。
实施例16
5,7-二甲氧基-3-(4-(N-甲基(1-(4-硝基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ16)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基) -4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(4-硝基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ16)的制备:
如实施例6第(5)步,产率:49.5%。
实施例17
5,7-二甲氧基-3-(4-(N-甲基(1-(苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ17)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ17)的制备:
如实施例7第(5)步,产率:49.5%。
实施例18
5,7-二甲氧基-3-(4-(N-甲基(1-(吡啶-2-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ18)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2- (3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(吡啶-2-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ18)的制备:
如实施例8第(5)步,产率:72.2%。
实施例19
5,7-二甲氧基-3-(4-(N-甲基(1-(喹啉-7-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ19)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(喹啉-7-基磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ19)的制备:
如实施例9第(5)步,产率:98.2%。
实施例20
5,7-二甲氧基-3-(4-(N-甲基(1-(2-硝基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目标化合物Ⅰ20)的制备方法如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
如实施例1第(1)步。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)的制备:
如实施例11第(2)步。
(3)4-(4-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-苯并吡喃-3-基)氧基)丁基)(甲基)氨基叔丁基)哌啶-1-羧酸叔丁酯(中间体c)的制备:
如实施例1第(3)步。
(4)5,7-二甲氧基-3-(4-(甲基(哌啶-4-基)氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d)的制备:
如实施例1第(4)步。
(5)5,7-二甲氧基-3-(4-(N-甲基(1-(2-硝基苯磺酰基)哌啶基))氨基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(目 标化合物Ⅰ20)的制备:
如实施例10第(5)步,产率:60.8%。
所合成含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物的理化性质和质谱数据见表1,核磁共振氢谱( 1H NMR)和碳谱( 13C NMR)数据见表2。
表1 实施例化合物I1-I20的理化性质
Figure PCTCN2019124090-appb-000007
表2 实施例化合物I1-I20的核磁共振谱数据
Figure PCTCN2019124090-appb-000008
Figure PCTCN2019124090-appb-000009
Figure PCTCN2019124090-appb-000010
Figure PCTCN2019124090-appb-000011
Figure PCTCN2019124090-appb-000012
Figure PCTCN2019124090-appb-000013
实施例21化合物I1-I20的抗植物细菌活性测试
(1)测试方法
采用浊度法,测试了目标化合物对柑橘溃疡病菌(X.citri)、烟草青枯病菌(R.solaNacearum)、水稻白叶枯病菌(X.oryzae)的抑制活性,具体操作步骤如下:
A.于2000mL烧杯中加入1000mL灭菌蒸馏水,在电磁搅拌下依次加入蛋白胨5.0g、酵母粉1.0g、葡萄糖10.0g、牛肉膏3.0g,待搅拌均匀后以氢氧化钠水溶液调节pH至中性(7.2±0.2);
B.将试管洗净灭菌后置于试管架上,使用移液枪向每支试管内移取第一步(1)中溶液4.0mL后加橡胶塞,每6支试管包装一次,使用灭菌锅在121℃灭菌20min后待用;
C.称取0.00375-0.0042g待测化合物样品于离心管中,以150μL DMSO溶解后分别移取80μL与40μL到灭菌后已编号的离心管中, 另补加40μL DMSO到装有40μL样品溶液的离心管,向上述离心管中各加入4mL Tween-20,同时设噻菌铜或叶枯唑作对照药剂,DMSO作空白对照;
D.每支离心管内溶液移取1mL到3支装第二步(2)中试管内(酒精灯前操作,防止其它细菌污染);
E.取空白96孔板,测空白OD值排除OD值大于0.05的孔,后向每个可用孔中加入200μL(4)中试管内溶液测OD值并记录,最后向每支试管中接入40μL活化后的柑橘溃疡病菌或烟草青枯病菌或水稻白叶枯病菌菌种,用报纸包好在30℃、180rpm恒温摇床中振荡培养24~48h,期间测试试管内溶液OD值以跟踪细菌生长状态,培养结束后在试管中取200μL溶液测OD值并记录;
F.化合物对细菌抑制率计算公式如下,
校正OD值=含菌培养基OD值-无菌培养基OD值
Figure PCTCN2019124090-appb-000014
(2)抗植物病菌的生物活性测试结果
表3 化合物I1-I20在设定浓度下分别对三种细菌的抑制率 a
Figure PCTCN2019124090-appb-000015
Figure PCTCN2019124090-appb-000016
a平均测试三次. b以商品噻菌酮、叶枯唑的抑制活性为阳性对照
采用浊度法,以商品药剂噻菌酮、叶枯唑为阳性对照,在供试浓度为100,50μg/mL时,测试了目标化合物对柑橘溃疡病菌、烟草青枯病菌、水稻百叶枯病菌的抑制活性(见表3)。该测试结果表明:所有化合物对所供试的植物细菌都具有一定的抑制率.其中,当浓度为100μg/mL,化合物Ⅰ1-8、Ⅰ14、Ⅰ16-20对柑橘溃疡病菌(Xac)的抑制率均超过噻菌酮(70.68%)、叶枯唑(66.63%);化合物Ⅰ10和Ⅰ11对烟草青枯病菌(Rs)的抑制率均超过噻菌酮(40.20%)、叶枯唑(65.69%);化合物Ⅰ1-2、Ⅰ11-18、Ⅰ20对水稻白叶枯病菌(Xoo)的抑制率均超过噻菌酮(70.12%)、叶枯唑(60.50%)。当浓度为50μg/mL,化合物Ⅰ1-8、Ⅰ14-20对柑橘溃疡病菌(Xac)的抑制率均超过噻菌酮(44.97%)、叶枯唑(50.60%);化合物Ⅰ10对烟草青枯病菌(Rs)的抑制率接近叶枯唑(57.63%);化合物Ⅰ1-2、Ⅰ10-15、Ⅰ17-18、Ⅰ20对水稻白叶枯病菌(Xoo)的抑制率均超过噻菌酮(58.92%)、叶枯唑(39.14%)。如上实验活性数据表明含 磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物对植物病菌(柑橘溃疡病菌、烟草青枯病菌、水稻百叶枯病菌)具有一定的抑制作用,其中部分目标化合物对植物病菌表现有优良抑制活性,可作为潜在的抑植物病菌药物,具有较好应用前景。
综合如上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,任何未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。

Claims (5)

  1. 一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其结构通式如下所示:
    Figure PCTCN2019124090-appb-100001
    其中,R为取代苯基、取代芳杂环基;n为碳链中碳的个数分别为2、3、4、5。
  2. 如权利要求1所述的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其中:取代苯基为苯环上邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子或氢原子。
  3. 如权利要求1所述的含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物,其中:取代芳杂环基为噻吩基、呋喃基、吡咯基、吡啶基等,芳杂环上的取代基为邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子或氢原子。
  4. 一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物的制备方法,其合成路线如下:
    (1)以杨梅苷和碘甲烷为原料,结晶碳酸钾为催化剂,酸性调节制备3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a):
    Figure PCTCN2019124090-appb-100002
    (2)以中间体a和不同链长的二溴烷烃为原料,用碳酸钾为催化剂,N,N-二甲基甲酰胺(DMF)为溶剂制备3-溴-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b),如下所示:
    Figure PCTCN2019124090-appb-100003
    (3)以中间体b和4-(N-甲基)氨基-N-Boc哌啶为原料,用碳酸钾为催化剂,乙腈为溶剂,80℃条件下回流搅拌制备3-(4-(N-甲基)氨基-N-Boc哌啶)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体c),如下所示:
    Figure PCTCN2019124090-appb-100004
    (4)以中间体c为原料,用HCl脱去Boc保护后得到3-(4-(N-甲基)氨基哌啶)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的盐酸盐(中间体d),如下所示:
    Figure PCTCN2019124090-appb-100005
    (5)以中间体d和取代磺酰氯为原料,碳酸钾为催化剂,无水乙醇作溶剂制备含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物(目标化合物I),如下所示:
    Figure PCTCN2019124090-appb-100006
  5. 一种含磺酰胺的4-(N-甲基)氨基哌啶杨梅素衍生物在抑制柑橘溃疡病菌和水稻白叶枯病菌方面的应用。
PCT/CN2019/124090 2019-06-18 2019-12-09 含磺酰胺的4-(n-甲基)氨基哌啶杨梅素衍生物、制备方法及用途 WO2020253152A1 (zh)

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