KR102051431B1 - Method For Preparing Penchinone A or Its Derivatives And Anti-inflammatory Composition Using the Same - Google Patents

Abstract

The present invention discloses a process for the preparation of fenchinone A derivatives characterized by the oxidative acylation of ketoximes derivatives and aldehydes under a Pd (II) catalyst and the anti-inflammatory use of the phenchinone A derivatives.

Description

Method for preparing penchinone A or its derivatives and anti-inflammatory composition using the same {Method For Preparing Penchinone A or Its Derivatives And Anti-inflammatory Composition Using the Same}

The present invention relates to a method for producing Fenchinone A or a derivative thereof and an anti-inflammatory composition using the same.

With the recent development of the economy, the proportion of lifestyle diseases such as cancer, diabetes, hypertension, obesity and vascular diseases continues to increase worldwide due to changes in living environment and diet. In addition, due to various factors, such as environmental changes due to the rapid industrial development of the modern society, and the resulting increase in stress, the inflammation caused by abnormal immune regulation continues to increase the onset of related diseases.

Inflammatory responses are mechanisms for repairing and regenerating damaged tissues, as well as external physical and chemical stimuli, as well as protective responses to various infectious agents (Zamora R et al., Mol. Med. 6: 347-373 (2000) Mariathasan S and Monack DM.Nat. Rev. Immunol. 7: 31-40 (2007); Lee HN et al., Korean J. Food Sci.Technol. 43: 65-71 (2011)). During the inflammatory reaction, plasma accumulates at the site of inflammation, diluting the toxicity secreted by bacteria, increasing blood flow, and accompanied by symptoms such as erythema, pain, edema, and fever. In normal cases, the living body restores normal structure and function by neutralizing or eliminating pathogens through inflammatory reactions and regenerating upper and lower tissues, but persistent or excessively occurring chronic inflammatory reactions cause tissue damage. This inflammatory response leads to progression to the stomach, colon, bladder, and prostate cancer, and causes various diseases such as rheumatoid arthritis and chronic infection (Hofseth LJ and Ying L. Biochim. Biophys. Acta 1765: 74-84 (2006). Yun HY et al., Rev. Neurobiol. 10: 291-316 (1996); Stuehr DJ et al., P. Natl. Acad. Sci. USA 88: 7773-7777 (1991)).

When inflammatory reactions occur, immune cells such as macrophages and monocytes produce nitric oxide (NO), prostagladin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL- 8, secrete inflammatory mediators such as IL-12 (Guha M and Mackman N. Cell Signal. 13: 85-94 (2001)). A representative example of the inflammatory response is the activation of toll like receptor (TLR) signaling systems in macrophages by pathogen associated molecular patterns (PAMPs). Lipopolysaccharide (LPS), a type of endotoxin in the outer membrane of Gram-negative bacteria, belongs to PAMPs, an inflammatory mediator present in external microorganisms. When bacteria enter the body, TLR4 recognizes LPS on the surface of macrophages with the help of MD-2 or CD14 (Miyake K. Trends Microbiol. 12: 186-192 (2004)). Induces activation and ultimately activates the transcription factor nuclear factor-κB (NF-κB) (Youn HS. Korean. J. Food Sci. Technol. 39: 481-487 (2007); Youn HS. Korean. Food Sci.Technol. 41: 477-482 (2009)). NF-κB migrated to the nucleus of inflammatory cytokine (TNF-α, IL-1β, IL-6, IL-8, IL-12, etc.), inducible nitiric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Induces gene expression, nitric oxide (NO) produced by iNOS intensifies inflammation (Noh KH et al., J. Korean Soc. Food Sci. Nutr. 40: 625-634 (2011) Weisz A et al., Biochem. J. 316: 209-215 (1996)). Nitric oxide, which is overproduced by iNOS in macrophages, reacts with superoxide to form peroxynitrite, which acts as a powerful oxidant that damages cells, causing various pathologies, including inflammation and cancer. Known to be involved in the process (Gupta SC et al., Exp Biol Med., 236: 658-671, (2011); Riehemann et al., FEBS Lett., 442: 89-94 (1999)).

Synthetic drugs such as ibuprofen, antihistamines, steroids, cortisones, immunosuppressants, and immunosuppressive drugs are used for the treatment of inflammation, but there are many side effects such as temporary or simple symptom relief, hypersensitivity reactions, and immune system deterioration. The underlying treatment of inflammation is difficult. Non-steroidal anti-inflammatory drugs (NSAIDS), which are currently widely used as anti-inflammatory agents, are also known to cause serious side effects such as gastrointestinal disorders, liver disorders, and renal disorders when used for a long time (Rainsford KD., Subcell biochem. , 42: 3-27, 2007; Guruprasad P. Aithal., Rheumatology., 7: 139-150, 2011; Praveen PN Rao et al., Pharmaceuticals., 3: 1530-1549, 2010).

Therefore, there is still a need for the development of new drugs that have anti-inflammatory activity and have fewer side effects and lasting effects.

Penchinones AD, on the other hand, was first isolated by Xiong and colleagues in 2015 as a substance that protects liver function from the water leaching of the octopus ( Penthorum chinense Pursh) (He YC et al. RSC Adv. 5: 76788). (2015)). Penchinones AD shows unique structural features that include two pairs of cis-trans isomers with rearranged carbon backbones.

<Penchinone structure>

The present invention discloses a method for producing fenchinone A or derivatives thereof and anti-inflammatory activity of the fenchinone A.

It is an object of the present invention to provide a process for preparing Penchinone A or its derivatives.

Another object of the present invention is to provide an anti-inflammatory composition using Penchinone A or a derivative thereof obtained by the above method.

Other and specific objects of the present invention will be presented below.

In one aspect, the present invention relates to a method for producing Penchinone A or a derivative thereof.

Method for producing a fenchinone A or a derivative thereof of the present invention, as confirmed in <Reaction Scheme 1> below, by (a) reacting a compound of the formula (1) and a compound of the formula (2) Obtaining an intermediate product which is a compound of Formula 3, and (b) an methyl part of an acetyl moiety (Ac), an imine moiety (-N =) and a methoxy group (OMe) Me) is removed to obtain phenchinone A of Formula 4 or a derivative thereof.

<Scheme 1>

Wherein R 1 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),

R2 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),

R 3 is H (hydrogen) or OH (hydroxy group).

In the method of the present invention, reference may be made to the following examples with respect to the preparation of the compound of Formula 1 below in step (a).

In the method of the present invention, the reaction of step (a) may use Pd salts such as Pd (OAc) ₂ , PD (OTf) ₂ , in particular Pd (OAc) ₂ as a catalyst. When Pd (OAc) ₂ is used, it is preferable to use 5 mol% or more (based on the compound of <Formula 1>), particularly 10 mol% or more.

In addition, in the method of the present invention, the reaction of step (a) may use TBHP (Tert-butyl hydroperoxide), AcOH (Acetic acid) or a mixture thereof as an additive (oxidizing agent), preferably 200 mol% or more of TBHP (Based on the compound of <Formula 1>), in particular 300 mol% or more can be used.

In the method of the present invention, the reaction of step (a) is performed using THF (Tetrahydrofuran), DCE (1,2-Dichloroethane), 1,4-dioxane (1,4-dioxane) or methanol as a reaction solvent. In particular, it is preferable to use DCE.

In addition, in the method of the present invention, the compound of <Formula 2> in the step (a) is preferably used more than 3 equivalents based on the compound of <Formula 1>.

In addition, in the method of the present invention, the reaction of step (b) may be carried out by carrying out an acid catalyst hydrolysis, particularly using HCl as the acid catalyst. As the reaction solvent, methanol, acetone or a mixed solvent thereof (particularly, a mixture of methanol and acetone in a volume ratio of 1: 1) can be used.

Other preferred reaction conditions of the process of the present invention, specifically, the concentration of the catalyst or additive, the reaction time, the reaction temperature and the like can be referred to the following examples.

In another aspect, the present invention relates to an anti-inflammatory composition comprising any one of the compounds 8a to 8g as an active ingredient.

The following examples and experimental examples show that the compounds inhibit the expression of NO, TNF-α and / or IL-6 when treated in mouse macrophage lines (RAW 264.7 cells) stimulated with lipopolysaccharide (LPS). In particular, among these compounds, compounds such as 8g, 8e and 8f showed superior activity to the dexamethasone used in the conventional in inhibiting the expression of NO, TNF-α and IL-6. In addition, the synthesized compounds (7a-7g and 8a-8g) using nitric oxide (LP) -derived RAW264.7 cells using nitrogen monoxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 ( Screening for anti-inflammatory activity that inhibits IL-6), fenchinone A derivatives strongly inhibited NO, TNF-α and IL-6 production compared to dexamethasone (positive control). In particular, Penchinone A (Compound 8g) and its derivatives (Compound 8e and Compound 8f) showed very good anti-inflammatory effects.

In addition, the term "active ingredient" as used herein means a component that can exhibit the desired activity alone or in combination with a carrier that is not active itself.

In addition, in the present specification, "anti-inflammatory" is meant to include improvement (reduction of symptoms), treatment, inhibition of the onset or delay of the inflammatory disease as defined below.

In addition, in the present specification, the "inflammatory disease" refers to an inflammatory response specified as a local or systemic biological defense response against external physical and chemical stimuli or infection or autoimmunity of an external infectious agent such as bacteria, fungi, viruses, and various allergens. It can be defined as a pathological symptom that causes. These inflammatory responses include activation of various inflammatory mediators and enzymes associated with immune cells (eg iNOS, COX-2, etc.), secretion of inflammatory mediators (eg, NO, TNF-α, IL-6, etc.), fluid infiltration, It is accompanied by a series of complex physiological reactions such as cell migration and tissue destruction, and is manifested externally by symptoms such as erythema, pain, edema, fever, deterioration or loss of certain functions of the body. The inflammatory disease may be acute, chronic, ulcerative, allergic or necrotic, so as long as any disease is included in the definition of an inflammatory disease as above, whether it is acute, chronic, ulcerative, allergic or Irrespective of necrosis Specifically, the inflammatory diseases include asthma, allergic and non-allergic rhinitis, chronic and acute rhinitis, chronic and acute gastritis or enteritis, ulcerative gastritis, acute and chronic nephritis, acute and chronic hepatitis, chronic obstructive pulmonary disease, pulmonary fibrosis Irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, fascia disease, viral infection (eg, type C infection), bacterial infection, fungal infection, burn, wound by surgical or dental surgery, pro Prolonged prostaglandin E, atherosclerosis, gout, arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, irisitis, scleritis, uveitis, dermatitis (including atopic dermatitis), eczema, multiple sclerosis Will be included.

The anti-inflammatory composition of the present invention may include the active ingredient in any amount (effective amount) as long as it can exhibit the improvement activity of an inflammatory disease intended to be treated according to the use, formulation, formulation purpose, etc. Effective amounts will be determined within the range of 0.001% to 15% by weight, based on the total weight of the composition. The term "effective amount" as used herein means that when the composition of the present invention is administered to a mammal, preferably a human, such as a medical expert or the like, during the administration period, improvement, treatment, or inhibition of the development of such pathological symptoms It refers to the amount of active ingredients that can exhibit the intended medical and pharmacological effects, such as delays. Such effective amounts can be determined experimentally within the range of ordinary skill in the art.

In addition to the active ingredient, the anti-inflammatory composition and the like of the present invention may further include any compound or natural extract that is known to have safety and has anti-inflammatory activity and the like for the enhancement and enhancement of the anti-inflammatory effect and the like. Specifically, such compounds or extracts have received MSM (dimethylsulfonylmethane), N-acetylglucosamine, glucosamine, and individual certifications in the Health Functional Food Code (KFDA notification, standards and standards of health functional foods) according to the Act on Health Functional Foods. Complex extracts such as CMO-containing FAC (Fatty acid Complex), Prickly Pear Extract, Turmeric Extract, Chicken Breast Cartilage Powder, Rose Hip Powder, Boswellia Extract, Beeswax Alcohol, Whole Extracts, Complex Extracts, Fatty Acid Complex, Perilla And complexes such as green lipped mussel extract oil, hop extract, and golden extract. One or more such compounds or natural extracts may be included in the anti-inflammatory composition of the present invention together with the active ingredients.

The anti-inflammatory composition of this invention etc. can be grasped | ascertained as a food composition in a specific aspect.

The food composition of the present invention may be prepared in any form, for example, beverages such as tea, juice, carbonated beverages, ionic beverages, processed oils such as milk, yogurt, gums, rice cakes, sweets, bread, sweets, noodles, and the like. Foodstuffs, tablets, capsules, pills, granules, liquids, powders, flakes, pastes, syrups, gels, jellies, bars, and the like can be prepared as functional food preparations. In addition, the food composition of the present invention can distinguish any product as long as it conforms to the enforcement regulations at the time of manufacture and distribution in the legal and functional divisions. For example, it is a health functional food according to the Act on Health Functional Food, or confectionary, soybean, soy milk, fermented beverage, special purpose food, etc. according to each food type in the Food Code of the Food Sanitation Act (KFDA Notification, Food Standards and Standards). Can be.

The food composition of the present invention may include food additives in addition to the active ingredient. Food additives can generally be understood as substances that are added to, mixed with, or infiltrated in the manufacture, processing, or preservation of foods, and because they are taken daily with food and for a long time, their safety must be ensured. The Food Additives Code of the Food Sanitation Act (KFDA Notification, Food Additives Standards and Standards) defines the food additives that are guaranteed to be safe by dividing them into chemical synthetics, natural additives, and mixed preparations.

These food additives may be divided into sweeteners, flavors, preservatives, emulsifiers, acidulants, thickeners, and the like in terms of their functionalities.

Sweeteners are used to impart a proper sweetness to foods, and may be natural or synthesized. Preferably, a natural sweetener is used. Examples of the natural sweetener include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose and maltose.

Flavoring agents can be used to enhance the taste or aroma, both natural and synthetic. It is the case of using a natural thing preferably. In addition to flavors, the use of natural ones can be combined with nutritional purposes. The natural flavor may be obtained from apples, lemons, citrus fruits, grapes, strawberries, peaches, and the like, or may be obtained from green tea leaves, round leaves, jujube leaves, cinnamon, chrysanthemum leaves, jasmine and the like. In addition, ginseng (red ginseng), bamboo shoots, aloe vera, ginkgo and the like can be used. Natural flavors can be liquid concentrates or solid extracts. In some cases, synthetic flavoring agents may be used, and synthetic flavoring agents may include esters, alcohols, aldehydes, terpenes, and the like.

Sodium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, EDTA (ethylenediaminetetraacetic acid), etc. may be used as a preservative, and as an emulsifier, acacia gum, carboxymethylcellulose, xanthan gum, Pectin etc. can be mentioned, As acidic acid, acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, phosphoric acid, etc. can be used. The acidulant may be added so that the food composition is at an appropriate acidity for the purpose of inhibiting the growth of microorganisms in addition to the purpose of enhancing the taste.

As the thickener, suspending implementers, sedimenting agents, gel formers, swelling agents and the like can be used.

In addition to the food additives described above, the food composition of the present invention may include a bioactive substance or minerals known in the art for the purpose of supplementing and reinforcing the functionality and nutritional properties and ensuring the stability as a food additive.

Examples of such physiologically active substances include catechins, vitamin B1, vitamin C, vitamin E, vitamin B12, tocopherol, dibenzoyl thiamine, and the like contained in green tea. Examples of the minerals include calcium preparations such as calcium citrate and magnesium stearate. Magnesium preparations such as iron, iron preparations such as iron citrate, chromium chloride, potassium iodine, selenium, germanium, vanadium, zinc and the like.

In the food composition of the present invention, the food additive as described above may be included in an amount that can achieve the purpose of addition according to the product type.

Regarding other food additives that may be included in the food composition of the present invention, reference may be made to food or food additives.

The anti-inflammatory composition of the present invention may be regarded as a pharmaceutical composition in another specific embodiment.

The pharmaceutical compositions of the present invention may be prepared in oral or parenteral formulations according to the route of administration by conventional methods known in the art, including pharmaceutically acceptable carriers in addition to the active ingredient. "Pharmaceutically acceptable" here means that the subject of application (prescription) is not toxic as far as adaptable without inhibiting the activity of the active ingredient.

When the pharmaceutical composition of the present invention is prepared in an oral dosage form, powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, suspensions, wafers according to methods known in the art with suitable carriers It may be prepared in a formulation such as. Examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol and xylitol, starch such as corn starch, potato starch, wheat starch, cellulose, methylcellulose, ethylcellulose, Celluloses such as sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyol, vegetable Yu etc. can be mentioned. If formulated, it may be formulated to include diluents and / or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, if necessary.

When the pharmaceutical compositions of the present invention are prepared in parenteral formulations, they may be formulated in the form of injections, transdermal administrations, nasal inhalants and suppositories with suitable carriers according to methods known in the art. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof. Preferably, PBS (phosphate buffered saline) containing Ringer's solution or triethanol amine or sterile for injection Water, isotonic solutions such as 5% dextrose, and the like. When formulated as a transdermal administration, it may be formulated in the form of an ointment, cream, lotion, gel, external solution, pasta, linen, aerosol and the like. Nasal inhalants can be formulated in the form of aerosol sprays using suitable propellants, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, etc. witepsol), tween 61, polyethylene glycols, cacao butter, laurin paper, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, sorbitan fatty acid esters, and the like.

Regarding the formulation of pharmaceutical compositions, it is known in the art and specific reference may be made to Remington's Pharmaceutical Sciences (19th ed., 1995) and the like. The document is considered part of this specification.

Preferred dosages of the pharmaceutical compositions of the present invention range from 0.001 mg / kg to 10 g / kg per day, preferably 0.001 mg / kg to 1 g, depending on the condition, body weight, sex, age, severity of the patient and route of administration. It can range from / kg. Administration can be done once a day or divided into several times. Such dosage should not be construed as limiting the scope of the invention in any aspect.

The anti-inflammatory composition of this invention can be grasped | ascertained as a cosmetic composition in another specific aspect. When the anti-inflammatory composition of the present invention is identified as a cosmetic composition, its use may be understood as a relief of inflammatory skin irritation.

The cosmetic composition of the present invention may include, in addition to the active ingredient, components conventionally used in the cosmetic composition, for example, conventional adjuvants such as stabilizers, solubilizers, surfactants, vitamins, pigments and pharmaceuticals, and carriers.

Cosmetic compositions of the present invention may be prepared in any formulation conventionally prepared in the art and include, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components. Can be.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.

When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

The cosmetic composition of the present invention can be prepared according to the manufacturing method of the cosmetic composition usually carried out in the art, except for including the active ingredient exhibiting anti-inflammatory activity and the like.

As described above, according to the present invention, it is possible to provide a method for preparing a penchinone A derivative and an anti-inflammatory composition using the derivative. The composition of the present invention may be commercialized as a food, drug or cosmetic.

1 is a diagram showing a reaction scheme for the production of ketoxime (5a), which is a discontinuous step compound for producing phenchinone A.
FIG. 2 is a diagram showing an acylation scheme and a reactant (7a) of ketoxime (5a) based on para-anisaldehyde (6a).
3 shows the reaction conditions for the production of reactants 7a.
[Figure 4] is a diagram showing the reaction scheme of the synthesis of phenchinone A derivatives through CH acylation and hydrolysis.

Hereinafter, the present invention will be described with reference to Examples and Experimental Examples. However, the scope of the present invention is not limited to these examples and experimental examples.

< Example > Penchinnon  a( Penchinone  A) and Preparation and Identification of Derivatives

1. Manufacturing Method

Synthesis of fenchinone A of the present invention proceeded with the production of an intermediate reactant ketoxime (compound 5a). The preparation process and the structure of the compound are shown in Figure 1 together with the compound number for the compound.

Preparation of <Compound 2>

phenol with an allyl group (ortho-allyl group) - p- hydroxy acetophenone (p- hydroxyacetophenone) ortho to a 71% yield for steps 2 through the screen and subsequent rearrangement Cloud Now (claisen) of allyl (Compound 1) (Compound 2) was obtained.

Specifically, a round bottom flask was dried p- hydroxyacetophenone (Compound 1) (2.7 g, 20 mmol, 100 mol%), K ₂ CO ₃ (5.5 g, 40 mmol, 200 mol%) and MeCN (20 ml) under room temperature air. (100 ml) was added allyl bromide (2.1 mL, 24 mmol, 120 mol%). The reaction mixture was stirred at 60 ° C. for 6 hours. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 × 60 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 2: 1) to give 1- (4- (allyloxy) phenyl) ethan-1-one (3.5 g, 99%) as a colorless oil. . Subsequently, 1- (4- (allyloxy) phenyl) ethan-1-one (2.8 g, 16 mmol, 100 mol%) was stirred in ortho-xylene (16 mL) at 220 ° C. for 18 hours. . The resulting mixture was cooled to rt, diluted with EtOAc (20 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 6: 1) to afford compound 2 (2.0 g, 71%) as a white solid.

Preparation of <Compound 3>

The olefin transfer of compound 2 was carried out by treatment of KO ^t Bu to obtain an internal olefin (compound 3) having a ratio of E: Z = 5: 1 in 95% yield.

Specifically, Compound 2 (1.8 g, 10 mmol, 100 mol%) and THF (40 mL) were added to a round bottom flask (100 mL) dried in an oven, and KO ^t Bu (4.5 g, 40 mmol, 400 mol%) was added under room temperature air. The reaction mixture was stirred at 80 ° C for 8 h. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH 4 Cl solution (2 × 60 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 5: 1) to afford compound 3 (1.7 g, 95%) as a white solid.

Preparation of <Compound 4>

Compound 3, a reactant product, was reacted with hydroxylamine hydrochloride to produce p -hydroxy ketoxime (compound 4).

Specifically, Compound 3 (1.1 g, 6 mmol, 100 mol%), ortho-methyl hydroxylamine hydrochloride (0.6 g, 7.2 mmol, 120 mol%), in a dried round bottom flask (100 ml), NaOAc (0.98 g, 12 mmol, 200 mol%) was added and MeOH (12 mL) was added under room temperature air. The reaction mixture was stirred at rt for 4 h. The resulting mixture was extracted with EtOAc (60 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 × 30 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 15: 1) to afford compound 4 (1.08 g, 87%) as a white solid.

Preparation of <Compound 5>

Acetylation of compound 4 resulted in a mixture of trans-product (compound 5a) (71%) and cis-product (compound 5b) (14%).

Specifically, Compound 4 (0.62 g, 3 mmol, 100 mol%), acetyl chloride (0.94 g, 12 mmol, 400 mol%), N, N-diisopropylethylamine (100 ml) were dried in a round bottom flask (100 ml). N, N-diisopropylethylamine) (0.94 g, 12 mmol, 400 mol%) was added and CH ₂ Cl ₂ (6 mL) was added under room temperature air. The reaction mixture was stirred at 60 ° C. for 6 hours. The resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 × 20 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 20: 1) to give a separable mixture of compound 5a (0.53 g, 71%) and compound 5b (0.11 g, 14%), respectively.

Preparation of <Compound 7a-7g>

Compound 7a was prepared by performing ketoxime-directed catalytic oxidative acylation of compound 5a using p - anisaldehyde (compound 6a) as a model substrate [FIG. 2]. For the preparation of 7a, the optimum reaction conditions were explored by varying the catalyst, the additive, the solvent, and the like, and the results are shown in FIG. 3.

As shown in item 1 of FIG. 3, no coupling reaction was observed between 5a and 6a when using cation Rh (III) as a catalyst. In addition, even when Ag ₂ CO ₃ as an external oxidant was treated, it was confirmed that the conversion efficiency was low (items 2 and 3 in FIG. 3). Using Pd (II) catalyst and TBHP oxidant yielded product 7a in 38% yield (item 4 in FIG. 3), when the amount of TBHP was increased to 3 equivalents, improved acylation product 7a. Yield (51%) was confirmed (items 5 and 6 in FIG. 3). Addition of additives (Ag ₂ CO ₃ ) and other Pd salts were not effective in improving the yield (items 7 and 8 in FIG. 3), but increased reactivity when Pd (OAc) ₂ was increased to 10 mol% to compound 7a. Yield increased to 61% (item 9 of FIG. 3). Various solvents were also screened, with DCE solvent being the most effective (items 9-12 in FIG. 3). In addition, experiments were performed in which the temperature and substrate concentration were modified, but no yield improvement was observed as shown in items 13 and 14 of FIG. 3. On the other hand, CH acylation reaction of phenolic compound 4 was also performed under various reaction conditions, but formation of a corresponding product was not observed due to interference of hydroxy and olefin functional groups on the Pd (II) center.

Compound 7a was prepared using the optimum reaction conditions found through the above procedure. Specifically, in a dried flask (100ml) Compound 5a (98.9mg, 0.4mmol, 100mol%), Pd (OAc) ₂ (9.0 mg, 0.04mmol, 10mol%), TBHP (0.24 mL, 1.2mmol, 300mol%, 5M in decane) was added and p- anisaldehyde (Compound 6a) (163.4 mg, 1.2 mmol, 300 mol%) and DCE (2 mL) were added under room temperature air. The reaction mixture was stirred at 80 ° C. for 20 h and the resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated NH ₄ Cl solution (2 × 15 mL), dried over MgSO ₄ , and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 10: 1) to give compound 7a (93.1 mg) in 61% yield.

Using the optimum reaction conditions, various allyl aldehyde compounds 6b-6g were reacted with ketoxime 5a. The reaction scheme and the structure of the compound are shown in FIG.

Para-OH-substituted benzaldehyde (Compound 6b) showed moderate reactivity to produce biaryl ketone (7b) in 51% yield. Acylation of meta-substituted benzaldehydes (compounds 6c and 6d) showed a relatively low reactivity under current reaction conditions (reactants 7c and 7d). In addition, the 3,4-disubstituted substrate (Compound 6e) was subjected to C-H acylation to obtain the desired product Compound 7e in 34% yield. For ortho-hydroxybenzaldehyde (Compound 6f), Compound 7f was produced in low yield (21%). The reaction conditions were also successfully applied to highly substituted benzaldehyde (compound 6g) to yield 7g, the synthetic precursor of fenchinone A.

Preparation of <Compound 8a-8g>

Acid catalyzed hydrolysis of all acylated compounds 7a-7g was performed to make fenchinone A and structural analogs thereof [FIG. 4]. The methyl, acetyl and imine moieties were easily removed under MeOH / acetone solvent using 0.5 M HCl at 80 ° C., yielding good yields of 8a-8 g of the corresponding products, respectively. The reaction schemes and structural formulas of the compounds are shown in FIG. 4. The spectroscopy data (1 H NMR and 13 C NMR) and physical properties of fenchinone A (8 g) were in full agreement with the reported values.

Specifically, Compound 7a (76.3 mg, 0.2 mmol, 100 mol%) was added to the dried sealing tube, and 0.5 M HCl (1 mL) and MeOH / acetone (1 mL, 1: 1 volume ratio) were added thereto. The reaction mixture was then stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, the reaction was terminated by addition of saturated NaHCO ₃ solution (1 mL), adjusted to pH 7 and extracted with EtOAc (2 × 10 mL). MgSO ₄ organic layer Dried over filtration and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes / EtOAc = 3: 1) to give compound 8a (32.9 mg) in 53% yield. Compounds 8b to 8g were prepared by the same reaction as described above for compounds 7b to 7g.

2. Identification of Compound

Spectroscopy data ( ¹ H and ¹³ C NMR) results of Compounds 2-4, 5a and 5b, 7a-7g, and 8a-8g according to the Penchinone A preparation step synthesized in the present invention are as follows.

<Compound 2>

1- (3-Allyl-4-hydroxyphenyl) ethan-1-one

2.0 g (71%); white solid; mp = 115.8-116.4 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79-7.76 (m, 2H), 7.04 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.05-5.98 (d, 1H), 5.16- 5.13 (m, 2 H), 3.45 (d, J = 6.3 Hz, 2H), 2.57 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 198.1, 159.2, 135.7, 131.3, 129.9, 129.2, 126.0, 116.7, 115.4, 34.6, 26.2; IR (KBr) υ 3078, 2933, 1672, 1655, 1595, 1508, 1422, 1358, 1273, 1172, 1120 1017, 996, 962, 919, 833 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₁ H ₁₃ O ₂ [M + H] ⁺ 177.0910, found 177.0905.

<Compound 3>

1- (4-Hydroxy-3- (prop-1-en-1-yl) phenyl) ethan-1-one

1.7 g (95%, E: Z = 5: 1); white solid; mp = 107.3-109.1 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.64-7.61 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H), 6.35-6.26 (m, 1H), 2.58 (s, 3H), 1.90 (d, J = 6.5 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 198.5, 157.8, 129.7, 128.9, 128.8, 128.3, 125.3, 124.6, 115.6, 26.2, 18.8; IR (KBr) υ 3282, 3041, 2964, 1651, 1583, 1505, 1421, 1357, 1302, 1274, 1254, 1202, 1125, 1073, 968, 890, 824, 771 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₁ H ₁₃ O ₂ [M + H] ⁺ 177.0910, found 177.0909.

<Compound 4>

(Z) -1- (4-Hydroxy-3-((E) -prop-1-en-1-yl) phenyl) ethan-1-one O-methyl oxime

1.08 g (87%, E: Z = 5: 1); white solid; mp = 105.8-107.3 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 16.0 Hz , 1H), 6.27-6.18 (m, 1H), 5.82 (br s, 1H), 3.97 (s, 3H), 2.20 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 154.7, 153.4, 131.6, 128.8, 125.8, 125.3, 125.1, 123.8, 115.6, 61.7, 18.8, 12.7; IR (KBr) υ 3323, 3037, 2936, 2818, 1654, 1595, 1504, 1435, 1366, 1315, 1274, 1221, 1177, 1120, 1049, 968, 913, 876, 821, 770 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₂ H ₁₆ NO ₂ [M + H] ⁺ 206.1176, found 205.1173.

<Compound 5a>

4-((E) -1- (Methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

0.53 g (71%, E-isomer); colorless oil; ¹ H NMR (700 MHz, CDCl ₃ ) δ 7.76 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (dd, J = 16.1, 2.1 Hz, 1H), 6.32-6.27 (m, 1H), 3.99 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 1.89 (dd, J = 7.0 , 2.1 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CDCl ₃ ) δ 169.2, 153.9, 147.9, 134.5, 130.3, 129.0, 125.3, 124.3, 124.1, 122.4, 61.9, 20.9, 18.8, 12.6; IR (KBr) ν 3036, 2937, 2817, 1759, 1654, 1603, 1487, 1441, 1367, 1318, 1263, 1197, 1169, 1116, 1046, 1009, 963, 906, 869, 832, 756 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₄ H ₁₈ NO ₃ [M + H] ⁺ 248.1281, found 248.1280.

<Compound 5b>

4-((E) -1- (Methoxyimino) ethyl) -2-((Z) -prop-1-enyl) phenyl acetate

0.11 g (14%, Z-isomer); colorless oil; ¹ H NMR (700 MHz, CDCl ₃ ) δ 7.57 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = 11.2, 1.4 Hz, 1H), 5.90-5.86 (m, 1H), 3.98 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.76 (dd, J = 7.0 , 2.1 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CDCl ₃ ) δ 169.0, 153.8, 147.0, 134.1, 130.2, 129.4, 128.1, 125.6, 124.1, 122.2, 61.9, 20.8, 14.5, 12.6; IR (KBr) ν 3038, 2935, 2816, 1759, 1651, 1605, 1485, 1440, 1351, 1311, 1258, 1197, 1169, 1113, 1035, 1008, 959, 902, 874, 824, 751 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₄ H ₁₈ NO ₃ [M + H] ⁺ 248.1281, found 248.1280.

<Compound 7a>

5- (4-Methoxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

93.1 mg (61%); orange sticky oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (dt, J = 9.6, 2.8 Hz, 2H), 7.58 (s, 1H), 7.12 (s, 1H), 6.88 (dt, J = 9.7, 2.8 Hz, 2H), 6.45-6.33 (m, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.92 (d, J = 5.1 Hz, 3H ); 13 C NMR (100 MHz, CDCl ₃ ) δ 194.7, 168.9, 163.3, 154.1, 146.9, 137.9, 134.7, 132.2, 131.9, 130.6, 130.5, 126.3, 123.6, 123.5, 113.5, 61.7, 55.4, 20.8, 18.9, 15.1; IR (KBr) υ 2958, 2937, 2841, 1762, 1718, 1658, 1598, 1575, 1509, 1458, 1420, 1368, 1316, 1255, 1197, 1170, 1154, 1125, 1042, 965, 910, 872, 847 , 775, 738 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₂₂ H ₂₄ NO ₅ [M + H] ⁺ 382.1649, found 382.1652.

<Compound 7b>

5- (4-Hydroxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

74.9 mg (51%); white solid; mp = 132.0-133.6 ^o C; ¹ H NMR (700 MHz, CD ₃ OD) δ 7.69 (s, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.10 (s, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.49-6.48 (m, 2H), 3.66 (s, 3H), 2.33 (s, 3H), 2.03 (s, 3H), 1.93 (dd, J = 3.5, 0.7 Hz, 3H); 13C {1H} NMR (175 MHz, CD ₃ OD) δ 197.2, 170.7, 163.8, 155.5, 148.5, 139.4, 135.7, 133.6, 131.9, 130.5, 127.2, 124.6, 124.5, 116.1, 61.9, 20.6, 19.1, 14.9; IR (KBr) υ 3341, 2934, 2855, 1763, 1650, 1599, 1582, 1511, 1437, 1368, 1317, 1274, 1195, 1166, 1153, 1125, 1040, 1008, 964, 911, 871, 850, 776 , 736 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₂₁ H ₂₂ NO ₅ [M + H] ⁺ 368.1492, found 368.1493.

<Compound 7c>

5- (3-Methoxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

74.8 mg (49%); brown sticky oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (s, 1H), 7.34 (q, J = 2.5 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (dt, J = 7.6, 1.3 Hz, 1H), 7.17 (s, 1H), 7.08 (ddd, J = 10.6, 4.7, 1.2 Hz, 1H), 6.46-6.35 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H ), 2.33 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 5.0 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 195.6, 168.8, 159.6, 154.0, 147.0, 139.2, 137.5, 134.9, 132.6, 130.8, 129.2, 126.2, 124.0, 123.5, 122.4, 119.5, 113.2, 61.7 , 55.4, 20.8, 18.9, 14.9; IR (KBr) υ 2930, 1769 , 1721, 1692, 1668, 1584, 1535, 1486, 1458, 1429, 136, 1319, 1270, 1193, 1151, 1119, 1043, 964, 875, 799, 758, 735 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C ₂₂ H ₂₄ NO ₅ [M + H] ⁺ 382.1649, found 382.1654.

<Compound 7d>

5- (3-Hydroxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

58.8 mg (40%); white solid; mp = 129.0-130.2 ^o C; ¹ H NMR (700 MHz, CD ₃ OD) δ 7.71 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.09-7.07 (m, 2H), 6.97 (ddd) , J = 10.6, 8.0, 1.1 Hz, 1H), 6.51-6.49 (m, 2H), 3.66 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 4.7 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CD ₃ OD) δ 198.2, 170.7, 158.8, 155.2, 148.7, 140.6, 139.2, 135.9, 134.1, 132.1, 130.5, 126.9, 124.7, 124.6, 121.6, 121.1, 116.5, 62.0, 20.6, 19.0, 14.6; IR (KBr) υ 3385, 2935 , 2856, 1768, 1651, 1596, 1564, 1553, 1485, 1446, 1368, 1317, 1282, 1194, 1143, 1120, 1043, 1009, 964, 874, 818, 764 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C ₂₁ H ₂₂ NO ₅ [M + H] ⁺ 368.1492, found 368.1495.

<Compound 7e>

5- (4-Hydroxy-3-methoxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

54.1 mg (34%); red sticky oil; ¹ H NMR (400 MHz, CD ₃ OD) δ 7.69 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (s, 1H ), 6.80 (d, J = 8.2 Hz, 1H), 6.50-6.49 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H) , 1.93 (d, J = 4.8 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 195.1, 168.8, 153.7, 151.4, 147.0, 146.4, 137.2, 133.9, 131.6, 130.0, 128.7, 125.3, 124.3, 122.7, 122.6, 113.7, 111.2, 60.0, 54.3, 18.6, 17.1, 13.1; IR (KBr) υ 3404, 2936, 28525, 1762, 1652, 1589, 1510, 1459, 1427, 1369, 1278, 1195, 1145, 1119, 1042, 965, 916, 874, 781 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₂₂ H ₂₄ NO ₆ [M + H] ⁺ 398.1598, found 398.1600.

<Compound 7f>

5- (2-Hydroxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

30.9 mg (21%); yellow sticky oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.86 (s, 1H), 7.62 (s, 1H), 7.43 (ddd, J = 15.6, 8.7, 1.7 Hz, 1H), 7.23 (dd, J = 8.9, 2.5 Hz, 1H), 7.11 (s, 1H), 6.99 (dd, J = 8.4, 0.8 Hz, 1H), 6.76 (ddd, J = 15.1, 8.1, 1.0 Hz, 1H), 6.46-6.35 (m, 2H) , 3.67 (s, 3H), 2.34 (s, 3H), 2.08 (s, 3H), 1.94 (d, J = 5.1 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CDCl ₃ ) δ 201.6, 168.8, 162.3, 152.7, 147.1, 136.3, 135.9, 133.6, 132.4, 132.1, 130.8, 125.9, 123.5, 123.1, 120.4, 118.8, 117.9, 61.7 , 20.8, 18.9, 13.9; IR (KBr) υ 2965, 2936 , 2818, 1765, 1630, 1612, 1484, 1446, 1367, 1331, 1294, 1243, 1192, 1149, 1130, 1112, 1046, 1009, 965, 912, 874, 835 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C ₂₁ H ₂₂ NO ₅ [M + H] ⁺ 368.1492, found 368.1508.

<Compound 7g>

5- (2,4-Dihydroxy-3-methoxybenzoyl) -4-((E) -1- (methoxyimino) ethyl) -2-((E) -prop-1-en-1-yl) phenyl acetate

29.8 mg (18%); yellow sticky solid; ¹ H NMR (700 MHz, CD ₃ OD) δ 7.72 (s, 1H), 7.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.1 Hz, 2H), 6.31 (d, J = 9.1 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 2.33 (s, 3H), 2.09 (s, 3H), 1.93 (d, J = 4.9 Hz, 3H ); ¹³ C { ¹ H} NMR (175 MHz, CD ₃ OD) δ 201.9, 170.7, 158.6, 158.4, 154.8, 148.6, 138.1, 136.1, 134.9, 133.7, 132.0, 130.1, 127.1, 124.5, 124.1, 115.7, 108.9, 62.0, 60.8, 20.6, 19.1, 14.3; IR (KBr) υ 3396, 2922, 2852, 1754, 1614, 1503, 1431, 1367, 1328, 1291, 1242, 1193, 1157, 1131, 1090, 1040, 1006, 963, 934, 872, 793 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₂₂ H ₂₄ NO ₇ [M + H] ⁺ 414.1547, found 414.1554.

<Compound 8a>

(E) -1- (4-Hydroxy-2- (4-methoxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

32.9 mg (53%); white solid; mp = 177.2-178.6 ^° C; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.65 (dt, J = 9.7, 2.8 Hz, 2H), 6.94 (dt, J = 7.2, 2.8 Hz, 2H), 6.74-6.70 (m, 1H), 6.68 (s, 1H), 6.53-6.48 (m, 1H), 3.84 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.5, 1.6 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 199.1, 199.0, 165.2, 159.5, 142.6, 132.5, 132.3, 131.3, 130.5, 129.8, 129.6, 129.2, 127.1, 125.9, 115.9, 114.7, 56.0, 26.8, 19.1; IR (KBr) υ 3295, 2926, 2841, 1671, 1595, 1570, 1509, 1420, 1359, 1302, 1256, 1170, 1150, 1129, 1025, 961, 898, 846, 771, 738 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₁₉ O ₄ [M + H] ⁺ 311.1278, found 311.1290.

<Compound 8b>

(E) -1- (4-Hydroxy-2- (4-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

42.2 mg (71%); white solid; mp = 233.1-234.9 ^o C; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (s, 1H), 7.58 (dt, J = 9.5, 2.7 Hz, 2H), 6.77 (dt, J = 9.5, 2.7 Hz, 2H), 6.74-6.99 (m, 1 H), 6.67 (s, 1 H), 6.54-6.45 (m, 1 H), 2.47 (s, 3 H), 1.93 (dd, J = 6.5, 1.6 Hz, 3 H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 199.2, 199.1, 163.8, 159.5, 142.7, 132.9, 130.5, 130.1, 129.5, 129.1, 127.1, 126.0, 116.1, 116.0, 26.9, 19.1; IR (KBr) υ 2924, 2852, 1773, 1636, 1599, 1562, 1414, 1359, 1312, 1260, 1195, 1166, 1129, 1051, 965, 914, 871, 773, 708 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₈ H ₁₇ O ₄ [M + H] ⁺ 297.1121, found 297.1122.

<Compound 8c>

(E) -1- (4-Hydroxy-2- (3-methoxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

24.9 mg (40%); brown sticky oil; ¹ H NMR (700 MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.30 (t, J = 1.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.12-7.10 (m, 2H ), 6.72 (dd, J = 15.9, 1.7 Hz, 1H), 6.71 (s, 1H), 6.53-6.50 (m, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.94 (dd, J = 6.5, 1.7 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CD ₃ OD) δ 199.6, 199.1, 161.2, 159.7, 142.4, 139.9, 130.5, 129.6, 129.3, 127.4, 125.9 (two-carbon overlap), 122.9, 120.1, 116.0, 114.1, 55.8, 26.6, 19.1; IR (KBr) υ 3274, 2923 , 2854, 1670, 1595, 1581, 1566, 1485, 1452, 1428, 1415, 1359, 1300, 1267, 1220, 1180, 1122, 1036, 968, 902, 877, 799 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₁₉ O ₄ [M + H] ⁺ 311.1278, found 311.1289.

<Compound 8d>

(E) -1- (4-Hydroxy-2- (3-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

26.6 mg (45%); white solid; mp = 215.0-216.5 ^° C; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.12-7.08 (m, 2H), 6.95 (ddd, J = 11.5, 8.0, 1.0 Hz, 1H), 6.74-6.71 (m, 1H), 6.70 (s, 1H), 6.53-6.48 (m, 1H), 2.47 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H ); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 197.9, 197.1, 157.7, 156.7, 140.5, 137.8, 128.5, 128.4, 127.6, 127.2, 125.3, 124.0, 119.5, 119.1, 114.3, 114.0, 24.6, 17.1; IR (KBr) ν 2957, 2927, 2854, 2366, 2325, 1769, 1649, 1597, 1559, 1448, 1361, 1269, 1199, 1129, 1047, 973, 832 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₈ H ₁₇ O ₄ [M + H] ⁺ 297.1121, found 297.1129.

<Compound 8e>

(E) -1- (4-Hydroxy-2- (4-hydroxy-3-methoxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

35.9 mg (55%); white solid; mp = 168.4-169.9 ^o C; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.2, 1.9 Hz, 1H), 6.76-6.70 (m , 2H), 6.69 (s, 1H), 6.53-6.47 (m, 1H), 3.87 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 197.3, 197.0, 157.4, 151.3, 147.1, 140.5, 128.5, 128.4, 127.7, 127.2, 125.1, 124.3, 124.0, 114.1, 113.5, 110.3, 54.3, 24.9, 17.1; IR (KBr) υ 3311, 2957, 2924, 2853, 1650, 1590, 1512, 1461, 1427, 1360, 1298, 1275, 1210, 1121, 1029, 970, 903, 781 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₁₉ O ₅ [M + H] ⁺ 327.1227, found 327.1239.

<Compound 8f>

(E) -1- (4-Hydroxy-2- (2-hydroxybenzoyl) -5- (prop-1-en-1-yl) phenyl) ethan-1-one

36.3 mg (61%); white solid; mp = 100.7-102.6 ^o C; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.44 (ddd, J = 15.6, 10.0, 1.7 Hz, 1H), 7.04 (dd, J = 7.9, 1.6 Hz, 1H), 6.95 (dd, J = 8.4, 0.8 Hz, 1H), 6.77-6.71 (m, 2H), 6.70 (s, 1H), 6.55-6.49 (m, 1H), 2.49 (s, 3H), 1.94 (dd, J = 6.6, 1.6 Hz, 3H); ¹³ C { ¹ H} NMR (100 MHz, CD ₃ OD) δ 203.2, 196.7, 161.3, 158.1, 138.7, 134.9, 131.2, 128.7, 127.4, 126.7, 125.5, 123.9, 119.5, 117.9, 116.7, 113.8, 24.5, 17.1; IR (KBr) υ 3236, 3063, 2914, 1627, 1600, 1566, 1484, 1448, 1413, 1359, 1331, 1305, 1267, 1242, 1217, 1159, 1034, 965, 906, 874, 814, 755, 712 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₈ H ₁₇ O ₄ [M + H] ⁺ 297.1121, found 297.1133.

<Compound 8g>

(E) -1- (2- (2,4-Dihydroxy-3-methoxybenzoyl) -4-hydroxy-5- (prop-1-en-1-yl) phenyl) ethan-1-one; penchinone A

41.2 mg (60%); white solid; mp = 111.2-113.9 ^o C; ¹ H NMR (700 MHz, CD ₃ OD) δ 8.05 (s, 1H), 6.72-6.70 (m, 2H), 6.68 (s, 1H), 6.53-6.48 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 2.50 (s, 3H), 1.94 (dd, J = 6.3, 1.4 Hz, 3H); ¹³ C { ¹ H} NMR (175 MHz, CD ₃ OD) δ 203.8, 198.9, 159.5, 158.5, 158.3, 140.7, 136.1, 130.7, 129.9, 129.3, 128.9, 127.3, 125.9, 115.9, 115.4, 108.8, 60.8, 26.8, 19.1; IR (KBr) υ 3279, 2923, 2853, 1651, 1601, 1501, 1445, 1359, 1290, 1158, 1107, 1090, 1042, 969, 812, 791 cm ⁻¹ ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₁₉ O ₆ [M + H] ⁺ 343.1176, found 343.1179.

Experimental Example Confirmation of Anti-inflammatory Activity

1. Experiment Method

RAW 264.7 macrophages derived from rats were purchased from the American Type Culture Collection (ATCC) and cultured at 37 ° C, 5 using a culture medium containing Dulbecco's modified Eagle's medium (DMEM), 10% fetal calf serum and 1% penicillin-streptomycin. Incubated in% CO ₂ conditions.

To confirm the NO concentration, RAW264.7 cells were treated with the compound as a sample for 2 hours, then treated with LPS (1 µg / mL) for 24 hours, and the NO concentration in the culture supernatant was measured. Specifically, 100 μl of Griess regent (1% sulfanilamide in 5% phosphoric acid, 1% α-naphthylamide in H ₂ O) was mixed with the culture supernatant, incubated at room temperature for 15 minutes, and then at 550 nm using a Molecular Device microplate reader. The NO production inhibitory activity by concentration was determined as a percentage of the sample-free group, and the result was expressed as IC ₅₀ (a concentration that inhibits NO production by 50% compared to the sample-free group).

In order to confirm the expression of TNF-α and IL-6, RAW264.7 cells were pretreated with the compound as a sample and then treated with LPS (1 μg / mL) and incubated for 24 hours. The concentrations of TNF-α and IL-6 in each compound-treated sample were measured according to the manufacturer's instructions using the DuoSet Elisa kit (R & D Systems), and the NO production inhibitory activity was determined as a percentage of the untreated group. The results are expressed as IC ₅₀ (concentration that inhibits NO production by 50% compared to the sample-free group).

The experimental results are expressed as means ± S.E.M. All experiments were performed at least three times and Student's t test (SigmaPlot) was used for comparison between groups. Multiple group comparisons of mean values were analyzed by one-way analysis of variance (ANOVA, GraphPad program).

2. Experimental Results

In vitro inhibitory activity of Fenchinone A and its derivatives (Compounds 7a-7g and 8a-8g) synthesized against nitric oxide (NO), TNF-α and IL-6, which are involved in inflammatory processes To evaluate it is shown in [Table 1].

Anti-inflammatory Effects of Compounds 7a-7g and 8a-8g (IC ₅₀ value (μM)) compound NO TNF-α IL-6 compound NO TNF-α IL-6 7a 7.60 ± 0.07 11.16 ± 0.06 8.68 ± 0.06 8a 4.38 ± 0.02 9.16 ± 0.04 7.66 ± 0.01 7b 6.26 ± 0.02 8.66 ± 0.07 5.60 ± 0.01 8b 5.40 ± 0.01 7.66 ± 0.01 6.53 ± 0.01 7c 2.73 ± 0.01 5.89 ± 0.01 4.26 ± 0.02 8c 2.00 ± 0.02 4.05 ± 0.00 2.15 ± 0.03 7d 2.78 ± 0.02 6.96 ± 0.02 4.14 ± 0.02 8d 6.21 ± 0.03 6.86 ± 0.02 7.70 ± 0.01 7e 5.77 ± 0.02 8.97 ± 0.07 6.88 ± 0.02 8e 1.81 ± 0.01 3.77 ± 0.02 3.10 ± 0.01 7f 4.95 ± 0.01 4.32 ± 0.02 3.23 ± 0.02 8f 0.94 ± 0.01 3.20 ± 0.03 2.07 ± 0.01 7 g 4.16 ± 0.07 6.24 ± 0.02 5.96 ± 0.01 8 g 1.01 ± 0.01 3.12 ± 0.01 2.10 ± 0.04 Dexamethasone 1.76 ± 0.02 4.52 ± 0.02 3.92 ± 0.01

A commercially available anti-inflammatory drug, dexamethasone, was used as a positive control (IC ₅₀ value (μM): 50% inhibition concentration for NO, TNF-α, and IL-6 production.The results are reported as mean value ± SEM for n = 3). The activities of compounds 7c, 7d, 8c and 8e-8g showed similar inhibitory activity to dexamethasone, a commercially available anti-inflammatory drug used as a positive control. In particular, fenchinone A (8 g) and its structural analogue 8f showed better NO production inhibitory activity than the positive control (IC ₅₀ = 1.01 ± 0.01 μM of compound 8g, IC ₅₀ = 0.94 ± 0.01 μM of compound 8f).

In addition, compounds 8c and 8e-8g were found to show higher TNF-α and IL-6 production inhibitory activity than dexamethasone.

Claims (12)

(a) reacting a compound of the following Chemical Formula 1 with a compound of the following Chemical Formula 2 to obtain an intermediate product, which is a compound of Chemical Formula 3, and
(b) Removing the acetyl moiety (Ac), the imine moiety (-N =) and the methyl moiety (Me) of the methoxy group (OMe) from the compound of <Formula 3> as an intermediate product to obtain the compound of <Formula 4> Comprising the steps,
Method for preparing a compound of Formula 4 below:

Wherein R 1 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),
R2 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),
R 3 is H (hydrogen) or OH (hydroxy group).
The method of claim 1,
The reaction of step (a) is characterized in that it is carried out using a Pd salt as a catalyst.
The method of claim 1,
The reaction of step (a) is characterized in that it is carried out using Pd (OAc) ₂ as a catalyst.
The method of claim 1,
The reaction of step (a) is characterized in that it is carried out using a tert-butyl hydroperoxide (TBHP), AcOH (Acetic acid) or a mixture thereof as an oxidizing agent as an additive.
The method of claim 1,
The reaction of step (a) is characterized in that it is carried out using the TBHP (Tert-butyl hydroperoxide) as an additive oxidant.
The method of claim 1,
The reaction of step (a) is characterized in that using the reaction solvent THF (Tetrahydrofuran), DCE (1,2-Dichloroethane), 1,4-dioxane (1,4-dioxane) or methanol.
The method of claim 1,
The reaction of step (b) is carried out by performing acid catalyst hydrolysis, characterized in that using HCl as the acid catalyst.
The method of claim 1,
The reaction of step (b) is characterized in that the reaction solvent is carried out using methanol, acetone or a mixed solvent thereof.
An anti-inflammatory composition comprising the compound of Formula 3 or a compound of Formula 4 as an active ingredient.
<Formula 3>

<Formula 4>

Wherein R 1 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),
R2 is H (hydrogen), OMe (methoxy group) or OH (hydroxy group),
R 3 is H (hydrogen) or OH (hydroxy group).
The method of claim 9,
The composition is an anti-inflammatory composition, characterized in that the food composition.
The method of claim 9,
The composition is an anti-inflammatory composition, characterized in that the pharmaceutical composition.
The method of claim 9,
The composition is an anti-inflammatory composition, characterized in that the cosmetic composition.

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