KR101152603B1 - Chromen-4-one derivatives for the treatment or prevention of diabetes - Google Patents

Abstract

The present invention relates to a chromium-4-one derivative showing a hypoglycemic action and a diabetes therapeutic composition containing the compound as an active ingredient.

Chromen-4-one, lowering blood sugar, treating diabetes

Description

Chromen-4-one derivatives for the treatment or prevention of diabetes}

The present invention relates to a chromium-4-one derivative showing a hypoglycemic action and a diabetes therapeutic composition containing the compound as an active ingredient.

Diabetes is a disease caused by glucose metabolic abnormalities characterized by persistent hyperglycemic symptoms.

Diabetic hyperglycemia is known to be caused by absolute deficiency of insulin (type 1 diabetes) or relative insulin deficiency (type 2 diabetes). Insulin is a hormone secreted by the β-cells of Rangelis in the pancreas that regulates glucose metabolism and promotes the transport of glucose from the blood to skeletal muscle, liver, adipose tissue and other tissues, which is used as an energy source or glycogen or fat. To be biosynthesized and stored. Glucagon, on the other hand, is a hormone secreted by the α-cells of Rangelis in the pancreas and antagonizes insulin.

The cause of insulin resistance, which is the main cause of type 2 diabetes, has not yet been precisely identified, but may occur when insulin action is impaired due to decreased insulin receptors, defects in receptors or post-receptor signaling systems.

Diabetes is generally classified into type 1 diabetes and type 2 diabetes. Type 1 diabetes develops extreme hyperglycemia due to reduced insulin production due to damage or dysfunction of pancreatic beta cells, often with ketoosis or ketoacidosis. Type 2 diabetes is known to be caused by insulin resistance, which is manifested by insulin secretion disorders, increased endogenous glucose production in the liver, and decreased glucose availability in peripheral insulin sensitive tissues. In either case, relative insulin deficiency occurs. Patients with type 2 diabetes also progress to hyperglycemia, but not as often as ketoosis or ketoacidosis.

 Long-term diabetes can lead to a variety of degenerative complications if left unchecked. For example, diabetic retinopathy, diabetic neurosis, kidney disease, atherosclerosis, myocardial disorders, skin disorders, diabetic foot syndrome and diseases of peripheral blood vessels. In general, it is known that improving hyperglycemia by controlling blood glucose levels in diabetics can delay or prevent the degenerative complications in diabetics. [Brownlee and Cerami, Annu. Rev. Biochem. 50, 385 (1981)] In the case of severe hyperglycemia, hyperosmolar viketone coma may occur due to high blood glucose levels. Therefore, lowering blood glucose levels in diabetics can prevent hyperosmolar viketone coma caused by hyperglycemia.

In Korea, about 5% of the population is reported to be diabetic, and more than 90% of these diabetics are type 2 diabetes. There are about 16 million people with diabetes in the United States, of whom 95% are type 2 diabetes and are more common in obese people after age 45. The prevalence of diabetes is increasing rapidly, and by 2005 it is expected that as many as 300 million people with diabetes worldwide. Diabetes is still one of the top 10 causes of death in the world.

In type 2 diabetic patients, loss of early insulin response is characteristic and late insulin secretion response reaches the highest insulin secretion, reducing glucose tolerance, and gradually deteriorating the function of β-cells. Bring it. Early insulin secretion is important for maintaining normal glucose tolerance. In addition, studies have shown that post-prandial blood sugar has a higher correlation with HbA1C (hemoglobin A1C) regulation than fasting blood glucose, and post-prandial hyperglycemia is associated with an increased risk of cardiovascular disease. Post-prandial blood sugar control is also emphasized. On the other hand, if you can show normal insulin secretion, you can reduce the risk of hypoglycemia later in the day after eating and avoid chronic hyperinsulinemia, which seems to be associated with weight gain, insulin resistance, lipid metabolism, and high blood pressure. . Therefore, research and efforts are being made to show strict glycemic control including postprandial blood sugar and normal insulin secretion for it.

Sulfonyl urea (Sulfonylurea) or Biguanide (Biguanide) drug, which is a conventional type 2 diabetes treatment, has many side effects despite its excellent hypoglycemic effect.

Preferred hypoglycemic agents should be ideal if, first of all, the action is expressed rapidly to prevent excessive blood sugar rise after meals, and then the effect is lost within a short time to not cause hypoglycemia, and also to improve the metabolic symptoms accompanying diabetes. to be.

Several types of drugs that partially overcome these shortcomings are currently in use or are being studied clinically. These drugs include thiazolidinedione-based insulin stimulators (Insulin Sensitizer-Avandia ™, Actos), α-glucose. Glucosidase inhibitors (Acarbose ™, Miglitol ™, Voglibose ™), short-acting insulinotropic agents-repaglinide, nateglinide, fast-acting insulin analogs (insulin lispro, insulin aspart), amylin Analogues (pancreatic hormone-amylin, pramlintide).

Nevertheless, the development of safer and more effective hypoglycemic agents is still urgently needed.

An object of the present invention is to provide a novel chromen-4-one compound effective in treating diabetes due to its excellent hypoglycemic effect.

It is another object of the present invention to provide a therapeutic agent for diabetes containing a novel chromen-4-one compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof as an active ingredient.

The present invention is characterized by a chromen-4-one derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof which is effective as a therapeutic agent for diabetes.

In Chemical Formula 1,

X is a single bond; O; S; S (O); SCH ₂ ; Se; NH; CH ₂ ; CH ₂ CH ₂ ; Or CH = CH,

R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarbonate and aminoC ₁ -C ₆ alkylcarbonate group; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups,

R ₂ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R ₃ is a hydrogen atom; Hydroxy; C ₁ -C ₆ alkoxy group; Or a C ₁ -C ₆ alkylcarbonate group,

R ₄ is a hydrogen atom; Halogen atom; Hydroxyl group; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group,

R ₅ is a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; Ethyl acetate group; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; A benzylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups; PyridinylC ₁ -C ₆ alkoxy group; Oxypyridinylmethoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group.

R ₆ is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; Or a C ₂ -C ₆ alkenyl group,

Or R ₅ and R ₆ combine with each other to form a 5-7 membered hetero ring containing an oxygen atom.

The compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt, for example, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrogen bromide and nitrate, or Salts with organic acids such as maleate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate and stearate Include.

Some of the compounds of the present invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases, solvates may be formed. In addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization, stoichiometric solvates, including hydrates, are also within the scope of the present invention.

The compound represented by Formula 1 may be an enantiomer, stereoisomer or tautomer. Different isomers can be separated or resolved by conventional methods, or any given isomer can be obtained by conventional synthesis or by stereospecific or asymmetric synthesis.

In addition, the present invention includes a radioactive derivative of the compound represented by Formula 1, and these radioactive compounds are useful in the field of biological research.

Specific examples of the compound represented by Formula 1 are shown in Table 1 below:                     

compound
number X R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ One O 4- (OH) Ph H OH MeO OH H 2 O 4- (OH) Ph H OH MeO OH H 3 S 4- (OH) Ph H OH MeO OH H 4 Se 4- (OH) Ph H OH MeO OH H 5 O 4- (OH) Ph H i -PrO MeO i -PrO H 6 S 4- (OH) Ph H i -PrO MeO i -PrO H 7 NH 4- (OH) Ph H OH MeO OH H 8 NH 4- (OH) Ph H i -PrO MeO i -PrO H 9 O 4- (OH) Ph H OH H OH H 10 O 4- (OH) Ph H i -PrO H i -PrO H 11 S 4- (OH) Ph H OH H OH H 12 S 4- (OH) Ph H i -PrO H i -PrO H 13 CH ₂ 4- (OH) Ph H OH MeO OH H 14 CH ₂ 4- (OH) Ph H i -PrO MeO i -PrO H 15 O Cy H OH MeO OH H 16 S Cy H OH MeO OH H 17 O Ph H OH MeO OH H 18 O Ph H i -PrO MeO i -PrO H 19 S Ph H OH MeO OH H 20 S Ph H i -PrO MeO i -PrO H 21 O 2-Py H OH MeO OH H 22 S 2-Py H OH MeO OH H 23 O 4-Py H OH MeO OH H 24 O 4-Py H i -PrO MeO i -PrO H 25 O 4-Py H OH MeO OH H 26 S 4-Py H OH MeO OH H 27 CH ₂ -CH ₂ 4- (OH) Ph H OH MeO OH H 28 SCH ₂ 4- (OH) Ph H OH MeO OH H 29 CH = CH 4- (OH) Ph H OH MeO OH H 30 CH = CH 4- ( i -PrO) Ph H i -PrO MeO i -PrO H 31 SO 4- (OH) Ph H OH MeO OH H 32 O 4- (MeO) Ph H MeO MeO MeO H 33 O Ph H OH MeO PMBO H 34 O Ph H OH H OH H 35 O Ph H OH H PMBO H 36 S Ph H OH MeO PMBO H 37 S Ph H OH H OH H 38 S Ph H OH H PMBO H 39 O 4- (OH) Ph H OH MeO PMBO H 40 O 4- (OH) Ph H OH H PMBO H 41 S 4- (OH) Ph H OH MeO PMBO H 42 S 4- (OH) Ph H OH H PMBO H 43 O 4-Py H OH H OH H 44 O 4-Py H OH H PMBO H

45 O 4- (MeCO ₂ ) Ph H MeCO ₂ MeO MeCO ₂ H 46 O 4- (EtCO ₂ ) Ph H EtCO ₂ MeO EtCO ₂ H 47 O 4- ( n -PrCO ₂ ) Ph H n -PrCO ₂ MeO n -PrCO ₂ H 48 O 4- ( i -PrCO ₂ ) Ph H i -PrCO ₂ MeO i -PrCO ₂ H 49 O 4- (EtCO ₂ ) Ph H H MeO EtCO ₂ H 50 O 4- ( i -PrCO ₂ ) Ph H OH MeO i -PrCO ₂ H 51 O 4- (OH) Ph H EtCO ₂ MeO EtCO ₂ H 52 O 4- (OH) Ph H i -PrCO ₂ MeO i -PrCO ₂ H 53 O (a) H OH MeO EtCO ₂ H 54 O (a) H OH MeO i -PrCO ₂ H 55 O 4- (OH) Ph H OH OH OH H 56 none OH H OH MeO PMBO H 57 S 4-Py H OH MeO PMBO H 58 S 2-Py H OH MeO PMBO H 59 S 4-Py H OH H PMBO H 60 S 2-Py H OH H PMBO H 61 S 4-Py H OH H OH H 62 S 2-Py H OH H OH H 63 O Ph H OH H OH H 64 O Ph H OH H Me H 65 O Ph H OH H OH Cl 66 O Ph Me OH H OH H 67 O Ph H OH MeO EtO H 68 O 4-Py H OH MeO EtO H 69 O Ph H OH MeO i -PrO H 70 O 4-Py H OH MeO i -PrO H 71 O Ph H OH MeO BnO H 72 O 4-Py H OH MeO BnO H 73 O Ph H OH MeO 4- (F) BnO H 74 O 4-Py H OH MeO 4- (F) BnO H 75 O Ph H OH MeO (b) H 76 O 4-Py H OH MeO (b) H 77 O Ph H H H OH H 78 O Ph H OH Me OH H 79 O Ph H OH H Cl H 80 O Ph H OH Cl OH H 81 O Ph H OH MeO (c) H 82 O 4-Py H OH MeO (c) H 83 O Ph H OH MeO (d) H 84 O 4-Py H OH MeO (d) H 85 O Ph H OH MeO (e) H 86 O 4-Py H OH MeO (e) H 87 O Ph H OH MeO (f) H 88 O 4-Py H OH MeO (f) H 89 O Ph H OH MeO (g) H 90 O 4-Py H OH MeO (g) H

91 O Ph H OH MeO (h) H 92 O Ph H OH H OH Me 93 O 4- (OMe) Ph H OH MeO EtO H 94 O Cy H OH MeO EtO H 95 O 4- (OMe) Ph H OH MeO i -PrO H 96 O Cy H OH MeO i -PrO H 97 O 4- (OMe) Ph H OH MeO BnO H 98 O Cy H OH MeO BnO H 99 O 4- (OMe) Ph H OH MeO 4- (F) BnO H 100 O Cy H OH MeO 4- (F) BnO H 101 O 4- (OMe) Ph H OH MeO (b) H 102 O Cy H OH MeO (b) H 103 O 4- (OMe) Ph H OH MeO (c) H 104 O Cy H OH MeO (c) H 105 O 4- (OMe) Ph H OH MeO (d) H 106 O Cy H OH MeO (d) H 107 O 4- (OMe) Ph H OH MeO (e) H 108 O Cy H OH MeO (e) H 109 O 4- (OMe) Ph H OH MeO (f) H 110 O Cy H OH MeO (f) H 111 O 4- (OMe) Ph H OH MeO (g) H 112 O Cy H OH MeO (g) H 113 O 4- (F) Ph H OH MeO EtO H 114 O 4- (F) Ph H OH MeO i -PrO H 115 O 4- (F) Ph H OH MeO BnO H 116 O 4- (F) Ph H OH MeO 4- (F) BnO H 117 O 4- (F) Ph H OH MeO (b) H 118 O 4- (F) Ph H OH MeO (c) H 119 O 4- (F) Ph H OH MeO (d) H 120 O 4- (F) Ph H OH MeO (e) H 121 O 4- (F) Ph H OH MeO (f) H 122 O 4- (F) Ph H OH MeO (g) H 123 O Ph H OH H i -PrO Cl 124 O 4-Py H OH H i -PrO Cl 125 O Ph H OH H (f) Cl 126 O Ph H OH H (g) Cl 127 O 4- (Me) piperidine H OH MeO EtO H 128 O 4- (Me) piperidine H OH MeO i -PrO H 129 O 4- (Me) piperidine H OH MeO BnO H 130 O 4- (Me) piperidine H OH MeO 4- (F) BnO H 131 O 4- (Me) piperidine H OH MeO (b) H 132 O 4- (Me) piperidine H OH MeO (c) H

133 none Ph H MeCO ₂ MeO MeCO ₂ (i) 134 none Ph H OH MeO MeCO ₂ (i) 135 none Ph H OH MeO OH (i) 136 5-hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-furo [2,3-h] chromen-4-one 137 O Ph H OH MeO OH (j) 138 O Ph H OH MeO OH (j) 139 O Ph H MeCO ₂ MeO MeCO ₂ (j) 140 O Ph H OH MeO OH (i) 141 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chromen-4-one 142 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenoxy-8H-pyrano [2,3-f] chromen-4-one

On the other hand, the present invention includes a process for preparing the chromen-4-one derivatives represented by the formula (1) and pharmaceutically acceptable salts thereof, the typical preparation method is represented by the following reaction schemes 1 to 36.                     

delete

The compound represented by Chemical Formula 1 may be chemically synthesized by a conventional method, and the present invention is to administer the compound represented by Chemical Formula 1 to a diabetic patient at a dose capable of lowering a therapeutically effective blood glucose level. Methods for delaying or preventing diabetic complications resulting from hyperglycemia associated with diabetes.

By patient described herein is meant a warm-blooded animal or mammal, including a person with insulin dependent or insulin independent diabetes mellitus as a primary or secondary disease state. Treatment of diabetic patients means a drop in blood glucose levels in the patient. Diagnosis of diabetics is within the skill and knowledge of those skilled in the art. For example, a person with symptoms of hyperglycemia exceeding normal levels, followed by hyperplegia, polyuria, polyphagia and weight loss, is considered to be in the diabetic category. Skilled clinicians in the art can easily determine this using clinical trials, physical examinations, medical examination / family history.

The therapeutically effective blood glucose lowering amount of the compound represented by the formula (1) is an amount effective to significantly reduce the blood glucose of the diabetic patient in a single or multiple doses. Effective dosages can be readily determined by using conventional techniques and observing results obtained under similar circumstances. In determining the effective dosage, it is not limited thereto, but the size, age, and general health of the patient, the severity or severity of the disease, the response of each patient, the specific compound administered, the dosage form, the bioavailability of the administered agent, the selected A number of factors are considered, including dosing and public dosing. In general, an effective hypoglycemic dose of the compound represented by Formula 1 may be about 1 mg / kg to about 500 mg / kg. When treating a patient, the compound represented by Formula 1 may be administered in any form or method, including oral and parenteral so that the compound has bioavailability in an effective amount. The compound can be administered, for example, orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like, in particular oral administration is preferred. One skilled in the art of formulation formulation can readily select the appropriate formulation and mode of administration depending on the severity of the disease and other relevant circumstances.

The compounds of the present invention may be administered in the form of a pharmaceutical composition or medicament prepared in combination with a pharmaceutically acceptable carrier or excipient and the proportions and types of the carrier or excipient are determined in accordance with the route of administration chosen and general pharmaceutical standard guidelines. . Pharmaceutical compositions or medicaments are prepared by methods known in the pharmaceutical art.                     

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Example 1 Synthesis of 5,7-Diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one [see Scheme 1]

75 g of 2,4,6-trihydroxyacetophenone monohydrate (500 g) After vacuum drying at ℃ for 1 day, the dried 2,4,6-trihydroxyacetophenone was dissolved in DMF (4.5L), and then i -PrBr (630 mL) and K ₂ CO ₃ (2.3 kg) were added in sequence. Stirred at rt for 1 h 30 min. After cooling the reaction to room temperature, the solid was filtered off. The filtrate was concentrated and the residue was extracted with H ₂ O (5 L) and EtOAc (2 L × 2). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (7% EtOAc / Hexane) to give 1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (458 g, 68%).

1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (40 g) was added to a 10% aqueous NaOH solution (710 mL) and stirred. Temperature 10 ~ 15 H ₂ O (1 L) solution in which K ₂ S ₂ O ₈ (52 g) was dissolved while slowly maintaining the temperature was slowly added to the reaction for 2 to 3 hours, and the temperature of the reaction was raised to room temperature and stirred overnight. C-HCl (150 mL) was added to the reaction mixture, and extracted with EtOAc (250 mL × 2). Na ₂ SO ₃ (50 g) was added to the H ₂ O layer, and c-HCl (200 mL) was added and refluxed for 30 minutes. The H ₂ O layer was cooled to room temperature, extracted with EtOAc (200 mL × 2), washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / Hexane) to give 1- (3,6-dihydroxy-2,4-diisopropoxy-phenyl) -ethanone (32 g, 38%). .

Dissolve 1- (3,6-dihydroxy-2,4-diisopropoxy-phenyl) -ethanone (72 g) in acetone (1 L), and then K ₂ CO ₃ (122 g), dimethyl sulfate (28 mL) was added sequentially and stirred overnight at room temperature. Dimethyl sulfate (2.6 mL) was further added to the reaction and stirred at reflux for 4 hours. After the reaction was cooled to room temperature, the solid was filtered and the filtrate was concentrated. The residue was extracted with 0.5% aqueous HCl solution (300 mL) and EtOAc (50 mL × 2). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / Hexane) to give 6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (117 g, 77%).

Toluene (500 mL) solution of potassium t- butoxide (133 g) was After the temperature was lowered to 占 폚, a solution of 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (53 g) toluene (250 mL) was added dropwise using a cannula. It was. Reactants 0 After stirring for 1 hour at ° C, toluene (250 mL) solution of CS ₂ (35 mL) was added dropwise using a cannula. Reactants 0 After stirring for 1 hour at room temperature, the temperature was raised to room temperature, followed by stirring overnight. An aqueous 10% H ₂ SO ₄ (350 mL) solution was added to the reaction, and stirred at room temperature for 5 hours, followed by further addition of an aqueous 10% H ₂ SO ₄ aqueous solution (350 mL) for 30 minutes at room temperature. The organic layer was extracted, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated to give a 5,7-diisopropoxy-2-mercapto-6-methoxy-2H-chromen-4-ol residue. It was vacuum dried at room temperature for 1 hour and then dissolved in DMF (500 mL), K ₂ CO ₃ (40 g), MeI (23 mL) were added sequentially, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure, and the residue was diluted with EA (500 mL) and washed three times with an aqueous 50% NaCl solution. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (50% EtOAc / Hexane) to give 5,7-diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one (43 g, 67%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.61 (s, 1H), 6.00 (s, 1H), 4.62 (septet, J = 6Hz, 1H), 4.52 (septet, J = 6Hz, 1H), 3.84 (s , 1H), 2.49 (s, 1H), 1.44 (d, J = 6.3Hz, 6H), 1.35 (d, J = 6.3Hz, 6H)

Example 2. Synthesis of 5,7-Diisopropoxy-2-methylsulfanyl-chromen-4-one [see Scheme 1]                     

Obtained in a similar manner to Example 1 using 1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (81 g). (72 g, 73%)

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.38 (d, J = 2.1 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.97 (s, 1H), 4.57 (septet, J = 6 Hz, 2H), 2.47 (s, 3H), 1.43 (d, J = 6.3 Hz, 6H), 1.38 (d, J-6.3 Hz, 6H)

Example 3. 5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (Compound No. 1) and 2- (4-hydroxy-phenoxy C) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 5) [See Scheme 1]

5,7-Diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one (36 g) was dissolved in CH ₂ Cl ₂ (600 mL) and m- CPBA (46 g) was dissolved. Put and stirred overnight at room temperature. The reaction was washed with saturated aqueous NaHCO ₃ (250 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF (350 mL), hydroquinone (35 g) and NaOH (25 g) were added sequentially, followed by stirring at room temperature for 2.5 hours. The reaction was concentrated under reduced pressure to about 100 mL, and the residue was added dropwise to 0.1 N aqueous HCl solution (1.2 L). The resulting crystals were filtered off and dried under reduced pressure. The dried crystals were washed with 50% EtOAc / hexane solution (1 L) and dried to afford 2- (4-hydroxy-phenoxy) -5,7-diisopropoxy-6-methoxy-chromen-4- Warm (37 g, 88%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.72 (s, 1 H), 7.15 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.86 (d, J = 8.7 Hz, 2H) , 4.90 (s, 1H), 4.81 (septet, J = 6.0 Hz, 1H), 4.36 (septet, J = 6.0 Hz, 1H), 3.71 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H) , 1.20 (d, J = 6.0 Hz, 6H)

2- (4-hydroxy-phenoxy) -5,7-diisopropoxy-6-methoxy-chromen-4-one (10 g) was dissolved in CH ₂ Cl ₂ (250 mL) and then -78 BCl ₃ (100 mL, 1M in CH ₂ Cl ₂ ) was added at ° C. -78 0 at ℃ It stirred for 1 hour after heating up to 1 degreeC over 1 hour. 1N HCl aqueous solution (140 mL) was added to the reaction to terminate the reaction. The reaction was extracted with 10% MeOH / CHCl ₃ (500 mL × 3), and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (4 g, 51%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.91 (s, 1H), 10.65 (br s, 1H), 9.84 (br s, 1H), 7.17 (d, J = 8.7 Hz, 2H), 6.87 ( d, J = 8.7 Hz, 2H), 6.46 (s, 1H), 5.04 (s, 1H), 3.73 (s, 3H)

Example 4. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenyl) -6-methoxy-chromen-4-one (Compound No. 2) [See Scheme 3]

1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (12.3 g, 43.7 mmol), 4-isopropoxy-benzaldehyde (7.2 g, 43.7 mmol) , EtOH (650 mL) solution of KOH (57 g) Stir overnight at ° C. After cooling to room temperature, it was concentrated under reduced pressure and H ₂ O (400 mL) was added. While stirring, the pH was adjusted to 4 with 1N HCl aqueous solution and extracted with EtOAc (200 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% EtOAc / Hexane) to give 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -3- (4-isopropoxy-phenyl) -Propenone (10.3 g, 55%) was obtained.

1- (6-Hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -3- (4-isopropoxy-phenyl) -propenone (10.3 g, 24 mmol) and SeO ₂ ( 14.6 g, 132 mmol) of i- amyl alcohol (250 mL) solution was refluxed overnight with stirring. The filtrate was concentrated under reduced pressure after filtration using hot celite. The residue was extracted with H ₂ O (200 mL) and EtOAc (150 mL × 2), and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (30% EtOAC / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-phenyl) -6- Methoxy-chromen-4-one (10.3 g) was obtained quantitatively.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 10.68 (br s, 1H), 10.33 (br s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 6.92 ( d, J = 8.7 Hz, 2H), 6.78 (s, 1H), 6.59 (s, 1H), 3.75 (s, 3H)

 Example 5. 5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-chromen-4-one (Compound No. 3) and 2- (4-hydroxy- Synthesis of Phenylsulfanyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 6) [See Scheme 2]

It obtained by the method of Example 3 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.10 (s, 1H), 11.13 (br s, 1H), 10.66 (br s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.35 ( d, J = 8.7 Hz, 2H), 6.80 (s, 1H), 5.91 (s, 1H), 4.12 (s, 3H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.08 (br s, 1 H), 7.34 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 5.59 (s, 1H), 4.65 (septet, J = 6.0 Hz, 1H), 4.50 (septet, J = 6.0 Hz, 1H), 3.84 (s, 3H), 1.46 (d, J = 6.0 Hz, 6H), 1.32 (d, J = 6.0 Hz, 6H)

Example 6. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenylselanyl) -6-methoxy-chromen-4-one (Compound No. 4) [See Scheme 2]

To a solution of 4,4'-diisopropyldiphenyl diselenide (4.19 g, 9.78 mmol) in THF (50 mL) was added NaBH ₄ (0.82 g, 21.2 mmol) to 0. It was put at ℃. The reaction was stirred at rt for 30 min and refluxed for 30 min. After cooling to room temperature, THF (50 mL) solution of the intermediate obtained in the method of Example 3 was slowly added to the reaction. H ₂ O (50 mL) was added to the reaction and extracted with EtOAc (50 mL × 1), CHCl ₃ (50 mL × 2). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was purified by MPLC (15% EtOAc / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-phenylselanyl) -6-methoxy-chromen-4-one (4.4 g, 54%).

This compound (6.31 g, 14.8 mmol) was prepared by the method of Example 3, 5,7-dihydroxy-2- (4-hydroxy-phenylselanyl) -6-methoxy-chromen-4-one (2.23 g, 47%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.66 (s, 1H), 10.72 (s, 1H), 10.12 (s, 1H), 7.56 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.38 (s, 1H), 5.75 (s, 1H), 3.71 (s, 3H)

Example 7. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenylamino) -6-methoxy-chromen-4-one (Compound No. 7) [See Scheme 4]

Obtained by the method of Example 3 using 4-aminophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.91 (s, 1H), 10.25 (br s, 1H), 9.88 (br s, 1H), 9.60 (br s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.28 (s, 1H), 5.10 (s, 1H), 3.71 (s, 3H)

Example 8. Synthesis of 2- (4-hydroxy-phenylamino) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 8) [See Scheme 2]

Obtained by the method of Example 3 using 4-aminophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 9.43 (br s, 1H), 9.25 (br s, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H) , 6.72 (s, 1H), 5.05 (s, 1H), 4.76 (septet, J = 6.0Hz, 1H), 4.38 (septet, J = 6.0Hz, 1H), 3.69 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H), 1.20 (d, J = 6.0 Hz, 6H)

Example 9. 5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -chromen-4-one (Compound No. 9) and 2- (4-hydroxy-phenoxy) -5, Synthesis of 7-diisopropoxy-chromen-4-one (Compound No. 10) [See Scheme 5]

Obtained by the method of Example 3 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.79 (s, 1H), 10.80 (br s, 1H), 9.77 (br s, 1H), 7.18 (d, J = 8.7 Hz, 2H), 6.86 ( d, J = 6.86 Hz, 2H), 6.35 (d, J = 1.8 Hz, 1H), 6.20 (d, J = 1.8 Hz, 1H), 5.02 (s, 1H)

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.86 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.83 (s, 1H), 4.78 (septet, J = 6.0 Hz, 1H), 4.62 (septet, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H), 1.26 (d, J = 6.0 Hz, 6H)

Example 10. 5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -chromen-4-one (Compound No. 11) and 2- (4-hydroxy-phenylsulfanyl)- Synthesis of 5,7-diisopropoxy-chromen-4-one (Compound No. 12) [See Scheme 5]

It obtained by the method of Example 3 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.59 (s, 1H), 10.84 (br s, 1H), 10.26 (br s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 6.95 ( d, J = 8.7 Hz, 2H), 6.28 (d, J = 2.1 Hz, 1H), 6.17 (d, J = 2.1 Hz, 1H), 5.51 (s, 1H)

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.19 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.77 (septet, J = 6.0 Hz, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 1.29 (d, J = 6.0 Hz , 6H), 1.25 (d, J = 6.0 Hz, 6H)

Example 11. 5,7-Dihydroxy-2- (4-hydroxy-benzyl) -6-methoxy-chromen-4-one (Compound No. 13) and 2- (4-hydroxy-benzyl) Synthesis of -5,7-Diisopropoxy-6-methoxy-chromen-4-one (Compound No. 14) [See Scheme 6]

Dissolve 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (5.11 g) in CH ₂ Cl ₂ (70 mL), and then add 0. Stir at ° C. Add NaOH (594 mg) to the reaction and add 0 After 30 minutes of stirring at chloromethyl ethyl ether (1.94 mL) was added to 0 Stir at 30 ° C. for 30 minutes. Saturated NH ₄ Cl aqueous solution (40 mL) and H ₂ O (40 mL) were added thereto, stirred for 10 minutes, and the organic layer was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / Hexane) to give 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (3.96 g, 64%). .

Dissolve 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (6.5 g) in THF (180 mL) and -78 The temperature was lowered to ℃ and stirred. Add lithium diisopropylamine (11.5 mL) to -78 Stir at 30 ° C. for 30 minutes. (4-triisopropylsilanyloxy-phenyl) -acetaldehyde (11.2 g) in THF (120 mL) Slowly add to the reaction at ℃ -78 Stir at 1 ° C. for 1 h, 0 Stir at 30 ° C. for 30 minutes. H ₂ O (100 mL) was added, followed by extraction with CH ₂ Cl ₂ (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (15% EtOAc / Hexane) to give an alcohol compound (12.05 g).

Oxalyl chloride (3.65 mL) was dissolved in CH ₂ Cl ₂ (150 mL) -78 Lower the temperature to ℃, add methyl sulfoxide (6.49 mL) while stirring, add -78 Stir at 30 ° C. for 30 minutes. The alcohol compound (12.05 g) obtained above was dissolved in CH ₂ Cl ₂ (80 mL). Slowly add to reactant at -50 ° C Stir at 1 ° C. for 1 h. Triethylamine (13.3 mL) was added thereto, stirred at room temperature for 30 minutes, and saturated aqueous NH ₄ Cl solution (100 mL) was added and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / Hexane) to 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-triisopropylsilanyloxy -Phenyl) -butane-1,3-dione (4.3 g, 36%) was obtained.

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-triisopropylsilanyloxy-phenyl) -butane-1,3-dione (4.2 g) dissolved in THF (60 mL) and then 0 The temperature was lowered to ℃ and slowly added 1M tetrabutylammonium fluoride solution (7.32 mL) and stirred for 1 hour at room temperature. H ₂ O (100 mL) was added, followed by extraction with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (25% EtOAc / Hexane) to obtain a dione compound (1.05 g).

The resulting dione (1.0 g) was dissolved in acetic acid (15 mL) and stirred at room temperature for 30 minutes, followed by addition of sulfuric acid (0.5 mL) and stirring at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution (20 mL) was added, followed by extraction with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (40% EtOAc / Hexane) to 2- (4-hydroxy-benzyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (560 mg, 66%) Got.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.08 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.78 (br s, 1H), 4.63 (septet, J = 6.3 Hz, 1H), 4.51 (septet, J = 6.3 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 2H), 1.43 (d, J = 6.3 Hz, 6H), 1.34 (d, J = 6.3 Hz, 6H)

2- (4-hydroxy-benzyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (511 mg) was dissolved in CH ₂ Cl ₂ (13 mL) and -78 BCl ₃ (5.13 mL, 1M with stirring at ° C) in CH ₂ Cl ₂ ) was added slowly. -20 Stir at 30 ° C. for 30 minutes Stir at 30 ° C. for 30 minutes. H ₂ O (30 mL) was added thereto, concentrated under reduced pressure, a portion of the solvent was removed, and then filtered to obtain a yellow solid. The aqueous layer was extracted with 20% MeOH in chloroform solution, combined with a yellow solid to dissolve, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-benzyl) -6-methoxy-chromen-4-one (189 mg, 47%). Got

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.84 (s, 1H), 10.68 (br s, 1H), 9.37 (br s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.74 ( d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 6.07 (s, 1H), 3.85 (s, 2H), 3.72 (s, 3H)

Example 12. Synthesis of 2-cyclohexyloxy-5,7-dihydroxy-6-methoxy-chromen-4-one (Compound No. 15) [See Scheme 2]

Obtained by the method of Example 3 using cyclohexanol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.18 (s, 1H), 10.54 (br s, 1H), 6.41 (s, 1H), 5.68 (s, 1H), 4.75-4.69 (m, 1H) , 3.72 (s, 3H), 2.02-1.90 (m, 2H), 1.75-1.60 (m, 2H), 1.60-1.23 (m, 6H)

Example 13. Synthesis of 2-cyclohexylsulfanyl-5,7-dihydroxy-6-methoxy-chromen-4-one (Compound No. 16) [See Scheme 2]

Obtained by the method of Example 3 using cyclohexyl mercaptan.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.83 (s, 1H), 10.42 (br s, 1H), 6.46 (s, 1H), 6.31 (s, 1H), 3.73 (s, 3H), 3.74-3.66 (m, 1H), 2.10-1.90 (m, 2H), 1.80-1.65 (m, 2H), 1.65-1.25 (m, 6H)

Example 14. 5,7-Dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 17) and 5,7-diisopropoxy-6-methoxy-2- Synthesis of phenoxy-chromen-4-one (Compound No. 18) [See Scheme 2]

It obtained by the method of Example 3 using a phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 10.70 (br s, 1H), 7.52 ~ 7.43 (m, 2H), 7.43 ~ 7.35 (m, 3H), 6.46 (s, 1H) , 5.15 (s, 1H), 3.74 (s, 1H)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.66 (s , 1H), 5.27 (s, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 4.51 (septet, J = 6.0 Hz, 1H), 3.84 (s, 1H), 1.44 (d, J = 6.0 Hz , 6H), 1.34 (d, J = 6.3 Hz, 6H)

Example 15. 5,7-Dihydroxy-6-methoxy-2-phenylsulfanyl-chromen-4-one (Compound No. 19) and 5,7-diisopropoxy-6-methoxy-2 Synthesis of Phenylsulfanyl-chromen-4-one (Compound No. 20) [See Scheme 2]

Obtained by the method of Example 3 using benzenethiol.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 10.79 (br s, 1H), 7.69-7.72 (m 2H), 7.53-7.66 (m, 3H), 6.36 (s, 1H ), 5.74 (s, 1H), 3.72 (s, 3H)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58-7.61 (m, 2H), 7.42-7.47 (m, 3H), 6.58 (s, 1H), 5.75 (s, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 4.46 (septet, J = 6.0 Hz, 1H), 3.82 (s, 3H), 1.42 (d, J = 6.0 Hz, 6H), 1.32 (d, J = 6.0 Hz, 6H)

Example 16 Synthesis of 5,7-Dihydroxy-6-methoxy-2- (pyridin-2-yloxy) -chromen-4-one (Compound No. 21) [See Scheme 2]

Obtained by the method of Example 3 using 2-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.80 (s, 1H), 10.76 (br s, 1H), 8.34 (dd, J ₁ = 3.0 Hz, J ₂ = 1.2 Hz, 1H), 8.04 (td , J = 9.0 Hz, 1.7 Hz, 1H), 7.38-7.43 (m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.44 (s, 1H), 5.87 (s, 1H), 3.75 (s , 3H)

Example 17. Synthesis of 5,7-dihydroxy-6-methoxy-2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 22) [See Scheme 2]

Obtained by the method of Example 3 using 2-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (s, 1H), 10.85 (br s, 1H), 8.57 (br d, J = 3.9 Hz, 1H), 7.88 (td, J ₁ = 7.5 Hz , J ₂ = 1.8Hz, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.40-7.44 (m, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 3.73 (s, 3H )

Example 18. 5,7-Dihydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 23) and 5-hydroxy-6-methoxy- Synthesis of 7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 25) [See Scheme 4]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1.3 g) was dissolved in acetone (50 mL), followed by 4-methoxybenzyl chloride (3.1 g), K ₂ CO ₃ (2.8 g) and NaI (0.38 g) were added sequentially and refluxed overnight. After cooling the reaction to room temperature, the solid was filtered off. The filtrate was concentrated and the residue was diluted with EtOAc (50 mL), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6-methoxy-5,7-bis- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (1.8). g, 73%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (s, 1H), 8.34 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.14 (s, 1H) , 6.99 (d, J = 8.7 Hz, 2H), 6.76 (s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 5.18 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H)

6-methoxy-5,7-bis- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (1.7 g) was dissolved in CH ₂ Cl ₂ (35 mL) and m - Place the CPBA (1.5 g) was stirred at room temperature overnight. The reaction was washed with saturated aqueous NaHCO ₃ (25 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF (15 mL), and hydroquinone (0.5 g) and NaOH (0.2 g) were added sequentially, followed by stirring at room temperature for 2 hours. The reaction was diluted with EtOAc (50 mL), washed with H ₂ O (50 mL × 3), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC to give 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (0.9 g, 68 %) Was obtained.

5-Hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (0.4 g) was added to CH ₂ Cl ₂ (5 mL) and 0 Trifluoroacetic acid was added at ℃. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was concentrated and the crystals washed with EtOAc (50 mL) and dried to give 5,7-dihydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (0.3 g, 99%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.70 (br s, 1H), 10.90 (br s, 1H), 8.34 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), 6.65 ( s, 1H), 6.31 (d, J = 7.8 Hz, 2H), 3.76 (s, 3H)

Example 19. Synthesis of 5,7-diisopropoxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 24) [See Scheme 2]

Obtained by the method of Example 3 using 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.84 (d, J = 7.8 Hz, 2H), 6.72 (s, 1H), 6.51 (d, J = 7.8 Hz, 2H), 6.12 (s, 1H) , 4.67 (septet, J = 6.0 Hz, 1H), 4.57 (septet, J = 6.0 Hz, 1H), 3.86 (s, 3H), 1.47 (d, J = 6.0 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H)

Example 20. Synthesis of 5,7-dihydroxy-6-methoxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 26) [See Scheme 2]

Obtained by the method of Example 3 using 4-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (s, 1H), 10.85 (s, 1H), 8.61 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H) , 6.52 (s, 1H), 6.38 (s, 1H), 3.74 (s, 3H)

Example 21. Synthesis of 5,7-dihydroxy-2- [2- (4-hydroxy-phenyl) -ethyl] -6-methoxy-chromen-4-one (Compound No. 27) Reference]

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (6.0 g) obtained by the method of Example 11 was dissolved in THF (120 mL) and -78 Lithium diisopropylamine (10.6 mL) was added while stirring at Stir at 30 ° C. for 30 minutes. Dissolve 3- (4-isopropoxy-phenyl) -propionaldehyde (6.8 g) in THF (50 mL) and add to the reaction. Stir at 1 ° C. for 1 h. 0 After further stirring at 10 ° C., saturated NH ₄ Cl aqueous solution (50 mL) was added thereto, and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -3-hydroxy-5- (4- Isopropoxy-phenyl) -pentan-1-one (7.9 g, 84%) was obtained.

Oxalyl chloride (11.9 mL) was dissolved in CH ₂ Cl ₂ (180 mL) -78 After stirring to lower the temperature to ℃, add methyl sulfoxide (2.8 mL) -78 Stir at 30 ° C. for 30 minutes. 1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -3-hydroxy-5- (4-isopropoxy-phenyl) -pentan-1-one ( 8.5 g) was dissolved in CH ₂ Cl ₂ (70 mL) -78 Slowly add to reactant at < RTI ID = 0.0 > Stir at 1 ° C. for 1 h. Triethylamine (11.2 mL) was added thereto, stirred at room temperature for 30 minutes, H ₂ O (100 mL) was added, and extracted with CH ₂ Cl ₂ (100 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-isopropoxy-phenyl) -Pentane-1,3-dione (6.2 g, 80%) was obtained.

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-isopropoxy-phenyl) -pentane-1, 3-dione (6.1 g ) Was dissolved in acetic acid (40 mL) and stirred for 30 minutes at room temperature, followed by adding sulfuric acid (0.5 mL) and stirring at room temperature for 2.5 hours. An aqueous sodium hydrogen carbonate solution (20 mL) was added, followed by extraction with CH ₂ Cl ₂ (50 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give chromenon (3.24 g, 62%).

The resulting chromenone (2.13 g) was dissolved in CH ₂ Cl ₂ (60 mL) and BCl ₃ (18.7 mL) was slowly added while stirring at −78 ° C. -78 30 minutes at ℃, -10 30 min at 0 ° C The mixture was stirred at 10 ° C. for 10 minutes, H ₂ O (30 mL) was added, and extracted with CH ₂ Cl ₂ (50 mL × 2) and 20% MeOH / CHCl ₃ (30 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (3% MeOH / CHCl ₃ ) to give 5,7-dihydroxy-2- [2- (4-hydroxy-phenyl) -ethyl] -6-methoxy-chromen-4-one ( 237 mg, 15.4%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.88 (s, 1H), 10.68 (br s, 1H), 9.17 (br s, 1H), 7.02 (d, J = 8.4Hz, 2H), 6.66 ( d, J = 8.4 Hz, 2H), 6.44 (s, 1H), 6.10 (s, 1H), 3.73 (s, 3H), 2.87 (s, 4H)

Example 22. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-benzylsulfanyl) -6-methoxy-chromen-4-one (Compound No. 28) [See Scheme 7]

To a solution of 5,7-diisopropoxy-2-mercapto-6-methoxy-2H-chromen-4-ol (5 g, 15.4 mmol) obtained in Example 1 in DMF (40 mL), K ₂ CO ₃ (3.2 g, 23.1 mmol) was added and stirred at room temperature. To this, a solution of DMF (10 mL) of 4-isopropoxybenzyl chloride (5.7 g, 30.8 mmol) was slowly added at room temperature and stirred for 15 minutes. EtOAc (100 mL) was added to the reaction and extracted with 50% aqueous NaCl solution (100 mL × 3) and the H ₂ O layer was extracted with EA (100 mL × 1). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-benzylsulfanyl) -6-methoxy-chromen-4-one. 5,7-Dihydroxy-2- (4-hydroxy-benzylsulfanyl) -6-methoxy-chromen-4-one (0.35 g, 46%) was obtained by the method of Example 3.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 10.71 (s, 1H), 9.47 (s, 1H), 7.24 (d, J = 8.1Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H), 6.27 (s, 1H), 4.35 (s, 2H), 3.73 (s, 3H)

Example 23. 5,7-Dihydroxy-2- [2- (4-hydroxy-phenyl) -vinyl] -6-methoxy-chromen-4-one (Compound No. 29) and 5,7- Synthesis of diisopropoxy-2- [2- (4-isopropoxy-phenyl) -vinyl] -6-methoxy-chromen-4-one (Compound No. 30) [See Scheme 3]

3- (4-isopropoxy-phenyl) -propenealdehyde (1.33 eq), Ba (OH) ₂ (4 eq) and cat. Obtained by the method of Example 4 using I ₂ / DMSO conditions.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.05 (s, 1 H), 10.71 (br s, 1 H), 10.00 (br s, 1 H), 7.58 (d, J = 15.3 Hz, 1 H), 7.57 ( d, J = 8.7 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.54 (s, 1H), 6.30 (s, 1H), 3.74 ( s, 3 H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.49 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 16.2 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.73 (s , 1H), 6.57 (d, J = 15.9 Hz, 1H), 6.09 (s, 1H), 4.50-4.73 (m, 3H), 3.85 (s, 3H), 1.47 (d, J = 6.0 Hz, 6H) , 1.37 (d, J = 6.0 Hz, 12H)

Example 24. Synthesis of 5,7-dihydroxy-2- (4-hydroxy-benzenesulfinyl) -6-methoxy-chromen-4-one (Compound No. 31) [See Scheme 8]

5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-chromen-4-one (0.2 g) was dissolved in methanol (6 mL) and then 0. Oxon (Oxone ™, 0.2 g) methanol solution was added at ℃. The temperature of the reaction was raised to room temperature and stirred overnight. The reaction was diluted with CHCl ₃ (30 mL), washed with water (10 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-benzenesulfinyl) -6-methoxy-chromen-4-one (0.1 g , 52%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.39 (s, 1H), 10.95 (s, 1H), 10.48 (s, 1H), 7.69 (d, J = 8.7Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 6.39 (s, 1H), 3.72 (s, 3H)

Example 25 Synthesis of 5,6,7-Trimethoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 32) [See Scheme 9]

5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (250 mg) was dissolved in DMF (10 mL) and K ₂ CO ₃ (436 mg ), Then add MeI (0.50 mL) 45-50 Stir at 18 ° C. for 18 h. The reaction was filtered, concentrated under reduced pressure and the residue was purified by MPLC (50% EtOAc / Hexane) to give 5,6,7-trimethoxy-2- (4-methoxy-phenoxy) -chromen-4-one (201 mg). , 71%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.30 (d, J = 9.3 Hz, 2H), 7.06 (d, J = 9.3 Hz, 2H), 7.04 (s, 1H), 4.99 (s, 1H) , 3.92 (s, 3H), 3.80 (s, 3H), 3.75 (s, 6H)

Example 26. Synthesis of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-phenoxy-chromen-4-one (Compound No. 33) [See Scheme 4]

It obtained by the method of Example 18 using phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.76 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 8.1 Hz, 2H), 7.43-7.39 (m, 5H), 6.98 (d, J = 8.7 Hz, 2H), 6.90 (s, 1H), 5.23 (s, 1H), 5.17 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H)

Example 27. Synthesis of 5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 34) [See Scheme 5]

It obtained by the method of Example 3 using a phenol.                     

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.76 (s, 1H), 10.85 (br s, 1H), 7.58-7.53 (m, 2H), 7.43-7.38 (m, 3H), 6.36 (d, J = 1.8 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 5.13 (s, 1H)

Example 28. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2-phenoxy-chromen-4-one (Compound No. 35) [See Scheme 10]

It obtained by the method of Example 18 using phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.69 (s, 1H), 7.47 (dd, J ₁ , J ₂ = 8.1 Hz, 2H), 7.36-7.31 (m, 3H), 7.19 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.26 (s, 1H), 5.03 ( s, 2H), 3.83 (s, 3H)

Example 29. Synthesis of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-phenylsulfanyl-chromen-4-one (Compound No. 36) [See Scheme 10]

Obtained by the method of Example 18 using benzenethiol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.51 (s, 1H), 7.73-7.70 (m, 2H), 7.62-7.58 (m, 3H), 7.40 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.83 (s, 1H), 5.76 (s, 1H), 5.15 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H)

Example 30. 5,7-Dihydroxy-2-phenylsulfanyl-chromen-4-one (Compound No. 37) and 5-hydroxy-7- (4-methoxy-benzyloxy) -2- Synthesis of Phenylsulfanyl-chromen-4-one (Compound No. 38) [See Scheme 10]

Obtained by the method of Example 18 using benzenethiol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.54 (s, 1H), 10.88 (br s, 1H), 7.70-7.73 (m, 2H), 7.54-7.63 (m, 3H), 6.25 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 5.73 (s, 1H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.56 (s, 1H), 7.61 (m, 2H), 7.45-7.52 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.38 (dd, J = 4.2 Hz, 2.1 Hz, 2H), 5.71 (s, 1H), 5.02 (s, 2H), 3.83 (s, 3H)

Example 31. of 5-hydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 39) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.80 (br s, 1H), 9.75 (br s, 1H), 7.42 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.91 (s, 1H), 6.88 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 5.12 (s, 1H), 3.77 ( s, 1H), 3.71 (s, 1H)

Example 32. Synthesis of 5-hydroxy-2- (4-hydroxy-phenoxy) -7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 40) [See Scheme 10] ]                     

Obtained by the method of Example 18 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.82 (br s, 1H), 9.75 (br s, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 2.1 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H) , 5.13 (s, 2H), 5.08 (s, 1H), 3.76 (s, 3H)

Example 33. 5-Hydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 41) Synthesis of Compounds [See Scheme 4]

Obtained by the method of Example 18 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.56 (s, 1H), 10.29 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H) , 6.98 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 5.53 (s, 1H), 5.16 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H)

Example 34. Synthesis of 5-hydroxy-2- (4-hydroxy-phenylsulfanyl) -7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 42) Reference]

Obtained by the method of Example 18 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (br s, 1H), 10.29 (br s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 4H), 6.65 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.52 (s, 1H), 5.11 (s, 2H), 3.76 (s, 3H)

Example 35. Synthesis of 5,7-dihydroxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 43) [See Scheme 5]

Obtained by the method of Example 9 using 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (s, 1H), 11.02 (br s, 1H), 8.33 (d, J = 8.0Hz, 2H), 6.68 (s, 1H), 6.55 (d , J = 1.8 Hz, 1H), 6.31 (d, J = 8.4 Hz, 2H), 6.25 (d, J = 2.1 Hz, 1H)

Example 36. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 44) [See Scheme 10]

Obtained by the method of Example 18 using 4-hydroxypyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.31 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.7 Hz , 2H), 6.52 (d, J = 1.5Hz, 1H), 6.51 (t, J = 2.1Hz, 2H), 6.14 (s, 1H), 5.07 (s, 2H), 3.83 (s, 3H)

Example 37 Synthesis of Acetic Acid 7-Acetoxy-2- (4-acetoxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 45) Reference]                     

Dissolve 5,7-dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (150 mg) in DMF (5 mL) and triethylamine (0.66 mL) , 4- (dimethylamino) pyridine (58 mg) and acetic anhydride (0.45 mL) were added sequentially, followed by stirring at room temperature for 2 hours. H ₂ O (30 mL) was added and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to MPLC to give acetic acid 5-acetoxy-2- (4-acetoxy-phenoxy) -chromen-4-one (176 mg, 84%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (s, 1H), 7.46 (d, J = 9,0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 5.19 (s, 1H ), 3.74 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H)

Example 38. Synthesis of propionic acid 6-methoxy-4-oxo-7-propionyloxy-2- (4-propionyloxy-phenoxy) -4H-chromen-5-yl ester (Compound No. 46) See Scheme 11]

Obtained by the method of Example 37 using propionic anhydride.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 5.19 (s, 1H) , 3.74 (s, 3H), 2.73-2.59 (m, 6H), 1.21-1.13 (m, 9H)

Example 39. Synthesis of Butyric Acid 7-butyryloxy-2- (4-butyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 47) See Scheme 11]

Obtained by the method of Example 37 using butyric anhydride.                     

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (s, 1 H), 7.46 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 5.19 (s, 1H) , 3.73 (s, 3H), 2.68-2.56 (m, 6H), 1.74-1.64 (m, 6H), 1.03-0.96 (m, 9H)

Example 40. Isobutyric acid 7-isobutyryloxy-2- (4-isobutyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 48) Synthesis of Compounds [See Scheme 11]

Obtained by the method of Example 37 using iso -butyric anhydride.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 5.21 (s, 1H) , 3.72 (s, 3H), 2.96-2.80 (m, 3H), 1.29-1.23 (m, 18H)

Example 41. Synthesis of propionic acid 5-hydroxy-6-methoxy-4-oxo-2- (4-propionyloxy-phenoxy) -4H-chromen-7-yl ester (Compound No. 49) 12]

To a solution of compound No. 1 (0.8 g, 2.53 mmol) and acetone (20 mL) of K ₂ CO ₃ (0.7 g, 5.1 mmol) was added propionic anhydride (0.9 mL, 5.1 mmol) and stirred at room temperature for 1 hour. The reaction was diluted with H ₂ O (50 mL) and the pH was adjusted to 3-4 with 1N HCl aqueous solution. After extracting with EA (50 mL × 2), the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was MPLCed to give propionic acid 5-hydroxy-6-methoxy-4-oxo-2- (4-propionyloxy-phenoxy) -4H-chromen-7-yl ester (1 g, 91%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.90 (s, 1H), 7.20 (s, 4H), 6.64 (s, 1H), 5.39 (s, 1H), 3.91 (s, 3H), 2.70-2.58 ( m, 4H), 1.33-1.26 (m, 6H)

Example 42 Synthesis of 5-isobutyric Acid 5-hydroxy-2- (4-isobutyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-7-yl ester (Compound No. 50) Reaction Scheme 12

Obtained by the method of Example 41 using i- butyric anhydride.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.19 (s, 4H), 5.39 (s, 1H), 3.90 (s, 3H), 2.85 (septet, J = 6.9Hz, 2H) , 1.35 (t, J = 6.3 Hz, 12H)

Example 43. Synthesis of propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (Compound No. 51) 13]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1 g, 3.93 mmol), DMAP (0.48 g, 3.93 mmol) obtainable by the method of Example 18 Et ₃ N (1.5 mL, 9.83 mmol) and propionic anhydride (1.7 mL, 9.86 mmol) were added to a solution of DMF (50 mL), followed by stirring at room temperature for 2 hours. 50% aqueous NaCl solution (70 mL) was added to the reaction and extracted with EtOAc (70 mL). The organic layer was washed with 50% aqueous NaCl solution (50 mL × 2), and the H ₂ O layer was extracted with EtOAc (70 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC for propionic acid 6-methoxy-2-methylsulfanyl-4-oxo-5-propionyloxy-4H-chromen-7-yl ester Was obtained quantitatively.

This was used together with 4-triisopropylsilanyloxy-phenol to propionate 6-methoxy-4-oxo-5-propionyloxy-2- (4-triisopropylsilanyloxy-phenoxy by the method of Example 3 C) -4H-chromen-7-yl ester (1.02 g, 60%) was obtained.

It is dissolved in THF (50 mL) solution and the temperature is 0 Lowered to ℃ and TBAF (1.1 eq, 1M in THF) was added. The reaction was heated to room temperature, stirred for 30 minutes, diluted with 50% aqueous NaCl solution (140 mL) and extracted with EtOAc (70 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was MPLCed to give propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (0.6 g, 61%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.16 (s, 4H), 6.88 (s, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 2.78 (quartet, J = 7.5 Hz, 2H) , 2.61 (quartet, J = 7.8 Hz, 2H), 1.33-1.25 (m, 6H)

Example 44 Synthesis of Isobutyric Acid 2- (4-Hydroxy-phenoxy) -5-isobutyryloxy-6-methoxy-4-oxo-4H-chromen-7-yl ester (Compound No. 52) See Scheme 13

Obtained by the method of Example 43 using i- butyric anhydride.

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.88 (s, 1H), 6.34 (s, 1H), 5.27 (s, 1H), 3.94 (s, 3H), 3.02 (septet, J = 6.9 Hz, 1H) , 2.81 (septet, J = 6.9 Hz, 1H), 1.39 (d, J = 7.2 Hz, 6H), 1.33 (d, J = 6.9 Hz, 6H)

Example 45. 2-Amino-3-methyl-butyric acid 4- (5-hydroxy-6-methoxy-4-oxo-7-propionyloxy-4H-chromen-2-yloxy) -phenyl ester hydrogen chloride Synthesis of Salt (Compound No. 53) [See Scheme 14]

Propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (0.46 g, 1.01 mmol) obtained in Example 43, EDC (1.5 eq) was added to a CH ₂ Cl ₂ (25 mL) solution of Boc-L-valine (1.3 eq) and DMAP (0.2 eq) and stirred overnight at room temperature. 50% aqueous NaCl solution (100 mL) was added to the reaction, the organic layer was extracted, and the H ₂ O layer was extracted with CH ₂ Cl ₂ (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, followed by MPLC to 2 -t -butoxycarbonylamino-3-methyl-butyric acid 4- (6-methoxy-4-oxo-5 , 7-bis-propionyloxy-4H-chromen-2-yloxy) -phenyl ester (0.6 g, 91%) was obtained.

This compound (0.3 g) was dissolved in CH ₂ Cl ₂ (15 mL), and the temperature was 0. Lowered to C and TFA was added slowly. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was concentrated under reduced pressure, diethyl ether (70 mL) was added to the residue, and 1N HCl (1 eq, in diethyl ether) was added slowly with stirring. The reaction was stirred at rt for 3 h, the resulting solid was filtered off and the solid was vacuum dried for 1 h. The solid was dissolved in H ₂ O (120 mL), membrane filtered and the filtrate was -78 After freezing at < RTI ID = 0.0 > C) -phenyl ester hydrogen chloride (0.15 g, 65%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.25 (br s, 1H), 8.75 (br s, 3H), 7.49 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.09 (s, 1H), 5.41 (s, 1H), 4.28 (br s, 1H), 3.82 (s, 3H), 2.63 (quartet, J = 7.5 Hz, 2H), 1.22-1.12 (m, 9H)

Example 46. 2-Amino-3-methyl-butyric acid 4- (5-hydroxy-7-isobutyryloxy-6-methoxy-4-oxo-4H-chromen-2-yloxy) -phenyl ester Synthesis of Hydrogen Chloride (Compound No. 54) [See Scheme 14]

It was obtained by the method of Example 45 using compound No. 52 obtained in Example 44.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.23 (br s, 1H), 8.72 (br s, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.09 (s, 1H), 5.41 (s, 1H), 4.25 (d, J = 4.8 Hz, 1H), 3.82 (s, 3H), 2.85 (septet, J = 7.2 Hz, 1H), 2.38 ( sextet, J = 6 Hz, 1H), 1.25 (d, J = 7.2 Hz, 6H), 1.22-1.12 (m, 9H)

Example 47. Synthesis of 5,6,7-trihydroxy-2- (4-hydroxy-phenoxy) -chromen-4-one (Compound No. 55) [See Scheme 2]

Obtained by the method of Example 3 using compound No. 5 (0.7 g) and BCl ₃ (7 eq).

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.88 (s, 1H), 6.34 (s, 1H), 5.27 (s, 1H), 3.94 (s, 3H), 3.02 (septet, J = 6.9 Hz, 1H) , 2.81 (septet, J = 6.9 Hz, 1H), 1.39 (d, J = 7.2 Hz, 6H), 1.33 (d, J = 6.9 Hz, 6H)

Example 48. Synthesis of 2,5-dihydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 56) [See Scheme 15]

Dissolve 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (0.5 g) in chloroform (25 mL), followed by m- CPBA. (0.7 g) was added and stirred at room temperature for 3 hours. The reaction was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was washed with diethyl ether (30 mL) and dried under reduced pressure. The dried product was dissolved in THF (15 mL) and LiOH monohydrate (0.2 g) dissolved in water (3 mL) was added. 70 The temperature was raised to ℃ and stirred overnight. The reaction was cooled to room temperature and concentrated. 0.5N HCl aqueous solution (7 mL) was added to the residue, followed by filtration to obtain crystals. The obtained crystals were dried under a reduced pressure to give 2,5-dihydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (0.3 g, 67%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.42 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.65 (s, 1H), 5.24 (s, 1H) , 5.12 (s, 2H), 3.77 (s, 3H), 3.67 (s, 3H)

Example 49. of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 57) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using 4-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.42 (s, 1 H), 8.61 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 6.60 (s, 1H), 5.14 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H)

Example 50. of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 58) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using 2-mercaptopyridine.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.82 (s, 3 H), 3.89 (s, 3 H), 5.09 (s, 2 H), 6.29 (s, 1 H), 6.41 (s, 1 H) , 6.89-6.94 (m, 2H), 7.28-7.36 (m, 3H), 7.48 (d, J = 7.5 Hz, 1 H), 7.73 (td, J ₁ = 7.5 Hz, J ₂ = 1.8 Hz, 1 H), 8.59-8.61 (m, 1 H), 12.42 (s, 1 H)

Example 51. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 59) [See Scheme 10] ]

Obtained by the method of Example 18 using 4-mercaptopyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.37 (s, 1 H), 8.65 (d, J = 5.7 Hz, 2H), 7.39 (d, J = 6.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.43 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.23 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H)

Example 52. 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 60) and 5,7-di Synthesis of hydroxy-2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 62) [See Scheme 10]

Obtained by the method of Example 18 using 2-mercaptopyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.48 (s, 1H), 8.61 (d, J = 3.6 Hz, 1H), 7.73 (td, J ₁ = 7.8 Hz, J ₂ = 2.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.42 (d , J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.29 (s, 1H), 5.00 (s, 2H), 3.82 (s, 3H)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.21-6.25 (m, 2 H), 6.50 (s, 1 H), 7.40-7.45 (m, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.89 (td, J ₁ = 7.5 Hz, J ₂ = 1.8 Hz, 1 H), 8.57-8.59 (m, 1 H), 10.98 (br s, 1 H), 12.51 (s, 1 H)

Example 53. Synthesis of 5,7-dihydroxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 61)

5,7-dihydroxy-2-methylsulfanyl-chromen-4-one (630 mg), acetone (50 mL) solution of K ₂ CO ₃ (1.3 eq) After lowering the temperature to ℃ ℃ acetic anhydride (1.2 eq) was added and the reaction stirred at room temperature for 1 hour. H ₂ O (100 mL) and saturated aqueous NaHCO ₃ solution (50 mL) were added to the reaction and stirred for 5 minutes. Extracted with 10% MeOH / CHCl ₃ (50 mL × 2) and the organic layer was washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, followed by MPLC (5% EtOAc / CHCl ₃ ) to 5-hydroxy-2-methylsulfanyl-4-oxo-4H-chromen-7-yl ester (675 mg, 91%) was obtained.

This was prepared by the method of Example 3 using 4-mercaptopyridine acetic acid 5-hydroxy-4-oxo-2- (pyridin-4-ylsulfanyl) -4H-chromen-7-yl ester (241 mg, 30%). The compound was dissolved in THF (20 mL) / H ₂ O (3 mL) solution, and then LiOH monohydrate (2.1 eq) was added thereto and refluxed for 2 hours. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with H ₂ O (50 mL), and the pH was adjusted to 5-6 with 1N HCl aqueous solution while stirring. The precipitated solid was filtered, washed with solids in that order, H ₂ O, EA, diethyl ether, and then dried in vacuo (1 hour, 60 ° C) gave 5,7-dihydroxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (160 mg, 77%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.47 (s, 1H), 10.97 (s, 1H), 8.61 (d, J = 5.1Hz, 2H), 7.58 (d, J = 6.0Hz, 2H) , 6.51 (s, 1H), 6.24 (d, J = 6.6 Hz, 2H)

Example 54. Synthesis of 5-hydroxy-2-phenoxy-chromen-4-one (Compound No. 63) [See Scheme 17]

It obtained by the method of Example 1 and Example 3 using 2, 6- dihydroxy acetophenone.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.58 (s, 1H), 7.46-7.53 (m, 3H), 7.36 (t, J = 7.5Hz, 1H), 7.20 (d, J = 8.1Hz, 2H) , 6.87 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.35 (s, 1H)

Example 55. Synthesis of 5-hydroxy-7-methyl-2-phenoxy-chromen-4-one (Compound No. 64) [See Scheme 18]

An acetone (200 mL) solution of orcinol (5.3 g, 42.2 mmol), K ₂ CO ₃ (18 g, 126.6 mmol), MeI (6.6 mL, 105.5 mmol) was refluxed overnight. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, 50% NaCl aqueous solution (100 mL) was added to the residue, and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (2% EtOAc / Hexane) to give 1,3-dimethoxy-5-methyl-benzene (3.8 g, 62%).

The method described in the literature using 1,3-dimethoxy-5-methyl-benzene ( Tetrahedron , 49 (47 ), 10843-10854, (1993)) to 1- (2,6-dimethoxy-4- Methyl-phenyl) -ethanone (3.9 g, 81%) was obtained.

Dissolve 1- (2,6-dimethoxy-4-methyl-phenyl) -ethanone in CH ₂ Cl ₂ (85 mL) and then adjust the temperature to -78. Lowered to ℃ and BBr ₃ (1M in CH ₂ Cl ₂ , 74 mL, 4 eq) was added slowly, the temperature of the reaction was slowly raised to room temperature and stirred overnight. 0 After the temperature was lowered to ℃, 0.5N HCl aqueous solution (100 mL) solution was slowly added, and the precipitated solid was completely dissolved in MeOH and extracted with 5% MeOH / CHCl ₃ (100 mL × 2) solution. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (25% EtOAc / Hexane) to 1- (2,6-dihydroxy-4-methyl-phenyl) -ethanone (2.5 g, 81%).

5-hydroxy-7-methyl-2-phenoxy-chromen- by the method of Example 1 and Example 3 using 1- (2,6-dihydroxy-4-methyl-phenyl) -ethanone 4-one (0.74 g) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.45 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz , 2H), 6.68 (s, 1H), 6.64 (s, 1H), 5.32 (s, 1H), 2.40 (s, 3H)

Example 56. Synthesis of 8-chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 65) [See Scheme 19]

5,7-Dihydroxy-2-methylsulfanyl-chromen-4-one (1.0 g, 4.460 mmol) was suspended in MeOH (100 mL), stirred at room temperature, concentrated with concentrated HCl solution (2 mL) and 30%. A mixture of H ₂ O ₂ aqueous solution (10 mL) was added dropwise, followed by stirring at room temperature under nitrogen stream for 25 hours. Pour the reaction solution into distilled water (500 mL) 15 After stirring at 20 ° C. for 20 minutes, the precipitated solid was filtered and dried under reduced pressure to obtain 8-chloro-5,7-dihydroxy-2-methanesulfinyl-chromen-4-one (675 mg, 55%). .

8-Chloro-5,7-dihydroxy-2-methanesulfinyl-chromen-4-one (600 mg, 2.184 mmol) was dissolved in DMF (30 mL), phenol (617 mg, 6.553 mmol) and K ₂ CO ₃ (453 mg, 3.277 mmol) was added and stirred at room temperature under nitrogen stream for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized with 1N- HCl aqueous solution, and extracted with 10% MeOH / CHCl ₃ (100 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (2% MeOH / CHCl ₃ ) to 8-chloro-5,7-dihydroxy-2-phenoxy-chromen- 4-one (597 mg, 90%) was obtained

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 5.33 (s, 1 H), 6.42 (s, 1 H), 7.40-7.45 (m, 3H), 7.53-7.59 (m, 2H), 12.77 (s, 1H)

Example 57. Synthesis of 5,7-dihydroxy-3-methyl-2-phenoxy-chromen-4-one (Compound No. 66) [See Scheme 20]

Phloroglucinol dihydrate (8.13 g, 50.14 mmol) and propionitrile (5.52 g, 100 mmol) were dissolved in diethyl ether and zinc chloride (3.34 g, 24.5 mmol) was added. The reaction solution was treated with hydrochloric acid gas and stirred at room temperature for 3 hours. Water was added thereto and stirred at reflux for 4 hours. The residue obtained by extraction with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure was purified by MPLC (50% EtOAc / Hexane) to 1- (2,4,6-trihydroxy-phenyl) -propane-1 -On (8.47 g, 78%) was obtained.

Using this compound, 5,7-dihydroxy-3-methyl-2-phenoxy-chromen-4-one was obtained using the method of Example 1 and Example 3.

¹ HNMR (CDCl ₃ , 300 MHz) δ 12.97 (s, 1 H), 7.44-7.39 (m, 2 H), 7.26-7.25 (m, 1 H), 7.12-7.09 (m, 2H), 6.28 (d, J = 2.1 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 5.56 (s, 1H), 2.03 (s, 3H).

Example 58. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 67) [See Scheme 21]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (3.5 g) was dissolved in acetone / DMF (1: 1, 150 mL) and K ₂ CO ₃ (2.5 g ), EtBr (1.23 mL) was added sequentially and stirred at room temperature for 10 minutes and then refluxed for 4 hours. Concentrated under reduced pressure at room temperature, adjusted to pH = 4 ~ 5 with 1N HCl aqueous solution and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to MPLC (10% EtOAc / CHCl ₃ ) to give 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (3.5 g, 90%).

Dissolve 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1.0 g) in CH ₂ Cl ₂ (50 mL) After lowering the temperature to ℃ m- CPBA (1.98 g) was added and stirred for 18 hours at room temperature. The reaction was washed with 50% aqueous sodium hydrogen carbonate solution (50 mL × 2), the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give sulfone (1.2 g).

The obtained sulfone (600 mg) was dissolved in acetone (30 mL), K ₂ CO ₃ (367 mg) and phenol (202 mg) were added sequentially, followed by stirring at room temperature for 18 hours. Acidified with 1N aqueous HCl solution, water (30 mL) was added, and extracted with 5% MeOH / CH ₂ Cl ₂ . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was MPLC (30% EtOAc / Hexane) to give 7-ethoxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (433 mg, 75%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.43-7.39 (m, 3H), 6.78 (s, 1H ), 5.23 (s, 1H), 4.16 (quartet, J = 6.9 Hz, 2H), 3.73 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H)

Example 59. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 68) [See Scheme 21]

Obtained by the method of Example 58 using EtBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.53 (s, 1H), 8.35 (d, J = 8.1 Hz, 2H), 7.01 (s, 1H), 6.75 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 4.19 (quartet, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1.41 (t, J = 6.9 Hz, 3H)

Example 60. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 69) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.73 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.83 (s, 1H ), 5.20 (s, 1H), 4.80 (septet. J = 5.7 Hz, 1H), 3.71 (s, 3H), 1.32 (d, J = 5.7 Hz, 6H)

Example 61. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 70) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.36 (d, J = 7.8 Hz, 2H), 7.04 (s, 1H), 6.74 (s, 1H), 6.33 (d, J = 7.8 Hz, 2H), 4.77 (septet, J = 6.0 Hz, 1H), 3.73 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H)

Example 62. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 71) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.77 (s, 1H), 7.58-7.36 (m, 10H), 6.91 (s, 1H), 5.27 (s, 2H), 5.24 (s, 1H), 3.74 (s, 3H)

Example 63. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 72) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.57 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 7.52-7.37 (m, 5H), 7.13 (s, 1H), 6.76 ( s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 5.28 (s, 2H), 3.77 (s, 3H)

Example 64. Synthesis of 7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 73) [See Scheme 21]

 Obtained by the method of Example 58 using 4-fluorobenzyl bromide and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.78 (s, 1H), 7.59-7.52 (m, 4H), 7.44-7.39 (m, 3H), 7.26 (t, J = 8.7 Hz, 2H), 6.91 (s, 1H), 5.24 (s, 3H), 3.72 (s, 3H)

Example 65 Synthesis of 7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 74) Reaction Scheme 21

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-hydroxypyridine

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.57 (s, 1H), 8.33 (d, J = 8.4 Hz, 2H), 7.56 (dd, J ₁ = 8.7 Hz, J ₂ = 5.7 Hz, 2H) , 7.27 (t, J = 8.7 Hz, 2H), 7.14 (s, 1H), 6.76 (s, 1H), 6.34 (d, J = 8.4 Hz, 2H), 5.26 (s, 2H), 3.45 (s, 3H)

Example 66. Synthesis of 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2-phenoxy-chromen-4-one (Compound No. 75) Reaction Scheme 21

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.73 (s, 1H), 7.55 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.43-7.38 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 5.23 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.72 (s, 3H ), 3.63 (s, 3H), 3.02 (t, J = 6.6 Hz, 2H)

Example 67. 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2- (pyridin-4-yloxy) -chromen-4-one ( Synthesis of Compound No. 76) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.51 (s, 1H), 8.35 (d, J = 8.1Hz, 2H), 7.28 (d, J = 8.4Hz, 2H), 7.06 (s, 1H) , 6.89 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 6.32 (d, J = 8.1 Hz, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H) , 3.66 (s, 3H), 3.06 (t, J = 6.6 Hz, 2H)

Example 68. Synthesis of 7-hydroxy-2-phenoxy-chromen-4-one (Compound No. 77) [See Scheme 22]

It obtained by the method of Example 1 and Example 3 using 2, 4- dihydroxy acetophenone.

Example 69. Synthesis of 5,7-dihydroxy-6-methyl-2-phenoxy-chromen-4-one (Compound No. 78) [See Scheme 23]

3,5-dimethoxy-phenol (10.0 g, 64.86 mmol) and TBDMSCl (11.7 g, 77.84 mmol) were dissolved in CH ₂ Cl ₂ (150 mL) and 0 Et ₃ N (18.0 mL, 129.73 mmol) was added dropwise while stirring at room temperature, followed by stirring at room temperature under nitrogen stream for 15 hours. Saturated NaHCO ₃ aqueous solution (100 mL) and distilled water (50 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (150 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and then the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to t- butyl- (3,5-dimethoxy-phenoxy) -dimethyl-silane. (16.3 g, 93%) was obtained.

t- Butyl- (3,5-dimethoxy-phenoxy) -dimethyl-silane (3.0 g, 11.18 mmol) was dissolved in THF (60 mL) and dried under nitrogen stream. 2.5 N n- BuLi / hexane solution (4.9 mL, 12.29 mmol) was added dropwise while stirring at room temperature, followed by stirring at room temperature for 3 hours. 0 back to reaction MeI (0.77 mL, 12.29 mmol) was added dropwise at 占 폚 and stirred at room temperature for 4 hours. Saturated NaCl aqueous solution (70 mL) and distilled water (30 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (150 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and then the obtained residue was purified by MPLC (2% EtOAc / Hexanes) and t- butyl- (3,5-dimethoxy-4-methyl-phenoxy)- Dimethyl-silane (1.97 g, 62%) was obtained.

t- Butyl- (3,5-dimethoxy-4-methyl-phenoxy) -dimethyl-silane (1.95 g, 6.903 mmol) was dissolved in THF (30 mL) and 0 1N TBAF / THF solution (8.3 mL, 8.284 mmol) was added dropwise while stirring at ° C, followed by stirring at room temperature under nitrogen stream for 30 minutes. The reaction solution was poured into a mixture of 1 N- HCl aqueous solution (30 mL) and saturated NaCl aqueous solution (70 mL), and extracted with CH ₂ Cl ₂ (100 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was purified by MPLC (50% EtOAc / Hexanes) to give 3,5-dimethoxy-4-methyl-phenol (1.10 g, 95%). Obtained.

3,5-dimethoxy-4-methyl-phenol (1.0 g, 5.945 mmol) was suspended in CH ₂ Cl ₂ (30 mL) and 0 Ac ₂ O (0.67 mL, 7.134 mmol) and Et ₃ N (1.66 mL, 11.890 mmol) were added dropwise while stirring at room temperature, followed by stirring at room temperature under nitrogen stream for 2 hours. Saturated NaHCO ₃ aqueous solution (20 mL) and distilled water (20 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to give acetic acid 3,5-dimethoxy-4-methyl-phenyl ester (1.23 g, 98%) Obtained.

Acetic acid 3,5-dimethoxy-4-methyl-phenyl ester (1.1 g, 5.232 mmol) was dissolved in benzene (25 mL), AlCl ₃ (837 mg, 6.279 mmol) was added, and the mixture was heated under nitrogen stream for 4 hours. Reflux. Reaction solution 0 1 N- HCl aqueous solution (30 mL) and saturated NaCl aqueous solution (50 mL) were added thereto, followed by extraction with CH ₂ Cl ₂ (70 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to give 1- (6-hydroxy-2,4-dimethoxy-3-methyl-phenyl). Ethanone (836 mg, 76%) was obtained.

5,7-dimethoxy-6 by the method of Example 1 using 1- (6-hydroxy-2,4-dimethoxy-3-methyl-phenyl) -ethanone (820 mg, 3.900 mmol) -Methyl-2-methylsulfanyl-chromen-4-one (485 mg, 47%) was obtained.

5,7-dimethoxy-6-methyl-2-methylsulfanyl-chromen-4-one (370 mg, 1.389 mmol) and oxone (Oxone ™, 1.28 g, 2.084 mmol) were mixed with MeOH (8 mL). It was suspended in a mixture of distilled water (4 mL) and stirred at room temperature for 1 hour. Distilled water (30 mL) was added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure and dried, and the residue and K ₂ CO ₃ (384 mg, 2.778 mmol) were dissolved in DMF (10 mL), stirred at room temperature, and dissolved in DMF (5 mL). Phenol (157 mg, 1.667 mmol) was added thereto and stirred at room temperature under nitrogen stream for 15 hours. The reaction solution was concentrated under reduced pressure, distilled water (20 mL) was added, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (2% MeOH / CH ₂ Cl ₂ ) to give 5,7-dihydroxy-6-methyl-2-phenoxy-chromen-. 4-one (390 mg, 90%) was obtained.

 5,7-Dihydroxy-6-methyl-2-phenoxy-chromen-4-one (330 mg, 1.057 mmol) was prepared in the manner of Example 55 using 5,7-dihydroxy-6-methyl-2 -Phenoxy-chromen-4-one (249 mg, 83%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.97 (s, 3 H), 5.14 (s, 1 H), 6.42 (s, 1 H), 7.38-7.43 (m, 3 H), 7.53-7.58 (m, 2H), 10.86 (brs, 1H), 12.99 (s, 1H)

Example 70. Synthesis of 7-chloro-5-hydroxy-2-phenoxy-chromen-4-one (Compound No. 79) [See Scheme 24]

1-chloro-3,5-dimethoxy-benzene was obtained through demethylation of BBr ₃ (Example 54) to 1-chloro-3,5-dihydroxy-benzene. This was dissolved in CH ₃ CN (0.2 M), NIS (1.1 eq) was added thereto, and the resultant was stirred at room temperature for 20 minutes. The reaction was diluted with EtOAc, and the organic layer was washed sequentially with saturated aqueous NaHSO ₃ solution and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (5% EtOAc / CH ₂ Cl ₂ ) to give 5-chloro-2-iodo-benzene-1,3-diol (62%). .

5-Chloro-2-iodo-benzene-1,3-diol was combined with dimethyl sulfate (2.5 eq), K ₂ CO ₃ (5.0 eq) in the manner of Example 1 to 5-chloro-2-iodo -1,3-dimethoxy-benzene (97%) was obtained.

Dissolve 5-chloro-2-iodo-1,3-dimethoxy-benzene in DMF (0.1M) solution and add CuCN (1.5 eq). The reaction was stirred for 3 h at < RTI ID = 0.0 > The reaction was cooled to room temperature, diluted with EtOAc and washed twice with dilute NH ₄ OH aqueous solution. The organic layer was washed with 50% aqueous NaCl solution, the H ₂ O layer was extracted with EtOAc, the organic layers were collected, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 4-chloro-2,6-dimethoxy-benzonitrile (92%).

4-Chloro-2,6-dimethoxy-benzonitrile was converted to 1- (4-chloro-2,6-dimethoxy- by the method of J. Am. Chem. Soc . 55 , 3032 (1933). Phenyl) -ethanone (75%) was obtained.

Example 65, Method of literature ( J. Med. Chem. , 43 , 4126-4134 (2000)), using 1- (4-chloro-2,6-dimethoxy-phenyl) -ethanone, Example 5,7-Dihydroxy-6-methyl-2-phenoxy-chromen-4-one was obtained using the method of 1.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.72 (s, 1H), 7.49 (t, J = 7.5Hz, 2H), 7.37 (t, J = 7.5Hz, 1H), 7.19 (d, J = 7.8Hz , 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 5.35 (s, 1H)

Example 71. Synthesis of 6-chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 80) [See Scheme 25]

CH ₂ Cl ₂ (50 mL) solution of 5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (1.0 g, 3.7 mmol) with AlCl ₃ (500 mg, 3.7 mmol) To NCS (526 mg, 3.7 mmol) was added. After 1 hour 30 minutes, poured into 10% aqueous HCl solution (100 mL) and stirred for 1 hour. After layer separation, the aqueous layer was extracted with 5% MeOH / CHCl ₃ (50 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 6-chloro-5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (580 mg, 51%).

By the method of Example 69 and Example 3 using 6-chloro-5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (450 mg, 1.5 mmol) obtained above Chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (218 mg, 81%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 5.22 (s, 1H), 6.56 (s, 1H), 7.40-7.44 (m, 3H), 7.53-7.59 (m, 2H), 11.72 (br s, 1H ), 13.53 (s, 1 H)

Example 72. Synthesis of 5-hydroxy-6-methoxy-2-phenoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 81) [See Scheme 26]

5-hydroxy-6-methoxy-2-methylsulfanyl-7- (pyridin-4-ylmethoxy) -chromen-4-one (600 mg) was added MeOH / H ₂ O (1: 4, 50 mL). ) In 1N HCl aqueous solution (3.47 mL) and add 0. Stir at ° C. Oxone (Oxone ™, 1.07 g) was added to the reaction mixture, stirred at room temperature for 3 hours, adjusted to pH = 10 with aqueous sodium bicarbonate solution, and extracted with 10% MeOH / CHCl ₃ . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (450 mg, 72%).

220 mg of 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one) was dissolved in DMF (20 mL) and K ₂ CO ₃ (126 mg) and phenol (70 mg) were added sequentially and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and then purified by MPLC (5% MeOH / CHCl ₃ ) to 5-hydroxy-6-methoxy-2-phenoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (166 mg, 70%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 8.62 (d, J = 5.4 Hz, 2H), 7.55 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.47- 7.39 (m, 3H), 7.46 (d, J = 5.4 Hz, 2H), 6.87 (s, 1H), 5.36 (s, 2H), 5.26 (s, 1H), 3.80 (s, 3H)

Example 73. Synthesis of 5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 82) [ See Scheme 26]

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.614 (s, 1H), 8.63 (d, J = 6.0Hz, 2H), 8.32 (d, J = 8.1Hz, 2H), 7.47 (d, J = 6.0 Hz, 2H), 7.09 (s, 1H), 6.77 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 5.37 (s, 2H), 3.82 (s, 3H)

Example 74. Synthesis of 5-hydroxy-6-methoxy-2-phenoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one (Compound No. 83) [ See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and phenol

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.43-7.39 (m, 3H), 6.85 (s, 1H ), 5.25 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.70 (t, J = 6.0 Hz, 2H), 2.46-2.43 (m, 4H), 1.52 -1.35 (m, 6H)

Example 75 5-Hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (compound Synthesis of No. 84) [see Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-hydroxypyridine.

¹ H NMR (MeOH-d ₄ , 300 MHz) δ 8.37 (d, J = 7.8 Hz, 2H), 6.92 (s, 1H), 6.57 (s, 1H), 6.54 (d, J = 7.8 Hz, 2H) , 4.42 (t, J = 5.1 Hz, 2H), 3.87 (s, 3H), 3.32-3.30 (m, 2H), 3.10-2.95 (br s, 4H), 1.83-1.75 (m, 4H), 1.65- 1.59 (m, 2 H)

Example 76. Synthesis of 5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -2-phenoxy-chromen-4-one (Compound No. 85) 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.84 (s, 1H ), 5.25 (s, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.73 (s, 3H), 3.57 (t, J = 5.7 Hz, 4H), 2.74 (t, J = 5.7 Hz, 2H )

Example 77. 5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 86) Synthesis [See Scheme 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.34 (d, J = 8.1Hz, 2H), 7.06 (s, 1H), 6.75 (s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 4.25 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.58 (t, J = 5.7 Hz, 4H), 2.78 (t, J = 5.7 Hz, 2H)

 Example 78. Synthesis of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-phenoxy-chromen-4-one (Compound No. 87) [See Scheme 27]                     

5-Hydroxy-6-methoxy-2-methylsulfanyl-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4-one (0.6 g) was added CH ₂ Cl ₂ (13 mL ) Dissolved in m- CPBA (0.6 g) and stirred at room temperature for 4 hours. The reaction was washed with saturated aqueous NaHCO ₃ (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in acetone (30 mL), then phenol (0.2 g) and K ₂ CO ₃ (0.3 g) were added and stirred overnight at room temperature. The reaction was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO ₃ (10 mL × 3), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to give 5-hydroxy-6-methoxy-2-phenoxy-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4 -On (0.6 g, 95%) was obtained. Dissolve 5-hydroxy-6-methoxy-2-phenoxy-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4-one (0.6 g) in THF (12 mL) 0 1.0 N tetrabutylammonium fluoride / THF solution (3 mL) was added. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was diluted with EtOAc (30 mL), washed with 0.3N aqueous HCl solution (10 mL), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-phenoxy-chromen-4-one (0.2 g , 42%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.80 (s, 1H ), 5.24 (s, 1H), 4.59 (t, J = 5.1 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.73 (s, 3H), 3.59 (td, J ₁ = 6.3 Hz, J ₂ = 5.1 Hz, 2H), 1.91 (quintet, J = 6.3 Hz, 2H)

Example 79. Synthesis of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 88) Reaction Scheme 27

Dissolve 5,7-dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (0.5 g) in acetone (10 mL) and DMF (10 mL), then 3-bromo-propane -1-ol (0.4 g) and K ₂ CO ₃ (0.4 g) were added. Reactants 70 The temperature was raised to ℃, and stirred for 3 hours. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL), washed with water (25 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (7% MeOH / CHCl ₃ ) to give 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-methylsulfanyl-chromen-4-one ( 0.6 g, 97%).

5-hydroxy-7- (3-hydroxypropoxy) -6-methoxy-2-methylsulfanyl-chromen-4-one (0.6 g) was added to methanol (12 mL) and H ₂ O (6 mL), Oxon (Oxone ™, 2.3 g) was added and stirred overnight at room temperature. The reaction was diluted with H ₂ O (20 mL) and extracted with 10% methanol / chloroform (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in acetone (30 mL), pyridine-4-ol (0.2 g) and K ₂ CO ₃ (0.3 g) were added, and the mixture was stirred at room temperature for 3 hours. The reaction was diluted with H ₂ O (20 mL) and then neutralized to pH 7 with 1N HCl aqueous solution. The neutralized reaction was extracted with 10% MeOH / CHCl ₃ (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% MeOH / CHCl ₃ ) to 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (pyridin-4-yloxy) -chromen-4 -On (0.3 g, 63%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.36 (d, J = 8.1Hz, 2H), 7.04 (s, 1H), 6.75 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 4.61 (t, J = 5.1 Hz, 1H), 4.20 (t, 6.3 Hz, 2H), 3.75 (s, 3H), 3.60 (td, J ₁ = 6.3 Hz, J ₂ = 5.1 Hz, 2H), 1.94 (quintet, J = 6.3 Hz, 2H)

Example 80. Synthesis of (5-hydroxy-6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 89) [See Scheme 21]

Obtained by the method of Example 58 using ethyl bromoacetate and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.43-7.39 (m, 3H), 6.81 (s, 1H), 5.24 (s, 1H ), 5.00 (s, 2H), 4.19 (quartet, J = 7.2 Hz, 2H), 3.77 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H)

Example 81. [5-hydroxy-6-methoxy-4-oxo-2- (pyridin-4-yloxy) -4H-chromen-7-yloxy] -acetic acid of ethyl ester (Compound No. 90) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using ethyl bromoacetate and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.58 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 7.02 (s, 1H), 6.76 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 5.00 (s, 2H), 4.20 (quartet, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.24 (t, 3H)

Example 82. Synthesis of 5-hydroxy-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -2-phenoxy-chromen-4-one (Compound No. 91) Reference]

5-hydroxy-6-methoxy-2-methylsulfanyl-7- (pyridin-4-ylmethoxy) -chromen-4-one (1.0 g) was dissolved in CH ₂ Cl ₂ (50 mL) and 0 After lowering to ℃ m- CPBA (1.62 g) was added and stirred for 18 hours at room temperature. The reaction was washed with aqueous sodium hydrogen carbonate solution (40 mL × 3) and the organic layers were collected. The aqueous layer was reextracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -Crommen-4-one (970 mg, 89%) was obtained.

5-hydroxy-2-methanesulfinyl-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -chromen-4-one (480 mg) was dissolved in acetone (30 mL) and K ₂ CO ₃ (264 mg) and phenol (145 mg) were added sequentially, followed by stirring at room temperature for 4 hours. H ₂ O (30 mL) was added and extracted with 5% MeOH / chloroform (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (7% MeOH / CHCl ₃ ) to 5-hydroxy-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -2-phenoxy-chromen-4-one ( 310 mg, 62%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 8.25 (d, J = 7.2 Hz, 2H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.48 ( d, J = 7.2 Hz, 2H), 7.43-7.39 (m, 3H), 6.88 (s, 1H), 5.27 (s, 2H), 5.26 (s, 1H), 3.77 (s, 3H)

Example 83. Synthesis of 5,7-dihydroxy-8-methyl-2-phenoxy-chromen-4-one (Compound No. 92) [See Scheme 29]

-10 in a solution of 3,5-dimethoxyphenol (10 g, 64.8 mmol) in BF ₃ .Et ₂ O (80 mL) CH (OEt) ₃ (10 mL, 64.8 mmol) was added at ° C. After stirring for 10 minutes, it was poured into 5% aqueous NaOAc solution (250 mL) and extracted with EtOAc (100 mL × 3)). Washed twice with saturated aqueous NaCl solution (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 2-hydroxy-4,6-dimethoxy-benzaldehyde (5.5 g, 46%). .

To MeOH (70 mL) solution of 2-hydroxy-4,6-dimethoxy-benzaldehyde (2.0 g, 11.0 mmol) obtained above was added 10% Pd / C (500 mg) and replaced with H ₂ 1 Stir for hours. The reaction was filtered through celite and concentrated under reduced pressure. The residue was dissolved in 50% EtOAc / Hexane and filtered through silica gel. Concentrated under reduced pressure and dried under vacuum to give 3,5-dimethoxy-2-methyl-phenol and used for the next reaction.

CH of 3,5-dimethoxy-2-methyl-phenol obtained above₂Cl₂0 in (60 mL) solution Ac at ℃₂O (1.3 mL, 13.2 mmol) and Et₃N (3.1 mL, 22.0 mmol) was added sequentially. After stirring for 2 hours, the mixture was poured into diluted aqueous NaCl solution (50 mL) and extracted. CH the water layer₂Cl₂Extracted once more with (30 mL) and the organic layer was washed with Na.₂SO₄Dried over, filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% EtOAc / Hexane) to give acetic acid 3,5-dimethoxy-2-methyl-phenyl ester (1.9 g, two steps 84%).

Acetic acid 3,5-dimethoxy-2-methyl-phenyl ester (1.9 g, 9.2 mmol) was added to the 5,7-dihydroxy-8-methyl-2-phenoxy-chromen using the method of Example 69. 4-one (136 mg, 89%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.98 (s, 3H), 5.20 (s, 1H), 6.30 (s, 1H), 7.38-7.43 (m, 3H), 7.53-7.58 (m, 2H) , 10.78 (br s, 1 H), 12.69 (s, 1 H)

Example 84. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 93) [See Scheme 21]                     

Obtained by the method of Example 58 using EtBr and 4-methoxyphenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.77 (s, 1 H), 7.34 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.78 (s, 1H) , 5.15 (s, 1H), 4.17 (quartet, J = 6.9Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 1.38 (6.9Hz, 3H)

Example 85. Synthesis of 2-cyclohexyloxy-7-ethoxy-5-hydroxy-6-methoxy-chromen-4-one (Compound No. 94) [See Scheme 30]

Dissolve 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (0.3 g) in CH ₂ Cl ₂ (10 mL) and then m- CPBA (0.4 g) Was added and stirred at room temperature for 2 hours. The reaction was washed with saturated aqueous NaHCO ₃ (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in THF (20 mL) and 0 Cyclohexanol (1 g) and potassium t- butoxide (0.2 g) were added at < RTI ID = 0.0 > The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was diluted with water (30 mL) and neutralized with 1N HCl aqueous solution. The neutralized reaction was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to give 2-cyclohexyloxy-7-ethoxy-5-hydroxy-6-methoxy-chromen-4-one (0.1 g, 41%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.85 (s, 1H), 6.36 (s, 1H), 5.44 (s, 1H), 4.56-4.47 (m, 1H), 4.12 (quartet, J = 6.9 Hz, 2H), 3.89 (s, 3H), 2.04-1.99 (m, 2H), 1.90-1.75 (m, 2H), 1.49 (t, J = 6.9 Hz, 3H), 1.72-1.37 (m, 6H)

Example 86. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 95) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.64 (s, 1H), 7.10 (d, J = 9.3 Hz, 2H), 6.96 (d, J = 9.3 Hz, 2H), 6.42 (s, 1H), 5.24 (s, 1H), 4.63 (septet, J = 6.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 1.43 (d, J = 6.0 Hz, 6H)

Example 87. Synthesis of 2-cyclohexyloxy-5-hydroxy-7-isopropoxy-6-methoxy-chromen-4-one (Compound No. 96) [See Scheme 30]

Obtained by the method of Example 85 using i- PrBr and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.84 (s, 1H), 6.37 (s, 1H), 5.43 (s, 1H), 4.60 (septet, J = 6.0Hz, 1H), 4.54-4.48 (m, 1H), 3.86 (s, 3H), 2.04-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.41 (d, J = 6.0 Hz, 6H), 1.75-1.33 (m, 6H)

Example 88. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 97) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-methoxyphenol.

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 12.69 (s, 1H), 7.46-7.34 (m, 5H), 7.09 (d, J = 9.3Hz, 2H), 6.95 (d, J = 9.3, 2H), 6.46 (s, 1H), 5.23 (s, 1H), 5.21 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H)

Example 89. Synthesis of 7-benzyloxy-2-cyclohexyloxy-5-hydroxy-6-methoxy-chromen-4-one (Compound No. 98) [See Scheme 30]

Obtained by the method of Example 85 using BnBr and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.44-7.31 (m, 5H), 6.40 (s, 1H), 5.43 (s, 1H), 5.19 (s, 2H), 4.52- 4.46 (m. 1H), 3.92 (2, 3H), 2.10-1.98 (m, 2H), 1.90-1.75 (m, 2H), 1.69-1.32 (m, 6H)

Example 90. of 7- (4-Fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 99) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-methoxyphenol.                     

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.70 (s, 1H), 7.42 (dd, J ₁ = 8.1 Hz, J ₂ = 5.1 Hz, 2H), 7.12-7.06 (m, 4H), 6.95 (d, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.24 (s, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H)

Example 91. Synthesis of 2-cyclohexyloxy-7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 100) See Scheme 30 ]

Obtained by the method of Example 85 using 4-fluorobenzyl bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.90 (s, 1 H), 7.41 (dd, J ₁ = 8.4 Hz, J ₂ = 5.4 Hz, 2H), 7.08 (t, J = 8,4 Hz, 2H), 6.38 (s, 1H), 5.43 (s, 1H), 5.14 (s, 2H), 4.54-4.45 (m, 1H), 3.90 (s, 3H), 2.04-1.99 (m, 2H), 1.90-1.75 ( m, 2H), 1.70-1.33 (m, 6H)

Example 92. 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one Synthesis of (Compound No. 101) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.66 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz , 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 5.25 (s, 1H), 4.22 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H)

Example 93. 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one (Compound No. 102) Synthesis of compounds [see Scheme 30]

Obtained by the method of Example 85 using 4-methoxyphenethyl bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.86 (s, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.34 (s, 1H), 5.43 (s, 1H), 4.54-4.48 (m, 1H), 4.20 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.11 (t, J = 7.2 Hz, 2H), 2.02-1.98 (m, 2H), 1.95-1.75 (m, 2H), 1.70-1.39 (m, 6H)

Example 94. Synthesis of 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 103) Reaction Scheme 26

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.75 (s, 1H), 8.65 (d, J = 5.4 Hz, 2H), 7.38 (d, J = 5.4 Hz, 2H), 7.09 (d, J = 9.0 Hz , 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.39 (s, 1H), 5.25 (s, 1H), 5.22 (s, 2H), 3.96 (s, 3H), 3.84 (s, 3H)

Example 95. Synthesis of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 104) [See Scheme 31]

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.95 (s, 1H), 8.64 (d, J = 5.4 Hz, 2H), 7.36 (d, J = 5.4 Hz, 2H), 6.32 (s, 1H), 5.44 (s, 1H), 5.21 (s, 2H), 4.54-4.45 (m, 1H), 3.95 (s, 3H), 2.04-1.98 (m, 2H), 1.90-1.75 (m, 2H), 1.70-1.33 (m, 6H)

Example 96. 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (2-piperidin-1-yl-ethoxy) -chromen-4-one ( Synthesis of Compound No. 105) [See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.67 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.60-2.50 (br s , 4H), 1.7-1.45 (m, 6H)

Example 97. of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one (Compound No. 106) Synthesis [See Scheme 31]

Obtained by the method of Example 95 using 1- (2-chloroethyl) piperidine hydrogen chloride and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 6.39 (s, 1H), 5.44 (s, 1H), 4.56-4.48 (m, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.85 (t, J = 6.0 Hz, 2H), 2.60-2.50 (br s, 4H), 2.10-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.30 (m, 12H)

Example 98. 5-Hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (compound Synthesis of No. 107) [See Scheme 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.68 (s, 1H), 7.11 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.43 (s, 1H), 5.26 (s, 1H), 4.20 (t, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73 (t, J = 4.8 Hz, 4H), 2.88 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.8 Hz, 4H)

Example 99. Synthesis of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (Compound No. 108) Reaction Scheme 31                     

Obtained by the method of Example 95 using 4- (2-chloroethyl) morpholine hydrogen chloride and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 6.38 (s, 1H), 5.44 (s, 1H), 4.55-4.49 (m, 1H), 4.19 (t, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.73 (t, J = 4.5 Hz, 4H), 2.87 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 4.5 Hz, 4H), 2.10-1.95 ( m, 2H), 1.90-1.75 (m, 2H), 1.75-1.33 (m, 6H)

Example 100. of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 109) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 3-bromo-1-propanol and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.69 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.45 (s, 1H), 5.26 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.93 (t, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.13 (quintet, J = 5.7 Hz, 2H), 1.92 (t, J = 2.1 Hz, 1H)

Example 101. Synthesis of 2-cyclohexyloxy-5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-chromen-4-one (Compound No. 110) [See Scheme 32] ]

Obtained by the method of Example 7, 58, 67 using 3-bromo-1-propanol and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 6.40 (s, 1H), 5.44 (s, 1H), 4.55-4.48 (m, 1H), 4.21 (t, J = 6.0Hz, 2H), 3.88 (s, 3H), 3.88 (t, J = 6.0 Hz, 2H), 2.16-2.08 (m, 2H), 2.08-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.75 -1.33 (m, 6H)

Example 102. [5-Hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -4-oxo-4H-chromen-7-yloxy] -acetic acid ethyl ester (Compound No. 111) Synthesis of compounds [see Scheme 21]

Obtained by the method of Example 58 using bromo ethyl acetate and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.75 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.33 (s, 1H), 5.25 (s, 1H), 4.76 (s, 2H), 4.28 (quartet, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H)

Example 103. Synthesis of (2-cyclohexyloxy-5-hydroxy-6-methoxy-4-oxo-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 112) Reference]

Obtained by the method of Example 7, 58, 67 using bromo ethyl acetate and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.95 (s, 1H), 6.28 (s, 1H), 5.45 (s, 1H), 4.74 (s, 2H), 4.55-4.48 (m, 1H), 4.24 ( quartet, J = 6.9 Hz, 2H), 3.94 (s, 3H), 2.10-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.33 (m, 6H), 1.30 (t, J = 6.9 Hz, 3H)

Example 104. Synthesis of 7-ethoxy-2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 113) [See Scheme 21]

Obtained by the method of Example 58 using EtBr and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.58 (s, 1H), 7.16 (d, J = 5.7 Hz, 4H), 6.41 (s, 1H), 5.27 (s, 1H), 4.14 (quartet, J = 6.9 Hz, 2H), 3.89 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H)

Example 105. Synthesis of 2- (4-fluoro-phenoxy) -5-hydroxy-7-isopropoxy-6-methoxy-chromen-4-one (Compound No. 114) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.57 (s, 1H), 7.16 (d, J = 6.0 Hz, 4H), 6.41 (s, 1H), 5.26 (s, 1H), 4.63 (septet, J = 6.0 Hz, 1H), 3.87 (s, 3H), 1.42 (d, J = 6.3 Hz, 6H)

Example 106. Synthesis of 7-benzyloxy-2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 115) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-fluorophenol.                     

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.61 (s, 1H), 7.33-7.46 (m, 5H), 7.15 (d, J = 6.0Hz, 4H), 6.46 (s, 1H), 5.25 (s, 1H), 5.21 (s, 2H), 3.93 (s, 3H)

Example 107. of 7- (4-Fluoro-benzyloxy) -2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 116) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.62 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 5.7 Hz , 4H), 7.09 (t, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 1H), 5.16 (s, 2H), 3.91 (s, 3H)

Example 108. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one Synthesis of (Compound No. 117) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.57 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 6.0 Hz, 4H), 6.86 (d, J = 8.4 Hz , 2H), 6.38 (s, 1H), 5.27 (s, 1H), 4.21 (t, J = 7.2Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.12 (t, J = 7.2 Hz, 2H)

Example 109. Synthesis of 2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 118) Reaction Scheme 26

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.68 (s, 1H), 8.65 (d, J = 5.7 Hz, 2H), 7.37 (d, J = 5.7 Hz, 2H), 7.16 (d, J = 6.3 Hz , 4H), 6.38 (s, 1H), 5.27 (s, 1H), 5.22 (s, 2H), 3.95 (s, 3H)

Example 110. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one ( Synthesis of Compound No. 119) [See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.59 (s, 1H) 7.17 (d, J = 6 Hz, 4H), 6.44 (s, 1H), 5.27 (s, 1H), 4.21 (br t, J = 6 Hz , 2H), 3.88 (s, 3H), 2.86 (br t, J = 5.4 Hz, 2H), 2.55 (br s, 4H), 1.60 (br s, 4H), 1.47 (br d, J = 4.8 Hz, 2H)

Example 111. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (compound Synthesis of number 120) [see Scheme 26]                     

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.60 (s, 1H), 7.17 (d, J = 6Hz, 4H), 6.43 (s, 1H), 5.28 (s, 1H), 4.20 (t, J = 6Hz , 2H), 3.88 (s, 3H), 3.73 (br t, J = 4.5Hz, 4H), 2.88 (t, J = 5.4Hz, 2H), 2.61 (br t, J = 4.5Hz, 4H)

Example 112. of 2- (4-Fluoro-phenoxy) -5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-chromen-4-one (Compound No. 121) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 3-bromo-1-propanol and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 2.60 (s, 1H) 7.17 (d, J = 6Hz, 4H), 6.43 (s, 1H), 5.27 (s, 1H), 4.22 (t, J = 6Hz, 2H), 3.88 (s, 5H), 2.13 (quintet, J = 6 Hz, 2H), 2.00 (br s, 1H)

Example 113. [2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-4-oxo-4H-chromen-7-yloxy] -acetic acid ethyl ester (Compound No. 122) Synthesis of compounds [see Scheme 21]

Obtained by the method of Example 58 using bromo ethyl acetate and 4-fluorophenol.                     

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.67 (s, 1H), 7.16 (d, J = 6Hz, 4H), 6.32 (s, 1H), 5.27 (s, 1H), 4.76 (s, 2H), 4.28 (quartet, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H)

Example 114. Synthesis of 8-chloro-5-hydroxy-7-isopropoxy-2-phenoxy-chromen-4-one (Compound No. 123) [See Scheme 33]

5-Hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (0.5 g) was dissolved in chloroform (20 mL), followed by 0 1.0 N sulfanyl chloride / dichloromethane (5 mL) was added thereto, followed by stirring for 1 hour. Saturated NaHCO ₃ aqueous solution (20 mL) was added to the reaction to terminate the reaction, followed by extraction with chloroform (30 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to 8-chloro-5-hydroxy-7-isopropoxy-2-methylsulpa. Neyl-chromen-4-one (0.4 g, 74%) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.77 (s, 1H), 7.47 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.38-7.21 (m, 3H), 6.44 (s, 1H), 5.29 (s, 1H), 4.67 (septet, J = 6.0 Hz, 1H), 1.43 (d, J = 6.0 Hz, 6H)

Example 115. Synthesis of 8-chloro-5-hydroxy-7-isopropoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 124) [See Scheme 33]

Obtained by the method of Example 114 using i- PrBr and 4-hydroxypyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.33 (s, 1H), 7.94 (d, J = 5.4 Hz, 2H), 6.54 (d, J = 5.4 Hz, 2H), 6.49 (s, 1H), 6.17 (s, 1H), 4.71 (septet, J = 6 Hz, 1H), 1.46 (d, J = 6.3 Hz, 6H)

Example 116. Synthesis of 8-chloro-5-hydroxy-7- (3-hydroxy-propoxy) -2-phenoxy-chromen-4-one (Compound No. 125) [See Scheme 33]

Obtained by the method of Example 114 using 3-bromo-1-propanol and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.92 (s, 1H), 7.57 (dd, J ₁ , J ₂ = 7.2 Hz, 2H), 7.46-7.40 (m, 3H), 6.71 (s, 1H ), 5.25 (s, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.59 (td, J ₁ = 6.0 Hz, J ₂ = 4.8 Hz, 2H ), 1.91 (tt, J ₁ , J ₂ = 6.0 Hz, 2H)

Example 117. Synthesis of (8-chloro-5-hydroxy-4-oxo-2-phenoxy-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 126) [See Scheme 33]

Obtained by the method of Example 114 using bromo ethyl acetate and phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.83 (s, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.8 Hz , 2H), 6.31 (s, 1H), 5.32 (s, 1H), 4.76 (s, 2H), 4.29 (quartet, J = 7.2Hz, 2H), 1.32 (t, J = 7.2Hz, 3H)

Example 118. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 127) [ See Scheme 30]

Obtained by the method of Example 85 using EtBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.79 (s, 1H), 6.36 (s, 1H), 5.44 (s, 1H), 4.58 (quintet, J = 3.9 Hz, 1H), 4.12 (quartet, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.68 to 2.70 (m, 2H), 2.35 (s, 5H), 2.04 to 2.12 (m, 2H), 1.89 to 2.00 (m, 2H), 1.49 (t , J = 7.2 Hz, 3H)

Example 119. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 128) Reaction Scheme 30

Obtained by the method of Example 85 using i- PrBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.78 (s, 1H), 6.37 (s, 1H), 5.44 (s, 1H), 4.60 (quintet, J = 6Hz, 2H), 3.86 (s, 3H), 2.65 to 2.71 (m, 2H), 2.33 (s, 5H), 2.05 to 2.10 (m, 2H), 1.92 to 2.01 (m, 2H), 1.41 (d, J = 6 Hz, 6H)

Example 120 Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 129) [ See Scheme 30]

Obtained by the method of Example 85 using BnBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 13.05 (s, 1H), 7.90 to 7.87 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.53 to 7.36 (m, 3H), 6.86 ( s, 1H), 5.23 (s, 2H), 4.80 (quintet, J = 3.6 Hz, 1H), 3.72 (s, 3H), 2.61-2.51 (m, 2H), 2.34 (br t, J = 8.4 Hz, 2H), 2.23 (s, 3H), 2.05-1.95 (m, 2H), 1.82-1.75 (m, 2H)

Example 121. 7- (4-Fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one ( Synthesis of Compound No. 130) [See Scheme 30]

Obtained by the method of Example 85 using 4-fluorobenzyl bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.84 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.08 (t, J = 8.7 Hz , 2H), 6.39 (s, 1H), 5.44 (s, 1H), 5.14 (s, 2H), 4.55 (quintet, J = 3.6Hz, 1H), 3.90 (s, 3H), 2.65 ~ 2.70 (m, 2H), 2.32 (s, 5H), 2.04-2.11 (m, 2H), 1.89-1.99 (m, 2H)

Example 122 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2- (1-methyl-piperidin-4-yloxy) -cro Synthesis of Menth-4-one (Compound No. 131) [See Scheme 30]

Obtained by the method of Example 85 using 4-methoxyphenethyl bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.79 (s, 1H), 7.22 (d, J = 9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.35 (s, 1H), 5.44 ( s, 1H), 4.57 (quintet, J = 3.3 Hz, 1H), 4.20 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H), 2.70 (br s, 2H), 2.33 (s, 5H), 2.03-2.17 (m, 2H), 1.90-1.99 (m, 3H)

Example 123. 5-Hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -7- (pyridin-4-ylmethoxy) -chromen-4-one (compound Synthesis of No. 132) [See Scheme 31]

Obtained by the method of Example 95 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.89 (s, 1H), 8.64 (d, J = 5.7 Hz, 2H), 7.35 (d, J = 5.7 Hz, 2H), 6.32 (s, 1H), 5.45 (s, 1H), 5.21 (s, 1H), 4.56 (br s, 2H), 3.95 (s, 3H), 2.69 (br s, 2H), 2.33 (s, 5H), 2.01-2.15 (m, 2H ), 1.91-1.99 (m, 2H)

Example 124. Acetic acid 7-acetoxy-8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenyl-4H-chromen-5-yl ester (Compound No. 133) Synthesis of [see Scheme 34]

Prenyl bromide (2.5 mL) was added to a suspension of DMF (70 mL) of Oroxylin A (4 g), K ₂ CO ₃ (5.8 g), and TBAI (520 mg), followed by stirring for 1 hour 30 minutes. The reaction suspension was diluted in H ₂ O (30 mL) and acidified with saturated aqueous NH ₄ Cl solution. The solution was extracted with EtOAc (200 mL), the organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and the residue obtained by distillation under reduced pressure was purified by MPLC (20% EtOAc / Hexane) to give 5-hydroxy. -6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (3.6 g, 73%) was obtained.

Ac ₂ to a mixture of 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (800 mg), NaOAc (427 mg) O (32 mL) was added and stirred at reflux for 24 hours. The reaction solution was cooled to room temperature and the reaction was stopped by addition of saturated NaHCO ₃ solution. The resulting solution was extracted with EA (200 mL), washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 5-acetoxy-8 acetate. -(1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (630 mg, 85%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 6H), 2.31 (s, 3H), 2.50 (s, 3H), 3.85 (s, 3H), 4.93-5.00 (m, 2H), 6.33 ( dd, J = 10.7 Hz, 17.6 Hz, 1H), 6.62 (s, 1H), 7.49-7.55 (m, 3H), 7.84-7.87 (m, 2H)

Example 125. Acetic Acid 8- (1,1-Dimethyl-allyl) -5-hydroxy-6-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (Compound No. 134) Synthesis of [see Scheme 34]

Compound No. 133 (300 mg) was dissolved in THF / MeOH 1: 1 solution (15 mL), 8M HCl solution (10 mL) was added, and the mixture was stirred overnight. The reaction solution was extracted with EtOAc, washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered and distilled under reduced pressure. The obtained residue was purified by MPLC (1% MeOH / CH ₂ Cl ₂ ) to acetic acid 8- (1,1-dimethyl-allyl) -5-hydroxy-6-methoxy-4-oxo-2-phenyl-4H-chrome Men-7-yl ester (225 mg, 83%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65 (s. 6H), 2.30 (s, 3H), 4.92-4.98 (m, 2H), 6.29 (dd, J ₁ = 10.7 Hz, J ₂ = 17.6 Hz, 1H), 6.71 (s, 1H), 7.50-7.57 (m, 3H), 7.89-7.91 (m, 2H), 13.27 (s, 1H)

Example 126. Synthesis of 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-one (Compound No. 135) [Scheme 34 Reference]

To a compound No. 133 (300 mg) was added 1: 1 solution (27 mL) of 1M NaOH aqueous solution and EtOH and stirred overnight. The reaction solution was quenched by the addition of 1M aqueous HCl solution and extracted with EtOAc. The obtained organic layer was washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was subjected to MPLC (1% MeOH / CH ₂ Cl ₂ ) to 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4- Warm (161 mg, 66%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70 (s, 6H), 4.06 (s, 3H), 4.92 (s, 2H), 4.97 (d, J = 7.8 Hz, 2H), 6.32 (dd, J ₁ = 10.7 Hz, J ₂ = 17.6 Hz, 1H), 6.64 (s, 1H), 7.04 (s, 1H), 7.48-7.55 (m, 3H), 7.88-7.91 (m, 2H), 13.41 (s, 1H) )

Example 127. 5-Hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-puro [2,3-h] chromen-4-one (Compound No. 136) Synthesis [See Scheme 34]

Add MeOH (14 mL) to Compound 133 (300 mg) and NaOH (274 mg) in 60 The reaction was overnight at ° C. After cooling to room temperature, the reaction was stopped by adding 1M aqueous HCl solution, and the organic layer obtained by extraction with EtOAc was washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was purified by MPLC (1% MeOH / CH ₂ Cl ₂ ) to 5-hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-puro [2,3- h] chromen-4-one (225 mg, 93%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.34 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.61 (s, 3H), 3.99 (s, 3H), 4.60 (q, J = 6.6 Hz, 1H), 6.34 (s, 1H), 7.52-7.56 (m, 3H), 7.84- 7.87 (m, 2H), 13.08 (s, 1H)

Example 128 Synthesis of 5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen-4-one (Compound No. 137) 34]

5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (600 mg) and toluene (34 mL) obtained in Example 124 Florisil (6 g) was added to a clear solution of and refluxed and stirred for 22 hours. The reaction solution was cooled to room temperature, diluted with 10% MeOH / CH ₂ Cl ₂ (30 mL), filtered and washed with 10% MeOH / CH ₂ Cl ₂ . The solvent of the obtained solution was distilled under reduced pressure, and the obtained residue was recrystallized from Hexane / EtOAc to give 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen. 4-one (130 mg, 22%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71 (s, 3H), 1.83 (s, 3H), 3.58 (d, J = 6.6 Hz, 2H), 4.05 (s, 3H), 5.27-5.31 (m, 1H), 6.6 (s, 1H), 6.67 (s, 1H), 7.49-7.56 (m. 3H), 7.88-7.91 (m, 2H), 12.93 (s, 1H)

Example 129. Synthesis of 5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy-chromen-4-one (Compound No. 138) [ See Scheme 35]

5-hydroxy-6-methoxy-7- (3-methyl obtained by the method of Example 124 using 5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one Toluene (30 mL) was added to a mixture of but-2-enyloxy) -2-phenoxy-chromen-4-one (500 mg) and Florisil (5 g), and the mixture was refluxed and stirred overnight. . The reaction solution was diluted with EtOAc (60 mL) and filtered. The resulting solution was distilled under reduced pressure and MPLC (1.5% MeOH / CH ₂ Cl ₂ ) to give 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy- Cromen-4-one (201 mg, 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 3H), 1.73 (s, 3H), 3.38 (d, J = 7.2 Hz, 2H), 4.02 (s, 3H), 5.14-5.19 (m, 1H), 5.32 (s, 1H), 6.53 (s, 3H), 7.18-7.21 (m, 2H), 7.31-7.36 (m, 1H), 7.44-7.49 (m, 1H)

Example 130. Acetic acid 5-acetoxy-8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yl ester (Compound No. 139) ) Synthesis [see Scheme 35]

Ac in a mixture of 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenoxy-chromen-4-one (400 mg), NaOAc (356 mg) ₂ O (20 mL) was added and refluxed and stirred for 24 hours. The reaction was cooled to room temperature and the reaction was stopped by addition of saturated aqueous NaHCO ₃ solution. The resulting solution was extracted with EtOAc (100 mL), washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. -8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yl ester (466 mg, 95%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.54 (s, 6H), 2.28 (s, 3H), 2.43 (s, 3H), 3.82 (s, 3H), 4.88-4.97 (m, 2H), 5.36 ( s, 1H), 6.16 (dd, J ₁ = 10.5 Hz, J ₂ = 17.1 Hz, 1H), 7.15-7.18 (m, 2H), 7.29-7.34 (m, 2H), 7.42-7.47 (m, 2H)

Example 131. Synthesis of 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 140) 35]

Dissolve 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenoxy-chromen-4-one (507 mg) in DMF (20 mL) and NaOMe Divided 70mg slowly two times and stirred for 5 hours. The reaction solution was quenched by adding 1M aqueous HCl solution and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was subjected to MPLC (MeOH / CH ₂ Cl ₂ ) to 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (160 mg, 39%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 3H), 1.73 (s, 3H), 3.38 (d, J = 7.2 Hz, 2H), 4.01 (s, 3H), 5.14-5.19 (m, 1H), 5.32 (s, 1H), 6.53 (s, 1H), 7.18-7.20 (m. 2H), 7.31-7.36 (m, 2H), 7.44-7.49 (m, 2H), 12.92 (s, 1H)

Example 132. Synthesis of 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chromen-4-one (Compound No. 141) [ See Scheme 34]                     

5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen-4-one (250 mg, 0.71 mmol) obtained by the method of Example 128 DDQ (214 mg, 0.92 mmol) was added to a benzene (20 mL) solution, and refluxed overnight. After cooling to room temperature the reaction was filtered. The filtrate was concentrated under reduced pressure and purified by MPLC (5% EtOAc / CHCl ₃ ) to give 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chrome. Men-4-one (115 mg, 46%) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.89 ~ 7.86 (m, 2H), 7.57 ~ 7.52 (m, 3H), 6.83 (d, J = 9.9Hz, 1H), 6.65 ( s, 1H), 5.65 (d, J = 9.9 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 6H)

Example 133. Synthesis of 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenoxy-8H-pyrano [2,3-f] chromen-4-one (Compound No. 142) Reaction Scheme 35

 Obtained by the method of Example 132 using 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy-chromen-4-one.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.8 Hz , 2H), 6.60 (d, J = 9.9 Hz, 1H), 5.60 (d, J = 10.2 Hz, 1H), 5.27 (s, 1H), 3.89 (s, 3H), 1.52 (s, 6H)

On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Tablet

Tablets for oral administration were prepared using the wet granulation method and the dry granulation method with the following composition using the compound of the present invention.

[Furtherance]

200 mg of active compound, 10 mg of hard silicic anhydride, 2 mg of magnesium stearate, 50 mg of microcrystalline cellulose, 25 mg of sodium starch glycolate, 113 mg of corn starch, proper amount of ethanol anhydride.

Preparation Example 2 Preparation of Ointment

Using the compound of the present invention was prepared an ointment with the following composition.

[Furtherance]

Active compound 5 g, cetyl palmitate 20 g, cetanol 40 g, stearyl alcohol 40 g, myristan isopropyl 80 g, monostearic acid sorbitan 20 g, polysorbate 60 g, paraoxybenzoic acid propyl 1 g, para 1 g of methyl oxyanate, phosphoric acid and purified water

Preparation Example 3 Preparation of Injection

Injections were prepared using the compounds of the present invention in the following compositions.

[Furtherance]

Active Compound 100 mg, mannitol 180 mg, sodium dihydrogen phosphate 25 mg, water for injection 2974 mg

Experimental Example 1. Analysis of glucose absorption

C2C12 cells, muscle cells, were cultured in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% bovine serum albumin (BSA). Three days after the cell culture was replaced with a culture solution containing 2% fetal bovine serum (FBS: Fetal Bovine Serum) was used for the experiment when cells were differentiated more than 85% by inducing cell differentiation for 6 days. After fully differentiating the cells, samples of the indicated concentrations were added to the cell culture and incubated for a while, and then washed twice with HBS (HEPES buffered saline, pH 7.4) to remove glucose present in the medium. Addition of 2-deoxy-glucose ^{(3.2 μCi / nmol) [3} H] to each well, and then allowed to stand for 10 minutes to remove the HBS buffer and stop the reaction by the addition of cold PBS. After washing twice with cold PBS, cells were lysed by adding Cell lysis buffer (1% SDS, 0.2N NaOH), and radioactivity was measured using a liquid radiometer.

Table 2 below shows the increased glucose uptake based on the control for each test compound.                     

Compound number Glucose absorption (fold) Compound number Glucose absorption (fold) 50 μm 100 μm 50 μm 100 μm One 1.62 1.78 31 0.03 0.03 2 1.15 ^a 1.01 ^{a, b} 32 0.54 3 1.90 0.10 33 0.90 0.85 4 2.02 ^a 1.18 ^{a, b} 34 2.19 1.29 5 0.56 ^a 0.47 ^{a, b} 35 0.93 0.85 6 0.53 ^a 0.54 ^{a, b} 36 0.82 1.01 7 1.33 ^a 1.24 ^{a, b} 37 1.18 0.05 8 0.82 ^a 0.87 ^{a, b} 38 1.01 1.01 9 1.38 1.94 39 0.99 0.81 10 0.92 ^a 0.91 ^{a, b} 40 1.12 0.77 11 0.64 0.10 41 0.10 0.15 12 0.87 ^a 0.73 ^{a, b} 42 1.04 0.99 13 0.85 1.30 43 1.15 0.86 14 0.43 0.03 44 1.12 0.43 15 0.93 2.00 45 Prodrug 16 1.43 0.03 46 Prodrug 17 0.92 1.73 47 Prodrug 18 0.75 0.60 48 Prodrug 19 0.85 1.68 49 Prodrug 20 0.50 0.38 50 Prodrug 21 0.81 0.85 51 Prodrug 22 0.66 1.18 52 Prodrug 23 1.23 1.53 53 Prodrug 24 1.03 1.10 54 Prodrug 25 1.25 2.99 55 1.27 1.18 26 0.95 0.78 56 Metabolite 27 0.94 1.20 57 1.16 28 0.85 0.53 58 1.73 29 0.88 0.53 59 1.68 30 0.68 0.55 60 1.52

Compound number Glucose absorption (fold) Compound number Glucose absorption (fold) 50 μm 100 μm 50 μm 100 μm 61 1.05 0.02 96 1.23 0.54 62 0.95 0.48 97 1.10 0.60 63 0.86 1.08 98 0.93 1.08 64 0.89 0.95 99 0.75 0.72 65 1.59 1.52 100 0.68 0.60 66 0.98 0.59 101 0.65 0.66 67 0.91 0.85 102 0.91 1.03 68 1.55 0.70 103 0.94 0.95 69 0.66 0.86 104 0.88 0.66 70 1.30 2.14 105 0.68 0.64 71 0.64 1.00 106 0.86 0.82 72 1.77 0.00 107 0.75 0.45 73 0.77 0.89 108 1.49 1.60 74 0.98 1.61 109 0.57 0.57 75 0.52 0.93 110 1.25 1.36 76 1.05 1.23 111 0.68 0.62 77 1.52 1.05 112 0.84 0.91 78 0.96 0.61 113 1.21 0.94 79 1.27 0.91 114 0.86 0.72 80 2.30 2.08 115 1.00 0.68 81 0.95 0.84 116 0.83 0.66 82 2.43 0.73 117 0.84 0.59 83 1.16 0.91 118 0.84 1.02 84 1.29 0.47 119 0.70 0.61 85 1.14 0.76 120 0.68 0.72 86 1.57 1.01 121 0.77 0.75 87 1.01 0.62 122 0.72 0.74 88 0.94 2.61 123 0.80 0.72 89 1.14 0.84 124 1.71 0.02 90 2.28 1.92 125 0.51 0.75 91 0.76 0.63 126 0.81 0.99 92 0.89 0.05 127 0.86 0.70 93 0.79 0.51 128 0.95 0.82 94 0.66 0.45 129 0.86 0.27 95 0.64 0.49 130 0.86 0.51

Compound number Glucose absorption (fold) Compound number Glucose absorption (fold) 50 μm 100 μm 50 μm 100 μm 131 1.03 0.00 137 1.12 0.98 132 0.79 0.60 138 0.98 1.20 133 1.20 1.02 139 0.85 1.24 134 1.00 0.85 140 1.10 0.85 135 1.29 0.77 141 0.88 0.68 136 0.76 0.22 142 0.76 0.24 * (+)-Control: Rosiglitazone,
Glucose absorption increased 1.7 ~ 3.0 times (100 mm)
L6 muscle cells: cultured for 22 ~ 24 hours
a: 4 hours incubation
b: 75 mm

As described above, the compound represented by the formula (1) according to the present invention is excellent as a hypoglycemic effect is useful as a diabetes treatment.

Claims (7)

Chromium-4-one derivative represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof: [Formula 1]

In Chemical Formula 1, X represents an oxygen atom (O), R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarbonate and aminoC ₁ -C ₆ alkylcarbonate group; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups, R ₂ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group, R ₃ is a hydrogen atom; Hydroxy; C ₁ -C ₆ alkoxy group; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; Halogen atom; Hydroxyl group; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; Ethyl acetate group; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; A benzylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups; PyridinylC ₁ -C ₆ alkoxy group; Oxypyridinylmethoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group. R ₆ is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; Or a C ₂ -C ₆ alkenyl group, Or R ₅ and R ₆ combine with each other to form a 5-7 membered hetero ring containing an oxygen atom. Chromen-4-one derivatives represented by the following formula (1), pharmaceutically acceptable salts, hydrates, solvates or isomers containing diabetes is preventive agent containing: [Formula 1]

In Formula 1, X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each as defined in claim 1 above. Chromium-4-one derivatives represented by the following formula (1), pharmaceutically acceptable salts, hydrates, solvates, or isomers containing obesity: [Formula 1]

In Formula 1, X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are each as defined in claim 1 above. 4. A medicament according to claim 2 or 3, formulated in a form suitable for oral, subcutaneous, intramuscular, intravenous, transdermal, intranasal or rectal administration. 5. A medicament according to claim 4, formulated as a tablet, ointment or injection. The method of claim 1, X represents an oxygen atom (O), R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups, R ₂ represents a hydrogen atom, R ₃ is hydroxy; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; Ethyl acetate group; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups; PyridinylC ₁ -C ₆ alkoxy group; Oxypyridinylmethoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Or a C ₂ -C ₆ alkenyl group, Or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered hetero ring containing an oxygen atom. The method of claim 1, X represents an oxygen atom (O); R ₁ represents a cyclohexyl group, a phenyl group, a hydroxyphenyl group, a fluorophenyl group, a toluene group, a methoxyphenyl group, an ethoxyphenyl group, a pyridine group, a piperidine group, or a methylpiperidine group; R ₂ represents a hydrogen atom; R ₃ represents a hydroxy group, a methyl carbonate group or an ethyl carbonate group; R ₄ represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group, or an ethoxy group; R ₅ is a hydroxy group, methyl group, ethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, benzyl group, methoxybenzyloxy group, ethoxybenzyloxy group, methyl carbonate group, ethyl carbonate group , Hydroxymethoxy group, hydroxyethoxy group, hydroxypropoxy group, hydroxybutoxy group, ethyl acetate group, pyridinylmethoxy, pyridinylethoxy, oxypyridinylmethoxy, oxypyridinylethoxy Piperidinylmethoxy, piperidinylethoxy, piperidinylpropoxy, morpholinylmethoxy or morpholinylethoxy; R ₆ represents a hydrogen atom, 3-methyl-but-2-enyl, or 1,1-dimethylallyl; Or R ₅ and R ₆ are bonded to each other to form a 5- or 6-membered hetero ring containing an oxygen atom.