Nothing Special   »   [go: up one dir, main page]

WO2023045302A1 - 一种双取代苯并二氢吡喃酮类化合物合成方法及治疗copd等肺部炎症中应用 - Google Patents

一种双取代苯并二氢吡喃酮类化合物合成方法及治疗copd等肺部炎症中应用 Download PDF

Info

Publication number
WO2023045302A1
WO2023045302A1 PCT/CN2022/086250 CN2022086250W WO2023045302A1 WO 2023045302 A1 WO2023045302 A1 WO 2023045302A1 CN 2022086250 W CN2022086250 W CN 2022086250W WO 2023045302 A1 WO2023045302 A1 WO 2023045302A1
Authority
WO
WIPO (PCT)
Prior art keywords
disubstituted
chroman
chemical structure
isobutyl
compound
Prior art date
Application number
PCT/CN2022/086250
Other languages
English (en)
French (fr)
Inventor
姚宏亮
李刚
关文
张亚莉
王华敏
韩日畴
Original Assignee
广东省科学院动物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东省科学院动物研究所 filed Critical 广东省科学院动物研究所
Publication of WO2023045302A1 publication Critical patent/WO2023045302A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • Y—GENERAL 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to 4',7-disubstituted chroman-4-one, a synthesis method thereof, and an application in preparing drugs for treating pulmonary inflammation such as COPD.
  • Pneumonia refers to inflammation of the distal lung, that is, the pulmonary interstitium, alveolar spaces, and terminal airways.
  • the factors that cause inflammation are mainly pathogenic microorganisms such as bacteria, parasites, fungi, and viruses, or chemical allergies, radiation, etc.
  • the clinical symptoms of pneumonia are mainly cough, fever, blood in sputum or expectoration, often accompanied by dyspnea or chest tightness.
  • pneumonia can be divided into viral pneumonia, fungal pneumonia, bacterial pneumonia, mycoplasma pneumonia, physical and chemical pneumonia, allergic pneumonia, other pathogenic pneumonia, immune pneumonia, etc.
  • the most common pneumonia is bacterial pneumonia. It accounts for more than 70% of adult pneumonia.
  • mitogen-activated protein kinase MNK
  • nuclear transcription factor- ⁇ B nuclear transcription factor- ⁇ B
  • other signaling pathways are activated, triggering an inflammatory response for immunity.
  • immune cells such as alveolar macrophages, neutrophils, and lymphocytes are activated by signal transduction pathways, and release inflammatory mediators such as tumor necrosis factor, interleukin, interferon, growth factor, and chemokine.
  • TNF- ⁇ , IL-6, IFN- ⁇ , IL-1 ⁇ , IL-12, IL-18, etc. perform feedback regulation on inflammatory responses and signal transduction pathways.
  • Pulmonary inflammation is an important part of many acute and chronic respiratory diseases such as COPD, asthma, ARDS, etc., which can cause patients to suffer from excessive mucus secretion, airway blockage, emphysema, pulmonary edema, etc., as well as some other organ tissues Concurrent diseases and even systemic diseases can endanger life in severe cases.
  • Flavonoids are widely used in the treatment of pulmonary inflammation due to their unique structural characteristics.
  • the mechanism of flavonoids against pneumonia mainly includes the following pathways: regulating MAPK, NF- ⁇ B and other signal transduction pathways, affecting the proliferation of inflammatory cells in the lung Accumulate, inhibit the release of cytokines, reduce the production of pro-inflammatory mediators, and inhibit the occurrence and development of inflammatory reactions.
  • the object of the present invention is to provide 4', 7-disubstituted chroman-4-one, its synthesis method and its application in the preparation of drugs for treating pulmonary inflammation such as COPD.
  • the 4', 7-disubstituted chroman-4-one of the present invention has a chemical structure as shown in the following formula (a):
  • R group is isobutyl, n-butyl, cyclopentylmethyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, 4-methoxybenzyl, tert-butyl Dimethylsilyl, (tetrahydro-2H-pyran-4-yl)methyl, 2-(piperidin-1-yl)ethyl, 2-morpholinoethyl, 2-(methyl(benzene base) amino) ethyl or 2-(1H-imidazol-1-yl) ethyl, the R group is tert-butyldimethylsilyl, isobutyl or cyclopentylmethyl.
  • the 4',7-disubstituted chroman-4-one of the present invention is preferably one of the following compounds:
  • the second object of the present invention is to provide a synthetic method of 4', 7-disubstituted chroman-4-one, which synthetic method (shown in reaction formula i) comprises the following steps:
  • Naringenin and tert-butyldimethylchlorosilane were catalyzed by imidazole and 4-dimethylaminopyridine to obtain compound a and compound b, and under the catalysis of triphenylphosphine and diisopropyl azodicarboxylate, Compound a is reacted with R 2 OH to obtain compound c, and then, after removing the TBS protecting group with TBAF, compound d is obtained, under the catalysis of triphenylphosphine and diisopropyl azodicarboxylate, compound d is reacted with R 1 OH Compound e is obtained; under the catalysis of triphenylphosphine and diisopropyl azodicarboxylate, compound b reacts with R 1 OH to obtain compound f, wherein R 1 group is isobutyl, n-butyl, cyclopentyl Methyl, cyclopropylmethyl,
  • the third object of the present invention is to provide the application of the above-mentioned 4', 7-disubstituted chroman-4-ones in the preparation of anti-inflammatory drugs.
  • the fourth object of the present invention is to provide an anti-inflammatory drug comprising the above-mentioned 4',7-disubstituted chroman-4-one as an active ingredient.
  • the anti-inflammatory drug is an anti-pulmonary inflammation drug.
  • the anti-inflammatory drug is a drug for treating chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the anti-inflammatory drug includes 4',7-disubstituted chroman-4-one and medically acceptable auxiliary materials.
  • the present invention synthesizes 4',7-disubstituted chroman-4-one, which can effectively inhibit pulmonary inflammatory response through experiments. Therefore, it can be used to suppress the inflammatory response of the lungs, and has broad applications.
  • Figure 1 shows that the structure of compound b was verified by NMR single crystal diffraction
  • Figure 2 is the results of the anti-inflammatory activity of the compounds.
  • Embodiment 1 The synthesis of the key intermediate of the present invention and the synthesis steps of the target product:
  • naringenin YPS 10g, 36.76mmol
  • transfer to a 500ml round bottom flask equipped with a stir bar add 30ml of dichloromethane, and stir at room temperature for 10min.
  • imidazole 5g, 73.52mmol
  • 4-dimethylaminopyridine 0.g, 7.4mmol
  • tert-butyldimethylsilyl chloride 5.6 g, 37.33 mmol
  • the derivatives of the present invention were tested for inhibition of the expression level of pneumonia cytokines, and the test method used conventional QPCR method.
  • Human lung epithelial cells BEAS-2B were cultured in DMEM high glucose medium (complete medium) added with 10% (V/V) FBS, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin.
  • the culture conditions are 37° C., 5% CO 2 , and the cells are subcultured when they reach 80%-90% confluence.
  • Cells in the logarithmic growth phase were used for experiments. Cells were seeded in 24-well plates at 1*10 5 cells/well, and cultured in an environment of 37°C and 5% CO 2 until the growth reached 90%, and they were ready for use. Set up grouping: blank stimulation group (
  • RT-PCR (20uL for each system), including 5x BUFFER 4 ⁇ L, Total RNA X ⁇ L (1pg-1ug, 200-400ng most of the time), DEPC-H 2 O (16-X) ⁇ L placed in 8 strips After entering the tube, mark the serial number, place it in a PCR machine and set it at 50°C for 15 minutes, 85°C for 5s, and 16°C ⁇ for reverse transcription;
  • ⁇ Ct target gene Ct target gene-Ct internal reference gene
  • ⁇ Ct target gene ⁇ Ct test group target gene- ⁇ Ct control group of genes of interest.
  • 2 - ⁇ Ct represents the expression fold of the target gene in the experimental group relative to the control group.
  • the present invention is aimed at the IL-6 gene, using GAPDH as an internal reference gene. Search for the target gene in the gene bank in NCBI, view the sequence of the target gene in GeneBank, and design the primer parameters according to the detection requirements, as shown in Table 1 below.
  • cDNA was synthesized using total RNA as a template, using 5x HiScript II Q Select RT SuperMix, each solution was vortexed and mixed before use, and the liquid remaining on the tube wall was collected after rapid centrifugation. Complete the preparation of the reaction system in an ice bath, and prepare the reverse transcription reaction system as shown in Table 2 after thawing the template RNA on ice:
  • Genome removal and reverse transcription reactions were performed in a Veriti 96 well Thermal Cycler PCR instrument.
  • the reaction program was: 50°C for 15 minutes, 85°C for 5s, and the reverse transcription products were stored in a -20°C refrigerator for later use.
  • Real-time qPCR Prepare the real-time qPCR reaction system as shown in Table 3.
  • the primer sequences used in this experiment are shown in Table 1.
  • the GAPDH gene was selected as the internal reference.
  • the primers were synthesized by Sangon Bioengineering (Shanghai) Co., Ltd.
  • the real-time qPCR reaction was performed in a CFX Connect Real-Time System real-time fluorescent quantitative PCR instrument.
  • the amplification program was: 95°C for 2min, and then 40 cycles: 95°C for 20s, 57°C for 20s, and 72°C for 20s. The temperature was increased from 55°C to 95°C to obtain a melting curve.
  • the results are automatically analyzed by the analysis software, the amplification curve is generated and the Ct value is calculated.
  • 2 - ⁇ ct represents the expression fold of the target gene in the experimental group relative to the control group, which is normalized based on the LPS stimulation group.
  • test results show that 4',7-disubstituted chroman-4-one can effectively inhibit the expression level of IL-6 in the tested human lung epithelial cell lines ( Figure 2), and compounds e8, e9 , e11 and e14 showed better anti-inflammatory activity.
  • the above experimental results show that the compound of the present invention has good anti-pneumonia activity and can be used in the research of anti-pneumonitis drugs.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了双取代苯并二氢吡喃酮合成方法及治疗COPD等肺部炎症中应用。4',7-双取代苯并二氢吡喃-4-酮，其化学结构如下式（a）所示，式（a）中，R1基团是异丁基、正丁基、环戊基甲基、环丙基甲基、环己基甲基、苄基、4-甲氧基苄基、叔丁基二甲基甲硅烷基、（四氢-2H-吡喃-4-基）甲基、2-（哌啶-1-基）乙基、2-吗啉乙基、2-（甲基（苯基）氨基）乙基或2-（1H-咪唑-1-基）乙基，R2基团是叔丁基二甲基甲硅烷基、异丁基或环戊基甲基。本发明合成了4',7-双取代苯并二氢吡喃-4-酮，实验发现，其可以有效抑制肺部炎症反应。因此可以将其用于抑制肺部炎症反应，具有广阔的用途。

Description

一种双取代苯并二氢吡喃酮类化合物合成方法及治疗COPD等肺部炎症中应用 技术领域：
本发明属于生物医药领域，具体涉及4’,7-双取代苯并二氢吡喃-4-酮及其合成方法和在制备治疗COPD等肺部炎症药物中的应用。
背景技术：
肺炎指的是远端肺部，也就是肺间质、肺泡腔以及终末气道出现的炎症。引起炎症的因素主要是细菌、寄生虫、真菌以及病毒等致病微生物，抑或化学过敏、放射线等。肺炎的临床症状主要是咳嗽、发热、痰中有血或者咳痰，经常伴随着呼吸困难或者胸闷等。按照病因学可以把肺炎划分成病毒性肺炎、真菌性肺炎、细菌性肺炎、支原体肺炎、理化性肺炎、变态反应性肺炎、其他病原体肺炎、免疫性肺炎等，最为常见的肺炎是细菌性肺炎，在成人肺炎中占据70％以上。当病原体入侵肺部组织时，机体的丝裂原活化蛋白激酶(MAPK)、核转录因子-κB等信号传导通路被激活，引发炎症反应以进行免疫。炎症反应中，肺泡巨噬细胞、中性粒细胞、淋巴细胞等免疫细胞被信号转导通路激活，并释放肿瘤坏死因子、白细胞介素、干扰素、生长因子、趋化因子等炎性介质，如TNF-α，IL-6，IFN-γ，IL-1β，IL-12，IL-18等对炎症反应以及信号转导通路进行反馈调节。肺部炎症是多种急慢性呼吸系统疾病如COPD、哮喘、ARDS等的重要组成部分，会致使患者出现粘液分泌过多、气道堵塞、肺气肿、肺水肿等病症，以及一些其他器官组织的并发疾病乃至全身性疾病，严重时殃及生命。
黄酮类化合物因其特有结构特点，被广泛的用于肺部炎症的治疗当中。与肺部组织炎症反应发生发展的病理过程特点相对应，黄酮类化合物对抗肺炎的机制主要有以下几个途径：对MAPK、NF-κB等信号传导通路进行调节，影响炎性细胞在肺内的积聚，抑制细胞因子的释放，减少促炎介质的产生，以抑制炎症反应的发生发展。
发明内容：
本发明的目的在于提供4’,7-双取代苯并二氢吡喃-4-酮及其合成方法和在制备治疗COPD等肺部炎症药物中的应用。
本发明的4’,7-双取代苯并二氢吡喃-4-酮，其化学结构如下式(a)所示，
Figure PCTCN2022086250-appb-000001
式(a)中，R 1基团是异丁基、正丁基、环戊基甲基、环丙基甲基、环己基甲基、苄基、4-甲氧基苄基、 叔丁基二甲基甲硅烷基、(四氢-2H-吡喃-4-基)甲基、2-(哌啶-1-基)乙基、2-吗啉乙基、2-(甲基(苯基)氨基)乙基或2-(1H-咪唑-1-基)乙基，R 2基团是叔丁基二甲基甲硅烷基、异丁基或环戊基甲基。
本发明所述的4’,7-双取代苯并二氢吡喃-4-酮优选下述化合物之一：
当R 1是正丁基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000002
当R 1是环戊甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000003
当R 1是环丙甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000004
当R 1是异丁基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000005
当R 1是环己甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000006
当R 1是4-甲氧基苄基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000007
当R 1是叔丁基二甲基甲硅烷基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000008
当R 1是异丁基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000009
当R 1是正丁基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000010
当R 1是环戊甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000011
当R 1是环丙甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000012
当R 1是环己甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000013
当R 1是吗啉乙基，R 2是叔丁基二甲基甲硅烷基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000014
当R 1是2-(N-甲基苯胺基)乙基，R 2是叔丁基二甲基甲硅烷基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
Figure PCTCN2022086250-appb-000015
本发明的第二个目的是提供4’,7-双取代苯并二氢吡喃-4-酮的合成方法，该合成方法(如反应式i所示)包括以下步骤：
将柚皮素与叔丁基二甲基氯硅烷在咪唑、4-二甲氨基吡啶的催化下得到化合物a和化合物b，在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物a与R 2OH反应得到化合物c，然后，用TBAF脱TBS保护基后，得到化合物d，在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物d与R 1OH反应得到化合物e；在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物b与R 1OH反应得到化合物f，其中R 1基团是异丁基、正丁基、环戊基甲基、环丙基甲基、环己基甲基、苄基、4-甲氧基苄基、叔丁基二甲基甲硅烷基、(四氢-2H-吡喃-4-基)甲基、2-(哌啶-1-基)乙基、2-吗啉乙基、2-(N-甲基苯胺基)乙基或2-(1H-咪唑-1-基)乙基，R 2基团是叔丁基二甲基甲硅烷基、异丁基或环戊基甲基；
上述方法的反应式如下所示：
Figure PCTCN2022086250-appb-000016
经过实验发现，上述4’,7-双取代苯并二氢吡喃-4-酮可以抑制细胞因子的释放，减少促炎介质的产生，以抑制炎症反应的发生发展。
因此，本发明的第三个目的是提供上述4’,7-双取代苯并二氢吡喃-4-酮在制备抗炎药物中的应用。
本发明的第四个目的是提供一种抗炎药物，其包括上述4’,7-双取代苯并二氢吡喃-4-酮作为活性成分。
优选，所述的抗炎药物是抗肺部炎症药物。
进一步优选，所述的抗炎药物是治疗慢性阻塞性肺疾病COPD的药物。
优选，所述的抗炎药物包括4’,7-双取代苯并二氢吡喃-4-酮和医学上可接受的辅料。
本发明合成了4’,7-双取代苯并二氢吡喃-4-酮，实验发现，其可以有效抑制肺部炎症反应。因此可以将其用于抑制肺部炎症反应，具有广阔的用途。
附图说明：
图1是化合物b的结构经过核磁单晶衍射得到验证；
图2是化合物的抗炎活性结果。
具体实施方式
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1本发明关键中间体的合成以及目标产物的合成步骤：
Figure PCTCN2022086250-appb-000017
称取柚皮素YPS(10g,36.76mmol)，转移至装有搅拌子的500ml圆底烧瓶中，再加入30ml二氯甲烷，室温搅拌10min。依次加入咪唑(5g,73.52mmol)与4-二甲氨基吡啶(0.9g,7.4mmol)，室温搅拌30min至溶液澄清。分批缓慢加入叔丁基二甲基氯硅烷(5.6g,37.33mmol)，室温搅拌过夜，TLC监控反应进程。翌日，待反应转化率约达80％以上时，加入30ml饱和碳酸氢钠溶液淬灭反应，用30ml二氯甲烷萃取三次，合并有机相，用饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤，旋干溶剂，过柱，得到黄色油状固体(中间体a)，产率：55.8％。IR(neat,cm -1):3358,2956,2932,2888,2859,1641,1569,1518,1469,1371,1345,1309,1269,1181,1089,1068,1018,836,784. 1H NMR(600MHz,Chloroform-d)δ11.95(s,1H),7.33(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.99(dd,J＝19.2,2.4Hz,2H),5.35(dd,J＝13.2,3.0Hz,1H),5.20(s,1H),3.09(dd,J＝17.4,13.2Hz,1H),2.77(dd,J＝17.4,3.0Hz,1H),0.96(s,9H),0.24(s,6H). 13C NMR(150MHz,Chloroform-d)δ196.2,165.0,163.8,162.8,156.1,130.5,127.9,115.6,103.5,101.2,99.8,78.8,43.2,25.4,18.1,-4.4.HRMS(CI +)m/z calculated for C 21H 27O 5Si[M+H] +387.1622,found 387.1617.
中间体b(结构经过核磁单晶衍射验证，图1)，米白色晶状固体，产率：33.4％。IR(neat,cm -1):3278,2957,2925,2855,1714,1641,1512,1464,1379,1340,1269,1165,1085,915,837,808,779. 1H NMR(600MHz,Chloroform-d)δ12.05(s,1H),7.31(d,J＝8.4Hz,2H),6.88(d,J＝9.0Hz,2H),6.41(s,1H),5.99(dd,J＝9.6,2.4Hz,2H),5.35(dd,J＝13.2,2.4Hz,1H),3.09(dd,J＝17.4,13.2Hz,1H),2.78(dd,J＝17.4,3.0Hz,1H),0.99(s,9H),0.21(s,6H). 13C NMR(150MHz,Chloroform-d)δ196.3,164.9,164.3,163.4,156.3,130.8,127.7,120.4,103.1,96.7,95.6,79.1,43.2,25.7,18.2,-4.4.HRMS(CI +)m/z calculated for C 21H 27O 5Si[M+H] +387.1622,found 387.1618.
中间体c的合成：
Figure PCTCN2022086250-appb-000018
将化合物a溶于四氢呋喃中，室温搅拌10min后，依次加入三苯基膦、R 2OH，室温搅拌10min后，在氮气氛围以及冰浴中滴入偶氮二甲酸二异丙酯逐渐恢复室温，室温反应3h，TLC检测反应结束后，进行 柱色谱分离，化合物c。
Figure PCTCN2022086250-appb-000019
R 2OH是异丁醇时，化合物C(黄色粉末状固体)，产率：56.0％。IR(neat,cm -1):3321,2964,2917,1631,1593,1566,1519,1466,1377,1348,1295,1270,1213,1177,1096,1054,1027,883,827,735. 1H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.33(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.05(dd,J＝9.2,2.0Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),5.05(s,1H),3.73(d,J＝6.4Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.10–2.03(m,1H),1.00(d,J＝6.4Hz,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,156.0,130.6,127.9,115.6,102.9,95.5,94.5,78.8,74.7,43.1,27.9,19.0.HRMS(CI +)m/z calculated for C 19H 21O 5[M+H] +329.1384,found 329.1379.
Figure PCTCN2022086250-appb-000020
R 2OH是环戊基甲醇时，化合物C(黄色油状固体)，产率：58.0％。IR(neat,cm -1):2955,2860,1644,1612,1574,1513,1464,1372,1341,1304,1268,1161,1091,1027,915,839,806,782,746. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.31(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.05(dd,J＝7.2,2.4Hz,2H),5.34(dd,J＝13.2,3.2Hz,1H),3.84(d,J＝6.8Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝16.8,2.8Hz,1H),2.40–2.28(m,1H),1.86–1.78(m,2H),1.64–1.58(m,4H),1.31(d,J＝19.6Hz,2H),0.99(s,9H),0.21(s,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,156.1,131.0,127.5,120.3,102.9,95.5,94.5,79.0,72.6,43.2,38.6,29.3,25.6,25.3,18.1,1.0.HRMS(CI +)m/z calculated for C 27H 37O 5Si 1[M+H] +469.2405,found 469.2398.
中间体d的合成：
Figure PCTCN2022086250-appb-000021
将化合物c溶于二氯甲烷中，冰浴中搅拌10min后，滴入四丁基氟化铵，冰浴中反应0.5h，TLC检测 反应结束后，进行柱色谱分离，即得化合物d。
Figure PCTCN2022086250-appb-000022
R 2OH是异丁醇时，化合物d(黄色粉末状固体)，产率：56.0％。IR(neat,cm -1):3321,2964,2917,1631,1593,1566,1519,1466,1377,1348,1295,1270,1213,1177,1096,1054,1027,883,827,735. 1H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.33(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.05(dd,J＝9.2,2.0Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),5.05(s,1H),3.73(d,J＝6.4Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.10–2.03(m,1H),1.00(d,J＝6.4Hz,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,156.0,130.6,127.9,115.6,102.9,95.5,94.5,78.8,74.7,43.1,27.9,19.0.HRMS(CI +)m/z calculated for C 19H 21O 5[M+H] +329.1384,found 329.1379.
Figure PCTCN2022086250-appb-000023
R 2OH是环戊基甲醇时，化合物d(黄色粉末状固体)，产率：46.8％。IR(neat,cm -1):3238,2960,2869,1735,1646,1596,1519,1460,1382,1358,1307,1273,1210,1166,1087,889,833,776,743. 1H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.33(d,J＝8.4Hz,2H),6.88(d,J＝8.8Hz,2H),6.05(dd,J＝9.6,2.4Hz,2H),5.35(dd,J＝13.2,3.2Hz,1H),5.00(s,1H),3.84(d,J＝6.8Hz,2H),3.08(dd,J＝16.8,12.8Hz,1H),2.78(dd,J＝17.2,2.8Hz,1H),2.39–2.28(m,1H),1.85–1.78(m,2H),1.65–1.60(m,4H),1.35–1.28(m,2H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.7,164.0,162.8,156.0,130.6,127.9,115.6,102.9,95.5,94.6,78.8,72.6,43.1,38.6,29.3,25.3.HRMS(CI +)m/z calculated for C 21H 21O 5[M-H] -353.1395,found 353.1400.
化合物e的合成：
Figure PCTCN2022086250-appb-000024
将化合物d溶于四氢呋喃中，室温搅拌10min后，依次加入三苯基膦、R 1OH，室温搅拌10min后， 在氮气氛围以及冰浴中滴入偶氮二甲酸二异丙酯逐渐恢复室温，室温反应4-14h，TLC检测反应结束后，进行柱色谱分离，得到目标化合物(化合物e)。
实施例2 7-环戊甲氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e1)的合成：
Figure PCTCN2022086250-appb-000025
除了使用相应的原料外，按照实施例1的方法制备，其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是环戊甲醇。产率：66.7％。IR(neat,cm -1):3053,2955,2869,1647,1617,1573,1518,1465,1427,1404,1337,1298,1254,1198,1163,1093,1073,1031,995,980,831,808,759,739. 1H NMR(600MHz,Chloroform-d)δ12.02(s,1H),7.36(d,J＝8.4Hz,2H),6.94(d,J＝9.0Hz,2H),6.04(dd,J＝13.8,2.4Hz,2H),5.35(dd,J＝12.6,3.0Hz,1H),3.85(d,J＝6.6Hz,2H),3.72(d,J＝6.6Hz,2H),3.09(dd,J＝17.4,13.2Hz,1H),2.77(dd,J＝17.4,3.0Hz,1H),2.38–2.36(m,1H),2.09–2.05(m,1H),1.87–1.82(m,2H),1.66–1.58(m,4H),1.39–1.5(m,2H),1.00(d,J＝7.2Hz,6H). 13C NMR(150MHz,Chloroform-d)δ196.0,167.7,164.1,162.9,159.8,130.2,127.7,114.8,95.6,94.6,79.0,74.8,72.4,43.2,39.0,29.5,28.0,25.4,19.1.HRMS(CI +)m/z calculated for C 25H 31O 5[M+H] +411.2166,found 411.2159.
实施例3 7-正丁氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e2)的合成：
Figure PCTCN2022086250-appb-000026
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是正丁醇。产率：80.0％。IR(neat,cm -1):2954,2872,1638,1585,1518,1462,1444,1376,1352,1306,1273,1209,1165,1085,1069,1028,972,888,829,796,744. 1H NMR(400MHz,Chloroform-d)δ12.02(s,1H),7.36(d,J＝8.4Hz,2H),6.94(d,J＝8.4Hz,2H),6.04(dd,J＝9.2,2.4Hz,2H),5.34(dd,J＝12.8,2.8Hz,1H),3.98(t,J＝6.8Hz,2H),3.72(d,J＝6.4Hz,2H),3.08(dd,J＝16.8,12.8Hz,1H),2.77(dd,J＝17.2,3.2Hz,1H),2.12–2.02(m,1H),1.82–1.74(m,2H),1.55–1.46(m,2H),1.01–0.97(m,9H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.5,130.1,127.6,114.6,102.9,95.4,94.5,78.9,74.7,67.7,43.1,31.2,27.9,19.1,19.0,13.8.HRMS(CI +)m/z calculated for C 23H 27O 5[M-H] -383.1864,found 383.1869.
实施例4 7-环丙甲氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e3)的合成：
Figure PCTCN2022086250-appb-000027
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是环丙醇。产率：76.7％。IR(neat,cm -1):2958,1632,1581,1517,1467,1445,1377,1352,1307,1280,1251,1211,1167,1084,1027,1010,886,840,803,744. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.36(d,J＝8.4Hz,2H),6.95(d,J＝8.8Hz,2H),6.04(dd,J＝9.2,2.4Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),3.82(d,J＝6.8Hz,2H),3.72(d,J＝6.4Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.12–2.02(m,1H),1.29–1.25(m,1H),1.00(d,J＝6.8Hz,6H),0.68–0.63(m,2H),0.38–0.34(m,2H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.4,130.3,127.6,114.7,95.5,94.5,78.9,74.7,72.8,43.1,27.9,19.0,10.1,3.2.HRMS(CI +)m/z calculated for C 23H 27O 5[M+H] +383.1853,found 383.1839.
实施例5 7-对甲氧基苄氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e4)的合成：
Figure PCTCN2022086250-appb-000028
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是对甲氧基苄醇。产率：66.7％。IR(neat,cm -1):3078,2959,2923,2857,1647,1627,1578,1516,1468,1398,1373,1349,1304,1245,1204,1165,1097,1066,1017,837,808,742. 1H NMR(600MHz,Chloroform-d)δ12.01(s,1H),7.37(dd,J＝8.4,5.4Hz,4H),7.01(d,J＝8.4Hz,2H),6.93(d,J＝9.0Hz,2H),6.04(dd,J＝15.0,2.4Hz,2H),5.36(dd,J＝12.6,3.0Hz,1H),5.01(s,2H),3.82(s,3H),3.72(d,J＝6.6Hz,2H),3.09(dd,J＝16.8,13.2Hz,1H),2.78(dd,J＝16.8,3.0Hz,1H),2.09–2.05(m,1H),1.00(d,J＝6.6Hz,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.5,159.2,130.5,129.2,128.6,127.6,115.0,114.0,102.9,95.5,94.5,78.9,74.7,69.8,55.3,43.1,27.9,19.0.HRMS(CI +)m/z calculated for C 27H 27O 6[M-H] -447.1813,found 447.1823.
实施例6 7-(叔丁基二甲基甲硅烷基)氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e5)的合成：
Figure PCTCN2022086250-appb-000029
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，不需要进行实施例1中的后2步反应得到化合物c(即，化合物e5)。产率：64.3％。IR(neat,cm -1):2958,2931,2859,1644,1612,1574,1513,1469,1372,1341,1304,1268,1163,1091,916,839,806,782. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.31(d,J＝8.4Hz,2H),6.88(d,J＝8.8Hz,2H),6.05(dd,J＝6.4,2.0Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),3.73(d,J＝6.8Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,2.8Hz,1H),2.12–2.02(m,1H),1.00–0.99(m,15H),0.22(s,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,156.1,131.0,127.5,120.3,102.9,95.5,94.5,79.0,74.7,43.2,27.9,25.6,19.0,18.1,1.0.HRMS(CI +)m/z calculated for C 25H 35O 5Si 1[M+H] +443.2248,found 443.2239.
实施例7 7-异丁氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e6)的合成：
Figure PCTCN2022086250-appb-000030
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是异丁醇。产率：76.7％。IR(neat,cm -1):3345,2963,2937,2913,2878,1653,1614,1573,1513,1470,1403,1357,1302,1263,1245,1169,1119,1095,1069,1034,845,763,742. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.36(d,J＝8.4Hz,2H),6.94(d,J＝8.8Hz,2H),6.04(dd,J＝8.8,2.0Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),3.73(t,J＝6.4Hz,4H),3.09(dd,J＝17.2,12.8Hz,1H),2.78(dd,J＝17.2,2.8Hz,1H),2.15–2.02(m,2H),1.02(dd,J＝14.0,6.8Hz,12H). 13C NMR(100MHz,Chloroform-d)δ196.1,167.8,164.3,163.1,159.9,130.4,127.8,115.0,103.2,95.7,94.8,79.1,74.9,74.7,43.4,28.4,28.2,19.4,19.2.HRMS(CI +)m/z calculated for C 23H 29O 5[M+H] +385.2010,found 385.2002.
实施例8 7-环己甲氧基-5-羟基-2-(4-异丁氧基苯基)苯并二氢吡喃-4-酮(e7)的合成：
Figure PCTCN2022086250-appb-000031
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是异丁醇，目标化合物e的合成中，R 1OH使用的是环己甲醇。产率：86.7％。IR(neat,cm -1):2926,2856,1635,1579,1518,1461,1399,1369,1309,1253,1163,1097,1069,1025,893,836,814,795,744. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.35(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.04(dd,J＝9.2,2.4Hz,2H),5.35(dd,J＝12.8,3.2Hz,1H),3.75(dd,J＝18.8,6.4Hz,4H),3.09(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝16.8,2.8Hz,1H),2.10–2.04(m,1H),1.90–1.89(m,1H),1.81–1.70(m,5H),1.35–1.19(m,5H),1.00(d,J＝6.8Hz,6H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.7,130.0,127.6,114.7,102.9,95.5,94.5,78.9,74.7,73.5,43.1,37.6,29.8,27.9,26.4,25.7,19.0.HRMS(CI +)m/z calculated for C 26H 33O 5[M+H] +425.2323,found 425.2319.
实施例9 7-正丁氧基-5-羟基-2-(4-环戊甲氧基苯基)苯并二氢吡喃-4-酮(e8)的合成：
Figure PCTCN2022086250-appb-000032
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是环戊基甲醇，目标化合物e的合成中，R 1OH使用的是正丁醇。产率：56.7％。IR(neat,cm -1):2951,2865,1651,1616,1579,1516,1464,1376,1330,1308,1278,1257,1244,1213,1168,1089,1029,974,889,829,795,746. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.36(d,J＝8.8Hz,2H),6.94(d,J＝8.4Hz,2H),6.08(dd,J＝9.2,2.4Hz,2H),5.35(dd,J＝12.8,3.2Hz,1H),3.98(t,J＝6.4Hz,2H),3.84(d,J＝7.2Hz,2H),3.09(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.39–2.28(m,1H),1.85–1.74(m,4H),1.65–1.55(m,4H),1.53–1.45(m,2H),1.35–1.29(m,2H),0.98(t,J＝7.2Hz,3H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.5,130.1,127.6,114.7,102.9,95.5,94.5,78.9,72.6,67.7,43.1,38.6,31.2,29.3,25.3,19.2,13.8.HRMS(CI +)m/z calculated for C 25H 29O 5[M-H] -409.2021,found 409.2029.
实施例10 7-异丁氧基-5-羟基-2-(4-环戊甲氧基苯基)苯并二氢吡喃-4-酮(e9)的合成：
Figure PCTCN2022086250-appb-000033
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是环戊基甲醇，目标化合物e的合成中，R 1OH使用的是异丁醇。产率：46.4％。IR(neat,cm -1):2957,2870,1644, 1574,1515,1467,1372,1341,1302,1253,1198,1160,1091,1030,887,830,743. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.36(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),6.04(dd,J＝9.2,2.4Hz,2H),5.35(dd,J＝12.8,3.2Hz,1H),3.84(d,J＝7.2Hz,2H),3.74(d,J＝6.8Hz,2H),3.09(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.39–2.28(m,1H),2.16–2.03(m,1H),1.86–1.78(m,2H),1.66–1.55(m,4H),1.36–1.29(m,2H),1.03(d,J＝6.4Hz,6H). 13C NMR(100MHz,Chloroform-d)δ196.1,167.9,164.3,163.1,159.9,130.4,127.8,115.0,103.2,95.7,94.8,79.1,74.7,72.8,43.4,38.9,29.5,28.4,25.5,19.4.HRMS(CI +)m/z calculated for C 25H 31O 5[M+H] +411.2166,found 411.2158.
实施例11 7-环己甲氧基-5-羟基-2-(4-环戊甲氧基苯基)苯并二氢吡喃-4-酮(e10)的合成：
Figure PCTCN2022086250-appb-000034
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是环戊基甲醇，目标化合物e的合成中，R 1OH使用的是环己甲醇。产率：75.0％。IR(neat,cm -1):3047,2962,2927,2854,1632,1579,1517,1465,1368,1311,1253,1179,1096,1070,1025,893,863,837,814,745. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.35(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.04(dd,J＝9.6,2.4Hz,2H),5.35(dd,J＝13.2,3.2Hz,1H),3.83(d,J＝6.8Hz,2H),3.77(d,J＝6.4Hz,2H),3.09(dd,J＝17.2,12.8Hz,1H),2.77(dd,J＝17.2,2.8Hz,1H),2.39–2.28(m,1H),1.89–1.84(m,3H),1.82–1.73(m,5H),1.64–1.58(m,4H),1.35–1.22(m,5H),1.10–1.01(m,2H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.7,130.0,127.6,114.7,102.9,95.5,94.5,78.9,73.5,72.6,43.1,38.6,37.6,29.8,29.3,26.4,25.7,25.3.HRMS(CI +)m/z calculated for C 28H 35O 5[M+H] +451.2479,found 451.2486.
实施例12 7-环戊甲氧基-5-羟基-2-(4-环戊甲氧基苯基)苯并二氢吡喃-4-酮(e11)的合成：
Figure PCTCN2022086250-appb-000035
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是环戊基甲醇，目标化合物e的合成中，R 1OH使用的是环戊甲醇。产率：50.0％。IR(neat,cm -1):3055,2955,2865,1648,1616,1572,1517,1464,1403,1344,1301,1251,1167,1123,1093,1073,1029,989,939,864,833,810,766,744. 1H NMR(600MHz,Chloroform-d)δ12.02(s,1H),7.36(d,J＝8.4Hz,2H),6.94(d,J＝9.0Hz,2H), 6.04(dd,J＝13.8,1.8Hz,2H),5.35(dd,J＝13.2,3.0Hz,1H),3.84(t,J＝7.2Hz,4H),3.09(dd,J＝17.4,13.2Hz,1H),2.77(dd,J＝16.8,3.0Hz,1H),2.41–2.30(m,2H),1.87–1.79(m,4H),1.68–1.56(m,8H),1.39–1.28(m,4H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.7,130.1,127.6,114.7,102.9,95.5,94.5,78.90,72.6,72.3,43.1,38.9,38.6,29.3(d,J＝16.4Hz),25.3(d,J＝10.3Hz).HRMS(CI +)m/z calculated for C 27H 33O 5[M+H] +437.2323,found 437.2309.
实施例13 7-环丙甲氧基-5-羟基-2-(4-环戊甲氧基苯基)苯并二氢吡喃-4-酮(e12)的合成：
Figure PCTCN2022086250-appb-000036
除了使用相应的原料外，按照实施例1的方法制备。其中，中间体c的合成中，R 2OH使用的是环戊基甲醇，目标化合物e的合成中，R 1OH使用的是环丙基甲醇。产率：82.1％。IR(neat,cm -1):3088,3009,2947,2865,1650,1613,1581,1515,1445,1404,1377,1330,1307,1280,1242,1215,1166,1089,1028,890,828,801,746. 1H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.36(d,J＝8.7Hz,2H),6.94(d,J＝8.8Hz,2H),6.04(dd,J＝9.2,2.0Hz,2H),5.35(dd,J＝13.2,3.2Hz,1H),3.83(dd,J＝7.2,4.8Hz,4H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,2.8Hz,1H),2.40–2.28(m,1H),1.85–1.78(m,2H),1.65–1.56(m,4H),1.34–1.26(m,3H),0.68–0.63(m,2H),0.36(dd,J＝10.8,4.8Hz,2H). 13C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,159.4,130.3,127.6,114.7,102.9,95.5,94.5,78.9,72.8,72.6,43.1,38.6,29.3,25.3,10.1,3.2.HRMS(CI +)m/z calculated for C 25H 29O 5[M+H] +409.2010,found 409.1998.
实施例14 7-吗啉乙氧基-5-羟基-2-(4-(叔丁基二甲基甲硅烷基)氧基苯基)苯并二氢吡喃-4-酮(e13)的合成：
Figure PCTCN2022086250-appb-000037
将化合物b溶于四氢呋喃中，室温搅拌10min后，依次加入三苯基膦、R 1OH，室温搅拌10min后，在氮气氛围以及冰浴中滴入偶氮二甲酸二异丙酯逐渐恢复室温，室温反应3h，TLC检测反应结束后，进行柱色谱分离，化合物f。
Figure PCTCN2022086250-appb-000038
当R 1OH使用的是吗啉乙醇时，化合物e13(即，化合物f1)的产率：61.7％。IR(neat,cm -1):3300,2960,2928,2855,1726,1638,1573,1512,1543,1454,1374,1342,1301,1267,1199,1165,1119,1089,1031,917,839,803,110. 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.30(d,J＝8.4Hz,2H),6.88(d,J＝8.0Hz,2H),6.05(d,J＝6.0Hz,2H),5.35(d,J＝10.4Hz,1H),4.11(t,J＝5.6Hz,2H),3.71(d,J＝4.8Hz,4H),3.08(dd,J＝16.8,12.8Hz,1H),2.79(d,J＝6.0Hz,2H),2.77(s,1H),2.56(s,4H),0.99(s,9H),0.21(s,6H). 13C NMR(125MHz,Chloroform-d)δ196.0,166.8,164.0,162.8,156.1,130.8,127.5,120.3,103.1,95.5,94.5,79.0,66.7,66.2,57.1,53.9,43.1,29.6,25.5,-4.5.HRMS(CI +)m/z calculated for C 27H 38NO 6Si[M+H] +500.2463,found 500.2458.
实施例15 7-(N-甲基(苯基)氨基)乙氧基-5-羟基-2-(4-(叔丁基二甲基甲硅烷基)氧基苯基)苯并二氢吡喃-4-酮(e14)的合成：
Figure PCTCN2022086250-appb-000039
除了使用相应的原料外，按照实施例14的方法制备。其中，R 1OH使用的是2-(N-甲基苯胺基)乙醇。化合物e14(即，化合物f2)的产率：36.7％。IR(neat,cm -1):3513,3292,2923,2848,1631,1568,1507,1444,1374,1349,1293,1260,1194,1172,1077,1036,822,800,742,686. 1H NMR  1H NMR(400MHz,Chloroform-d)δ11.99(s,1H),7.31(d,J＝8.0Hz,2H),7.23(d,J＝7.2Hz,2H),6.88(d,J＝8.0Hz,2H),6.73(t,J＝8.0Hz,3H),6.02(d,J＝9.6Hz,2H),5.34(d,J＝10.8Hz,1H),4.14(t,J＝5.6Hz,2H),3.74(t,J＝5.6Hz,2H),3.07(dd,J＝17.2,4.0Hz,1H),3.02(s,3H),2.78(dd,J＝17.2,3.2Hz,1H),0.88(s,1H). 13C NMR(125MHz,Chloroform-d)δ195.9,166.9,164.0,162.8,156.1,148.6,130.4,129.2,127.8,116.7,115.6,112.1,103.1,95.4,94.5,78.8,65.8,51.5,43.1,39.0.HRMS(CI +)m/z calculated for C 24H 24NO 5[M+H] +406.1649,found 406.1645.
实施例16 4’,7-双取代苯并二氢吡喃-4-酮在抗炎活性方面的研究
对本发明的衍生物进行了肺炎细胞因子表达水平的抑制试验，试验方法采用常规的QPCR法。
一、细胞的培养
人源肺上皮细胞BEAS-2B采用加入10％(V/V)FBS、100U/mL青霉素及100μg/mL链霉素的DMEM高糖培养基(完全培养基)进行培养。培养条件为37℃、5％CO 2，细胞长至80％-90％融合度时进行传代。
二、细胞给药与诱导细胞炎症
采用处于对数生长期的细胞进行实验，细胞以1*10 5个/孔接种于24孔板，37℃、5％CO 2的环境中培养至生长到90％，待用。设置分组：空白刺激组(|)，LPS刺激组(+)，阳性对照组(柚皮素)和给药组(e1-14)。小心的去除培养基，阳性对照组和给药组分别加入含有100μM化合物的新鲜完全培养基，空白刺激组和LPS刺激组则加入等体积的DMSO。1小时后，除空白刺激组，均分别加入1μg/mL LPS 2小时以诱导细胞炎症。
三、RNA的提取及qPCR的测定
1.将培养好的细胞完全弃去培养基后，每孔加入0.5mL RNA提取试剂盒中的RA2进行裂解(可在-80℃冻存一晚上，裂解效果更佳，也可在4℃裂解10min后收集)；
2.收集细胞裂解物按试剂盒说明书提取Total RNA，并用超微量紫外可见分光光度计测其浓度；
3.RT-PCR(每个体系20uL)，包括5x BUFFER 4μL，Total RNA X μL(1pg-1ug，大多数时候取200-400ng)，DEPC-H 2O(16-X)μL置于8连管中后，标记序号，置于PCR仪中设置50℃15min，85℃5s，16℃∝的时长进行逆转录；
4.转录后的cDNA加80μL DEPC-H 2O至100μL，离心混匀，-20℃备用；
5.按(SYBR 10μL+DEPC-H 2O 10μL+引物0.5μL)乘以样品数，取18μL/孔至96孔板中，再加入2μL cDNA，构成20μL体系，1200rpm 1min离心混匀；
6.将样品板放入CFX Connect Real-Time System(实时荧光定量PCR仪)中进行检测，按照(95℃ 2min，95℃ 20s，57℃ 20s，72℃ 20s)共循环39次，95℃ 1min，55℃ 30s，95℃ 30s的程序进行检测，仪器共耗时2.5h；
7.2h后保存数据并分析，采用2 -ΔΔCt法分析实验结果，计算公式如下：△Ct目的基因＝Ct目的基因-Ct内参基因，△△Ct目的基因＝△Ct实验组目的基因-△Ct对照组目的基因。2 -ΔΔCt表示实验组相对于对照组目的基因的表达倍数。
扩增引物的设计：本发明针对的是IL-6基因，以GAPDH为内参基因。在NCBI里的基因库中搜索目的基因，查看GeneBank中的目的基因序列，根据检测要求进行引物参数的设计，如下表1所示。
表1
Figure PCTCN2022086250-appb-000040
cDNA的合成：以总RNA为模板合成cDNA，采用5x HiScript II Q Select RT SuperMix，使用前将每种溶液涡旋振荡混匀，快速离心后收集残留在管壁的液体。在冰浴中完成反应体系的配制，在冰上解冻模板RNA后，按照表2所示配制反转录反应体系：
表2
Figure PCTCN2022086250-appb-000041
在Veriti 96 well Thermal Cycler PCR仪中进行去除基因组及反转录反应，反应程序为：50℃ 15min,85℃ 5s，反转录产物置于-20℃冰箱中保存备用。
Real-time qPCR：按照表3所示配制real-time qPCR反应体系，在本实验中使用的引物序列见表1，选择GAPDH基因作为内参，引物由生工生物工程(上海)股份有限公司合成。
表3
Figure PCTCN2022086250-appb-000042
在CFX Connect Real-Time System实时荧光定量PCR仪中进行real-time qPCR反应，扩增程序为：95℃2min，然后进行40个循环：95℃ 20s,57℃ 20s，72℃ 20s。温度从55℃升至95℃，得到熔解曲线。结果由分析软件自动分析，生成扩增曲线并计算Ct值。采用2 -ΔΔct法分析实验结果，计算公式如下：△Ct 目的基因＝Ct 目的基因-Ct 内参基因，△△Ct 目的基因＝△Ct 实验组目的基因-△Ct 对照组目的基因。2 -ΔΔct表示实验组相对于对照组目的 基因的表达倍数，以LPS刺激组为基准进行归一化处理。
结果如表4所示：
表4
Figure PCTCN2022086250-appb-000043
测试结果显示，4’,7-双取代苯并二氢吡喃-4-酮在所测试的人肺源上皮细胞株中能有效抑制IL-6的表达水平(图2)，化合物e8，e9，e11和e14表现出来更好的抗炎活性。以上实验结果表明，本发明的化合物具有良好的抗肺炎活性，可用于抗肺部炎症药物的研究。

Claims (10)

  1. 4’,7-双取代苯并二氢吡喃-4-酮，其化学结构如下式(a)所示，
    Figure PCTCN2022086250-appb-100001
    式(a)中，R 1基团是异丁基、正丁基、环戊基甲基、环丙基甲基、环己基甲基、苄基、4-甲氧基苄基、叔丁基二甲基甲硅烷基、(四氢-2H-吡喃-4-基)甲基、2-(哌啶-1-基)乙基、2-吗啉乙基、2-(N-甲基苯胺基)乙基或2-(1H-咪唑-1-基)乙基，R 2基团是叔丁基二甲基甲硅烷基、异丁基或环戊基甲基。
  2. 根据权利要求1所述的4’,7-双取代苯并二氢吡喃-4-酮，其特征在于，所述的4’,7-双取代苯并二氢吡喃-4-酮为以下任一所示：
    当R 1是正丁基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100002
    当R 1是环戊甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100003
    当R 1是环丙甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100004
    当R 1是异丁基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100005
    当R 1是环己甲基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100006
    当R 1是4-甲氧基苄基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100007
    当R 1是叔丁基二甲基甲硅烷基，R 2是异丁基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100008
    当R 1是异丁基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100009
    当R 1是正丁基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100010
    当R 1是环戊甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100011
    当R 1是环丙甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100012
    当R 1是环己甲基，R 2是环戊甲基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100013
    当R 1是吗啉乙基，R 2是叔丁基二甲基甲硅烷基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100014
    当R 1是2-(N-甲基苯胺基)乙基，R 2是叔丁基二甲基甲硅烷基时，所述的4’,7-双取代苯并二氢吡喃-4-酮的化学结构为：
    Figure PCTCN2022086250-appb-100015
  3. 一种权利要求1所述的4’,7-双取代苯并二氢吡喃-4-酮的合成方法，其特征在于，该合成方法的如反应式i所示，包括以下步骤：
    将柚皮素与叔丁基二甲基氯硅烷在咪唑、4-二甲氨基吡啶的催化下得到化合物a和化合物b，在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物a与R 2OH反应得到化合物c，然后，用TBAF脱TBS保护基后，得到化合物d，在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物d与R 1OH反应得到化合物e；在三苯基膦与偶氮二甲酸二异丙酯的催化下，化合物b与R 1OH反应得到化合物f，其中R 1基团是异丁基、正丁基、环戊基甲基、环丙基甲基、环己基甲基、苄基、4-甲氧基苄基、叔丁基二甲基甲硅烷基、(四氢-2H-吡喃-4-基)甲基、2-(哌啶-1-基)乙基、2-吗啉乙基、2-(N-甲基苯胺基)乙基或2-(1H-咪唑-1-基)乙基，R 2基团是叔丁基二甲基甲硅烷基、异丁基或环戊基甲基；
    上述方法的反应式如下所示：
    Figure PCTCN2022086250-appb-100016
  4. 权利要求1所述的4’,7-双取代苯并二氢吡喃-4-酮在制备抗炎药物中的应用。
  5. 根据权利要求4所述的应用，其特征在于，所述的抗炎药物是抗肺部炎症药物。
  6. 根据权利要求5所述的应用，其特征在于，所述的抗炎药物是治疗慢性阻塞性肺疾病COPD的药物。
  7. 一种抗炎药物，其特征在于，包括权利要求1所述的4’,7-双取代苯并二氢吡喃-4-酮作为活性成分。
  8. 根据权利要求7所述的抗炎药物，其特征在于，所述的抗炎药物是抗肺部炎症药物。
  9. 根据权利要求8所述的抗炎药物，其特征在于，所述的抗炎药物是治疗慢性阻塞性肺疾病COPD的药物。
  10. 根据权利要求7所述的抗炎药物，其特征在于，所述的抗炎药物包括4’,7-双取代苯并二氢吡喃-4-酮和医学上可接受的辅料。
PCT/CN2022/086250 2021-09-26 2022-04-12 一种双取代苯并二氢吡喃酮类化合物合成方法及治疗copd等肺部炎症中应用 WO2023045302A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111129637.7A CN113816934B (zh) 2021-09-26 2021-09-26 双取代苯并二氢吡喃酮合成方法及治疗copd等肺部炎症中应用
CN202111129637.7 2021-09-26

Publications (1)

Publication Number Publication Date
WO2023045302A1 true WO2023045302A1 (zh) 2023-03-30

Family

ID=78921275

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/086250 WO2023045302A1 (zh) 2021-09-26 2022-04-12 一种双取代苯并二氢吡喃酮类化合物合成方法及治疗copd等肺部炎症中应用

Country Status (2)

Country Link
CN (1) CN113816934B (zh)
WO (1) WO2023045302A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101891730A (zh) * 2010-07-30 2010-11-24 西南大学 7-烷氧基甲基橙皮素的合成及其制药用途
CN107445935A (zh) * 2017-07-10 2017-12-08 安徽医科大学 一种酰胺基取代的橙皮素类衍生物及其制备和作为抗炎的药物中的应用
US20200308132A1 (en) * 2017-09-28 2020-10-01 Kinki University T-type calcium channel inhibitor
CN113045527A (zh) * 2021-03-22 2021-06-29 广东省科学院动物研究所 二氢色原酮衍生物及其合成方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI282276B (en) * 2005-04-12 2007-06-11 Univ Taipei Medical Pharmaceutical composition containing flavonoids which possess selective inhibition on phosphodiesterase 4 or 3/4

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101891730A (zh) * 2010-07-30 2010-11-24 西南大学 7-烷氧基甲基橙皮素的合成及其制药用途
CN107445935A (zh) * 2017-07-10 2017-12-08 安徽医科大学 一种酰胺基取代的橙皮素类衍生物及其制备和作为抗炎的药物中的应用
US20200308132A1 (en) * 2017-09-28 2020-10-01 Kinki University T-type calcium channel inhibitor
CN113045527A (zh) * 2021-03-22 2021-06-29 广东省科学院动物研究所 二氢色原酮衍生物及其合成方法和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HOANG T. KIM-DUNG, HUYNH T. KIM-CHI, NGUYEN THANH-DANH: "Synthesis, characterization, anti-inflammatory and anti-proliferative activity against MCF-7 cells of O-alkyl and O-acyl flavonoid derivatives", BIOORGANIC CHEMISTRY, vol. 63, 1 December 2015 (2015-12-01), US , pages 45 - 52, XP093052450, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2015.09.005 *
HUANG AI-LING, ZHANG YI-LONG, DING HAI-WEN, LI BO, HUANG CHENG, MENG XIAO-MING, LI JUN: "Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 61, 1 August 2018 (2018-08-01), NL , pages 82 - 91, XP093052447, ISSN: 1567-5769, DOI: 10.1016/j.intimp.2018.05.009 *
ZHANG YILONG, ZHENG YAN, SHI WEN, GUO YAHUI, XU TAO, LI ZENG, HUANG CHENG, LI JUN: "Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7-O-Amide Hesperetin Derivatives", MOLECULES, vol. 24, no. 20, 11 October 2019 (2019-10-11), pages 1 - 18, XP093052454, DOI: 10.3390/molecules24203663 *

Also Published As

Publication number Publication date
CN113816934B (zh) 2023-08-01
CN113816934A (zh) 2021-12-21

Similar Documents

Publication Publication Date Title
CN102753553B (zh) 6-氨基-2-{[(1s)-1-甲基丁基]氧基}-9-[5-(1-哌啶基)-7,9-二氢-8h-嘌呤-8-酮马来酸盐
CN113825754B (zh) 包括甲基和三氟甲基的双取代磺酰胺类选择性bcl-2抑制剂
CN116199686A (zh) 三氟甲基取代的磺酰胺类化合物
CN101012211A (zh) 取代的穿心莲内酯衍生物、制备方法及其药物组合物
WO2023045302A1 (zh) 一种双取代苯并二氢吡喃酮类化合物合成方法及治疗copd等肺部炎症中应用
CN109553653B (zh) 一种人参二醇苷衍生物及其制备方法和应用
WO2023236809A1 (zh) 一种2,6-二苯亚甲基环己酮肟类化合物及其制备方法和应用
CN109180649B (zh) 一种含吲哚环的ido抑制剂及其制备方法
HRP20030603A2 (en) Substituted furochromene compounds of antiinflammatory action
CN113004253B (zh) 二-(苯并咪唑)-1,2,3-三唑衍生物及其制备和在炎症性皮肤病中的应用
CN113773295B (zh) 单取代二氢色原酮合成方法及治疗copd等肺部炎症中应用
Boggu et al. Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors
WO2024221972A1 (zh) 顺式烯酰胺类衍生物及其在制备抗炎药物中的应用
CN118084693A (zh) (z)-3-甲氧基-n-甲基-n-苯乙烯基苯甲酰胺及其在制备抗炎药物中的应用
WO2008154801A1 (fr) Dérivé d'acide trans-cinnamique, son procédé de préparation et son utilisation
CN118084712A (zh) (z)-n-甲基-n-苯乙烯基苯甲酰胺及其在制备抗炎药物中的应用
CN113735920B (zh) 一种氰苷类化合物Menisdaurin F在制备抗乙肝病毒药物组合物中的应用
CN112999227B (zh) 一种包含二-(苯并咪唑)-1,2,3-三唑衍生物的药物
CN113773188A (zh) 查尔酮衍生物合成方法及治疗copd等肺部炎症药物中的应用
CN113292532B (zh) 一种多取代萘醌衍生物及其制备方法与应用
JP6338276B2 (ja) 抗癌剤
WO2024109937A1 (zh) 一种喹啉胺类化合物的可药用盐、晶型及其制备方法
WO2023070373A1 (zh) 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用
JP7348214B2 (ja) Ｈｄａｃ６選択的阻害剤の結晶形及びその使用
CN116284048A (zh) 一种化合物及其制备方法、药物组合物和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22871365

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 10.07.2024)