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WO2023090908A1 - Novel flavonoid derivative and pharmaceutical composition comprising same as active ingredient for prevention or treatment of metabolic disease - Google Patents

Novel flavonoid derivative and pharmaceutical composition comprising same as active ingredient for prevention or treatment of metabolic disease Download PDF

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Publication number
WO2023090908A1
WO2023090908A1 PCT/KR2022/018229 KR2022018229W WO2023090908A1 WO 2023090908 A1 WO2023090908 A1 WO 2023090908A1 KR 2022018229 W KR2022018229 W KR 2022018229W WO 2023090908 A1 WO2023090908 A1 WO 2023090908A1
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formula
hydroxy
nmr
mhz
meoh
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PCT/KR2022/018229
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French (fr)
Korean (ko)
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변영주
안명환
김세윤
박승은
최지연
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고려대학교 세종산학협력단
한국과학기술원
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Priority claimed from KR1020220154592A external-priority patent/KR20230074404A/en
Publication of WO2023090908A1 publication Critical patent/WO2023090908A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to a novel flavonoid derivative, and more particularly, to a flavonoid derivative compound exhibiting efficacy in the prevention or treatment of metabolic diseases by inhibiting inositol kinases IPMK and IP6K, and prevention and treatment of metabolic diseases containing the same as an active ingredient It relates to a pharmaceutical composition for treatment.
  • Inositol phosphates have been recognized as secondary messengers involved in various biological processes ranging from cell growth to death.
  • inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5PP-IP5, abbreviation 5-IP7) are 1 or a 'high energy' diphosphate group at position 5.
  • 5-IP7 In mammals, including humans, the biosynthesis of 5-IP7 is catalyzed by three isoforms (IP6K1, IP6K2, and IP6K3) of the IP6 kinase (IP6K) family. 5-IP7 is created. It has been reported that metabolic changes that improve obesity and diabetes appear in the IP6K knockout model.
  • IPMK Mammalian inositol polyphosphate multikinase
  • IP4 Ins(1,3,4,5)P 4 and Ins(1,4,5,6)P 4
  • IP5 Ins(1, 3, 4,5,6)P 5
  • IPMK Mammalian inositol polyphosphate multikinase
  • IPMK deletion significantly reduces cellular levels of downstream IPs such as IP5 and IP7.
  • IPMK can phosphorylate PIP2 at the C-3 position to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
  • IPMK-deficient MEFs produced about 50% less PIP3 than wild-type MEFs and showed significantly less PIP3-dependent Akt phosphorylation and downstream signaling activity, suggesting that IPMK acts as a PI3-kinase for cell growth, inflammation and metabolism in mammalian cells. that control signal transduction.
  • Non-Patent Document 1 Britton RG, Horner-Glister E, Pomenya OA, et al. Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents. Eur J Med Chem 2012;54:952-958.
  • Non-Patent Document 2 Vasselin DA, Westwell AD, Matthews CS, et al. Structural studies on bioactive compounds. Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted 3-phenyl-4h-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related 2-phenylbenzothiazoles. J Med Chem 2006;49:3973-3981.
  • the present inventors completed the present invention by designing, synthesizing, and evaluating flavonoid-based analogs having modifications in the A-ring to identify IP6K2 inhibitors that are superior to natural flavonoids, and identifying novel flavonoid derivatives exhibiting strong IP6K2 inhibitory effects.
  • an object of the present invention is to provide novel flavonoid derivatives exhibiting efficacy in the prevention or treatment of metabolic diseases including obesity and diabetes.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the novel flavonoid derivative as an active ingredient.
  • the present inventors confirmed that the flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b] effectively inhibit the activity of IPMK and IP6K, which are key factors inducing metabolic diseases, and based on this, the present invention was completed. .
  • the present invention relates to a novel flavonoid derivative exhibiting efficacy in preventing or treating metabolic diseases and a pharmaceutical composition for preventing or treating metabolic diseases comprising the same as an active ingredient.
  • One aspect of the present invention relates to flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b]:
  • R' is , , , and any one selected from
  • R 1 and R 2 are the same as or different from each other, and are each independently any one selected from hydrogen, halogen, -OH, -COOH, -CF 3 , -Ph, -OPh, and an alkyl group having 1 to 4 carbon atoms, and
  • X, Y and Z are each independently selected from hydrogen and -OH.
  • the range of the flavonoid derivative represented by [Formula 1a] or [Formula 1b] is not limited thereby, but may be any one selected from flavonoid derivatives represented by [Formula 2] to [Formula 27]. there is.
  • flavonoid derivatives represented by [Formula 1a] or [Formula 1b] are represented by the following [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] ] may be any one selected from flavonoid derivatives represented by
  • the flavonoid derivatives represented by [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] according to the present invention have a carboxylic acid (- COOH) substituted, and exhibits excellent IP6K2 inhibitory activity.
  • the flavonoid derivatives represented by [Formula 2] to [Formula 27] according to the present invention can be specifically prepared through the following synthesis process, and the following [1] is a flavonoid represented by [Formula 1a] according to the present invention It is a flow chart schematically showing the synthesis process of the derivative, and [2] below is a flow chart schematically showing the synthesis process of the flavonoid derivative represented by [Formula 1b] according to the present invention.
  • the flavonoid derivative according to the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • free acid inorganic acids and organic acids can be used.
  • the pharmaceutically acceptable salts of the flavonoid derivatives of the present invention are hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, fumarate, gluconate. , methanesulfonate, glycolate, succinate, 4-toluenesulfonate, gluturonate, embonate, glutamate, or aspartate, but may be selected from the group consisting of, but is not limited thereto, and is commonly used in the art. Salts formed using the various inorganic and organic acids used are all included.
  • the flavonoid derivative according to the present invention may also exist in the form of a solvate (for example, a hydrate).
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases containing the flavonoid derivative represented by [Formula 1a] or [Formula 1b], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • the flavonoid derivative represented by [Formula 1a] or [Formula 1b], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. will be.
  • the composition controls intracellular signal transduction by IPMK and IP6K, and inhibits the activity of IPMK and IP6K.
  • metabolic disease is a general term for diseases caused by an imbalance of carbohydrates, lipids, proteins, vitamins, minerals, and water. include obesity and diabetes.
  • the metabolic disease may be obesity, hypertension, arteriosclerosis, hyperlipidemia, liver disease, cardiomyopathy, myocardial infarction, cerebral infarction, sarcopenia, hyperinsulinemia, hyperglycemia, diabetes or insulin resistance disease, but is not limited thereto.
  • prevention refers to any activity that suppresses or delays the progression of metabolic diseases by administration of the pharmaceutical composition according to the present invention.
  • treatment refers to all activities in which symptoms of metabolic diseases are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
  • the component is included in an amount necessary or sufficient to realize a desired biological effect.
  • the amount to be included as an active ingredient is an amount to treat a target disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition to be treated, the type of composition to be administered, It can vary according to various factors such as the size of the subject, or the severity of the disease or condition. Effective amounts of individual compositions can be determined empirically without undue experimentation by those skilled in the art to which this invention pertains.
  • the pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin), or It means that it reacts with alkali metal ions such as sodium and potassium to form metal salts thereof, or reacts with ammonium ions to form another type of pharmaceutically acceptable salt.
  • an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid
  • pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of a compound.
  • the pharmaceutical composition according to the present invention includes the above-described flavonoid derivative as an active ingredient, and may further include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is one commonly used in formulation, and includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, etc. It is not, and if necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants, etc. may be additionally added to formulate formulations for injections such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • a suitable pharmaceutically acceptable carrier and formulation it can be preferably formulated according to each component using the method disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in dosage form, but may be formulated as an injection, an inhalant, or an external skin preparation.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage depends on the patient's condition, body weight and disease. Depending on the degree, drug form, administration route and time, it can be appropriately selected by those skilled in the art.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitantly used drugs, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
  • the present invention relates to a novel flavonoid derivative compound, and the flavonoid derivative compound according to the present invention can effectively inhibit the activity of IPMK and IP6K, and can fundamentally prevent or treat metabolic diseases using a pharmaceutical composition containing the same. It is expected that there will be
  • 1a is a dose-response IPMK inhibitory activity result of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
  • 1c is a dose-response IP6K2 inhibitory activity result by Experimental Example 1-2) of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
  • FIG. 2 is an in silico molecular docking analysis result for a flavonoid derivative (Compound 20s) (FIG. 2a) and a control quercetin (FIG. 2b) synthesized according to an embodiment of the present invention.
  • Method A mobile phase was acetonitrile and water (55:45, v/v, 0.1% trifluoroacetic acid); Method B mobile phase was acetonitrile and water (50:50, v/v, 0.1% trifluoroacetic acid); Method C mobile phase was acetonitrile and water (45:55, v/v, 0.1% trifluoroacetic acid); Method D mobile phase was acetonitrile and water (40:60, v/v, 0.1% trifluoroacetic acid); Method E mobile phase was acetonitrile and water (35:65, v/v, 0.1% trifluoroacetic acid); Method F mobile phase was acetonitrile and water (30:70, v/v, 0.1% trifluoroacetic acid); Method G mobile phase was acetonitrile and water (25:75, v/v, 0.1% trifluoroacetic acid); Method H mobile phase was acetononitrile and water (55:45, v/v,
  • the crude material was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH or hexane/EtOAc) or washed with an organic solvent such as ether or hexane to give compounds 16a-16d and 20a-20s .
  • the IPMK/IP6K2 inhibitory activity of the flavonoid derivatives according to the present invention synthesized in the Synthesis Example was evaluated by an ADP-Glo kinase assay [using ADP-Glo Kinase Assay (Promega)].
  • the kinase reaction mixture was first shaken and incubated with the respective drugs (diluted in DMSO) at RT for 15 min for pre-incubation, followed by the addition of ATP (final 10 ⁇ M) to initiate the reaction.
  • 20 ng of human recombinant IPMK protein was used per 25 ⁇ L of IPMK reaction mixture (50 mM Hepes, pH 7.4, 10 mM MgCl 2 , 50 mM KCl, 10 ⁇ M IP(1,4,5,6) 4 ).
  • the kinase reaction was carried out at 37° C.
  • kinase assays were prepared in 384-well plates (using 20 ng of recombinant human IP6K2 protein as replicates) for IC 50 estimation of compounds.
  • 20 ng of human recombinant IP6K2 protein was used per 20 ⁇ L of the reaction mixture (50 mM Tris-HCl, pH 6.8, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 ⁇ M IP6).
  • the kinase reaction was carried out for 1 hour at -25 °C with shaking at 300 rpm, and ADP production was measured using a Synergy Neo microplate reader (Biotek) according to the manufacturer's protocol.
  • IP6K2 human recombinant IP6K2 protein was used per 25 ⁇ L of IP6K2 reaction mixture (50 mM Tris-HCl, pH 6.9, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 ⁇ M IP6).
  • Compound 23b [Formula 26] in which the methylpyrazole group was substituted showed a strong inhibitory effect on IPMK with an IC 50 value of 0.77 ⁇ M. This means that the heterocyclic substituent can increase the IPMK inhibitory effect.
  • compound 20s [formula 24] was confirmed to be the most potent inhibitor against IP6K2 with an IC 50 value of 0.55 ⁇ M (FIG. 1b).
  • IP6K2 homology model (UniProt: Q9UHH9) was downloaded from the AlphaFold2 structural database (https://alphafold.ebi.ac.uk) in PDB and FASTA formats.
  • both compound 20s and quercetin formed one hydrogen bond with Lys42 and one hydrogen bond with Leu209.
  • compound 20s formed an additional hydrogen bond with Asp383 through the -OH group of the A ring compared to quercetin.
  • the -COOH group in the B ring of compound 20s formed one hydrogen bond with Thr210 and an additional hydrogen bond with Gln260, while the 3-OH group of quercetin's C ring formed one hydrogen bond with Thr210. , Therefore, it was found that compound 20s is a more potent IP6K2 inhibitor than quercetin.

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Abstract

The present invention relates to a novel flavonoid derivative compound. The flavonoid derivative compound according to the present invention can effectively inhibit the activity of IPMK and IP6K and it is expected that a pharmaceutical composition comprising same can be used to fundamentally prevent or treat metabolic diseases.

Description

신규 플라보노이드 유도체 및 이를 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물Novel flavonoid derivatives and pharmaceutical compositions containing them as active ingredients for preventing or treating metabolic diseases
본 발명은 신규한 플라보노이드 유도체에 관한 것으로서, 더욱 상세하게는 이노시톨 인산화 효소인 IPMK와 IP6K를 저해하여 대사성 질환의 예방 또는 치료에 효능을 나타내는 플라보노이드 유도체 화합물 및 이를 유효성분으로 함유하는 대사성 질환의 예방 및 치료용 약학 조성물에 관한 것이다.The present invention relates to a novel flavonoid derivative, and more particularly, to a flavonoid derivative compound exhibiting efficacy in the prevention or treatment of metabolic diseases by inhibiting inositol kinases IPMK and IP6K, and prevention and treatment of metabolic diseases containing the same as an active ingredient It relates to a pharmaceutical composition for treatment.
이노시톨 포스페이트(Inositol phosphates, IPs)는 세포 성장에서 사멸에 이르는 다양한 생물학적 과정에 관여하는 2차 메신저로 인식되어 왔다. 이 중 5-디포스포이노시톨 펜타키스포스페이트(5-diphosphoinositol pentakisphosphate, 5PP-IP5, 약칭 5-IP7)와 같은 이노시톨 피로포스페이트(inositol pyrophosphates)는 이노시톨 헥사키스포스페이트(inositol hexakisphosphate, IP6, 피트산)의 1 또는 5 위치에 '고 에너지' 디포스페이트(diphosphate) 그룹을 가지고 있다.Inositol phosphates (IPs) have been recognized as secondary messengers involved in various biological processes ranging from cell growth to death. Among them, inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5PP-IP5, abbreviation 5-IP7) are 1 or a 'high energy' diphosphate group at position 5.
인간을 포함한 포유동물에서 5-IP7의 생합성은 IP6 키나아제(IP6K)의 세 가지 이소형(IP6K1, IP6K2 및 IP6K3) 패밀리에 의해 촉매되는데, IP6K는 ATP와 IP6을 이용하여 포스포에스테르 결합을 형성하여 5-IP7이 생성된다. IP6K 녹아웃 모델에서 비만, 당뇨 등이 개선되는 대사변화가 나타나는 것으로 보고된 바 있다.In mammals, including humans, the biosynthesis of 5-IP7 is catalyzed by three isoforms (IP6K1, IP6K2, and IP6K3) of the IP6 kinase (IP6K) family. 5-IP7 is created. It has been reported that metabolic changes that improve obesity and diabetes appear in the IP6K knockout model.
포유류의 이노시톨 폴리포스페이트 멀티키나아제(Inositol polyphosphate multikinase, IPMK)는 IP4[Ins(1,3,4,5)P4 및 Ins(1,4,5,6)P4]와 IP5[Ins(1,3, 4,5,6)P5]의 합성에 필수적인 요소로 처음 특징되었다. 특히, IPMK의 이노시톨 6-키나아제 활성은 이 효소를 IP5 합성을 위한 고유한 인자로 만들었다. Mammalian inositol polyphosphate multikinase (IPMK) is IP4 [Ins(1,3,4,5)P 4 and Ins(1,4,5,6)P 4 ] and IP5 [Ins(1, 3, 4,5,6)P 5 ] was first characterized as an essential element for the synthesis. In particular, the inositol 6-kinase activity of IPMK made this enzyme a unique factor for IP5 synthesis.
마우스 배아 섬유아세포(MEF) 및 인간 암 세포와 같은 다른 많은 포유동물 세포에서 IPMK 결실은 IP5 및 IP7과 같은 다운스트림 IP의 세포 수준을 현저하게 감소시킨다. 또한 IPMK는 C-3 위치에서 PIP2를 인산화하여 포스파티딜이노시톨 3,4,5-삼인산(phosphatidylinositol 3,4,5-trisphosphate, PIP3)을 생성할 수 있다. IPMK가 결핍된 MEF는 야생형 MEF보다 약 50% 적은 PIP3를 생성하고 PIP3 의존성 Akt 인산화 및 다운스트림 신호전달 활성이 현저히 적었으며, 이는 IPMK가 PI3-키나아제로 작용하여 포유류 세포에서 세포 성장, 염증 및 대사 신호 전달을 제어함을 시사한다.In many other mammalian cells, such as mouse embryonic fibroblasts (MEFs) and human cancer cells, IPMK deletion significantly reduces cellular levels of downstream IPs such as IP5 and IP7. In addition, IPMK can phosphorylate PIP2 at the C-3 position to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). IPMK-deficient MEFs produced about 50% less PIP3 than wild-type MEFs and showed significantly less PIP3-dependent Akt phosphorylation and downstream signaling activity, suggesting that IPMK acts as a PI3-kinase for cell growth, inflammation and metabolism in mammalian cells. that control signal transduction.
[선행기술문헌][Prior art literature]
[비특허문헌][Non-Patent Literature]
비특허문헌 1: Britton RG, Horner-Glister E, Pomenya OA, et al. Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents. Eur J Med Chem 2012;54:952-958.Non-Patent Document 1: Britton RG, Horner-Glister E, Pomenya OA, et al. Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents. Eur J Med Chem 2012;54:952-958.
비특허문헌 2: Vasselin DA, Westwell AD, Matthews CS, et al. Structural studies on bioactive compounds. Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted 3-phenyl-4h-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related 2-phenylbenzothiazoles. J Med Chem 2006;49:3973-3981.Non-Patent Document 2: Vasselin DA, Westwell AD, Matthews CS, et al. Structural studies on bioactive compounds. Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted 3-phenyl-4h-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related 2-phenylbenzothiazoles. J Med Chem 2006;49:3973-3981.
본 발명자들은 천연 플라보노이드보다 우수한 IP6K2 억제제를 식별하기 위해 A-고리에 변형이 있는 플라보노이드 기반 유사체를 설계, 합성 후 평가하여 강력한 IP6K2 억제 효과를 나타내는 신규 플라보노이드 유도체를 확인함으로써, 본 발명을 완성하였다.The present inventors completed the present invention by designing, synthesizing, and evaluating flavonoid-based analogs having modifications in the A-ring to identify IP6K2 inhibitors that are superior to natural flavonoids, and identifying novel flavonoid derivatives exhibiting strong IP6K2 inhibitory effects.
따라서, 본 발명의 목적은 비만과 당뇨를 포함하는 대사성 질환의 예방 또는 치료에 효능을 나타내는 신규한 플라보노이드 유도체를 제공하는 것이다.Accordingly, an object of the present invention is to provide novel flavonoid derivatives exhibiting efficacy in the prevention or treatment of metabolic diseases including obesity and diabetes.
본 발명의 다른 목적은 상기 신규한 플라보노이드 유도체를 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the novel flavonoid derivative as an active ingredient.
본 발명자들은 하기 [화학식 1a]와 [화학식 1b]로 표시되는 플라보노이드 유도체가 대사성 질환을 유도하는 핵심적인 인자인 IPMK와 IP6K의 활성을 효과적으로 저해함을 확인하였으며, 이를 기반으로 본 발명을 완성하게 되었다.The present inventors confirmed that the flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b] effectively inhibit the activity of IPMK and IP6K, which are key factors inducing metabolic diseases, and based on this, the present invention was completed. .
따라서, 본 발명은 대사성 질환의 예방 또는 치료에 효능을 나타내는 신규한 플라보노이드 유도체 및 이를 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.Accordingly, the present invention relates to a novel flavonoid derivative exhibiting efficacy in preventing or treating metabolic diseases and a pharmaceutical composition for preventing or treating metabolic diseases comprising the same as an active ingredient.
이하, 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 양태는 하기 [화학식 1a] 및 [화학식 1b]로 표시되는 플라보노이드 유도체에 관한 것이다:One aspect of the present invention relates to flavonoid derivatives represented by the following [Formula 1a] and [Formula 1b]:
[화학식 1a][Formula 1a]
Figure PCTKR2022018229-appb-img-000001
Figure PCTKR2022018229-appb-img-000001
[화학식 1b][Formula 1b]
Figure PCTKR2022018229-appb-img-000002
Figure PCTKR2022018229-appb-img-000002
상기 [화학식 1a] 및 [화학식 1b]에서,In [Formula 1a] and [Formula 1b],
R'는
Figure PCTKR2022018229-appb-img-000003
,
Figure PCTKR2022018229-appb-img-000004
,
Figure PCTKR2022018229-appb-img-000005
, 및
Figure PCTKR2022018229-appb-img-000006
중에서 선택되는 어느 하나이고,R' is
Figure PCTKR2022018229-appb-img-000003
,
Figure PCTKR2022018229-appb-img-000004
,
Figure PCTKR2022018229-appb-img-000005
, and
Figure PCTKR2022018229-appb-img-000006
any one selected from
상기 R1 및 R2는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 할로겐, -OH, -COOH, -CF3, -Ph, -OPh, 및 탄소수 1 내지 4의 알킬기 중에서 선택되는 어느 하나이고, 및R 1 and R 2 are the same as or different from each other, and are each independently any one selected from hydrogen, halogen, -OH, -COOH, -CF 3 , -Ph, -OPh, and an alkyl group having 1 to 4 carbon atoms, and
X, Y 및 Z는 각각 독립적으로 수소 및 -OH 중에서 선택되는 어느 하나이다.X, Y and Z are each independently selected from hydrogen and -OH.
상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체는 이에 의해서 그 범위가 제한되는 것은 아니나, 구체적으로 하기 [화학식 2] 내지 [화학식 27]로 표시되는 플라보노이드 유도체 중에서 선택되는 어느 하나일 수 있다.The range of the flavonoid derivative represented by [Formula 1a] or [Formula 1b] is not limited thereby, but may be any one selected from flavonoid derivatives represented by [Formula 2] to [Formula 27]. there is.
Figure PCTKR2022018229-appb-img-000007
Figure PCTKR2022018229-appb-img-000007
Figure PCTKR2022018229-appb-img-000008
Figure PCTKR2022018229-appb-img-000008
보다 구체적으로, 상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체는 하기 [화학식 2], [화학식 3], [화학식 4], [화학식 5], [화학식 23], 및 [화학식 24]로 표시되는 플라보노이드 유도체 중에서 선택되는 어느 하나일 수 있다.More specifically, the flavonoid derivatives represented by [Formula 1a] or [Formula 1b] are represented by the following [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] ] may be any one selected from flavonoid derivatives represented by
Figure PCTKR2022018229-appb-img-000009
Figure PCTKR2022018229-appb-img-000009
본 발명에 따른 상기 [화학식 2], [화학식 3], [화학식 4], [화학식 5], [화학식 23], 및 [화학식 24]로 표시되는 플라보노이드 유도체는 B-고리에 카르복실산(-COOH) 치환된 것을 특징으로 하며, 우수한 IP6K2 억제 활성을 나타낸다.The flavonoid derivatives represented by [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 24] according to the present invention have a carboxylic acid (- COOH) substituted, and exhibits excellent IP6K2 inhibitory activity.
본 발명에 따른 [화학식 2] 내지 [화학식 27]로 표시되는 플라보노이드 유도체는 구체적으로 하기와 같은 합성과정을 통하여 제조할 수 있으며, 하기 [1]은 본 발명에 따른 [화학식 1a]로 표시되는 플라보노이드 유도체의 합성과정을 개략적으로 도시한 흐름도이고, 하기 [2]는 본 발명에 따른 [화학식 1b]로 표시되는 플라보노이드 유도체의 합성과정을 개략적으로 도시한 흐름도이다.The flavonoid derivatives represented by [Formula 2] to [Formula 27] according to the present invention can be specifically prepared through the following synthesis process, and the following [1] is a flavonoid represented by [Formula 1a] according to the present invention It is a flow chart schematically showing the synthesis process of the derivative, and [2] below is a flow chart schematically showing the synthesis process of the flavonoid derivative represented by [Formula 1b] according to the present invention.
[1][One]
Figure PCTKR2022018229-appb-img-000010
Figure PCTKR2022018229-appb-img-000010
[2][2]
Figure PCTKR2022018229-appb-img-000011
Figure PCTKR2022018229-appb-img-000011
본 발명에 따른 플라보노이드 유도체는 약제학적으로 허용가능한 염의 형태로 사용될 수 있으며, 염으로는 약제학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있다.The flavonoid derivative according to the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. As the free acid, inorganic acids and organic acids can be used.
바람직하게는, 본 발명의 플라보노이드 유도체의 약제학적 허용 가능한 염은 염산염, 브롬산염, 황산염, 인산염, 구연산염, 아세트산염, 트리플루오로아세트산염, 젖산염, 주석산염, 말레인산염, 푸마린산염, 글루콘산염, 메탄설폰산염, 글리콘산염, 숙신산염, 4-톨루엔설폰산염, 글루투론산염, 엠본산염, 글루탐산염, 또는 아스파트산염으로 구성된 군으로부터 선택될 수 있으나, 이에 제한되지 않고 당업계에서 통상적으로 사용되는 다양한 무기산 및 유기산을 이용하여 형성되는 염이 모두 포함된다.Preferably, the pharmaceutically acceptable salts of the flavonoid derivatives of the present invention are hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, fumarate, gluconate. , methanesulfonate, glycolate, succinate, 4-toluenesulfonate, gluturonate, embonate, glutamate, or aspartate, but may be selected from the group consisting of, but is not limited thereto, and is commonly used in the art. Salts formed using the various inorganic and organic acids used are all included.
또한, 본 발명에 따른 플라보노이드 유도체는 용매화물(예를 들면 수화물)의 형태로도 존재할 수 있다.In addition, the flavonoid derivative according to the present invention may also exist in the form of a solvate (for example, a hydrate).
본 발명의 다른 일 양태는 상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 함유하는 대사성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases containing the flavonoid derivative represented by [Formula 1a] or [Formula 1b], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. will be.
상기 조성물은 IPMK와 IP6K에 의한 세포내 신호 전달을 제어하고, IPMK와 IP6K의 활성을 저해하는 것을 특징으로 한다.The composition controls intracellular signal transduction by IPMK and IP6K, and inhibits the activity of IPMK and IP6K.
본 명세서에서 "대사성 질환"은 당질, 지질, 단백질, 비타민, 미네랄 및 수분 등의 불균형에 의한 질환을 총칭하며, 이중 지질관련 대사성 질환은 생체 내 과도한 지질 축적에 의해서 발생하는 질환을 의미하고, 구체적으로 비만, 당뇨 등이 있다.In the present specification, "metabolic disease" is a general term for diseases caused by an imbalance of carbohydrates, lipids, proteins, vitamins, minerals, and water. include obesity and diabetes.
상기 대사성 질환은 비만, 고혈압, 동맥경화증, 고지혈증, 간질환, 심근병증, 심근경색, 뇌경색, 근감소증, 과인슐린혈증, 과혈당증, 당뇨병 또는 인슐린 저항성 질환일 수 있으나, 이에 한정되는 것은 아니다.The metabolic disease may be obesity, hypertension, arteriosclerosis, hyperlipidemia, liver disease, cardiomyopathy, myocardial infarction, cerebral infarction, sarcopenia, hyperinsulinemia, hyperglycemia, diabetes or insulin resistance disease, but is not limited thereto.
본 발명에서 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 대사성 질환을 억제시키거나 이의 진행을 지연시키는 모든 행위를 의미한다.In the present invention, "prevention" refers to any activity that suppresses or delays the progression of metabolic diseases by administration of the pharmaceutical composition according to the present invention.
본 발명에서 "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 대사성 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "treatment" refers to all activities in which symptoms of metabolic diseases are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
또한, "유효성분으로 포함"은 원하는 생물학적 효과를 실현하는데 필요하거나 또는 충분한 양으로 해당 성분이 포함되는 것을 의미한다. 실제 적용에 있어서 유효 성분으로 포함되는 양의 결정은 대상 질병을 치료하기 위한 양으로서, 다른 독성을 야기하지 않는 사항을 고려해서 결정될 수 있으며, 예를 들어 치료되는 질병 또는 병태, 투여되는 조성물의 형태, 피험체의 크기, 또는 질병 또는 병태의 심각도 등과 같은 다양한 인자에 따라서 변화될 수 있다. 본 발명이 속하는 분야에서 통상의 기술을 지닌 기술자라면 과도한 실험을 동반하지 않고 개별적 조성물의 유효량을 경험적으로 결정할 수 있다.In addition, "included as an active ingredient" means that the component is included in an amount necessary or sufficient to realize a desired biological effect. In actual application, the amount to be included as an active ingredient is an amount to treat a target disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition to be treated, the type of composition to be administered, It can vary according to various factors such as the size of the subject, or the severity of the disease or condition. Effective amounts of individual compositions can be determined empirically without undue experimentation by those skilled in the art to which this invention pertains.
본 발명에서 약제학적으로 허용 가능한 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염, 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 염을 형성하는 것을 의미한다.In the present invention, the pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin), or It means that it reacts with alkali metal ions such as sodium and potassium to form metal salts thereof, or reacts with ammonium ions to form another type of pharmaceutically acceptable salt.
본 발명에서 "약제학적으로 허용 가능한"이라 함은 화합물의 생물학적 활성과 물성을 손상시키지 않는 성질을 의미한다.In the present invention, "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of a compound.
본 발명에 따른 약학적 조성물은 상술한 플라보노이드 유도체를 유효성분으로 포함하며, 약학적으로 허용 가능한 담체를 더 포함할 수 있다.The pharmaceutical composition according to the present invention includes the above-described flavonoid derivative as an active ingredient, and may further include a pharmaceutically acceptable carrier.
상기 약학적으로 허용 가능한 담체는 제제 시에 통상적으로 이용되는 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 사이클로덱스트린, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 리포좀 등을 포함하지만 이에 한정되지 않으며, 필요에 따라 항산화제, 완충액 등 다른 통상의 첨가제를 더 포함할 수 있다. The pharmaceutically acceptable carrier is one commonly used in formulation, and includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, etc. It is not, and if necessary, other conventional additives such as antioxidants and buffers may be further included.
또한, 희석제, 분산제, 계면활성제, 결합제, 윤활제 등을 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. In addition, diluents, dispersants, surfactants, binders, lubricants, etc. may be additionally added to formulate formulations for injections such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
적합한 약학적으로 허용되는 담체 및 제제화에 관해서는 레밍턴의 문헌에 개시되어 있는 방법을 이용하여 각 성분에 따라 바람직하게 제제화할 수 있다. 본 발명의 약학적 조성물은 제형에 특별한 제한은 없으나 주사제, 흡입제, 피부 외용제 등으로 제제화할 수 있다.Regarding a suitable pharmaceutically acceptable carrier and formulation, it can be preferably formulated according to each component using the method disclosed in Remington's literature. The pharmaceutical composition of the present invention is not particularly limited in dosage form, but may be formulated as an injection, an inhalant, or an external skin preparation.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) depending on the desired method, and the dosage depends on the patient's condition, body weight and disease. Depending on the degree, drug form, administration route and time, it can be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concomitantly used drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로, 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
본 발명은 신규한 플라보노이드 유도체 화합물에 관한 것으로, 본 발명에 따른 플라보노이드 유도체 화합물은 IPMK 및 IP6K의 활성을 효과적으로 억제할 수 있는 것으로서, 이를 포함하는 약학 조성물을 이용하여 대사성 질환을 근본적으로 예방하거나 치료할 수 있을 것으로 기대된다.The present invention relates to a novel flavonoid derivative compound, and the flavonoid derivative compound according to the present invention can effectively inhibit the activity of IPMK and IP6K, and can fundamentally prevent or treat metabolic diseases using a pharmaceutical composition containing the same. It is expected that there will be
도 1a는 본 발명의 일 실시예에 따라 합성된 플라보노이드 유도체(화합물 20s)의 용량-반응 IPMK 저해 활성 결과이다.1a is a dose-response IPMK inhibitory activity result of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
도 1b는 본 발명의 일 실시예에 따라 합성된 플라보노이드 유도체(화합물 20s)의 실험예 1-1)에 의한 용량-반응 IP6K2 저해 활성 결과이다.1b is a dose-response IP6K2 inhibitory activity result by Experimental Example 1-1) of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
도 1c는 본 발명의 일 실시예에 따라 합성된 플라보노이드 유도체(화합물 20s)의 실험예 1-2)에 의한 용량-반응 IP6K2 저해 활성 결과이다.1c is a dose-response IP6K2 inhibitory activity result by Experimental Example 1-2) of a flavonoid derivative (Compound 20s) synthesized according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따라 합성된 플라보노이드 유도체(화합물 20s)(도 2a) 및 대조군 케르세틴(Quercetin)(도 2b)에 대한 In silico 분자 도킹 분석 결과이다.2 is an in silico molecular docking analysis result for a flavonoid derivative (Compound 20s) (FIG. 2a) and a control quercetin (FIG. 2b) synthesized according to an embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
합성예. 본 발명예 따른 플라보노이드 유도체의 합성synthetic example. Synthesis of flavonoid derivatives according to examples of the present invention
상술한 화합물의 합성과정 흐름도 [1], [2]에 따라 본 발명에 따른 [화학식 2] 내지 [화학식 27]의 플라보노이드 유도체들을 하기 방법에 의해서 합성하였다.According to the flowcharts [1] and [2] of the synthesis process of the above-mentioned compounds, the flavonoid derivatives of [Formula 2] to [Formula 27] according to the present invention were synthesized by the following methods.
이때, 하기의 화합물 11-13은 상업적으로 이용 가능하다:At this time, the following compounds 11-13 are commercially available:
1-(2-Hydroxy-4,5-dimethoxyphenyl)ethan-1-one (11) 1-(2-Hydroxy-4,5-dimethoxyphenyl)ethan-1-one ( 11 )
1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one (12) 1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one ( 12 )
1-(2-Hydroxy-5-nitrophenyl)ethan-1-one (13) 1-(2-Hydroxy-5-nitrophenyl)ethan-1-one ( 13 )
반응에 사용된 모든 화학물질 및 용매는 Sigma-Aldrich, TCI 및 Acros에서 구입하였고 추가 정제 없이 사용하였다. 반응 과정은 실리카 겔 60F254(Merck, Germany) 플레이트에서 TLC로 모니터링하고, UV254 빛 및/또는 KMnO4 염색으로 시각화하였다. 컬럼 크로마토그래피는 실리카 겔(Silica gel 60; 230-400 mesh ASTM, Merck)에서 수행되었다. HSM 실험에는 ~1 mg의 양이 사용되었다. 가열 속도는 2 ℃/분이었고 이미지는 용융 기간 동안 1분마다 자동으로 캡처되었다. NMR 스펙트럼은 Bruker Ultrashield 600MHz Plus(1H, 600 MHz; 13C, 150 MHz) 분광계에서 기록되었다. 모든 화학적 이동은 테트라메틸실란(δ=0)으로부터 백만분율(ppm)로 기록되었으며, 샘플이 분석된 용매(CDCl3: δ 7.26 for 1H NMR, δ 77.0 for 13C NMR; MeOH-d 4: δ 3.31 for 1H NMR, δ 49.0 for 13C NMR; DMSO-d 6: δ 2.50 for 1H NMR, δ 39.5 for 13C NMR)에 대해 측정되었다. 1H NMR 이동 값은 chemical shift(δ), corresponding integral, multiplicity(s = singlet, br = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, td = triplet of doublets, qd = quartet of doublets), coupling constant(J in Hz) 및 assignments로 기록되었다. HRMS는 Agilent 6530 Accurate Mass Q-TOF LC/MS 분광계에서 기록되었다. 모든 최종 화합물의 순도는 C18 컬럼(Phenomenex, 150mm x 4.6mm, 3μm, 110Å)이 있는 Agilent 1260 Infinity(Agilent)에서 역상 분석용 HPLC로 측정되었다. RP-HPLC는 다음 등용매 조건을 사용하여 수행되었다: 방법 A 이동상은 아세토니트릴 및 물(55:45, v/v, 0.1% 트리플루오로아세트산); 방법 B 이동상은 아세토니트릴 및 물(50:50, v/v, 0.1% 트리플루오로아세트산); 방법 C 이동상은 아세토니트릴 및 물(45:55, v/v, 0.1% 트리플루오로아세트산); 방법 D 이동상은 아세토니트릴 및 물(40:60, v/v, 0.1% 트리플루오로아세트산); 방법 E 이동상은 아세토니트릴 및 물(35:65, v/v, 0.1% 트리플루오로아세트산); 방법 F 이동상은 아세토니트릴 및 물(30:70, v/v, 0.1% 트리플루오로아세트산); 방법 G 이동상은 아세토니트릴 및 물(25:75, v/v, 0.1% 트리플루오로아세트산); 방법 H 이동상은 아세토니트릴 및 물(20:80, v/v, 0.1% 트리플루오로아세트산); 방법 I 이동상은 아세토니트릴 및 물(15:85, v/v, 0.1% 트리플루오로아세트산); 방법 J 이동상은 아세토니트릴 및 물(12:88, v/v, 0.1% 트리플루오로아세트산)이었다. 모든 화합물은 1 mL/min의 유속으로 용리되었고, UV 검출기(220 nm 또는 254 nm)에서 모니터링되었다. 테스트된 화합물의 순도는 >95 %였다.All chemicals and solvents used in the reaction were purchased from Sigma-Aldrich, TCI and Acros and were used without further purification. The reaction progress was monitored by TLC on silica gel 60F254 (Merck, Germany) plates and visualized by UV254 light and/or KMnO4 staining. Column chromatography was performed on silica gel (Silica gel 60; 230-400 mesh ASTM, Merck). An amount of ~1 mg was used for HSM experiments. The heating rate was 2 °C/min and images were automatically captured every 1 min during the melting period. NMR spectra were recorded on a Bruker Ultrashield 600 MHz Plus ( 1 H, 600 MHz; 13 C, 150 MHz) spectrometer. All chemical shifts were reported in parts per million (ppm) from tetramethylsilane (δ = 0) and the solvent in which the samples were analyzed (CDCl 3 : δ 7.26 for 1 H NMR, δ 77.0 for 13 C NMR; MeOH- d 4 : δ 3.31 for 1 H NMR, δ 49.0 for 13 C NMR; DMSO- d 6 : δ 2.50 for 1 H NMR, δ 39.5 for 13 C NMR). 1 H NMR shift values are chemical shift (δ), corresponding integral, multiplicity (s = singlet, br = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, td = triplet of doublets, qd = quartet of doublets), coupling constant (J in Hz) and assignments. HRMS was recorded on an Agilent 6530 Accurate Mass Q-TOF LC/MS spectrometer. The purity of all final compounds was determined by reverse phase analytical HPLC on an Agilent 1260 Infinity (Agilent) with a C18 column (Phenomenex, 150 mm x 4.6 mm, 3 μm, 110 Å). RP-HPLC was performed using the following isocratic conditions: Method A mobile phase was acetonitrile and water (55:45, v/v, 0.1% trifluoroacetic acid); Method B mobile phase was acetonitrile and water (50:50, v/v, 0.1% trifluoroacetic acid); Method C mobile phase was acetonitrile and water (45:55, v/v, 0.1% trifluoroacetic acid); Method D mobile phase was acetonitrile and water (40:60, v/v, 0.1% trifluoroacetic acid); Method E mobile phase was acetonitrile and water (35:65, v/v, 0.1% trifluoroacetic acid); Method F mobile phase was acetonitrile and water (30:70, v/v, 0.1% trifluoroacetic acid); Method G mobile phase was acetonitrile and water (25:75, v/v, 0.1% trifluoroacetic acid); Method H mobile phase was acetonitrile and water (20:80, v/v, 0.1% trifluoroacetic acid); Method I mobile phase was acetonitrile and water (15:85, v/v, 0.1% trifluoroacetic acid); Method J mobile phase was acetonitrile and water (12:88, v/v, 0.1% trifluoroacetic acid). All compounds were eluted at a flow rate of 1 mL/min and monitored on a UV detector (220 nm or 254 nm). The purity of the tested compounds was >95%.
(i) 화합물 14a-14d 합성 방법:(i) Methods for synthesizing compounds 14a-14d:
메탄올 (MeOH) 또는 에탄올 (EtOH) 중 치환된 아세토페논 (1113)의 교반 용액에 수산화바륨 (2.0 eq) 및 적절한 알데하이드 (1.2 eq)를 실온에서 첨가하였다. 반응 혼합물을 TLC 분석 (일반적으로 1-20 시간)에 의해 모니터링되는 완전한 전환이 될 때까지 아르곤 하에 40-50 ℃에서 교반하고, 아세트산으로 켄칭한 후, EtOAc 및 H2O로 추출하였다. 유기층을 포화 수성 NaHCO3로 세척하고, MgSO4로 건조시킨 후, 여과하고, 감압 하에 농축시켰다. 조 잔류물(crude residue)을 실리카 겔 상에서 컬럼 크로마토그래피로 정제하여 화합물 14a14d를 수득하였다.To a stirred solution of substituted acetophenone ( 1113 ) in methanol (MeOH) or ethanol (EtOH) was added barium hydroxide (2.0 eq) and the appropriate aldehyde (1.2 eq) at room temperature. The reaction mixture was stirred under argon at 40-50 °C until complete conversion monitored by TLC analysis (typically 1-20 hours), quenched with acetic acid, then extracted with EtOAc and H 2 O. The organic layer was washed with saturated aqueous NaHCO 3 , dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to give compound 14a14d .
1) (E)-Ethyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (1) (E)-Ethyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 14a14a ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄-1-온 (11) (200 mg, 1.02 mmol), 메틸 테레프탈알데하이데이트 (251 mg, 1.5 eq), 수산화바륨 (350 mg, 2.0 eq)을 17 시간 동안 70 ℃에서 교반하여 화합물 14a를 70 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 8:1 to 4:1)로 정제하였다.According to the above synthetic method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethan-1-one ( 11 ) (200 mg, 1.02 mmol), methyl terephthalaldehyde in ethanol (10 mL) (251 mg, 1.5 eq) and barium hydroxide (350 mg, 2.0 eq) were stirred at 70° C. for 17 hours to obtain compound 14a in 70% yield, yellow powder. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 8:1 to 4:1).
Rf = 0.21 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) 13.30 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 15.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 15.5 Hz, 1H), 7.24 (s, 1H), 6.50 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) 191.01, 165.91, 162.01, 157.38, 142.93, 142.07, 138.86, 131.98, 130.12, 128.30, 122.46, 111.93, 110.88, 100.84, 61.26, 56.94, 56.24, 14.31. HRMS m/z calculated for C20H20O6 [M - H]-: 355.1187; found: 355.1203. R f = 0.21 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) 13.30 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 15.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 15.5 Hz, 1H), 7.24 (s, 1H), 6.50 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) 191.01, 165.91, 162.01, 157.38, 142.93, 142.07, 138.86, 131.98, 130.12, 128.30, 122.46, 111.93, 110.88, 100.84, 61.26, 56 .94, 56.24, 14.31. HRMS m / z calculated for C 20 H 20 O 6 [M - H] - : 355.1187; found: 355.1203.
2) (E)-Ethyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (2) (E)-Ethyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 14b14b ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄-1-온 (11) (200 mg, 1.02 mmol), 메틸 3-포밀벤조에이트 (200 mg, 1.2 eq), 수산화바륨 (350 mg, 2.0 eq)을 20 시간 동안 40 ℃에서 교반하여 화합물 14b를 26 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 8:1 to 3:1)로 정제하였다.According to the above synthetic method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethan-1-one ( 11 ) (200 mg, 1.02 mmol), methyl 3-formylbenzo in ethanol (10 mL) Eight (200 mg, 1.2 eq) and barium hydroxide (350 mg, 2.0 eq) were stirred at 40° C. for 20 hours to give compound 14b as a yellow powder in 26% yield. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 8:1 to 3:1).
Rf = 0.28 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) 13.33 (s, 1H), 8.35 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 15.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 15.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 4.5 Hz, 2H), 6.53 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) 191.21, 166.08, 161.96, 157.32, 143.31, 142.07, 135.13, 132.88, 131.36, 131.32, 129.17, 129.11, 121.53, 111.95, 111.01, 100.86, 61.39, 57.04, 56.25, 14.34. HRMS m/z calculated for C20H20O6 [M + H]+: 357.1333; found: 357.1333.R f = 0.28 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) 13.33 (s, 1H), 8.35 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 15.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 15.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 4.5 Hz, 2H), 6.53 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) 191.21, 166.08, 161.96, 157.32, 143.31, 142.07, 135.13, 132.88, 131.36, 131.32, 129.17, 129.11, 121.53, 111.95, 111.01, 1 00.86, 61.39, 57.04, 56.25, 14.34. HRMS m / z calculated for C 20 H 20 O 6 [M + H] + : 357.1333; found: 357.1333.
3) (E)-Ethyl 4-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3) (E)-Ethyl 4-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 14c14c ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 1-(2-하이드록시-4,6-다이메톡시페닐)에탄-1-온 (12) (200 mg, 1.02 mmol), 메틸 테레프탈알데하이데이트 (200 mg, 1.2 eq), 수산화바륨 (350 mg, 2.0 eq)을 18 시간 동안 40 ℃에서 교반하여 화합물 14c를 16 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 8:1 to 3:1)로 정제하였다.According to the above synthetic method, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one ( 12 ) (200 mg, 1.02 mmol), methyl terephthalaldehyde in ethanol (10 mL) (200 mg, 1.2 eq) and barium hydroxide (350 mg, 2.0 eq) were stirred at 40° C. for 18 hours to give compound 14c as a yellow powder in 16% yield. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 8:1 to 3:1).
Rf = 0.24 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) 14.18 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 6.12 (d, J = 1.9 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 4.40 (q, J = 7.9 and 15.1 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, MeOD) 192.29, 168.48, 166.52, 166.12, 162.52, 140.61, 139.80, 131.40, 130.06, 129.76, 128.07, 106.33, 93.83, 91.37, 61.18, 55.93, 55.65, 14.32. HRMS m/z calculated for C20H20O6 [M + H]+: 357.1333; found: 357.1343R f = 0.24 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) 14.18 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 6.12 (d, J = 1.9 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 4.40 (q, J = 7.9 and 15.1 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13 C NMR (150 MHz, MeOD) 192.29, 168.48, 166.52, 166.12, 162.52, 140.61, 139.80; 131.40, 130.06, 129.76, 128.07, 106.33, 93.83, 91.37, 61.18, 55.93, 55.65, 14.32. HRMS m / z calculated for C 20 H 20 O 6 [M + H] + : 357.1333; found: 357.1343
4) (E)-Ethyl 3-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (4) (E)-Ethyl 3-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 14d14d ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 1-(2-하이드록시-4,6-다이메톡시페닐)에탄-1-온 (12) (200 mg, 1.02 mmol), 메틸 3-포밀벤조에이트 (200 mg, 1.2 eq), 수산화바륨 (350 mg, 2.0 eq)을 17 시간 동안 40 ℃에서 교반하여 화합물 14d를 83 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 200:1 to 100:1)로 정제하였다.According to the above synthetic method, 1-(2-hydroxy-4,6-dimethoxyphenyl)ethan-1-one ( 12 ) (200 mg, 1.02 mmol), methyl 3-formylbenzo in ethanol (10 mL) Eight (200 mg, 1.2 eq) and barium hydroxide (350 mg, 2.0 eq) were stirred at 40° C. for 17 hours to give compound 14d as a yellow powder in 83% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 200:1 to 100:1).
Rf = 0.35 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) 14.22 (s, 1H), 8.30 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 15.6 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 6.12 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.1 Hz, 1H), 4.41 (q, J =7.1 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) 192.40, 1686.47, 166.43, 166.15, 162.53, 140.89, 135.93, 132.48, 131.19, 130.73, 129.12, 128.95, 128.85, 128.76, 93.82, 91.32, 61.23, 55.88, 55.63, 14.33. HRMS m/z calculated for C20H20O6 [M + H]+: 357.1333; found: 357.1328.R f = 0.35 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) 14.22 (s, 1H), 8.30 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 15.6 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.49 (t , J = 7.9 Hz, 1H), 6.12 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.1 Hz, 1H), 4.41 (q, J =7.1 Hz, 2H), 3.94 (s, 3H) ), 3.85 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) 192.40, 1686.47, 166.43, 166.15, 162.53, 140.89, 135.93, 132.48, 131.19, 130.73, 129.12, 128.95, 128.85, 128.76, 93.82, 9 1.32, 61.23, 55.88, 55.63, 14.33. HRMS m / z calculated for C 20 H 20 O 6 [M + H] + : 357.1333; found: 357.1328.
(ii) 화합물 15a-15d 합성 방법:(ii) Methods for synthesizing compounds 15a-15d:
다이메틸설폭사이드 (DMSO) 중 칼콘 화합물 (14a14d)의 교반 용액에 아이오다인 (0.1 eq)을 25 ℃에서 첨가하였다. 반응 혼합물을 TLC 분석 (일반적으로 6-24 시간)에 의해 모니터링되는 완전한 전환이 될 때까지 아르곤 하에 100 ℃에서 교반하고, 1 M 싸이오황산나트륨 용액으로 켄칭한 후, EtOAc 및 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후, 여과하고, 감압 하에 농축시켰다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc or CH2Cl2/MeOH)로 정제하여 화합물 15a15d를 수득하였다.To a stirred solution of chalcone compound ( 14a14d ) in dimethylsulfoxide (DMSO) was added iodine (0.1 eq) at 25 °C. The reaction mixture was stirred at 100 °C under argon until complete conversion monitored by TLC analysis (typically 6-24 hours), quenched with 1 M sodium thiosulfate solution, then extracted with EtOAc and H 2 O. . The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc or CH 2 Cl 2 /MeOH) to give compound 15a15d .
1) l 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (1) l 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15a15a ) )
상기 합성 방법에 따라, DMSO (5 mL) 중에서 (E)-에틸 4-(3-(2-하이드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (14a) (241 mg, 0.70 mmol), 아이오다인 (18 mg, 0.1 eq)을 11 시간 동안 교반하여 화합물 15a를 43 %의 수율, 백색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 5:1 to 1:1 and then CH2Cl2/MeOH = 50:1 to 30:1)로 정제하였다.According to the above synthetic method, (E)-ethyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1- in DMSO (5 mL) 1) Benzoate ( 14a ) (241 mg, 0.70 mmol) and iodine (18 mg, 0.1 eq) were stirred for 11 hours to obtain compound 15a in 43% yield as a white powder. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 5:1 to 1:1 and then CH 2 Cl 2 /MeOH = 50:1 to 30:1).
Rf = 0.34 (hexane/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) 8.15 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 1.44 (t, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) 177.44, 165.74, 161.44, 154.72, 152.33, 147.88, 135.85, 132.78, 130.12, 125.96, 117.40, 108.21, 104.36, 99.80, 61.45, 56.55, 56.39, 14.31. HRMS m/z calculated for C20H18O6 [M + H]+: 355.1176; found: 355.1184.R f = 0.34 (hexane/EtOAc = 1:1). 1 H NMR (600 MHz, CDCl 3 ) 8.15 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 1.44 (t, J = 6.7 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) 177.44, 165.74, 161.44, 154.72, 152.33, 147.88, 135.85, 132.78, 130.12, 125.96, 117.40, 108.21, 104.36, 99.80, 61.45, 56. 55, 56.39, 14.31. HRMS m / z calculated for C 20 H 18 O 6 [M + H] + : 355.1176; found: 355.1184.
2) Ethyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (2) Ethyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15b15b ))
상기 합성 방법에 따라, DMSO (8 mL) 중에서 (E)-에틸 3-(3-(2-하이드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (14b) (70 mg, 0.19 mmol), 아이오다인 (5 mg, 0.1 eq)을 12 시간 동안 교반하여 화합물 15b를 정량 수율, 백색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 2:1 to 1:1 and then CH2Cl2/MeOH = 10:1)로 정제하였다.According to the above synthetic method, (E)-ethyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1- in DMSO (8 mL) 1) Benzoate ( 14b ) (70 mg, 0.19 mmol) and iodine (5 mg, 0.1 eq) were stirred for 12 hours to obtain compound 15b in quantitative yield as a white powder. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1 to 1:1 and then CH 2 Cl 2 /MeOH = 10:1).
Rf = 0.19 (hexnae/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) 8.61 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.06 (s, 1H), 6.86 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). HRMS m/z calculated for C20H18O6 [M + H]+: 355.1176; found: 355.1184.R f = 0.19 (hexnae/EtOAc = 1:1). 1 H NMR (600 MHz, CDCl 3 ) 8.61 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.06 (s, 1H), 6.86 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H) ). HRMS m / z calculated for C 20 H 18 O 6 [M + H] + : 355.1176; found: 355.1184.
3) Ethyl 4-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (3) Ethyl 4-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15c15c ))
상기 합성 방법에 따라, DMSO (8 mL) 중에서 (E)-에틸 4-(3-(2-하이드록시-4,6-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (14c) (116 mg, 0.34 mmol), 아이오다인 (8.7 mg, 0.1 eq)을 11 시간 동안 교반하여 화합물 15c를 87 %의 수율, 백색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 10:1)로 정제하였다.According to the above synthetic method, (E)-ethyl 4-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1- in DMSO (8 mL) 1) Benzoate ( 14c ) (116 mg, 0.34 mmol) and iodine (8.7 mg, 0.1 eq) were stirred for 11 hours to obtain compound 15c as a white powder in 87% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 10:1).
Rf = 0.28 (hexane/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) 8.2 (d, J =8.3 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 6.74 (s, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). HRMS m/z calculated for C20H18O6 [M + H]+: 355.1176; found: 355.1169.R f = 0.28 (hexane/EtOAc = 1:1). 1 H NMR (600 MHz, CDCl 3 ) 8.2 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 6.74 (s, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). HRMS m / z calculated for C 20 H 18 O 6 [M + H] + : 355.1176; found: 355.1169.
4) Ethyl 3-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4) Ethyl 3-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15d15d ))
상기 합성 방법에 따라, DMSO (10 mL) 중에서 (E)-에틸 3-(3-(2-하이드록시-4,6-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (14d) (271 mg, 0.76 mmol), 아이오다인 (19.3 mg, 0.1 eq)을 16 시간 동안 교반하여 화합물 15d를 81 %의 수율, 백색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 200:1 to 60:1)로 정제하였다.According to the above synthetic method, (E)-ethyl 3-(3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxoprop-1-en-1- in DMSO (10 mL) 1) Benzoate ( 14d ) (271 mg, 0.76 mmol) and iodine (19.3 mg, 0.1 eq) were stirred for 16 hours to prepare compound 15d as a white powder in 81% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 200:1 to 60:1).
Rf = 0.37 (CH2Cl2/MeOH = 20:1). 1H NMR (600 MHz, CDCl3) 8.56 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) 177.36, 165.75, 164.19, 160.87, 159.83, 159.49, 131.94, 131.86, 131.35, 129.87, 129.08, 126.98, 109.49, 109.23, 96.34, 92.88, 61.47, 56.42, 55.84, 14.35. HRMS m/z calculated for C20H18O6 [M + H]+: 355.1176; found: 355.1174.R f = 0.37 (CH 2 Cl 2 /MeOH = 20:1). 1 H NMR (600 MHz, CDCl 3 ) 8.56 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) 177.36, 165.75, 164.19, 160.87, 159.83, 159.49, 131.94, 131.86, 131.35, 129.87, 129.08, 126.98, 109.49, 109.23, 96.34, 92 .88, 61.47, 56.42, 55.84, 14.35. HRMS m / z calculated for C 20 H 18 O 6 [M + H] + : 355.1176; found: 355.1174.
(iii) 화합물 16a-16d, 20a-20s 합성 방법:(iii) Compound 16a-16d, 20a-20s synthesis method:
다이클로로메탄 (CH2Cl2) 중 고리화된 화합물 (15a-15d 및 19a-19t)의 교반 용액에 삼브롬화붕소 (5-12 eq)을 0 ℃에서 첨가하였다. 반응 혼합물을 TLC 분석 (일반적으로 14-20 시간)에 의해 모니터링되는 완전한 전환이 될 때까지 아르곤 하에 50 ℃에서 교반하고, 얼음 물 및 농축 CH2Cl2로 켄칭하였다. 조 잔류물을 EtOAc로 추출하였다. 유기층을 포화 NaHCO3 용액으로 세척하고, MgSO4로 건조시킨 후, 여과하고, 감압 하에 농축시켰다. 조 물질을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH or hexane/EtOAc)로 정제하거나 에테르 또는 헥산과 같은 유기 용매로 세척하여 화합물 16a-16d 및 20a-20s를 수득하였다.To a stirred solution of cyclized compounds ( 15a-15d and 19a-19t ) in dichloromethane (CH 2 Cl 2 ) was added boron tribromide (5-12 eq) at 0 °C. The reaction mixture was stirred at 50 °C under argon until complete conversion monitored by TLC analysis (typically 14-20 hours), quenched with ice water and concentrated CH 2 Cl 2 . The crude residue was extracted with EtOAc. The organic layer was washed with saturated NaHCO 3 solution, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH or hexane/EtOAc) or washed with an organic solvent such as ether or hexane to give compounds 16a-16d and 20a-20s .
1) One) [화학식 2][Formula 2] 4-(6,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 4-(6,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 16a16a ))
상기 합성 방법에 따라, 다이클로로메탄 (30 mL) 중에서 에틸 4-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (15a) (82 mg, 0.23 mmol), 삼브롬화붕소 (2.78 mL, 12 eq)를 18 시간 동안 50 ℃에서 교반하여 화합물 16a를 87 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 에테르, 헥산 및 메탄올로 세척하였다. Ethyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15a ) (82 mg, 0.23 mmol) according to the above synthetic method in dichloromethane (30 mL) ), boron tribromide (2.78 mL, 12 eq) was stirred at 50 °C for 18 hours to obtain compound 16a in 87% yield, yellow powder. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was washed with ether, hexane and methanol.
Rf = 0.19 (CH2Cl2/MeOH = 10:1). m.p: 500-502 ℃. 1H NMR (600 MHz, MeOD) 8.18 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.42 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H). HRMS m/z calculated for C16H10O6 [M - H]-: 297.0404; found: 297.0418. >95% purity (as determined by RP-HPLC, method H, tR = 14.84 min).R f = 0.19 (CH 2 Cl 2/ MeOH = 10:1). mp: 500-502 °C. 1 H NMR (600 MHz, MeOD) 8.18 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.42 (s, 1H), 7.08 (s, 1H), 6.90 (s , 1H). HRMS m/z calculated for C 16 H 10 O 6 [M - H] - : 297.0404; found: 297.0418. >95% purity (as determined by RP-HPLC, method H, t R = 14.84 min).
2) 2) [화학식 3][Formula 3] 3-(6,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 3-(6,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 16b16b ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 에틸 3-(6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (15b) (50.4 mg, 0.14 mmol), 삼브롬화붕소 (1.71 mL, 12 eq)를 17 시간 동안 50 ℃에서 교반하여 화합물 16b를 87 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 에테르, 헥산 및 메탄올로 세척하였다.According to the above synthetic method, ethyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15b ) (50.4 mg, 0.14 mmol) in dichloromethane (15 mL) ), boron tribromide (1.71 mL, 12 eq) was stirred at 50 °C for 17 hours to prepare compound 16b as a yellow powder in 87% yield. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was washed with ether, hexane and methanol.
Rf = 0.24 (CH2Cl2/MeOH = 10:1). m.p: 416-418 ℃. 1H NMR (600 MHz, MeOD) 8.64 (t, J = 1.6 Hz, 1H), 8.27 - 8.21 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 6.92 (s, 1H); 13C NMR (150 MHz, MeOD) 178.28, 167.30, 162.78, 153.77, 152.44, 145.33, 132.24, 132.03, 131.75, 130.16, 129.19, 126.93, 115.79, 106.95, 105.41, 102.53. HRMS m/z calculated for C16H10O6 [M - H]-: 297.0404; found: 297.0399. >95% purity (as determined by RP-HPLC, method G, tR = 6.70 min). R f = 0.24 (CH 2 Cl 2/ MeOH = 10:1). mp: 416-418 °C. 1H NMR (600 MHz, MeOD) 8.64 (t, J = 1.6 Hz, 1H), 8.27 - 8.21 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 6.92 (s, 1H); 13 C NMR (150 MHz, MeOD) 178.28, 167.30, 162.78, 153.77, 152.44, 145.33, 132.24, 132.03, 131.75, 130.16, 129.19, 126.93, 115.79, 1 06.95, 105.41, 102.53. HRMS m/z calculated for C 16 H 10 O 6 [M - H] - : 297.0404; found: 297.0399. >95% purity (as determined by RP-HPLC, method G, t R = 6.70 min).
3) 3) [화학식 4][Formula 4] 4-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 4-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 16c16c ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 에틸 4-(5,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (15c) (30 mg, 0.08 mmol), 삼브롬화붕소 (1.02 mL, 12 eq)를 18 시간 동안 50 ℃에서 교반하여 화합물 16c를 50 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 에테르, 헥산 및 메탄올로 세척하였다.According to the above synthetic method, ethyl 4-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15c ) (30 mg, 0.08 mmol) in dichloromethane (15 mL) ), boron tribromide (1.02 mL, 12 eq) was stirred at 50 °C for 18 hours to obtain compound 16c in 50% yield, yellow powder. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was washed with ether, hexane and methanol.
Rf = 0.26 (CH2Cl2/MeOH = 10:1). m.p: 337-339 ℃. 1H NMR (600 MHz, MeOD) 8.08 (d, J = 7.9 Hz, 2H), 8.00 (d, J = 7.5 Hz, 2H), 6.75 (s, 1H), 6.42 (s, 1H), 6.15 (s, 1H). HRMS m/z calculated for C16H10O6 [M - H]-: 297.0404; found: 297.0419. >95% purity (as determined by RP-HPLC, method E, tR = 7.99 min).R f = 0.26 (CH 2 Cl 2/ MeOH = 10:1). mp: 337-339 °C. 1 H NMR (600 MHz, MeOD) 8.08 (d, J = 7.9 Hz, 2H), 8.00 (d, J = 7.5 Hz, 2H), 6.75 (s, 1H), 6.42 (s, 1H), 6.15 (s , 1H). HRMS m/z calculated for C 16 H 10 O 6 [M - H] - : 297.0404; found: 297.0419. >95% purity (as determined by RP-HPLC, method E, t R = 7.99 min).
4) 4) [화학식 5][Formula 5] 3-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 3-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 16d16d ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 에틸 3-(5,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (15d) (104 mg, 0.29 mmol), 삼브롬화붕소 (3.54 mL, 12 eq)를 18 시간 동안 50 ℃에서 교반하여 화합물 16d를 70 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 10:1 to 3:1)로 정제하였다.According to the above synthetic method, ethyl 3-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 15d ) (104 mg, 0.29 mmol) in dichloromethane (15 mL) ), boron tribromide (3.54 mL, 12 eq) was stirred at 50 °C for 18 h to give compound 16d as a yellow powder in 70% yield. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 10:1 to 3:1).
Rf = 0.40 (CH2Cl2/MeOH = 10:1). m.p: 450-452 ℃. 1H NMR (600 MHz, DMSO) 12.79 (s, 1H), 8.50 (s, 1H), 8.31 (d, J = 5.4 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.54 (s, 1H), 6.24 (s, 1H); 13C NMR (150 MHz, DMSO) 182.28, 167.22, 165.07, 162.78, 161.96, 157.95, 132.92, 132.57, 131.70, 131.06, 130.06, 127.26, 106.37, 104.48, 99.58, 94.62. HRMS m/z calculated for C16H10O6 [M - H]-: 297.0404; found: 297.0398. >95% purity (as determined by RP-HPLC, method E, tR = 7.18 min).R f = 0.40 (CH 2 Cl 2/ MeOH = 10:1). mp: 450-452 °C. 1H NMR (600 MHz, DMSO) 12.79 (s, 1H), 8.50 (s, 1H), 8.31 (d, J = 5.4 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.71 (s , 1H), 7.03 (s, 1H), 6.54 (s, 1H), 6.24 (s, 1H); 13 C NMR (150 MHz, DMSO) 182.28, 167.22, 165.07, 162.78, 161.96, 157.95, 132.92, 132.57, 131.70, 131.06, 130.06, 127.26, 106.37, 1 04.48, 99.58, 94.62. HRMS m/z calculated for C 16 H 10 O 6 [M - H] - : 297.0404; found: 297.0398. >95% purity (as determined by RP-HPLC, method E, t R = 7.18 min).
5) 5) [화학식 6][Formula 6] 2-(3,4-Dihydroxyphenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(3,4-Dihydroxyphenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20a20a ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 2-(3,4-다이메톡시페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19a) (120 mg, 0.34 mmol), 삼브롬화붕소 (5.04 mL, 15 eq)를 15 시간 동안 50 ℃에서 교반하여 화합물 20a를 89 %의 수율, 갈색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 에테르, 헥산 및 메탄올로 세척하였다.According to the above synthetic method, 2-(3,4-dimethoxyphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19a ) (120 mg, 0.34 mmol), boron tribromide (5.04 mL, 15 eq) was stirred at 50 °C for 15 h to prepare compound 20a in 89% yield, brown powder. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was washed with ether, hexane and methanol.
Rf = 0.13 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.41 (s, 1H), 9.71 (s, 1H), 9.46 (s, 1H), 9.24 (s, 1H), 8.85 (s, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H). HRMS m/z calculated for C15H10O7 [M + H]+: 301.0354; found: 301.0351. R f = 0.13 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.41 (s, 1H), 9.71 (s, 1H), 9.46 (s, 1H), 9.24 (s, 1H), 8.85 (s, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H). HRMS m/z calculated for C 15 H 10 O 7 [M + H] + : 301.0354; found: 301.0351.
6) 6) [화학식 7][Formula 7] 3,6,7-Trihydroxy-2-phenyl-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-phenyl-4H-chromen-4-one ( 20b20b ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-페닐-4H-크로멘-4-온 (19b) (40 mg, 0.11 mmol), 삼브롬화붕소 (1.13 mL, 10 eq)를 6 시간 동안 50 ℃에서 교반하여 화합물 20b를 41 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the above synthetic method, 3-hydroxy-6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 19b ) (40 mg, 0.11 mmol) in dichloromethane (15 mL), Boron tribromide (1.13 mL, 10 eq) was stirred at 50° C. for 6 hours to give compound 20b in 41% yield, brown powder. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.39 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.15 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.32 (s, 1H), 6.97 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.83, 152.64, 150.27, 144.42, 143.70, 138.05, 131.71, 129.34, 128.46, 127.26, 114.04, 106.91, 102.65. HRMS m/z calculated for C15H10O5 [M + H]+: 269.0455; found: 269.0464. >95% purity (as determined by RP-HPLC, method F, t R = 13.617 min).R f = 0.39 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.15 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.32 (s, 1H), 6.97 (s, 1H); 13 C NMR (150 MHz, DMSO) Δ 171.83, 152.64, 150.27, 144.42, 143.70, 138.05, 131.71, 129.34, 128.46, 127.26, 114.04, 106.91, 102.65. HRMS m / z calculated for C 15 H 10 O 5 [M + H] + : 269.0455; found: 269.0464. >95% purity (as determined by RP-HPLC, method F, t R = 13.617 min).
7) 7) [화학식 8][Formula 8] 3,6,7-Trihydroxy-2-(p-tolyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(p-tolyl)-4H-chromen-4-one ( 20c20c ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(p-톨일)-4H-크로멘-4-온 (19c) (90 mg, 0.29 mmol), 삼브롬화붕소 (3.46 mL, 12 eq)를 6 시간 동안 50 ℃에서 교반하여 화합물 20c를 29 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 10:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(p-tolyl)-4H-chromen-4-one ( 19c ) (90 mg, 0.29 mmol) and boron tribromide (3.46 mL, 12 eq) were stirred at 50 °C for 6 h to obtain compound 20c in 29% yield, yellow powder. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 10:1 to 4:1).
Rf = 0.23 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.12 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.98 (s, 1H), 2.41 (s, 3H). 13C NMR (150 MHz, DMSO) δ 171.75, 152.60, 150.20, 144.39, 143.94, 139.11, 137.73, 129.07, 128.94, 127.18, 114.00, 106.90, 102.64, 21.01. HRMS m/z calculated for C16H12O5 [M + H]+: 285.0758; found: 285.0766. >95% purity (as determined by RP-HPLC, method E, t R = 12.49 min).R f = 0.23 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.12 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.98 (s, 1H), 2.41 ( s, 3H). 13 C NMR (150 MHz, DMSO) δ 171.75, 152.60, 150.20, 144.39, 143.94, 139.11, 137.73, 129.07, 128.94, 127.18, 114.00, 106.90, 102.64, 21.01. HRMS m / z calculated for C 16 H 12 O 5 [M + H] + : 285.0758; found: 285.0766. >95% purity (as determined by RP-HPLC, method E, t R = 12.49 min).
8) 8) [화학식 9][Formula 9] 3,6,7-Trihydroxy-2-(m-tolyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(m-tolyl)-4H-chromen-4-one ( 20d20d ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(m-톨일)-4H-크로멘-4-온 (19d) (70 mg, 0.25 mmol), 삼브롬화붕소 (3.69 mL, 15 eq)를 13 시간 동안 50 ℃에서 교반하여 화합물 20d를 20 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the synthesis method above, 3-hydroxy-6,7-dimethoxy-2-(m-tolyl)-4H-chromen-4-one ( 19d ) (70 mg, 0.25 mmol), boron tribromide (3.69 mL, 15 eq) was stirred for 13 h at 50 °C to give compound 20d as a brown powder in 20% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.50 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.06 - 7.97 (m, 2H), 7.38 (dd, J = 15.1, 7.4 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 6.98 (s, 3H), 2.42 (s, 3H); 13C NMR (150 MHz, MeOD) δ 174.31, 154.43, 152.87, 146.49, 145.91, 139.21, 133.01, 131.37, 129.36, 129.34, 129.03, 125.93, 115.45, 107.76, 103.46, 21.63. HRMS m/z calculated for C16H12O5 [M - H]-: 283.0612; found: 283.0606. >95% purity (as determined by RP-HPLC, method D, t R = 11.64 min).R f = 0.50 (CH 2 Cl 2 /MeOH = 10:1). 1 H NMR (600 MHz, MeOD) δ 8.06 - 7.97 (m, 2H), 7.38 (dd, J = 15.1, 7.4 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 6.98 (s, 3H) ), 2.42 (s, 3H); 13 C NMR (150 MHz, MeOD) δ 174.31, 154.43, 152.87, 146.49, 145.91, 139.21, 133.01, 131.37, 129.36, 129.34, 129.03, 125.93, 115.45, 107.76, 103.46, 21.63. HRMS m / z calculated for C 16 H 12 O 5 [M - H] - : 283.0612; found: 283.0606. >95% purity (as determined by RP-HPLC, method D, t R = 11.64 min).
9) 9) [화학식 10][Formula 10] 2-(3,4-Dimethylphenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(3,4-Dimethylphenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20e20e ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 2-(3,4-다이메틸페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19e) (40 mg, 0.12 mmol), 삼브롬화붕소 (1.22 mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20e를 85 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 30:1 to 4:1)로 정제하였다.According to the above synthesis method, 2-(3,4-dimethylphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19e ) in dichloromethane (20 mL) ( 40 mg, 0.12 mmol), boron tribromide (1.22 mL, 10 eq) was stirred at 50 °C for 16 h to give compound 20e as a brown powder in 85% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 30:1 to 4:1).
Rf = 0.45 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 7.94 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 2.31 (d, J = 7.0 Hz, 3H), 2.29 (s, 3H); 13C NMR (150 MHz, DMSO) δ 171.72, 152.51, 150.20, 144.35, 144.12, 137.99, 137.70, 136.27, 129.58, 129.27, 128.03, 124.92, 114.03, 106.93, 102.67, 40.06, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 19.65, 19.39. HRMS m/z calculated for C17H14O5 [M + H]+: 299.0914; found: 299.0922. >95% purity (as determined by RP-HPLC, method D, t R = 10.22 min).R f = 0.45 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 7.94 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.98 ( s, 1H), 2.31 (d, J = 7.0 Hz, 3H), 2.29 (s, 3H); 13 C NMR (150 MHz, DMSO) δ 171.72, 152.51, 150.20, 144.35, 144.12, 137.99, 137.70, 136.27, 129.58, 129.27, 128.03, 124.92, 114.03, 106.93, 102.67, 40.06, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 19.65, 19.39. HRMS m / z calculated for C 17 H 14 O 5 [M + H] + : 299.0914; found: 299.0922. >95% purity (as determined by RP-HPLC, method D, t R = 10.22 min).
10) 10) [화학식 11][Formula 11] 2-(4-Fluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(4-Fluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20f20f ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 2-(4-플루오로페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19f) (40 mg, 0.13 mmol), 삼브롬화붕소 (1.26 mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20f를 66 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the above synthetic method, 2-(4-fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19f ) (40 mg, 0.13 mmol), boron tribromide (1.26 mL, 10 eq) was stirred at 50 °C for 16 h to give compound 20f as a brown powder in 66% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.37 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.20 - 8.15 (m, 2H), 7.40 - 7.32 (m, 2H), 7.31 (s, 1H), 6.99 (s, 1H); 13C NMR (150 MHz, DMSO) δ 172.19, 168.24, 163.61, 161.96, 152.79, 150.65, 148.27, 144.63, 143.59, 137.96, 130.16, 130.11, 128.43, 116.04, 115.89, 114.43, 107.24, 103.01, 79.36. HRMS m/z calculated for C15H9FO5 [M - H]-: 287.0361; found: 287.0375. >95% purity (as determined by RP-HPLC, method E, t R = 9.18 min).R f = 0.37 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, DMSO) δ 8.20 - 8.15 (m, 2H), 7.40 - 7.32 (m, 2H), 7.31 (s, 1H), 6.99 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 172.19, 168.24, 163.61, 161.96, 152.79, 150.65, 148.27, 144.63, 143.59, 137.96, 130.16, 130.11, 128.43, 116.04, 115.89, 114.43, 107.24, 103.01, 79.36. HRMS m / z calculated for C 15 H 9 FO 5 [M - H] - : 287.0361; found: 287.0375. >95% purity (as determined by RP-HPLC, method E, t R = 9.18 min).
11) 11) [화학식 12][Formula 12] 2-(3-Fluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(3-Fluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20g20g ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 2-(3-플루오로페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19g) (110 mg, 0.35 mmol), 삼브롬화붕소 (5.2 mL, 15 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20g를 92 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다. 2-(3-fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19 g ) (110 mg, 0.35 mmol), boron tribromide (5.2 mL, 15 eq) was stirred for 16 h at 50 °C to give 20 g of the compound as a brown powder in 92% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.35 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.53 (s, 1H), 9.81 (s, 1H), 9.47 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 10.8 Hz, 1H), 7.58 (dd, J = 14.5, 7.9 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.02 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.87, 162.87, 161.26, 152.85, 150.28, 144.55, 142.14, 138.64, 133.99, 130.61, 130.56, 123.25, 116.16, 116.02, 114.07, 113.89, 113.73, 106.90, 102.77. HRMS m/z calculated for C15H9FO5 [M - H]-: 287.0361; found: 287.0367. >95% purity (as determined by RP-HPLC, method E, t R = 10.17 min).R f = 0.35 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.53 (s, 1H), 9.81 (s, 1H), 9.47 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 10.8 Hz, 1H), 7.58 (dd, J = 14.5, 7.9 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.02 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.87, 162.87, 161.26, 152.85, 150.28, 144.55, 142.14, 138.64, 133.99, 130.61, 130.56, 123.25, 116.16, 116.02, 114.07, 113.89, 113.73, 106.90, 102.77. HRMS m / z calculated for C 15 H 9 FO 5 [M - H] - : 287.0361; found: 287.0367. >95% purity (as determined by RP-HPLC, method E, t R = 10.17 min).
12) 12) [화학식 13][Formula 13] 2-(3,4-Difluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(3,4-Difluorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20h20h ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 2-(3,4-다이플루오로페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19h) (40 mg, 0.12 mmol), 삼브롬화붕소 (1.20 mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20h를 40 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the above synthesis method, 2-(3,4-difluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19 h in dichloromethane (15 mL) ) (40 mg, 0.12 mmol), boron tribromide (1.20 mL, 10 eq) was stirred at 50 °C for 16 h to give compound 20h as a brown powder in 40% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.42 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.18 (s, 1H), 8.04 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.07 - 6.96 (m, 1H); 13C NMR (150 MHz, DMSO) 171.81, 152.81, 150.2, 144.54, 141.47, 138.40, 129.29, 124.53, 117.87, 117.76, 116.32, 116.19, 114.05, 106.89, 102.78. HRMS m/z calculated for C15H8F2O5 [M - H]-: 305.0267; found: 305.0281. >95% purity (as determined by RP-HPLC, method E, t R = 12.85 min,).R f = 0.42 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.18 (s, 1H), 8.04 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.07 - 6.96 (m, 1H) ); 13 C NMR (150 MHz, DMSO) 171.81, 152.81, 150.2, 144.54, 141.47, 138.40, 129.29, 124.53, 117.87, 117.76, 116.32, 116.19, 114.05, 10 6.89, 102.78. HRMS m / z calculated for C 15 H 8 F 2 O 5 [M - H] - : 305.0267; found: 305.0281. >95% purity (as determined by RP-HPLC, method E, t R = 12.85 min,).
13) 13) [화학식 14][Formula 14] 3,6,7-Trihydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 20i20i ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(4-(트라이플루오로메틸)페닐)-4H-크로멘-4-온 (19i) (27 mg, 0.07 mmol), 삼브롬화붕소 (1.10 mL, 15 eq)를 13 시간 동안 50 ℃에서 교반하여 화합물 20i를 35 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 19i ) (27 mg, 0.07 mmol), boron tribromide (1.10 mL, 15 eq) was stirred for 13 h at 50 °C to give compound 20i as a brown powder in 35% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 4:1).
Rf = 0.26 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.57 (s, 1H), 9.83 (s, 1H), 9.62 (s, 1H), 8.37 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.00 (s, 1H). 13C NMR (150 MHz, DMSO) δ 171.91, 152.97, 150.37, 144.62, 144.60, 141.84, 139.18, 135.71, 129.01, 128.81, 127.79, 125.39, 125.37, 114.10, 106.91, 102.67. HRMS m/z calculated for C16H9F3O5 [M - H]-: 337.0329; found: 337.0343. >95% purity (as determined by RP-HPLC, method D, t R = 13.83 min).R f = 0.26 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.57 (s, 1H), 9.83 (s, 1H), 9.62 (s, 1H), 8.37 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.00 (s, 1H). 13 C NMR (150 MHz, DMSO) δ 171.91, 152.97, 150.37, 144.62, 144.60, 141.84, 139.18, 135.71, 129.01, 128.81, 127.79, 125.39, 125.37, 114.10, 106.91, 102.67. HRMS m / z calculated for C 16 H 9 F 3 O 5 [M - H] - : 337.0329; found: 337.0343. >95% purity (as determined by RP-HPLC, method D, t R = 13.83 min).
14) 14) [화학식 15][Formula 15] 3,6,7-Trihydroxy-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 20j20j ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(3-(트라이플루오로메틸)페닐)-4H-크로멘-4-온 (19j) (40 mg, 0.11 mmol), 삼브롬화붕소 (1.64 mL, 15 eq)를 15 시간 동안 50 ℃에서 교반하여 화합물 20j를 57 %의 수율, 갈색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 19j ) (40 mg, 0.11 mmol), boron tribromide (1.64 mL, 15 eq) was stirred for 15 h at 50 °C to give compound 20j as a brown powder in 57% yield. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 4:1).
Rf = 0.21 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.57 (s, 1H), 8.47 (s, 1H), 7.76 - 7.69 (m, 2H), 7.42 (s, 1H), 7.01 (s, 1H). 13C NMR (150 MHz, DMSO) δ 171.85, 152.89, 150.31, 144.57, 141.82, 138.81, 132.78, 130.71, 129.78, 125.65, 125.02, 123.66, 123.22, 114.11, 106,90, 102.77. HRMS m/z calculated for C16H9F3O5 [M - H]-: 337.0329; found: 337.0332. >95% purity (as determined by RP-HPLC, method A, t R = 6.91 min).R f = 0.21 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, MeOD) δ 8.57 (s, 1H), 8.47 (s, 1H), 7.76 - 7.69 (m, 2H), 7.42 (s, 1H), 7.01 (s, 1H). 13 C NMR (150 MHz, DMSO) δ 171.85, 152.89, 150.31, 144.57, 141.82, 138.81, 132.78, 130.71, 129.78, 125.65, 125.02, 123.66, 123.22, 114.11, 106,90, 102.77. HRMS m / z calculated for C 16 H 9 F 3 O 5 [M - H] - : 337.0329; found: 337.0332. >95% purity (as determined by RP-HPLC, method A, t R = 6.91 min).
15) 15) [화학식 16][Formula 16] 2-(4-Chlorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(4-Chlorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20k20k ))
상기 합성 방법에 따라, 다이클로로메탄 (15 mL) 중에서 2-(4-클로로페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19k) (40 mg, 0.12 mmol), 삼브롬화붕소 (1.20 mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20k를 55 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다. 2-(4-chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19k ) (40 mg according to the above synthetic method) in dichloromethane (15 mL) , 0.12 mmol) and boron tribromide (1.20 mL, 10 eq) were stirred at 50 °C for 16 h to give compound 20k as a brown powder in 55% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.48 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.18 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 6.97 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.79, 152.85, 150.24, 144.53, 142.50, 138.35, 133.82, 130.62, 128.93, 128.59, 114.01, 106.87, 102.63. HRMS m/z calculated for C15H9ClO5 [M - H]-: 303.0066; found: 303.0078. >95% purity (as determined by RP-HPLC, method D, t R = 9.11 min).R f = 0.48 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, DMSO) δ 8.18 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 6.97 (s, 1H); 13 C NMR (150 MHz, DMSO) Δ 171.79, 152.85, 150.24, 144.53, 142.50, 138.35, 133.82, 130.62, 128.93, 128.59, 114.01, 106.87, 102.63. HRMS m / z calculated for C 15 H 9 ClO 5 [M - H] - : 303.0066; found: 303.0078. >95% purity (as determined by RP-HPLC, method D, t R = 9.11 min).
16) 16) [화학식 17][Formula 17] 2-(3-Chlorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-(3-Chlorophenyl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20l20l ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 2-(3-클로로페닐)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19l) (65 mg, 0.20 mmol), 삼브롬화붕소 (2.92 mL, 15 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20l을 66 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the above synthetic method, 2-(3-chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19l ) (65 mg) in dichloromethane (20 mL) , 0.20 mmol) and boron tribromide (2.92 mL, 15 eq) were stirred at 50 °C for 16 h to give compound 20l as a brown powder in 66% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.39 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.21 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.31 (s, 1H), 7.01 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.83, 152.88, 150.31, 144.56, 141.93, 138.67, 133.77, 133.28, 130.44, 129.03, 126.75, 125.62, 114.06, 106.86, 102.74. HRMS m/z calculated for C15H9ClO5 [M - H]-: 303.0066; found: 303.0077. >95% purity (as determined by RP-HPLC, method D, t R = 8.87).R f = 0.39 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.21 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.31 (s, 1H), 7.01 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.83, 152.88, 150.31, 144.56, 141.93, 138.67, 133.77, 133.28, 130.44, 129.03, 126.75, 125.62, 114.06, 106.86, 102.74. HRMS m / z calculated for C 15 H 9 ClO 5 [M - H] - : 303.0066; found: 303.0077. >95% purity (as determined by RP-HPLC, method D, t R = 8.87).
17) 17) [화학식 18][Formula 18] 2-([1,1'-Biphenyl]-4-yl)-3,6,7-trihydroxy-4H-chromen-4-one ( 2-([1,1'-Biphenyl]-4-yl)-3,6,7-trihydroxy-4H-chromen-4-one ( 20m20m ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 2-([1,1'-바이페닐]-4-일)-3-하이드록시-6,7-다이메톡시-4H-크로멘-4-온 (19m) (300 mg, 0.80 mmol), 삼브롬화붕소 (4.0 mL, 5 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20m을 87 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 30:1 to 10:1)로 정제하였다.According to the above synthesis method, 2-([1,1'-biphenyl]-4-yl)-3-hydroxy-6,7-dimethoxy-4H-chromen- in dichloromethane (20 mL) 4-one ( 19m ) (300 mg, 0.80 mmol), boron tribromide (4.0 mL, 5 eq) was stirred for 16 h at 50 °C to give compound 20m as a brown powder in 87% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 30:1 to 10:1).
Rf = 0.33 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.49 (s, 1H), 9.78 (s, 1H), 9.28 (s, 1H), 8.27 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.01 (s, 1H); 13C NMR (150 MHz, DMSO) δ 172.24, 153.11, 150.72, 144.89, 143.91, 141.16, 139.73, 138.72, 131.22, 129.53, 128.42, 128.25, 127.20, 127.11, 114.57, 107.41, 103.16, 31.16. HRMS m/z calculated for C21H14O5 [M - H]-: 345.0708; found: 345.0739. >95% purity (as determined by RP-HPLC, method C, t R = 13.94 min).R f = 0.33 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.49 (s, 1H), 9.78 (s, 1H), 9.28 (s, 1H), 8.27 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.01 ( s, 1H); 13 C NMR (150 MHz, DMSO) δ 172.24, 153.11, 150.72, 144.89, 143.91, 141.16, 139.73, 138.72, 131.22, 129.53, 128.42, 128.25, 127.20, 127.11, 114.57, 107.41, 103.16, 31.16. HRMS m / z calculated for C 21 H 14 O 5 [M - H] - : 345.0708; found: 345.0739. >95% purity (as determined by RP-HPLC, method C, t R = 13.94 min).
18) 18) [화학식 19][Formula 19] 3,6,7-Trihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(4-phenoxyphenyl)-4H-chromen-4-one ( 20n20n ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(4-페녹시페닐)-4H-크로멘-4-온 (19n) (70 mg, 0.19 mmol), 삼브롬화붕소 (2.29 mL, 12 eq)를 6 시간 동안 50 ℃에서 교반하여 화합물 20n을 41 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 4:1)로 정제하였다.According to the above synthetic method, 3-hydroxy-6,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one ( 19n ) (70 mg, 0.19 mmol), boron tribromide (2.29 mL, 12 eq) was stirred for 6 h at 50 °C to give compound 20n as a brown powder in 41% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 4:1).
Rf = 0.28 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.49 (s, 1H), 9.77 (s, 1H), 9.14 (s, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.32 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (dd, J = 20.6, 8.4 Hz, 4H), 6.97 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.74, 157.63, 155.91, 152.54, 150.17, 144.41, 143.60, 137.61, 130.27, 130.25, 129.34, 126.66, 124.13, 119.25, 118.07, 114.10, 106.99, 102.66. HRMS m/z calculated for C21H14O6 [M - H]-: 361.0717; found: 361.0716. >95% purity (as determined by RP-HPLC, method C, t R = 11.28 min).R f = 0.28 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.49 (s, 1H), 9.77 (s, 1H), 9.14 (s, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.32 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (dd, J = 20.6, 8.4 Hz, 4H), 6.97 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.74, 157.63, 155.91, 152.54, 150.17, 144.41, 143.60, 137.61, 130.27, 130.25, 129.34, 126.66, 124.13, 119.25, 118.07, 114.10, 106.99, 102.66. HRMS m / z calculated for C 21 H 14 O 6 [M - H] - : 361.0717; found: 361.0716. >95% purity (as determined by RP-HPLC, method C, t R = 11.28 min).
19) 19) [화학식 20][Formula 20] 3,6,7-Trihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(3-phenoxyphenyl)-4H-chromen-4-one ( 20o20o ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(3-페녹시페닐)-4H-크로멘-4-온 (19o) (180 mg, 0.46 mmol), 삼브롬화붕소 (2.29 mL, 12 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20o를 22 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:1 to 10:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one ( 19o ) (180 mg, 0.46 mmol), boron tribromide (2.29 mL, 12 eq) was stirred for 16 h at 50 °C to give compound 20o as a brown powder in 22% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:1 to 10:1).
Rf = 0.48 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (t, 1H), 7.08 (dd, J = 14.0, 4.9 Hz, 3H), 6.94 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.80, 156.57, 156.55, 152.83, 150.24, 144.51, 142.68, 138.40, 133.61, 130.26, 130.19, 130.14, 124.12, 123.61, 122.31, 119.48, 118.57, 117.55, 113.97, 106.86, 102.62. HRMS m/z calculated for C21H14O6 [M - H]-: 361.0717; found: 361.0727. >95% purity (as determined by RP-HPLC, method C, t R = 11.54 min).R f = 0.48 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (t, 1H), 7.08 (dd, J = 14.0, 4.9 Hz, 3H), 6.94 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.80, 156.57, 156.55, 152.83, 150.24, 144.51, 142.68, 138.40, 133.61, 130.26, 130.19, 130.14, 124.12, 123.61, 122.31, 119.48, 118.57, 117.55, 113.97, 106.86, 102.62. HRMS m / z calculated for C 21 H 14 O 6 [M - H] - : 361.0717; found: 361.0727. >95% purity (as determined by RP-HPLC, method C, t R = 11.54 min).
20) 20) [화학식 21][Formula 21] 3,6,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 20p20p ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(4-메톡시페닐)-4H-크로멘-4-온 (19p) (180 mg, 0.633 mmol), 삼브롬화붕소 (6.33 mL, 10 eq)를 15 시간 동안 50 ℃에서 교반하여 화합물 20p를 89 %의 수율, 갈색 분말로 제조하였다. 반응 혼합물을 여과지로 여과하고 감압 농축하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 20:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one ( 19p ) (180 mg, 0.633 mmol), boron tribromide (6.33 mL, 10 eq) was stirred for 15 h at 50 °C to give compound 20p as a brown powder in 89% yield. The reaction mixture was filtered through filter paper and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 20:1 to 4:1).
Rf = 0.30 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.41 (s, 1H), 9.98 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 6.99 - 6.87 (m, 3H). HRMS m/z calculated for C15H10O6 [M - H]-: 285.0404; found: 285.0399. R f = 0.30 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.41 (s, 1H), 9.98 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 6.99 - 6.87 (m, 3H). HRMS m / z calculated for C 15 H 10 O 6 [M - H] - : 285.0404; found: 285.0399.
21) 21) [화학식 22][Formula 22] 3,6,7-Trihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one ( 20q20q ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(3-메톡시페닐)-4H-크로멘-4-온 (19q) (96 mg, 0.292 mmol), 삼브롬화붕소 (4.38 mL, 15 eq)를 15 시간 동안 50 ℃에서 교반하여 화합물 20q를 87 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 20:1 to 4:1)로 정제하였다. 3-hydroxy-6,7-dimethoxy-2-(3-methoxyphenyl)-4H-chromen-4-one ( 19q ) (96 mg, 0.292 mmol), boron tribromide (4.38 mL, 15 eq) was stirred for 15 h at 50 °C to give compound 20q as a brown powder in 87% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 20:1 to 4:1).
Rf = 0.32 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 7.61 - 7.58 (m, 2H), 7.32 (d, J = 14.4 Hz, 2H), 6.91 (s, 1H), 6.85 (d, J = 6.0 Hz 1H). HRMS m/z calculated for C15H10O6 [M - H]-: 285.0404; found: 285.0410. R f = 0.32 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, DMSO) δ 7.61 - 7.58 (m, 2H), 7.32 (d, J = 14.4 Hz, 2H), 6.91 (s, 1H), 6.85 (d, J = 6.0 Hz 1H). HRMS m / z calculated for C 15 H 10 O 6 [M - H] - : 285.0404; found: 285.0410.
22) 22) [화학식 23][Formula 23] 4-(3,6,7-Trihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 4-(3,6,7-Trihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 20r20r ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 메틸 4-(3-하이드록시-6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (19r) (80 mg, 0.22 mmol), 삼브롬화붕소 (3.36 mL, 15 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20r을 9 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 메탄올로 재결정화하였다.According to the above synthetic method, methyl 4-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 19r ) in dichloromethane (20 mL) ( 80 mg, 0.22 mmol), boron tribromide (3.36 mL, 15 eq) was stirred at 50 °C for 16 h to give compound 20r as a brown powder in 9% yield. The crude residue was recrystallized from methanol.
Rf = 0.05 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.33 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.41 (s, 1H), 7.01 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.83, 165.84, 153.50, 150.53, 144.77, 142.02, 139.24, 136.22, 129.53, 129.25, 127.26, 113.81, 106.64, 102.49. HRMS m/z calculated for C15H10Cl2O5 [M - H]-: 313.0354; found: 313.0342. >95% purity (as determined by RP-HPLC, method G, t R = 8.65 min).R f = 0.05 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, MeOD) δ 8.33 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.41 (s, 1H), 7.01 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.83, 165.84, 153.50, 150.53, 144.77, 142.02, 139.24, 136.22, 129.53, 129.25, 127.26, 113.81, 106.64, 102.49. HRMS m / z calculated for C 15 H 10 Cl 2 O 5 [M - H] - : 313.0354; found: 313.0342. >95% purity (as determined by RP-HPLC, method G, t R = 8.65 min).
23) 23) [화학식 24][Formula 24] 3-(3,6,7-Trihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 3-(3,6,7-Trihydroxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 20s20s ))
상기 합성 방법에 따라, 다이클로로메탄 (20 mL) 중에서 메틸 3-(3-하이드록시-6,7-다이메톡시-4-옥소-4H-크로멘-2-일)벤조에이트 (19s) (76 mg, 0.21 mmol), 삼브롬화붕소 (3.20 mL, 15 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 20s를 26 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 메탄올로 재결정화하였다.According to the above synthesis method, methyl 3-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 19s ) in dichloromethane (20 mL) ( 76 mg, 0.21 mmol), boron tribromide (3.20 mL, 15 eq) was stirred for 16 h at 50 °C to give compound 20s as a brown powder in 26% yield. The crude residue was recrystallized from methanol.
Rf = 0.08 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.87 (t, J = 1.6 Hz, 1H), 8.51 - 8.42 (m, 1H), 8.13 - 8.05 (m, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 4.3 Hz, 1H), 7.02 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.86, 167.06, 152.79, 150.29, 144.52, 142.70, 138.50, 132.13, 131.09, 131.05, 129.93, 128.95, 128.26, 114.11, 106.96, 102.65. HRMS m/z calculated for C16H10O7 [M - H]-: 313.0354; found: 313.0365. >95% purity (as determined by RP-HPLC, method G, t R = 10.22 min).R f = 0.08 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, MeOD) δ 8.87 (t, J = 1.6 Hz, 1H), 8.51 - 8.42 (m, 1H), 8.13 - 8.05 (m, 1H), 7.63 (t, J = 7.8 Hz, 1H) ), 7.41 (d, J = 4.3 Hz, 1H), 7.02 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 171.86, 167.06, 152.79, 150.29, 144.52, 142.70, 138.50, 132.13, 131.09, 131.05, 129.93, 128.95, 128.26, 114.11, 106.96, 102.65. HRMS m / z calculated for C 16 H 10 O 7 [M - H] - : 313.0354; found: 313.0365. >95% purity (as determined by RP-HPLC, method G, t R = 10.22 min).
24) 24) [화학식 25][Formula 25] 3,6,7-Trihydroxy-2-(naphthalen-2-yl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(naphthalen-2-yl)-4H-chromen-4-one ( 23a23a ))
상기 합성 방법에 따라, 다이클로로메탄 (10 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(나프탈렌-2-일)-4H-크로멘-4-온 (22a) (35 mg, 0.11 mmol), 삼브롬화붕소 (1.07mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 23a를 57 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 30:1 to 4:1)로 정제하였다. 3-hydroxy-6,7-dimethoxy-2-(naphthalen-2-yl)-4H-chromen-4-one ( 22a ) (35 according to the synthesis method above) in dichloromethane (10 mL) mg, 0.11 mmol), boron tribromide (1.07 mL, 10 eq) was stirred at 50 °C for 16 h to obtain compound 23a in 57% yield, brown powder. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 30:1 to 4:1).
Rf = 0.45 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.75 (s, 1H), 8.29 (dd, J = 8.7, 1.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 8.02 - 7.96 (m, 1H), 7.66 - 7.52 (m, 2H), 7.36 (s, 1H), 7.06 (s, 1H); 13C NMR (150 MHz, DMSO) δ 172.29, 153.14, 150.84, 144.93, 144.17, 138.91, 133.38, 133.00, 129.72, 129.23, 128.36, 128.03, 127.75, 127.70, 127.17, 124.74, 114.60, 107.43, 103.20. HRMS m/z calculated for C19H12O5 [M - H]-: 319.0612; found: 319.0609. >95% purity (as determined by RP-HPLC, method C, t R = 12.43 min, method Q, t R = 7.45 min).R f = 0.45 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 8.75 (s, 1H), 8.29 (dd, J = 8.7, 1.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 8.02 - 7.96 (m, 1H) ), 7.66 - 7.52 (m, 2H), 7.36 (s, 1H), 7.06 (s, 1H); 13 C NMR (150 MHz, DMSO) δ 172.29, 153.14, 150.84, 144.93, 144.17, 138.91, 133.38, 133.00, 129.72, 129.23, 128.36, 128.03, 127.75, 127.70, 127.17, 124.74, 114.60, 107.43, 103.20. HRMS m / z calculated for C 19 H 12 O 5 [M - H] - : 319.0612; found: 319.0609. >95% purity (as determined by RP-HPLC, method C, t R = 12.43 min, method Q, t R = 7.45 min).
25) 25) [화학식 26][Formula 26] 3,6,7-Trihydroxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one ( 23b23b ))
상기 합성 방법에 따라, 다이클로로메탄 (10 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(1-메틸-1H-피라졸-4-일)-4H-크로멘-4-온 (22b) (177 mg, 0.59 mmol), 삼브롬화붕소 (5.85mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 23b를 27 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 30:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4 in dichloromethane (10 mL) -One ( 22b ) (177 mg, 0.59 mmol), boron tribromide (5.85 mL, 10 eq) was stirred at 50 °C for 16 h to give compound 23b in 27% yield, brown powder. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 30:1 to 4:1).
Rf = 0.34 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.35 (s, 1H), 9.65 (s, 1H), 9.10 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.30 (s, 1H), 6.91 (s, 1H), 3.94 (s, 3H); 13C NMR (150 MHz, DMSO) δ 171.29, 152.32, 150.05, 144.53, 142.53, 137.77, 135.76, 130.99, 114.99, 114.20, 107.65, 103.06, 49.07. HRMS m/z calculated for C13H10N2O5 [M - H]-: 273.0524; found: 273.0523. >95% purity (as determined by RP-HPLC, method H, tR = 5.97 min).R f = 0.34 (CH 2 Cl 2/ MeOH = 10:1). 1 H NMR (600 MHz, DMSO) δ 10.35 (s, 1H), 9.65 (s, 1H), 9.10 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.30 (s, 1H) ), 6.91 (s, 1H), 3.94 (s, 3H); 13 C NMR (150 MHz, DMSO) δ 171.29, 152.32, 150.05, 144.53, 142.53, 137.77, 135.76, 130.99, 114.99, 114.20, 107.65, 103.06, 49.07. HRMS m / z calculated for C 13 H 10 N 2 O 5 [M - H] - : 273.0524; found: 273.0523. >95% purity (as determined by RP-HPLC, method H, t R = 5.97 min).
26) 26) [화학식 27][Formula 27] 3,6,7-Trihydroxy-2-(thiophen-2-yl)-4H-chromen-4-one ( 3,6,7-Trihydroxy-2-(thiophen-2-yl)-4H-chromen-4-one ( 23c23c ))
상기 합성 방법에 따라, 다이클로로메탄 (10 mL) 중에서 3-하이드록시-6,7-다이메톡시-2-(싸이오펜-2-일)-4H-크로멘-4-온 (22c) (75 mg, 0.25 mmol), 삼브롬화붕소 (2.46 mL, 10 eq)를 16 시간 동안 50 ℃에서 교반하여 화합물 23c를 39 %의 수율, 갈색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 30:1 to 4:1)로 정제하였다.According to the above synthesis method, 3-hydroxy-6,7-dimethoxy-2-(thiophen-2-yl)-4H-chromen-4-one ( 22c ) in dichloromethane (10 mL) ( 75 mg, 0.25 mmol), boron tribromide (2.46 mL, 10 eq) was stirred for 16 h at 50 °C to give compound 23c as a brown powder in 39% yield. The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 30:1 to 4:1).
Rf = 0.45 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.47 (s, 1H), 9.79 (s, 1H), 9.75 (s, 1H), 7.91 - 7.85 (m, 1H), 7.83 (dd, J = 5.0, 0.8 Hz, 1H), 7.32 (s, 1H), 7.27 (dd, J = 4.9, 3.9 Hz, 1H), 6.95 (s, 1H); 13C NMR (150 MHz, DMSO) δ 171.55, 152.85, 150.13, 144.75, 142.36, 136.32, 133.29, 130.33, 128.13, 127.88, 114.93, 107.65, 103.04. HRMS m/z calculated for [M - H]-: 275.0019; found: 275.0026. >95% purity (as determined by RP-HPLC, method F, tR = 10.00 min).R f = 0.45 (CH 2 Cl 2/ MeOH = 10:1). 1H NMR (600 MHz, DMSO) δ 10.47 (s, 1H), 9.79 (s, 1H), 9.75 (s, 1H), 7.91 - 7.85 (m, 1H), 7.83 (dd, J = 5.0, 0.8 Hz , 1H), 7.32 (s, 1H), 7.27 (dd, J = 4.9, 3.9 Hz, 1H), 6.95 (s, 1H); 13 C NMR (150 MHz, DMSO) Δ 171.55, 152.85, 150.13, 144.75, 142.36, 136.32, 133.29, 130.33, 128.13, 127.88, 114.93, 107.65, 103.04. HRMS m / z calculated for [M - H] - : 275.0019; found: 275.0026. >95% purity (as determined by RP-HPLC, method F, t R = 10.00 min).
(iv) 화합물 18a-18s 합성 방법:(iv) Methods for synthesizing compounds 18a-18s:
테트라하이드로퓨란 (THF) 중 치환된 아세토페논 화합물의 교반 용액에 적절한 알데하이드 (1.2 eq 또는 1.5 eq)를 실온에서 첨가하였다. 반응 혼합물에 메탄올 용액 중 소듐 메톡사이드 (5.4 M, 1.2 eq)를 0 ℃에서 첨가하고 5분 동안 교반하였다. 반응 혼합물을 실온으로 가온하고, TLC 분석 (일반적으로 12-16 시간)에 의해 모니터링되는 완전한 전환이 될 때까지 실온에서 교반하고, 아세트산으로 켄칭한 후, EtOAc 및 H2O로 추출하였다. 유기층을 포화 수성 NaHCO3로 세척하고, MgSO4로 건조시킨 후, 여과하고, 감압 하에 농축시켰다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피로 정제하여 화합물 18a-18t를 수득하였다.To a stirred solution of the substituted acetophenone compound in tetrahydrofuran (THF) was added the appropriate aldehyde (1.2 eq or 1.5 eq) at room temperature. To the reaction mixture was added sodium methoxide (5.4 M, 1.2 eq) in methanol solution at 0 °C and stirred for 5 minutes. The reaction mixture was warmed to room temperature and stirred at room temperature until complete conversion monitored by TLC analysis (generally 12-16 hours), quenched with acetic acid, then extracted with EtOAc and H 2 O. The organic layer was washed with saturated aqueous NaHCO 3 , dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to give compounds 18a-18t .
1) (E)-3-(3,4-Dimethoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (1) (E)-3-(3,4-Dimethoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18a18a ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (200 mg, 1.02 mmol), 3,4-다이메톡시벤즈알데하이드 (202 mg, 1.2 eq), 소듐 메톡사이드 용액 (0.23 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 18a를 53 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 4:1 to 1:1)로 정제하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (200 mg, 1.02 mmol), 3,4-dimethoxybenzaldehyde (202 mg, 1.2 eq), and sodium methoxide solution (0.23 mL, 1.2 eq) were stirred at room temperature for 16 hours to obtain 53% compound 18a . Yield, prepared as a yellow powder. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 4:1 to 1:1).
Rf = 0.54 (hexane/EtOAc = 2:1). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 15.3 Hz, 1H), 7.37 (d, J = 15.3 Hz, 1H), 7.28 (t, J = 4.1 Hz, 2H), 7.16 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 3.97 (s, 3H), 3.94 (d, J = 3.1 Hz, 6H), 3.92 (s, 3H). HRMS m/z calculated for C19H20O6 [M + H]+: 345.1333; found: 345.1336.R f = 0.54 (hexane/EtOAc = 2:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.87 (d, J = 15.3 Hz, 1H), 7.37 (d, J = 15.3 Hz, 1H), 7.28 (t, J = 4.1 Hz, 2H), 7.16 (s , 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 3.97 (s, 3H), 3.94 (d, J = 3.1 Hz, 6H), 3.92 (s, 3H). HRMS m / z calculated for C 19 H 20 O 6 [M + H] + : 345.1333; found: 345.1336.
2) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one (2) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one ( 18b18b ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (300 mg, 1.53 mmol), 벤즈알데하이드 (187 μL, 1.2 eq), 소듐 메톡사이드 용액 (0.33 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 18b를 97 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 10:1 to 6:1)로 정제하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (300 mg, 1.53 mmol), benzaldehyde (187 μL, 1.2 eq) and sodium methoxide solution (0.33 mL, 1.2 eq) were stirred at room temperature for 16 h to prepare compound 18b in 97% yield, yellow powder. . The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 10:1 to 6:1).
Rf = 0.63 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 15.4 Hz, 1H), 7.66 (dd, J = 6.4, 2.7 Hz, 2H), 7.51 (d, J = 11.7 Hz, 1H), 7.46 - 7.40 (m, 3H), 6.52 (s, 1H), 3.94 (s, 9H), 3.92 (s, 3H). HRMS m/z calculated for C17H16O4 [M + H]+: 285.1122; found: 285.1112.R f = 0.63 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 15.4 Hz, 1H), 7.66 (dd, J = 6.4, 2.7 Hz, 2H), 7.51 (d, J = 11.7 Hz, 1H), 7.46 - 7.40 (m, 3H), 6.52 (s, 1H), 3.94 (s, 9H), 3.92 (s, 3H). HRMS m / z calculated for C 17 H 16 O 4 [M + H] + : 285.1122; found: 285.1112.
3) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(p-tolyl)prop-2-en-1-one (3) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(p-tolyl)prop-2-en-1-one ( 18c18c ))
상기 합성 방법에 따라, THF (10 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (200 mg, 1.02 mmol), 벤즈알데하이드 (252 μL, 1.05 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.2 eq)을 15 시간 동안 실온에서 교반하여 화합물 18c를 85 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 20:1 to 3:1)로 정제하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (10 mL) (200 mg, 1.02 mmol), benzaldehyde (252 μL, 1.05 eq) and sodium methoxide solution (0.56 mL, 1.2 eq) were stirred at room temperature for 15 h to prepare compound 18c in 85% yield, yellow powder. . The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 20:1 to 3:1).
Rf = 0.30 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) δ 13.41 (s, 1H), 7.89 (d, J = 15.4 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 15.4 Hz, 1H), 7.26 (d, J = 1.5 Hz, 2H), 7.24 (d, J = 2.7 Hz, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.41 (s, 3H). HRMS m/z calculated for C18H18O4 [M + H]+: 299.1278; found: 299.1283.R f = 0.30 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl 3 ) δ 13.41 (s, 1H), 7.89 (d, J = 15.4 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 15.4 Hz) , 1H), 7.26 (d, J = 1.5 Hz, 2H), 7.24 (d, J = 2.7 Hz, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.41 (s, 3H). HRMS m / z calculated for C 18 H 18 O 4 [M + H] + : 299.1278; found: 299.1283.
4) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(m-tolyl)prop-2-en-1-one (4) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(m-tolyl)prop-2-en-1-one ( 18d18d ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), m-톨루벤즈알데하이드 (445 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 15 시간 동안 실온에서 교반하여 화합물 18d를 65 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), m- tolubenzaldehyde (445 μL, 1.5 eq), sodium methoxide solution (0.7 mL, 1.5 eq) was stirred for 15 h at room temperature to give compound 18d in 65% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.35 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 15.4 Hz, 1H), 7.49 (dd, J = 16.3, 11.6 Hz, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.42 (s, 3H). HRMS m/z calculated for C18H18O4 [M + H]+: 299.1278; found: 299.1270.R f = 0.35 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.88 (d, J = 15.4 Hz, 1H), 7.49 (dd, J = 16.3, 11.6 Hz, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.42 (s, 3H). HRMS m / z calculated for C 18 H 18 O 4 [M + H] + : 299.1278; found: 299.1270.
5) (E)-3-(3,4-Dimethylphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (5) (E)-3-(3,4-Dimethylphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18e18e ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 3,4-다이메틸벤즈알데하이드 (405 μL, 1.2 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.2 eq)을 12 시간 동안 실온에서 교반하여 화합물 18e를 74 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), 3,4-dimethylbenzaldehyde (405 μL, 1.2 eq), sodium methoxide solution (0.56 mL, 1.2 eq) was stirred at room temperature for 12 hours to obtain compound 18e in 74% yield. , prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.45 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 15.4 Hz, 1H), 7.47 (d, J = 15.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.28 (d, J = 4.5 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). HRMS m/z calculated for C19H20O4 [M + H]+: 313.1435; found: 313.1426.R f = 0.45 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.87 (d, J = 15.4 Hz, 1H), 7.47 (d, J = 15.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.28 (d, J = 4.5 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). HRMS m / z calculated for C 19 H 20 O 4 [M + H] + : 313.1435; found: 313.1426.
6) (E)-3-(4-Fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (6) (E)-3-(4-Fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18f18f ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (300 mg, 1.53 mmol), 4-플루오로벤즈알데하이드 (196 μL, 1.2 eq), 소듐 메톡사이드 용액 (0.33 mL, 1.2 eq)을 12 시간 동안 실온에서 교반하여 화합물 18f를 81 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (300 mg, 1.53 mmol), 4-fluorobenzaldehyde (196 μL, 1.2 eq), sodium methoxide solution (0.33 mL, 1.2 eq) was stirred at room temperature for 12 h to obtain compound 18f in 81% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.28 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 15.4 Hz, 1H), 7.66 (dd, J = 6.4, 2.7 Hz, 2H), 7.52 (d, J = 15.4 Hz, 1H), 7.47 - 7.40 (m, 3H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C17H15FO4 [M + H]+: 303.1027; found: 303.1032.R f = 0.28 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 15.4 Hz, 1H), 7.66 (dd, J = 6.4, 2.7 Hz, 2H), 7.52 (d, J = 15.4 Hz, 1H), 7.47 - 7.40 (m, 3H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 17 H 15 FO 4 [M + H] + : 303.1027; found: 303.1032.
7) (E)-3-(3-Fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (7) (E)-3-(3-Fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18g18g ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (400 mg, 2.04 mmol), 3-플루오로벤즈알데하이드 (324 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.5 eq)을 12 시간 동안 실온에서 교반하여 화합물 18g를 91 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (400 mg, 2.04 mmol), 3-fluorobenzaldehyde (324 μL, 1.5 eq), sodium methoxide solution (0.56 mL, 1.5 eq) was stirred at room temperature for 12 h to give compound 18 g in 91% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.46 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 15.4 Hz, 1H), 7.50 (d, J = 15.4 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.36 (d, J = 9.5 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.52 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C17H15FO4 [M + H]+: 303.1027; found: 303.1025.R f = 0.46 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.85 (d, J = 15.4 Hz, 1H), 7.50 (d, J = 15.4 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.36 (d, J = 9.5 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.52 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 17 H 15 FO 4 [M + H] + : 303.1027; found: 303.1025.
8) (E)-3-(3,4-Difluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (8) (E)-3-(3,4-Difluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18h18h ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (400 mg, 2.04 mmol), 3,4-다이플루오로벤즈알데하이드 (337 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18h를 56 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (400 mg, 2.04 mmol), 3,4-difluorobenzaldehyde (337 μL, 1.5 eq), sodium methoxide solution (0.56 mL, 1.5 eq) was stirred at room temperature for 16 hours to obtain 56% compound 18h . Yield, prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.52 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 14.2 Hz, 1H), 7.54 - 7.46 (m, J = 15.5, 8.7, 5.0 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.25 - 7.19 (m, 2H), 6.52 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C17H14F2O4 [M + H]+: 321.0933; found: 321.0918.R f = 0.52 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.81 (d, J = 14.2 Hz, 1H), 7.54 - 7.46 (m, J = 15.5, 8.7, 5.0 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.25 - 7.19 (m, 2H), 6.52 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 17 H 14 F 2 O 4 [M+H] + : 321.0933; found: 321.0918.
9) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (9) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one ( 18i18i ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (200 mg, 1.02 mmol), 4-(트라이플루오로메틸)벤즈알데하이드 (508 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18i를 89 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (200 mg, 1.02 mmol), 4-(trifluoromethyl)benzaldehyde (508 μL, 1.5 eq), sodium methoxide solution (0.7 mL, 1.5 eq) was stirred at room temperature for 16 h to obtain 89% compound 18i . yield, prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.49 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 15.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.57 (d, 1H), 7.24 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m/z calculated for C18H15F3O4 [M + H]+: 353.0995; found: 353.0988.R f = 0.49 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.90 (d, J = 15.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.57 (d , 1H), 7.24 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m / z calculated for C 18 H 15 F 3 O 4 [M+H] + : 353.0995; found: 353.0988.
10) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one (10) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one ( 18j18j ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (200 mg, 1.02 mmol), 3-(트라이플루오로메틸)벤즈알데하이드 (508 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18j를 67 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (200 mg, 1.02 mmol), 3-(trifluoromethyl)benzaldehyde (508 μL, 1.5 eq), sodium methoxide solution (0.7 mL, 1.5 eq) was stirred at room temperature for 16 h to obtain 67% compound 18j . yield, prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.33 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 15.4 Hz, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.57 (dd, J = 18.3, 11.6 Hz, 2H), 7.25 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m/z calculated for C18H15F3O4 [M + H]+: 353.0995; found: 353.0982.R f = 0.33 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 (d, J = 15.4 Hz, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.57 (dd , J = 18.3, 11.6 Hz, 2H), 7.25 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m / z calculated for C 18 H 15 F 3 O 4 [M+H] + : 353.0995; found: 353.0982.
11) (E)-3-(4-Chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (11) (E)-3-(4-Chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18k18k ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (300 mg, 1.53 mmol), 4-클로로벤즈알데하이드 (257 μL, 1.2 eq), 소듐 메톡사이드 용액 (0.33 mL, 1.2 eq)을 12 시간 동안 실온에서 교반하여 화합물 18k를 86 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (300 mg, 1.53 mmol), 4-chlorobenzaldehyde (257 μL, 1.2 eq), sodium methoxide solution (0.33 mL, 1.2 eq) was stirred at room temperature for 12 h to give compound 18k in 86% yield, yellow powder was made with The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.24 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 15.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 15.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C17H15ClO4 [M + H]+: 319.0732; found: 319.0736.R f = 0.24 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.85 (d, J = 15.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 15.4 Hz, 1H), 7.41 (d , J = 8.4 Hz, 2H), 7.24 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 17 H 15 ClO 4 [M + H] + : 319.0732; found: 319.0736.
12) (E)-3-(3-Chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (12) (E)-3-(3-Chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18l18l ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 3-클로로벤즈알데하이드 (346 μL, 1.2 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.2 eq)을 12 시간 동안 실온에서 교반하여 화합물 18l을 68 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), 3-chlorobenzaldehyde (346 μL, 1.2 eq), sodium methoxide solution (0.56 mL, 1.2 eq) was stirred at room temperature for 12 h to give compound 18l in 68% yield, yellow powder was made with The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.50 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 15.4 Hz, 1H), 7.65 (s, 1H), 7.51 (t, J = 10.4 Hz, 2H), 7.42 - 7.36 (m, 2H), 7.23 (s, 1H), 6.52 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m/z calculated for C17H15ClO4 [M + H]+: 319.0732; found: 319.0746.R f = 0.50 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.82 (d, J = 15.4 Hz, 1H), 7.65 (s, 1H), 7.51 (t, J = 10.4 Hz, 2H), 7.42 - 7.36 (m, 2H) , 7.23 (s, 1H), 6.52 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H). HRMS m / z calculated for C 17 H 15 ClO 4 [M + H] + : 319.0732; found: 319.0746.
13) (E)-3-([1,1'-Biphenyl]-4-yl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (13) (E)-3-([1,1'-Biphenyl]-4-yl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18m18m ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 바이페닐-4-카복스알데하이드 (557 mg, 1.2 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18m을 52 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), biphenyl-4-carboxaldehyde (557 mg, 1.2 eq), and sodium methoxide solution (0.7 mL, 1.5 eq) were stirred at room temperature for 16 h to obtain compound 18m in 52% yield. , prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.44 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 15.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.56 (d, J = 15.4 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.41 - 7.37 (m, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). HRMS m/z calculated for C23H20O4 [M + H]+: 361.1417; found: 361.1447.R f = 0.44 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.95 (d, J = 15.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.56 (d, J = 15.4 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.41 - 7.37 (m, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). HRMS m / z calculated for C 23 H 20 O 4 [M + H] + : 361.1417; found: 361.1447.
14) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(4-phenoxyphenyl)prop-2-en-1-one (14) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(4-phenoxyphenyl)prop-2-en-1-one ( 18n18n ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 4-페녹시벤즈알데하이드 (658 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18n을 89 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), 4-phenoxybenzaldehyde (658 μL, 1.5 eq), sodium methoxide solution (0.7 mL, 1.5 eq) was stirred at room temperature for 16 h to give compound 18n in 89% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.44 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 15.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.48 - 7.35 (m, 3H), 7.25 (s, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.52 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H). HRMS m/z calculated for C23H20O5 [M + H]+: 377.1384; found: 377.1384.R f = 0.44 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.89 (d, J = 15.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.48 - 7.35 (m, 3H), 7.25 (s, 1H) , 7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.52 (s, 1H), 3.94 (s, 3H) , 3.91 (s, 3H). HRMS m / z calculated for C 23 H 20 O 5 [M + H] + : 377.1384; found: 377.1384.
15) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(3-phenoxyphenyl)prop-2-en-1-one (15) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(3-phenoxyphenyl)prop-2-en-1-one ( 18o18o ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 3-페녹시벤즈알데하이드 (658 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.7 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18o를 35 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), 3-phenoxybenzaldehyde (658 μL, 1.5 eq), sodium methoxide solution (0.7 mL, 1.5 eq) was stirred at room temperature for 16 h to give compound 18o in 35% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.44 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 11.7 Hz, 1H), 7.46 (d, J = 11.7 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.31 (s, 1H), 7.21 (s, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.51 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H). HRMS m/z calculated for C23H20O5 [M + H]+: 377.1384; found: 377.1393.R f = 0.44 (hexane/EtOAc = 3:1). 1 H NMR (600 MHz, CDCl 3 ) δ 7.82 (d, J = 11.7 Hz, 1H), 7.46 (d, J = 11.7 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.31 (s, 1H) , 7.21 (s, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.51 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H). HRMS m / z calculated for C 23 H 20 O 5 [M + H] + : 377.1384; found: 377.1393.
16) (E)-3-(4-Methoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (16) (E)-3-(4-Methoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18p18p ))
상기 합성 방법에 따라, THF (36 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (2,350 mg, 12 mmol), p-아니스알데하이드 (1.747 ml, 1.2 eq), 소듐 메톡사이드 용액 (2.66 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 18p를 84 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (36 mL) (2,350 mg, 12 mmol), p -anisaldehyde (1.747 ml, 1.2 eq) and sodium methoxide solution (2.66 mL, 1.2 eq) were stirred at room temperature for 16 h to give compound 18p as a yellow powder in 84% yield. manufactured. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.33 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) 7.88 (d, J = 15.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 13.8 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H). HRMS (ESI) m/z calculated for C18H18O5 [M + H]+: 315.1227; found: 315.1141.R f = 0.33 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) 7.88 (d, J = 15.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 13.8 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H). HRMS (ESI) m/z calculated for C 18 H 18 O 5 [M + H] + : 315.1227; found: 315.1141.
17) (E)-3-(3-Methoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (17) (E)-3-(3-Methoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one ( 18q18q ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 12 mmol), m-아니스알데하이드 (465 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.84 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 18q를 35 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (hexane/EtOAc = 10:1 to 4:1)로 정제하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 12 mmol), m -anisaldehyde (465 μL, 1.5 eq), sodium methoxide solution (0.84 mL, 1.5 eq) was stirred at room temperature for 16 h to give compound 18q as a yellow powder in 35% yield. manufactured. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc = 10:1 to 4:1).
Rf= 0.41 (hexane-E.A = 2:1, v/v). 1 H NMR (300 MHz, CDCl3) δ 13.48 (s, 1H), 7.88 (d, J=15.3Hz, 1H), 7.64 (d, J =8.7Hz, 1H), 7.63 (dd, J =4.5 and 9.6 Hz, 1H), 7.41 (d, J =15.3Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 6.96 (dd, J=4.5 and 9.6Hz, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H). HRMS (ESI) m/z calculated for C18H18O5 [M + H]+: 315.1227; found: 315.1242.Rf = 0.41 (hexane-EA = 2:1, v/v). 1H NMR (300 MHz, CDCl3) δ 13.48 (s, 1H), 7.88 (d, J=15.3Hz, 1H), 7.64 (d, J =8.7Hz, 1H), 7.63 (dd, J =4.5 and 9.6 Hz, 1H), 7.41 (d, J =15.3Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 6.96 (dd, J=4.5 and 9.6Hz, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H). HRMS (ESI) m/z calculated for C 18 H 18 O 5 [M + H] + : 315.1227; found: 315.1242.
18) (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (18) (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 18r18r ))
상기 합성 방법에 따라, THF (36 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (2,350 mg, 12 mmol), 메틸 테레프탈알데하이데이트 (2,360 mg, 1.2 eq), 소듐 메톡사이드 용액 (3.28 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 18r을 37 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (36 mL) (2,350 mg, 12 mmol), methyl terephthalaldehyde (2,360 mg, 1.2 eq), sodium methoxide solution (3.28 mL, 1.2 eq) was stirred at room temperature for 16 h to obtain compound 18r in 37% yield, yellow powder was made with The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.61 (hexane/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 15.5 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 15.5 Hz, 1H), 7.25 (s, 1H), 6.52 (s, 1H), 3.95 (s, 6H), 3.92 (s, 3H). HRMS m/z calculated for C19H18O6 [M + H]+: 343.1176; found: 343.1179.R f = 0.61 (hexane/EtOAc = 1:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.10 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 15.5 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.58 (d , J = 15.5 Hz, 1H), 7.25 (s, 1H), 6.52 (s, 1H), 3.95 (s, 6H), 3.92 (s, 3H). HRMS m / z calculated for C 19 H 18 O 6 [M + H] + : 343.1176; found: 343.1179.
19) (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (19) (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 18s18s ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (1,000 mg, 5.10 mmol), 메틸 3-포밀벤조에이트 (1,000 mg, 1.2 eq), 소듐 메톡사이드 용액 (1.13 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 18s를 19 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (1,000 mg, 5.10 mmol), methyl 3-formylbenzoate (1,000 mg, 1.2 eq), and sodium methoxide solution (1.13 mL, 1.2 eq) were stirred at room temperature for 16 h to obtain compound 18s in 19% yield, yellow Made into powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.49 (hexane/EtOAc = 2:1). 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 8.12 - 8.05 (m, 1H), 7.92 (d, J = 15.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.58 (d, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 6.52 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H). HRMS m/z calculated for C19H18O6 [M + H]+: 343.1176; found: 343.1181.R f = 0.49 (hexane/EtOAc = 2:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.35 (s, 1H), 8.12 - 8.05 (m, 1H), 7.92 (d, J = 15.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H) , 7.58 (d, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 6.52 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 ( s, 3H). HRMS m / z calculated for C 19 H 18 O 6 [M + H] + : 343.1176; found: 343.1181.
20) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one (20) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one ( 21a21a ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 2.55 mmol), 3-나프탈알데하이드 (477 mg, 1.2 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 21a를 54 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 2.55 mmol), 3-naphthalaldehyde (477 mg, 1.2 eq), sodium methoxide solution (0.56 mL, 1.2 eq) was stirred at room temperature for 16 h to give compound 21a in 54% yield, yellow powder was made with The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.32 (hexane/EtOAc = 4:1). 1H NMR (600 MHz, CDCl3) δ 8.07 (d, J = 15.1 Hz, 2H), 7.98 - 7.84 (m, 3H), 7.81 (dd, J = 8.5, 1.2 Hz, 1H), 7.63 (d, J = 15.4 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.32 (s, 1H), 6.53 (s, 1H), 3.95 (s, 6H). HRMS m/z calculated for C21H18O4 [M+H]+ : 335.1278; found: 335.1259.R f = 0.32 (hexane/EtOAc = 4:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.07 (d, J = 15.1 Hz, 2H), 7.98 - 7.84 (m, 3H), 7.81 (dd, J = 8.5, 1.2 Hz, 1H), 7.63 (d, J = 15.4 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.32 (s, 1H), 6.53 (s, 1H), 3.95 (s, 6H). HRMS m / z calculated for C 21 H 18 O 4 [M+H] + : 335.1278; found: 335.1259.
21) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-en-1-one (21) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)prop-2-en-1-one ( 21b21b ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (500 mg, 1.53 mmol), 1-메틸피라졸-4-카복스알데하이드 (0.52 mL, 1.5 eq), 소듐 메톡사이드 용액 (0.56 mL, 1.2 eq)을 16 시간 동안 실온에서 교반하여 화합물 21b를 54 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (500 mg, 1.53 mmol), 1-methylpyrazole-4-carboxaldehyde (0.52 mL, 1.5 eq), sodium methoxide solution (0.56 mL, 1.2 eq) was stirred at room temperature for 16 hours to obtain compound 21b at 54 % yield, prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.12 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.81 (d, J = 15.0 Hz, 1H), 7.67 (s, 1H), 7.26 (s, 1H), 7.24 (d, J = 15.6 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C15H16N2O4 [M + H]+: 289.1183; found: 289.1195.R f = 0.12 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 7.85 (s, 1H), 7.81 (d, J = 15.0 Hz, 1H), 7.67 (s, 1H), 7.26 (s, 1H), 7.24 (d, J = 15.6 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 15 H 16 N 2 O 4 [M + H] + : 289.1183; found: 289.1195.
22) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one (22) (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one ( 21c21c ))
상기 합성 방법에 따라, THF (20 mL) 중에서 1-(2-하이드록시-4,5-다이메톡시페닐)에탄온 (11) (300 mg, 1.53 mmol), 2-싸이오펜카복스알데하이드 (209 μL, 1.5 eq), 소듐 메톡사이드 용액 (0.43 mL, 1.5 eq)을 16 시간 동안 실온에서 교반하여 화합물 21c를 99 %의 수율, 황색 분말로 제조하였다. 조 잔류물을 에틸 아세테이트 및 헥산으로 재결정화하였다.According to the above synthesis method, 1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone (11) in THF (20 mL) (300 mg, 1.53 mmol), 2-thiophenecarboxaldehyde (209 μL, 1.5 eq), sodium methoxide solution (0.43 mL, 1.5 eq) was stirred at room temperature for 16 hours to obtain compound 21c in 99% yield, Prepared as a yellow powder. The crude residue was recrystallized from ethyl acetate and hexanes.
Rf = 0.34 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 15.0 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.22 (s, 1H), 7.12 - 7.08 (m, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m/z calculated for C15H14O4S [M + H]+: 291.0686; found: 291.0678.R f = 0.34 (hexane/EtOAc = 3:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.03 (d, J = 15.0 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.30 (d , J = 3.6 Hz, 1H), 7.22 (s, 1H), 7.12 - 7.08 (m, 1H), 6.51 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H). HRMS m / z calculated for C 15 H 14 O 4 S [M + H] + : 291.0686; found: 291.0678.
(v) 화합물 19a-19s, 22a-22c 합성 방법:(v) Methods for synthesizing compounds 19a-19s, 22a-22c:
MeOH 또는 EtOH 중 칼콘 화합물 (19a19s 및 22a22c)의 교반 용액에 소듐 하이드록사이드 (NaOH, 3M aq.) 또는 소듐 메톡사이드 (NaOCH3, 5.4 M in methanol solution, 4 eq) 및 과산화수소 (H2O2, 35% aq., 4 eq)를 실온에서 첨가하였다. 반응 혼합물을 TLC 분석 (일반적으로 5-16 시간)에 의해 모니터링되는 완전한 전환이 될 때까지 아르곤 하에 40℃에서 교반하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 유기층을 MgSO4로 건조시키고, 여과한 후, 감압 하에 농축시켰다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피로 정제하여 화합물 19a19s 및 22a22c를 수득하였다.Sodium hydroxide (NaOH, 3M aq.) or sodium methoxide (NaOCH 3 , 5.4 M in methanol solution, 4 eq) and hydrogen peroxide (H 2 O 2 , 35% aq., 4 eq) was added at room temperature. The reaction mixture was stirred at 40° C. under argon until complete conversion monitored by TLC analysis (usually 5-16 hours). The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to give compounds 19a19s and 22a22c .
1) 2-(3,4-Dimethoxyphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (1) 2-(3,4-Dimethoxyphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19a19a ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-3-(3,4-다이메톡시페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18a) (185 mg, 0.54 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 209 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19a를 68 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 8:1)로 정제하였다.According to the above synthesis method, (E)-3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2 in ethanol (10 mL) Compound 19a was obtained by stirring -en-1-one ( 18a ) (185 mg, 0.54 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 209 μL, 4 eq) for 16 h. Yield 68%, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 8:1).
Rf = 0.35 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 7.91 - 7.78 (m, 2H), 7.53 (s, 1H), 7.05 - 6.95 (m, 3H), 4.03 (s, 3H), 4.00 (s, 6H), 3.98 (d, J = 6.4 Hz, 3H). HRMS m/z calculated for C19H18O7 [M + H]+: 359.1126; found: 359.1132.R f = 0.35 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 - 7.78 (m, 2H), 7.53 (s, 1H), 7.05 - 6.95 (m, 3H), 4.03 (s, 3H), 4.00 (s, 6H), 3.98 (d, J = 6.4 Hz, 3H). HRMS m / z calculated for C 19 H 18 O 7 [M + H] + : 359.1126; found: 359.1132.
2) 3-Hydroxy-6,7-dimethoxy-2-phenyl-4H-chromen-4-one (2) 3-Hydroxy-6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 19b19b ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-페닐프로프-2-엔-1-온 (18b) (200 mg, 0.70 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 273 μL, 4 eq)를 5 시간 동안 교반하여 화합물 19b를 24 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 30:1)로 정제하였다.According to the above synthetic method, (E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one ( 18b ) in ethanol (10 mL) (200 mg, 0.70 mmol), NaOH (3 M aq., 2 mL) and hydrogen peroxide (35% aq., 273 μL, 4 eq) for 5 h to prepare compound 19b in 24% yield, yellow powder did The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 30:1).
Rf = 0.39 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.23 (d, J = 7.5 Hz, 2H), 7.57 - 7.51 (m, 3H), 7.46 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H), 7.00 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m/z calculated for C17H14O5 [M + H]+: 299.0554; found: 299.0914.R f = 0.39 (CH 2 Cl 2 /MeOH = 100:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.23 (d, J = 7.5 Hz, 2H), 7.57 - 7.51 (m, 3H), 7.46 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H) , 7.00 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m / z calculated for C 17 H 14 O 5 [M + H] + : 299.0554; found: 299.0914.
3) 3-Hydroxy-6,7-dimethoxy-2-(p-tolyl)-4H-chromen-4-one (3) 3-Hydroxy-6,7-dimethoxy-2-(p-tolyl)-4H-chromen-4-one ( 19c19c ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(p-톨일)프로프-2-엔-1-온 (18c) (180 mg, 0.60 mmol), NaOH (3 M aq., 1.5 mL), 과산화수소 (35 % aq., 274 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19c를 58 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(p-tolyl)prop-2-en-1- in ethanol (10 mL) A mixture of ( 18c ) (180 mg, 0.60 mmol), NaOH (3 M aq., 1.5 mL), and hydrogen peroxide (35% aq., 274 μL, 4 eq) was stirred for 16 h to obtain compound 19c in 58% yield, Prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf =0.19 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 4.4 Hz, 2H), 4.03 (s, 3H), 4.00 (s, 3H), 2.44 (s, 3H). HRMS m/z calculated for C18H16O5 [M + H]+: 313.1070; found: 313.1069.R f =0.19 (CH 2 Cl 2 /MeOH = 100:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.13 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 4.4 Hz) , 2H), 4.03 (s, 3H), 4.00 (s, 3H), 2.44 (s, 3H). HRMS m / z calculated for C 18 H 16 O 5 [M + H] + : 313.1070; found: 313.1069.
4) 3-Hydroxy-6,7-dimethoxy-2-(m-tolyl)-4H-chromen-4-one (4) 3-Hydroxy-6,7-dimethoxy-2-(m-tolyl)-4H-chromen-4-one ( 19d19d ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(m-톨일)프로프-2-엔-1-온 (18d) (480 mg, 1.60 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 625 μL, 4 eq)를 20 시간 동안 교반하여 화합물 19d를 16 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(m-tolyl)prop-2-en-1- in methanol (10 mL) On ( 18d ) (480 mg, 1.60 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 625 μL, 4 eq) was stirred for 20 h to obtain compound 19d in 16% yield, Prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.21 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.01 (s, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 2.47 (s, 3H). R f = 0.21 (CH 2 Cl 2 /MeOH = 100:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.04 (d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.7 Hz) , 1H), 7.01 (s, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 2.47 (s, 3H).
5) 2-(3,4-Dimethylphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (5) 2-(3,4-Dimethylphenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19e19e ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-3-(3,4-다이메톡시페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18e) (120 mg, 0.38 mmol), NaOH (3 M aq., 1 mL), 과산화수소 (35 % aq., 149 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19e를 32 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 20:1)로 정제하였다.According to the above synthesis method, (E)-3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2 in ethanol (10 mL) Compound 19e was obtained by stirring -en-1-one ( 18e ) (120 mg, 0.38 mmol), NaOH (3 M aq., 1 mL), and hydrogen peroxide (35% aq., 149 μL, 4 eq) for 16 h. Yield of 32%, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 20:1).
Rf = 0.55 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.05 - 7.91 (m, 2H), 7.53 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H). (s, 3H), 4.01 (s, 3H), 2.47 (s, 3H). HRMS m/z calculated for C19H18O5 [M + H]+: 327.1227; found: 327.1207.R f = 0.55 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.05 - 7.91 (m, 2H), 7.53 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H). (s, 3H), 4.01 (s, 3H), 2.47 (s, 3H). HRMS m / z calculated for C 19 H 18 O 5 [M + H] + : 327.1227; found: 327.1207.
6) 2-(4-Fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (6) 2-(4-Fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19f19f ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-3-(4-플루오로페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18f) (300 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 386 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19f를 33 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-3-(4-fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-ene- in ethanol (10 mL) Compound 19f was prepared at 33% concentration by stirring 1-one ( 18f ) (300 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), and hydrogen peroxide (35% aq., 386 μL, 4 eq) for 16 h. Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.29 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.25 (dd, J = 8.8, 5.4 Hz, 2H), 7.53 (s, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.04 (s, 1H), 6.99 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).R f = 0.29 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.25 (dd, J = 8.8, 5.4 Hz, 2H), 7.53 (s, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.04 (s, 1H) , 6.99 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).
7) 2-(3-Fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (7) 2-(3-Fluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19g19g ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-3-(3-플루오로페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18g) (300 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 386 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19g를 80 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-3-(3-fluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-ene- in methanol (10 mL) 1-one ( 18 g ) (300 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35 % aq., 386 μL, 4 eq) was stirred for 16 h to obtain compound 19 g at 80% concentration. Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.52 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 7.9 Hz, 1H), 7.96 (dd, J = 10.5, 1.9 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.19 - 7.07 (m, J = 35.4, 20.7, 11.4 Hz, 2H), 7.00 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H).R f = 0.52 (CH 2 Cl 2 /MeOH = 100:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.06 (d, J = 7.9 Hz, 1H), 7.96 (dd, J = 10.5, 1.9 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.19 - 7.07 ( m, J = 35.4, 20.7, 11.4 Hz, 2H), 7.00 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H).
8) 2-(3,4-Difluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (8) 2-(3,4-Difluorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19h19h ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-3-(3,4-다이플루오로페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18h) (200 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 242 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19h를 29 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-3-(3,4-difluorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2 in methanol (10 mL) Compound 19h was obtained by stirring -en-1-one ( 18h ) (200 mg, 0.99 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 242 μL, 4 eq) for 16 h. 29% yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.27 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.14 - 8.04 (m, J = 11.9, 7.7, 2.2 Hz, 1H), 8.07 - 7.99 (m, 1H), 7.52 (s, 1H), 7.37 - 7.27 (m, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.99 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H).R f = 0.27 (CH 2 Cl 2 /MeOH = 100:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.14 - 8.04 (m, J = 11.9, 7.7, 2.2 Hz, 1H), 8.07 - 7.99 (m, 1H), 7.52 (s, 1H), 7.37 - 7.27 (m , 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.99 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H).
9) 3-Hydroxy-6,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one (9) 3-Hydroxy-6,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 19i19i ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(4-(트라이플루오로메틸)페닐)프로프-2-엔-1-온 (18i) (220 mg, 0.62 mmol), NaOH (3 M aq., 1.5 mL), 과산화수소 (35 % aq., 242 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19i를 16 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(4-(trifluoromethyl)phenyl)prop- Compound 19i was obtained by stirring 2-en-1-one ( 18i ) (220 mg, 0.62 mmol), NaOH (3 M aq., 1.5 mL), hydrogen peroxide (35% aq., 242 μL, 4 eq) for 16 h. was prepared in a yield of 16%, as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 30:1).
Rf = 0.63 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.36 (d, J = 8.3 Hz, 6H), 7.78 (d, J = 8.4 Hz, 6H), 7.53 (s, 3H), 7.16 (s, 2H), 7.01 (s, 3H), 4.04 (s, 9H), 4.01 (s, 9H).R f = 0.63 (CH 2 Cl 2 /MeOH = 100:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.36 (d, J = 8.3 Hz, 6H), 7.78 (d, J = 8.4 Hz, 6H), 7.53 (s, 3H), 7.16 (s, 2H), 7.01 (s, 3H), 4.04 (s, 9H), 4.01 (s, 9H).
10) 3-Hydroxy-6,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (10) 3-Hydroxy-6,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one ( 19j19j ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(3-(트라이플루오로메틸)페닐)프로프-2-엔-1-온 (18j) (589 mg, 1.67 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 651 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19j를 8 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(3-(trifluoromethyl)phenyl)prop- Compound 19j was obtained by stirring 2-en-1-one ( 18j ) (589 mg, 1.67 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 651 μL, 4 eq) for 16 h. was prepared in 8% yield, yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 30:1).
Rf = 0.32 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.48 (d, J = 6.5 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H).R f = 0.32 (CH 2 Cl 2 /MeOH = 100:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.48 (d, J = 6.5 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.53 (s , 1H), 7.14 (s, 1H), 7.03 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H).
11) 2-(4-Chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (11) 2-(4-Chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19k19k ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-3-(4-클로로페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18k) (300 mg, 0.94 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 366 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19k를 40 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-3-(4-chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1 in ethanol (10 mL) -One ( 18k ) (300 mg, 0.94 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 366 μL, 4 eq) was stirred for 16 h to obtain compound 19k in 40% yield. , prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.3 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.6 Hz, 2H), 7.57 - 7.46 (m, 3H), 7.08 (s, 1H), 6.99 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).R f = 0.3 (CH 2 Cl 2 /MeOH = 100:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.19 (d, J = 8.6 Hz, 2H), 7.57 - 7.46 (m, 3H), 7.08 (s, 1H), 6.99 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).
12) 2-(3-Chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (12) 2-(3-Chlorophenyl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19l19l ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-3-(3-클로로페닐)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18l) (300 mg, 0.94 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 288 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19l을 29 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-3-(3-chlorophenyl)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1 in methanol (10 mL) -One ( 18l ) (300 mg, 0.94 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 288 μL, 4 eq) was stirred for 16 h to obtain compound 19l in 29% yield. , prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.35 (CH2Cl2/MeOH = 100:1). 1H NMR (600 MHz, CDCl3) δ 8.21 (t, J = 1.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.39 (m, 2H), 7.09 (d, J = 11.1 Hz, 1H), 7.01 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). HRMS m/z calculated for C17H13ClO5 [M + H]+: 333.0525; found: 333.0525.R f = 0.35 (CH 2 Cl 2 /MeOH = 100:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.21 (t, J = 1.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.39 (m, 2H) , 7.09 (d, J = 11.1 Hz, 1H), 7.01 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). HRMS m / z calculated for C 17 H 13 ClO 5 [M + H] + : 333.0525; found: 333.0525.
13) 2-([1,1'-Biphenyl]-4-yl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one (13) 2-([1,1'-Biphenyl]-4-yl)-3-hydroxy-6,7-dimethoxy-4H-chromen-4-one ( 19m19m ))
상기 합성 방법에 따라, 메탄올 (20 mL) 중에서 (E)-3-([1,1'-바이페닐]-4-일)-1-(2-하이드록시-4,5-다이메톡시페닐)프로프-2-엔-1-온 (18m) (400 mg, 1.11 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 431 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19m을 72 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-3-([1,1'-biphenyl]-4-yl)-1-(2-hydroxy-4,5-dimethoxyphenyl in methanol (20 mL) ) Prop-2-en-1-one ( 18m ) (400 mg, 1.11 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 431 μL, 4 eq) for 16 hours Stirring gave compound 19m as a yellow powder in 72% yield. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.29 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.32 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 3.8 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 6.3 Hz, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). HRMS m/z calculated for C23H18O5 [M + H]+: 375.1227; found: 375.1240.R f = 0.29 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.32 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.64 (d , J = 3.8 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 6.3 Hz, 1H), 7.11 (s, 1H), 7.03 (s , 1H), 4.04 (s, 3H), 4.02 (s, 3H). HRMS m / z calculated for C 23 H 18 O 5 [M + H] + : 375.1227; found: 375.1240.
14) 3-Hydroxy-6,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one (14) 3-Hydroxy-6,7-dimethoxy-2-(4-phenoxyphenyl)-4H-chromen-4-one ( 19n19n ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(4-페녹시페닐)프로프-2-엔-1-온 (18n) (500 mg, 0.69 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 516 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19n을 16 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(4-phenoxyphenyl)prop-2-ene- in methanol (10 mL) Compound 19n was prepared at 16% concentration by stirring 1-one ( 18n ) (500 mg, 0.69 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 516 μL, 4 eq) for 16 h. Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.29 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.98 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H). HRMS m/z calculated for C23H18O6 [M + H]+: 391.1176; found: 391.1181.R f = 0.29 (CH 2 Cl 2 /MeOH = 30:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.21 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.18 (t, J = 7.4 Hz) , 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.98 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H). HRMS m / z calculated for C 23 H 18 O 6 [M + H] + : 391.1176; found: 391.1181.
15) 3-Hydroxy-6,7-dimethoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one (15) 3-Hydroxy-6,7-dimethoxy-2-(3-phenoxyphenyl)-4H-chromen-4-one ( 19o19o ))
상기 합성 방법에 따라, 메탄올 (20 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(3-페녹시페닐)프로프-2-엔-1-온 (18o) (800 mg, 0.69 mmol), NaOH (3 M aq., 4 mL), 과산화수소 (35 % aq., 990 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19o를 32 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(3-phenoxyphenyl)prop-2-ene- in methanol (20 mL) Compound 19o was prepared at 32% concentration by stirring 1-one ( 18o ) (800 mg, 0.69 mmol), NaOH (3 M aq., 4 mL), and hydrogen peroxide (35% aq., 990 μL, 4 eq) for 16 h. Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.33 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 7.10 - 7.01 (m, 4H), 6.97 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H). HRMS m/z calculated for C23H18O6 [M + H]+: 391.1176; found: 391.1191.R f = 0.33 (CH 2 Cl 2 /MeOH = 30:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.02 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 7.10 - 7.01 (m, 4H), 6.97 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H). HRMS m / z calculated for C 23 H 18 O 6 [M + H] + : 391.1176; found: 391.1191.
16) 3-Hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (16) 3-Hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one ( 19p19p ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(4-페녹시페닐)프로프-2-엔-1-온 (18p) (300 mg, 0.95 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 371 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19p를 58 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 8:1)로 정제하였다.According to the above synthesis method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(4-phenoxyphenyl)prop-2-ene- in methanol (10 mL) 1-One ( 18p ) (300 mg, 0.95 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 371 μL, 4 eq) was stirred for 16 h to obtain 58% of compound 19p . Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 8:1).
Rf = 0.21 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 5.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.99 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.90 (s, 3H).R f = 0.21 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.20 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 5.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.99 (s , 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.90 (s, 3H).
17) 3-Hydroxy-6,7-dimethoxy-2-(3-methoxyphenyl)-4H-chromen-4-one (17) 3-Hydroxy-6,7-dimethoxy-2-(3-methoxyphenyl)-4H-chromen-4-one ( 19q19q ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(3-메톡시페닐)프로프-2-엔-1-온 (18q) (300 mg, 0.95 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 371 μL, 4 eq)를 16 시간 동안 교반하여 화합물 19q를 43 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 10:1)로 정제하였다.According to the above synthesis method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(3-methoxyphenyl)prop-2-ene- in methanol (10 mL) 1-One ( 18q ) (300 mg, 0.95 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 371 μL, 4 eq) was stirred for 16 h to obtain 19q at 43% concentration. Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 10:1).
Rf = 0.16 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 7.88 - 7.77 (m, 2H), 7.53 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.10 - 6.95 (m, 3H), 4.03 (s, 3H), 4.01 (s, 3H), 3.91 (s, 3H). R f = 0.16 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 7.88 - 7.77 (m, 2H), 7.53 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.10 - 6.95 (m, 3H), 4.03 ( s, 3H), 4.01 (s, 3H), 3.91 (s, 3H).
18) Methyl 4-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (18) Methyl 4-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 19r19r ))
상기 합성 방법에 따라, 메탄올 (30 mL) 중에서 (E)-메틸 4-(3-(2-하이드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (18r) (800 mg, 0.68 mmol), NaOCH3 (5.4 M in methanol solution, 1.7 mL, 4 eq), 과산화수소 (35 % aq., 908 μL, 4 eq)를 12 시간 동안 교반하여 화합물 19r을 17 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 50:0 to 10:1)로 정제하였다.According to the above synthetic method, (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1- in methanol (30 mL) 1) Benzoate ( 18r ) (800 mg, 0.68 mmol), NaOCH 3 (5.4 M in methanol solution, 1.7 mL, 4 eq), hydrogen peroxide (35% aq., 908 μL, 4 eq) were stirred for 12 hours Compound 19r was prepared in 17% yield, yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 50:0 to 10:1).
Rf = 0.44 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 8.6 Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.53 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H). HRMS m/z calculated for C19H16O7 [M + H]+: 357.0969; found: 357.0976.R f = 0.44 (CH 2 Cl 2 /MeOH = 10:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.33 (d, J = 8.6 Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.53 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H). HRMS m / z calculated for C 19 H 16 O 7 [M + H] + : 357.0969; found: 357.0976.
19) Methyl 3-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (19) Methyl 3-(3-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 19s19s ))
상기 합성 방법에 따라, 메탄올 (10 mL) 중에서 (E)-메틸 3-(3-(2-하이드록시-4,5-다이메톡시페닐)-3-옥소프로프-1-엔-1-일)벤조에이트 (18s) (330 mg, 0.96 mmol), NaOCH3 (5.4 M in methanol solution, 0.7 mL, 4 eq), 과산화수소 (35 % aq., 374 μL, 4 eq)를 12 시간 동안 교반하여 화합물 19s를 18 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:1 to 8:1)로 정제하였다.According to the above synthetic method, (E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1- in methanol (10 mL) 1) Benzoate ( 18s ) (330 mg, 0.96 mmol), NaOCH 3 (5.4 M in methanol solution, 0.7 mL, 4 eq), hydrogen peroxide (35% aq., 374 μL, 4 eq) were stirred for 12 hours. Compound 19s was prepared in 18% yield, yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:1 to 8:1).
Rf = 0.43 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz, CDCl3) δ 8.84 (s, 1H), 8.48 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.51 (s, 1H), 7.04 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (d, J = 10.6 Hz, 3H). HRMS m/z calculated for C19H16O7 [M + H]+: 357.0969; found: 357.0969.R f = 0.43 (CH 2 Cl 2 /MeOH = 10:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.84 (s, 1H), 8.48 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz , 1H), 7.51 (s, 1H), 7.04 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (d, J = 10.6 Hz, 3H). HRMS m / z calculated for C 19 H 16 O 7 [M + H] + : 357.0969; found: 357.0969.
20) 3-Hydroxy-6,7-dimethoxy-2-(naphthalen-2-yl)-4H-chromen-4-one (20) 3-Hydroxy-6,7-dimethoxy-2-(naphthalen-2-yl)-4H-chromen-4-one ( 22a22a ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(나프탈렌-2-일)프로프-2-엔-1-온 (21a) (230 mg, 0.69 mmol), NaOH (3 M aq., 1.5 mL), 과산화수소 (35 % aq., 267 μL, 4 eq)를 15 시간 동안 교반하여 화합물 22a를 15 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthesis method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(naphthalen-2-yl)prop-2-en- 1-One ( 21a ) (230 mg, 0.69 mmol), NaOH (3 M aq., 1.5 mL), hydrogen peroxide (35% aq., 267 μL, 4 eq) was stirred for 15 h to obtain 15% compound 22a . Yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.58 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H), 8.32 (dd, J = 8.7, 1.7 Hz, 1H), 7.99 (dd, J = 11.3, 7.9 Hz, 2H), 7.93 - 7.86 (m, 1H), 7.62 - 7.52 (m, 3H), 7.14 (s, 1H), 7.08 (d, J = 6.2 Hz, 1H), 4.06 (s, 3H), 4.02 (s, 3H). HRMS m/z calculated for C21H16O5 [M + H]+: 349.1071; found: 349.1077.R f = 0.58 (CH 2 Cl 2 /MeOH = 30:1). 1H NMR (600 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.32 (dd, J = 8.7, 1.7 Hz, 1H), 7.99 (dd, J = 11.3, 7.9 Hz, 2H), 7.93 - 7.86 ( m, 1H), 7.62 - 7.52 (m, 3H), 7.14 (s, 1H), 7.08 (d, J = 6.2 Hz, 1H), 4.06 (s, 3H), 4.02 (s, 3H). HRMS m / z calculated for C 21 H 16 O 5 [M + H] + : 349.1071; found: 349.1077.
21) 3-Hydroxy-6,7-dimethoxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one (21) 3-Hydroxy-6,7-dimethoxy-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one ( 22b22b ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(1-메틸-1H-피라졸-4-일)프로프-2-엔-1-온 (21b) (338 mg, 1.35 mmol), NaOH (3 M aq., 2 mL), 과산화수소 (35 % aq., 523 μL, 4 eq)를 15 시간 동안 교반하여 화합물 22b를 46 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl) in ethanol (10 mL) Stir prop-2-en-1-one ( 21b ) (338 mg, 1.35 mmol), NaOH (3 M aq., 2 mL), hydrogen peroxide (35% aq., 523 μL, 4 eq) for 15 h Thus, compound 22b was prepared as a yellow powder in a yield of 46%. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.39 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 8.15 (s, 1H), 8.11 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H). HRMS m/z calculated for C15H14N2O5 [M + H]+: 303.0976; found: 303.0971.R f = 0.39 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 8.15 (s, 1H), 8.11 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H). HRMS m / z calculated for C 15 H 14 N 2 O 5 [M + H] + : 303.0976; found: 303.0971.
22) 3-Hydroxy-6,7-dimethoxy-2-(thiophen-2-yl)-4H-chromen-4-one (22) 3-Hydroxy-6,7-dimethoxy-2-(thiophen-2-yl)-4H-chromen-4-one ( 22c22c ))
상기 합성 방법에 따라, 에탄올 (10 mL) 중에서 (E)-1-(2-하이드록시-4,5-다이메톡시페닐)-3-(싸이오펜-2-일)프로프-2-엔-1-온 (21c) (273 mg, 0.94 mmol), NaOH (3 M aq., 1.5 mL), 과산화수소 (35 % aq., 365 μL, 4 eq)를 15 시간 동안 교반하여 화합물 22c를 22 %의 수율, 황색 분말로 제조하였다. 반응 혼합물을 H2O에 붓고 3 N HCl(pH=2)로 산성화한 후 CH2Cl2로 추출하였다. 조 잔류물을 실리카 겔 상에서 컬럼 크로마토그래피 (CH2Cl2/MeOH = 100:0 to 30:1)로 정제하였다.According to the above synthetic method, (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-ene in ethanol (10 mL) -1-one ( 21c ) (273 mg, 0.94 mmol), NaOH (3 M aq., 1.5 mL), hydrogen peroxide (35% aq., 365 μL, 4 eq) was stirred for 15 h to obtain 22c of compound 22c. yield, prepared as a yellow powder. The reaction mixture was poured into H 2 O, acidified with 3 N HCl (pH=2) and extracted with CH 2 Cl 2 . The crude residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 100:0 to 30:1).
Rf = 0.58 (CH2Cl2/MeOH = 30:1). 1H NMR (600 MHz, CDCl3) δ 7.98 - 7.90 (m, 1H), 7.59 (dd, J = 4.8 Hz and 1.2 Hz, 1H), 7.52 (s, 1H), 7.24 - 7.22 (m, 1H), 6.98 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H). HRMS m/z calculated for C15H12O5S [M + H]+: 305.0477; found: 305.0469.R f = 0.58 (CH 2 Cl 2 /MeOH = 30:1). 1 H NMR (600 MHz, CDCl 3 ) δ 7.98 - 7.90 (m, 1H), 7.59 (dd, J = 4.8 Hz and 1.2 Hz, 1H), 7.52 (s, 1H), 7.24 - 7.22 (m, 1H) , 6.98 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H). HRMS m / z calculated for C 15 H 12 O 5 S [M + H] + : 305.0477; found: 305.0469.
실험예 1. IPMK/IP6K2 저해 효능 평가(ADP-Glo 키나아제 분석)Experimental Example 1. IPMK/IP6K2 inhibitory efficacy evaluation (ADP-Glo kinase assay)
상기 합성예에서 합성된 본 발명에 따른 플라보노이드 유도체에 대하여, ADP-Glo 키나아제 분석 방법[ADP-Glo쪠 Kinase Assay(Promega)를 사용]으로 IPMK/IP6K2 저해 활성을 평가하였다.The IPMK/IP6K2 inhibitory activity of the flavonoid derivatives according to the present invention synthesized in the Synthesis Example was evaluated by an ADP-Glo kinase assay [using ADP-Glo Kinase Assay (Promega)].
1-1. 실험 방법1-1. Experiment method
1) 키나아제 반응 혼합물은 사전 배양하기 위해 15분 동안 RT에서 개별 약물(DMSO 희석)로 먼저 흔들어서 배양한 후 ATP를 첨가(최종 10μM)하여 반응을 개시하였다. IPMK 반응 혼합물(50 mM Hepes, pH 7.4, 10 mM MgCl2, 50 mM KCl, 10 μM IP(1,4,5,6)4) 25 μL 당 20 ng의 인간 재조합 IPMK 단백질을 사용하였다. 키나아제 반응은 37 ℃에서 100 rpm 흔들림으로 30분간 진행하였으며, 제조자 프로토콜에 따라 미트라스 LB940 플레이트 리더(Berthold)를 사용하여 백색 플레이트에서 ADP의 생성량을 측정하였다. 각 검출세트는 96-웰(25 μL 키나아제 반응)에서 중복으로 준비되었다. 결과 효소 활성은 활성(%)=([ADPexperimental]/[ADPDMSO])Х100으로 계산되었다.1) The kinase reaction mixture was first shaken and incubated with the respective drugs (diluted in DMSO) at RT for 15 min for pre-incubation, followed by the addition of ATP (final 10 μM) to initiate the reaction. 20 ng of human recombinant IPMK protein was used per 25 μL of IPMK reaction mixture (50 mM Hepes, pH 7.4, 10 mM MgCl 2 , 50 mM KCl, 10 μM IP(1,4,5,6) 4 ). The kinase reaction was carried out at 37° C. for 30 minutes with shaking at 100 rpm, and the amount of ADP produced was measured on a white plate using a Mithras LB940 plate reader (Berthold) according to the manufacturer's protocol. Each detection set was prepared in duplicate in 96-well (25 μL kinase reaction). The resulting enzyme activity was calculated as activity (%) = ([ADP experimental ]/[ADP DMSO ])Х100.
화합물의 IC50 추정을 위해 384-웰 플레이트(재조합 인간 IP6K2 단백질 20 ng을 복제물로 사용)에 키나아제 분석을 준비하였다. 반응 혼합물(50 mM Tris-HCl, pH 6.8, 10 mM MgCl2, 2.5 mM DTT, 0.02 % Triton X-100, 10 μM IP6) 20 μL당 20 ng의 인간 재조합 IP6K2 단백질을 사용하였다. 키나아제 반응은 -25 ℃에서 300 rpm의 흔들림으로 1시간동안 진행하였으며, 제조자 프로토콜에 따라 Synergy Neo microplate reader(Biotek)를 사용하여 ADP 생산량을 측정하였다.Kinase assays were prepared in 384-well plates (using 20 ng of recombinant human IP6K2 protein as replicates) for IC 50 estimation of compounds. 20 ng of human recombinant IP6K2 protein was used per 20 μL of the reaction mixture (50 mM Tris-HCl, pH 6.8, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 μM IP6). The kinase reaction was carried out for 1 hour at -25 °C with shaking at 300 rpm, and ADP production was measured using a Synergy Neo microplate reader (Biotek) according to the manufacturer's protocol.
IC50 추정을 포함한 모든 통계 분석은 Prism 7 또는 Prism 9(Graphpad Software)를 사용하여 수행되었다. All statistical analyzes including IC 50 estimation were performed using Prism 7 or Prism 9 (Graphpad Software).
2) 키나아제 반응 혼합물은 사전 배양하기 위해 10분 동안 25 ℃, 350 rpm의 속도로 개별 약물(DMSO 희석)과 함께 먼저 배양한 후 ATP를 첨가(최종 10 μM)하여 반응을 개시하였다. IP6K2 반응 혼합물(50 mM Tris-HCl, pH 6.9, 10 mM MgCl2, 2.5 mM DTT, 0.02 % Triton X-100, 10 μM IP6) 25 μL 당 40 ng의 인간 재조합 IP6K2 단백질을 사용하였다. 키나아제 반응은 37 ℃에서 350 rpm 흔들림으로 35분간 진행하였으며, 제조자 프로토콜에 따라 미트라스 LB940 플레이트 리더(Brthold)를 사용하여 백색 플레이트에서 ADP의 생성량을 측정하였다. 각 검출세트는 96-웰(25 μl 키나아제 반응) 중복으로 준비되었다. 결과 효소 활성은 활성(%)=([ADPexperiment]/[ADPDMSO])Х100으로 계산되었다. 2) The kinase reaction mixture was first incubated with individual drugs (diluted in DMSO) at 25 °C and 350 rpm for 10 minutes for pre-incubation, and then the reaction was initiated by adding ATP (final 10 μM). 40 ng of human recombinant IP6K2 protein was used per 25 μL of IP6K2 reaction mixture (50 mM Tris-HCl, pH 6.9, 10 mM MgCl 2 , 2.5 mM DTT, 0.02% Triton X-100, 10 μM IP6). The kinase reaction was carried out at 37 °C for 35 minutes with shaking at 350 rpm, and the amount of ADP produced was measured on a white plate using a Mitras LB940 plate reader (Brthold) according to the manufacturer's protocol. Each detection set was prepared in duplicate of 96-well (25 μl kinase reaction). The resulting enzyme activity was calculated as activity (%) = ([ADP experiment ]/[ADP DMSO ])Х100.
IC50 추정을 포함한 모든 통계 분석은 prism 7(Graphpad Software)를 사용하여 수행되었다.All statistical analyzes including IC 50 estimation were performed using prism 7 (Graphpad Software).
1-2. 실험 결과1-2. Experiment result
Figure PCTKR2022018229-appb-img-000012
Figure PCTKR2022018229-appb-img-000012
상기 표 1의 ADP-Glo 분석 결과에 따르면, B-고리에 치환기가 없는 화합물 20b를 대조 화합물로 비교하였을 때, -CH3 그룹이 치환된 화합물(20c 내지 20e) 및 -Cl 그룹이 치환된 화합물(20k 및 20l)은 약하게 IPMK 억제를 유도했으며, 이러한 결과는 B-고리의 소수성 치환기가 IPMK 억제를 감소시킨다는 것을 시사한다. 나아가, -F 그룹이 치환된 화합물(20f 내지 20h) 및 -CF3 그룹이 치환된 화합물(20i 및 20j) 또한 20b보다 덜 강력한 IPMK 억제 효과를 나타냈다. 이치환된 화합물(20e 및 20h)은 약한 IPMK 억제효과를 나타냈으며, 이것은 소수성 치환체의 부피가 증가하기 때문일 수 있다. 소수성 치환체로 인한 부피 증가의 부정적인 영향은 -Ph 및 -OPh 그룹과 같이 부피가 크고 소수성인 치환체를 갖는 화합물(20m 내지 20o)에서 확인되었다. 하지만 친수성이 있는 치환체를 갖는 화합물 20s[화학식 24]는 IPMK에 대해 IC50 값이 0.47μM인 가장 강력한 억제제임을 확인하였다(도 1a).According to the results of the ADP-Glo analysis in Table 1, when comparing compound 20b without a substituent on the B-ring with the control compound, -CH 3 group-substituted compounds (20c to 20e) and -Cl group-substituted compounds (20k and 20l) weakly induced IPMK inhibition, suggesting that the hydrophobic substituents in the B-ring reduce IPMK inhibition. Furthermore, the -F group substituted compounds (20f to 20h) and -CF 3 group substituted compounds (20i and 20j) also showed a less potent IPMK inhibitory effect than 20b. The disubstituted compounds (20e and 20h) showed weak IPMK inhibitory effects, which may be due to the increase in the volume of the hydrophobic substituent. The negative effect of volume increase due to hydrophobic substituents was confirmed in the compounds (20m to 20o) with bulky and hydrophobic substituents such as -Ph and -OPh groups. However, compound 20s [Formula 24] having a hydrophilic substituent was confirmed to be the strongest inhibitor with an IC 50 value of 0.47 μM for IPMK (FIG. 1a).
한편, 메틸피라졸 그룹이 치환된 화합물 23b[화학식 26]는 IPMK에 대해 IC50 값이 0.77μM로 강한 억제 효과를 나타내었다. 이는 헤테로고리 치환기가 IPMK 억제효과를 증가시킬 수 있음을 의미한다. On the other hand, Compound 23b [Formula 26] in which the methylpyrazole group was substituted showed a strong inhibitory effect on IPMK with an IC 50 value of 0.77 μM. This means that the heterocyclic substituent can increase the IPMK inhibitory effect.
Figure PCTKR2022018229-appb-img-000013
Figure PCTKR2022018229-appb-img-000013
상기 표 2의 ADP-Glo 분석 결과에 따르면, B-고리의 메타(16b 및 16d) 위치에서 카르복실산 치환은 파라(16a 및 16c) 치환에 비해 우수한 IP6K2 억제를 유도했다. According to the ADP-Glo analysis results in Table 2, carboxylic acid substitutions at the meta (16b and 16d) positions of the B-ring induced superior IP6K2 inhibition compared to para (16a and 16c) substitutions.
반면, B-고리에 치환기가 없는 화합물 20b를 대조 화합물로 비교하였을 때, -CH3 그룹이 치환된 화합물(20c 내지 20e) 및 -Cl 그룹이 치환된 화합물(20k 및 20l)은 덜 강력한 IP6K2 억제를 유도했으며, 이러한 결과는 B-고리의 소수성 치환기가 IP6K2 억제를 감소시킨다는 것을 시사한다. 나아가, -F 그룹이 치환된 화합물(20f 내지 20h) 및 -CF3 그룹이 치환된 화합물(20i 및 20j) 또한 20b보다 덜 강력한 IP6K2 억제 효과를 나타냈다. 특히, 이치환된 화합물(20e 및 20h)은 IP6K2에 대한 억제 활성을 완전히 상실했으며, 이것은 소수성 치환체의 부피가 증가하기 때문일 수 있다. 친유성 치환체로 인한 부피 증가의 부정적인 영향은 -Ph 및 -OPh 그룹과 같이 부피가 크고 소수성인 치환체를 갖는 화합물(20m 내지 20o)에서 확인되었다. On the other hand, when comparing compound 20b without a substituent on the B-ring as a control compound, the -CH 3 group substituted compounds (20c to 20e) and -Cl group substituted compounds (20k and 20l) showed less strong IP6K2 inhibition. induced, and these results suggest that the hydrophobic substituent of the B-ring reduces IP6K2 inhibition. Furthermore, the -F group substituted compounds (20f to 20h) and -CF 3 group substituted compounds (20i and 20j) also showed a less potent IP6K2 inhibitory effect than 20b. In particular, the disubstituted compounds (20e and 20h) completely lost their inhibitory activity against IP6K2, which may be due to the increase in the volume of the hydrophobic substituent. The negative effect of volume increase due to lipophilic substituents was confirmed in compounds (20m to 20o) with bulky and hydrophobic substituents such as -Ph and -OPh groups.
한편, 6,7-dihydroxyl 그룹을 가진 화합물(16a, 16b, 20a)은 5,7-dihydroxyl 그룹이 있는 화합물(16c 및 16d)보다 IP6K2에 대한 더 강한 억제 효과를 나타냈다. On the other hand, the compounds (16a, 16b, 20a) with 6,7-dihydroxyl group showed a stronger inhibitory effect on IP6K2 than the compounds (16c and 16d) with 5,7-dihydroxyl group.
특히, 화합물 20s[화학식 24]는 IP6K2에 대해 IC50 값이 0.55μM인 가장 강력한 억제제임을 확인하였다(도 1b).In particular, compound 20s [formula 24] was confirmed to be the most potent inhibitor against IP6K2 with an IC 50 value of 0.55 μM (FIG. 1b).
실험예 2. 화합물 20s에 대한 IP6K2 분자 도킹 분석Experimental Example 2. IP6K2 molecular docking assay for compound 20s
IP6K2 상동성 모델(homology model)을 사용하여 화합물 20s와 IP6K2 억제제로 알려진 대조군 케르세틴(Quercetin)의 In silico 분자 도킹 분석(molecular docking studies)을 수행하였다. IP6K2 상동성 모델 (UniProt: Q9UHH9)은 AlphaFold2 구조 데이터베이스(https://alphafold.ebi.ac.uk)에서 PDB 및 FASTA 형식으로 다운로드되었다. In silico molecular docking studies of compound 20s and the control Quercetin, known as an IP6K2 inhibitor, were performed using an IP6K2 homology model. The IP6K2 homology model (UniProt: Q9UHH9) was downloaded from the AlphaFold2 structural database (https://alphafold.ebi.ac.uk) in PDB and FASTA formats.
그 결과, 도 2에서 확인할 수 있듯이, 화합물 20s와 케르세틴은 모두 Lys42와 하나의 수소 결합을 형성하고 Leu209와 하나의 수소 결합을 형성하였다. 그러나 화합물 20s는 케르세틴과 비교하여 A 고리의 -OH기를 통해 Asp383과 추가적인 수소 결합을 형성하였다. 또한, 화합물 20s의 B 고리 중 -COOH기는 Thr210과 하나의 수소 결합을 형성하였고 Gln260과 추가적인 수소 결합을 형성한 반면, 케르세틴의 C 고리의 3-OH기만이 Thr210과 하나의 수소 결합을 형성하였다., 따라서, 화합물 20s가 케르세틴보다 더 강력한 IP6K2 억제제임을 알 수 있었다.As a result, as can be seen in FIG. 2, both compound 20s and quercetin formed one hydrogen bond with Lys42 and one hydrogen bond with Leu209. However, compound 20s formed an additional hydrogen bond with Asp383 through the -OH group of the A ring compared to quercetin. In addition, the -COOH group in the B ring of compound 20s formed one hydrogen bond with Thr210 and an additional hydrogen bond with Gln260, while the 3-OH group of quercetin's C ring formed one hydrogen bond with Thr210. , Therefore, it was found that compound 20s is a more potent IP6K2 inhibitor than quercetin.

Claims (7)

  1. 하기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체:A flavonoid derivative represented by the following [Formula 1a] or [Formula 1b]:
    [화학식 1a][Formula 1a]
    Figure PCTKR2022018229-appb-img-000014
    Figure PCTKR2022018229-appb-img-000014
    [화학식 1b][Formula 1b]
    Figure PCTKR2022018229-appb-img-000015
    Figure PCTKR2022018229-appb-img-000015
    상기 [화학식 1a] 및 [화학식 1b]에서,In [Formula 1a] and [Formula 1b],
    R'는
    Figure PCTKR2022018229-appb-img-000016
    ,
    Figure PCTKR2022018229-appb-img-000017
    ,
    Figure PCTKR2022018229-appb-img-000018
    , 및
    Figure PCTKR2022018229-appb-img-000019
    중에서 선택되는 어느 하나이고,    R' is
    Figure PCTKR2022018229-appb-img-000016
    ,
    Figure PCTKR2022018229-appb-img-000017
    ,
    Figure PCTKR2022018229-appb-img-000018
    , and
    Figure PCTKR2022018229-appb-img-000019
    any one selected from
    상기 R1 및 R2는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 할로겐, -OH, -COOH, -CF3, -Ph, -OPh, 및 탄소수 1 내지 4의 알킬기 중에서 선택되는 어느 하나이고, 및R 1 and R 2 are the same as or different from each other, and are each independently any one selected from hydrogen, halogen, -OH, -COOH, -CF 3 , -Ph, -OPh, and an alkyl group having 1 to 4 carbon atoms, and
    X, Y 및 Z는 각각 독립적으로 수소 및 -OH 중에서 선택되는 어느 하나이다.X, Y and Z are each independently selected from hydrogen and -OH.
  2. 제1항에 있어서, 상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체는 하기 [화학식 2] 내지 [화학식 27]로 표시되는 유도체 중에서 선택되는 어느 하나인 것을 특징으로 하는 플라보노이드 유도체:The flavonoid derivative according to claim 1, wherein the flavonoid derivative represented by [Formula 1a] or [Formula 1b] is any one selected from derivatives represented by [Formula 2] to [Formula 27]:
    Figure PCTKR2022018229-appb-img-000020
    Figure PCTKR2022018229-appb-img-000020
    Figure PCTKR2022018229-appb-img-000021
    Figure PCTKR2022018229-appb-img-000021
  3. 제2항에 있어서, 상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체는 하기 [화학식 2], [화학식 3], [화학식 4], [화학식 5], [화학식 23], 및 [화학식 24]로 표시되는 유도체 중에서 선택되는 어느 하나인 것을 특징으로 하는 플라보노이드 유도체:The method of claim 2, wherein the flavonoid derivatives represented by [Formula 1a] or [Formula 1b] are the following [Formula 2], [Formula 3], [Formula 4], [Formula 5], [Formula 23], and [Formula 23]. A flavonoid derivative characterized in that it is any one selected from derivatives represented by Formula 24]:
    Figure PCTKR2022018229-appb-img-000022
    Figure PCTKR2022018229-appb-img-000022
  4. 제1항에 있어서, 상기 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체는 IPMK 및 IP6K 활성 저해 효과를 갖는 것을 특징으로 하는 플라보노이드 유도체.The flavonoid derivative according to claim 1, wherein the flavonoid derivative represented by [Formula 1a] or [Formula 1b] has an effect of inhibiting IPMK and IP6K activities.
  5. 제1항에 따른 [화학식 1a] 또는 [화학식 1b]로 표시되는 플라보노이드 유도체, 이의 약제학적 허용 가능한 염 또는 이의 용매화물을 유효성분으로 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating metabolic diseases comprising a flavonoid derivative represented by [Formula 1a] or [Formula 1b] according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  6. 제5항에 있어서, 상기 조성물은 IPMK와 IP6K 활성 저해 효과를 갖는 것을 특징으로 하는 대사성 질환의 예방 또는 치료용 약학 조성물.The pharmaceutical composition for preventing or treating metabolic diseases according to claim 5, wherein the composition has an activity inhibitory effect on IPMK and IP6K.
  7. 제5항에 있어서, 상기 대사성 질환은 비만, 고혈압, 동맥경화증, 고지혈증, 간질환, 심근병증, 심근경색, 뇌경색, 근감소증, 과인슐린혈증, 과혈당증, 당뇨병 및 인슐린 저항성 질환으로 이루어진 군으로부터 선택된 것을 특징으로 하는 대사성 질환의 예방 또는 치료용 약학 조성물.The method of claim 5, wherein the metabolic disease is selected from the group consisting of obesity, hypertension, arteriosclerosis, hyperlipidemia, liver disease, cardiomyopathy, myocardial infarction, cerebral infarction, sarcopenia, hyperinsulinemia, hyperglycemia, diabetes and insulin resistance disease. A pharmaceutical composition for the prevention or treatment of metabolic diseases characterized by
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