NEW DERIVATE COMPOUND OF (S)-7-HYDROXY-8,8-DIMETHOXY-7,8-DIHYDRO-2H,6H-PYRANO[3,2,-g]CROMEN-2-ON AND PREPARING METHOD THEREOF

Abstract

The present invention relates to a novel derivative compound represented by Formula 1 and a method for preparing the same, for improving the pharmacological properties of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compounds.

Description

Technology Field

[0001] The present invention relates to a novel derivative compound for improving the pharmacological properties of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compounds and a method for preparing the same. Background Technology

[0003] (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one (Decursinol) was first isolated from *Angelica decursiva* (Fr. et Sav.) and its structure was confirmed by the Heita & Sano group at Kyoto University in 1966 (Tetrahedron Letters No.14, pp. 1461-1463, 1966). In addition, Decursinol is a precursor of Decursin and Decursinol angelate, which are dihydropyranocoumarin derivatives reported to be extracted from Angelica gigas nakai, a plant of the Umbelliferae family (J. Pharm. Soc. Korea, 11, 22–26, 1967 and 13, 47–50, 1969). A method of obtaining Decursin and Decursinol angelate by extracting them from Angelica root powder with alcohol and hydrolyzing them under basic conditions has been disclosed in Korean Registered Patent No. 10-0397950.

[0004] In Northeast Asia, including China, Japan, and Korea, pharmacologically useful components have long been extracted from the young leaves or roots of plants and used as medicinal materials for treating various diseases, such as pain relief, nephrotoxicity reduction, and diabetic hypertension (J.Pharmacogn., 1, pp.25, 1970). With the advancement of science and technology, pharmacological activity studies on decursin and decursinol angelate extracted from Angelica gigas have been conducted, and they have been identified as pharmacologically active substances effective for various diseases. Decursin has been reported to inhibit IL-8, MCP-1, and TNF-α, which are cytokines that induce inflammation, by inhibiting NF-kB in macrophages, which are cells that mediate inflammation (Mol. Pharmacology, 69(6), pp1783-1790, 2006), and has been reported to inhibit the differentiation of prostate cancer cell lines independently of androgens by promoting β-catenin degradation (Mol. Pharmacol. 2007, 72(6), 1599-1606.).

[0005] In addition, as a PKC activator, various pharmacological activities have been reported, including antagonistic effects against carcinogens, apoptotic effects on cancer cells, anti-androgen activity related to prostate cancer and inhibition of androgen receptor activity, antitumor pharmacological activities such as cytotoxicity, improvement of circulatory system diseases, inhibition of the metabolic enzyme Cytochrome P-450 (CYP 450), anti-inflammatory effects, antioxidant effects, and improvement of cognitive function (Yakhak Hoeji Vol. 53, No. 6 303~313, 2009).

[0006] In a study in which Angelica gigas nakai extracts with the pharmacological effects described above were administered orally and intravenously to mice and metabolites were evaluated, decursin and decursinol angelate were found to be converted to decursinol in major metabolic reactions (J. Microbiol. Biotechnol. 19(12) p1569-1572, 2009). In a study evaluating the pharmacokinetics of its active metabolite, decursinol, it was reported that decursin is converted to decursinol by hepatic first-pass metabolism (Planta. Med. 78(09) p909-913, 2012). This suggests that decursin is not directly associated with biological activity and may act as a natural prodrug of decursinol.

[0007] A prodrug is a compound that transforms into a drug with desired pharmacological properties within the body after administration. It refers to a drug that acquires its original pharmacological characteristics through chemical modification or enzymatic action within the body, even though the original compound is pharmacologically useful but possesses unsuitable properties regarding side effects, stability, solubility, absorption, or duration of action.

[0008] Tenofovir Disoproxil (Viread), approved by the U.S. Food and Drug Administration (FDA) in 2001 ®Tenofovir is a drug used to treat HIV-1 infection and chronic hepatitis B, and is a prodrug of tenofovir. Although pharmacologically effective, tenofovir has limited potential for use due to its low oral bioavailability and cellular permeability, which restrict its efficacy in vivo and even cause nephrotoxicity and osteotoxicity. To overcome this, various studies have been conducted, specifically focusing on various types of ester prodrugs. As a result of these studies, tenofovir diisoproxyl was developed by introducing methyl diisopropyl carboxylate to the phosphate group of tenofovir to increase oral bioavailability. It has been reported that after oral administration, this drug is absorbed into the body, rapidly converted to tenofovir, and then metabolized within cells into its active metabolite, tenofovir diphosphate, to exert its pharmacological effects (Clin. Pharmacokinet. 43 (9), 595-612, 2004).

[0009] Fosamprenavir (Lexiva), approved by the FDA in 2003 ® Amprenavir (Agenerase), a protease inhibitor and antiretroviral used as a treatment for HIV infection. ® It is a prodrug that has a structure in which a phosphate group is introduced to the hydroxyl group and is activated by a phosphatase enzyme. Due to its poor solubility in water (0.04 ml / g, at 25°C), amprenavir presents the difficulty of oral administration, requiring a dosage of 1,200 mg twice a day (24 capsules of 50 mg each), meaning 12 capsules must be taken per dose. To overcome this difficulty, its solubility in water was improved to 0.31 mg / mL (at 25°C), thereby overcoming the difficulty of administration by reducing the dosage to twice a day (2 tablets of 700 mg).

[0010] Fospropofol disodium (Lusedra), approved by the FDA in 2008 ®Propofol (Diprivan), an intravenous sedative and sleeping pill ® It is a prodrug of propofol. It has a structure in which a methyl phosphate is attached to the hydroxyl group of propofol, and after intravenous injection, it acts by being broken down into its active metabolite, propofol, by the body's alkaline phosphatase enzyme. In other words, it is a pharmacologically active substance with improved solubility to utilize the metabolite. Since propofol is insoluble in water, microemulsification is required as a formulation method for injectables. Lipid components such as soybean oil and egg lecithin are used as solubilizers for this purpose. Such microemulsified injectables must be refrigerated because there is a risk of the solubilizer separating or deterioration depending on storage conditions and time. However, phosphpropofol disodium, a prodrug structurally similar to propofol, can be converted into a pharmacologically active substance through body metabolism. This allows for improved water solubility while maintaining pharmacological effects, and it is advantageous in terms of storage and the risk of deterioration caused by auxiliary agents, as it can be simply dissolved in sterile water at a concentration of 35 mg / ml.

[0011] As described above, there is a growing need for research to develop novel derivative compounds capable of enhancing the pharmacological, physical, and chemical properties of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compounds, which possess high pharmacological specificity but are poorly soluble (insoluble) in water. Prior art literature

[0013] Republic of Korea Registered Patent No. 10-0397950

[0014] K. Hata, K. Sano ; The constitution of decursin, a new coumarin isolated from the root of fr. a saw. ( umbelliferae ) ; Tetrahedron Letters No.14, 1461-1463, 1966 (Kyung Soo Ryu), Young (Chang Soo Yook) ; Studies on the Coumarins of the Root of Angelica gigas NAKAI (I) ; J. Pharm. Soc. Korea, 11, 22∼26, 1967 (Hyung Joon Chi) ; Studies on the components of Umbelliferous plants in Korea (IV) ; J. Pharm. Soc. Korea, 13, 47∼50, 1969; 지형준 (Hyung Joon Chi) ; 한국산 산형과 식물의 성분연구 ; J.Pharmacogn., 1, 25, 1970 Jung-Hee Kim, Ji-Hye Jeong, Sung-Tak Jeon, et al. ; Decursin Inhibits Induction of Inflammatory Mediators by Blocking Nuclear Factor-B Activation in Macrophages ; Mol. Pharmacology, 69(6), 1783-1790, 2006Gyu-Yong Song, Jee-Hyun Lee ; Decursin Suppresses Human Androgen-Independent PC3 Prostate Cancer Cell Proliferation by Promoting the Degradation of β-Catenin ; Mol. Pharmacol.2007, 72(6), 1599-1606Chu-Young Son, In-Hwan Baek; Pharmacological Effect of Decursin and Decursinol Angelate from Angelica gigas Nakai ; Yakhak Hoeji Vol. 53, no. 6 303~313, 2009Kang Min Kim, Myo Jeong Kim, and Jae Seon Kang ; Absorption, Distribution, Metabolism, and Excretion of Decursin and Decursinol angelate from Angelica gigas Nakai ; J. Microbiol. Biotechnology. 19(12) 1569-1572, 2009Hyun Seo Park, Byunghyun Kim ; First-pass Metabolism of Decursin, a Bioactive Compound of Angelica gigas, in RatsPlanta. ; Med. 78(09) 909-913, 2012Brian P. Kearney, John F. Flaherty, Jaymin Shah; Tenofovir Disoproxil Fumarate ; Clin. Pharmacokinet. 43 (9), 595-612, 2004. The problem to be solved

[0015] The present invention aims to provide a novel derivative compound capable of improving the pharmacological and physical and chemical properties of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compounds, and a method for preparing the same.

[0016] The present invention is not limited to the purposes mentioned above, and other unmentioned purposes and advantages of the present invention may be understood from the following description and will be more clearly understood by the embodiments of the present invention. Furthermore, it will be readily apparent that the purposes and advantages of the present invention can be realized by the means and combinations thereof set forth in the claims. means of solving the problem

[0018] According to a first aspect of the present invention, a phosphate or phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl represented by the following chemical formula 1 may be provided.

[0019] [Chemical Formula 1]

[0020]

[0021] In the above chemical formula 1,

[0022] n is an integer of 0 or 1, and

[0023] R1 and R2 are identical or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and

[0024] The above metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of ).

[0026] According to a second aspect of the present invention, a method for preparing a phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl represented by the following chemical formula 1 can be provided.

[0027] [Chemical Formula 1]

[0028]

[0029] (In the above chemical formula 1, n is 1, and R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of )

[0030] a') A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl diethylphosphonate compound by mixing a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl methyl diethylphosphonate compound with a diethylphosphonate compound having a leaving functional group;

[0031] b') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diethyl phosphonate compound by mixing the above (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound with an alkyl (C1-C2) silyl halide compound; and

[0032] c') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate compound prepared in step b'); comprising

[0033] A manufacturing method in which the above step c') is one selected from the following steps c'-1) and c'-2):

[0034] c'-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diester phosphonate compound prepared in step b'),

[0035] c'-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound prepared in step b') above with a metal base.

[0037] According to a third aspect of the present invention, a method for preparing a phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl represented by the following chemical formula 1 can be provided.

[0038] [Chemical Formula 1]

[0039]

[0040] (In the above chemical formula 1, n is 1, and R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of )

[0041] a') A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nylmethyl diethylphosphonate compound by mixing a base with a diethylphosphonate compound having a leaving functional group on a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nylmethyl diethylphosphonate compound;

[0042] b') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diethyl phosphonate compound by mixing the above (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound with an alkyl (C1-C2) silyl halide compound; and

[0043] c') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate compound prepared in step b'); comprising

[0044] A manufacturing method in which the above step c') is one selected from the following steps c'-1) and c'-2):

[0045] c'-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diester phosphonate compound prepared in step b'),

[0046] c'-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound prepared in step b') above with a metal base. Effects of the invention

[0048] The novel compound represented by Chemical Formula 1 of the present invention can have improved physical and chemical properties, such as pharmacological properties and solubility in water, compared to decursinol, which is a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compound represented by Chemical Formula 2 below.

[0049] [Chemical Formula 2]

[0050]

[0051] According to the method for manufacturing a compound represented by Chemical Formula 1 of the present invention, a compound represented by Chemical Formula 1 can be efficiently manufactured. Specific details for implementing the invention

[0053] The aforementioned objectives, features, and advantages are described in detail below, thereby enabling those skilled in the art to easily implement the technical concept of the present invention. In describing the present invention, detailed descriptions of known technologies related to the present invention are omitted if it is determined that such descriptions would unnecessarily obscure the essence of the invention. Hereinafter, preferred embodiments according to the present invention will be described in detail. Furthermore, where it is stated that a component is "connected," "combined," or "connected" to another component, it should be understood that while the components may be directly connected or connected to each other, other components may be "interposed" between each component, or each component may be "connected," "combined," or "connected" through other components.

[0054] The “compound” referred to in the present invention includes various forms of isomers depending on the type of substituent, includes mixtures thereof, and may also include derivatives and salts thereof. The salt is a pharmaceutically acceptable salt of the compound, and depending on the type of substituent, it may form an acid addition salt or a salt with a base.

[0055] Specifically, the salt may include an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, nitric acid, or phosphoric acid, or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, or glutamic acid, an inorganic base such as sodium, potassium, magnesium, calcium, or aluminum, an organic base such as methylamine, ethylamine, ethanolamine, lysine, or ornithine, or an ammonium salt with various amino acids and amino acid derivatives such as acetyleucine.

[0056] The present invention provides a novel derivative compound represented by Formula 1, in which pharmacological, physical, and chemical properties are improved by introducing a phosphate or phosphonate derivative into the compound (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one (Formula 2), and a method for preparing the same.

[0057] A phosphate or phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl according to the present invention can be represented by the following chemical formula 1.

[0058] [Chemical Formula 1]

[0059]

[0060] In the above chemical formula 1,

[0061] n can be an integer of 0 or 1, and

[0062] R1 and R2 may be identical or different from each other and may each be independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and

[0063] The above metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It could be one of ).

[0065] According to one example of the present invention, R1 and R2 can be selected identically.

[0067] According to one example of the present invention, since the phosphate derivative compound or phosphonate derivative compound represented by Formula 1 is easily converted into a salt of an organic base and a metal ion, the phosphate or phosphonate derivative compound may exist in a salt state, for example, the salt may be a sodium salt, and the metal ion may be a sodium ion (Na + It can be.

[0068] According to one example of the present invention, the phosphate derivative compound or phosphonate derivative compound represented by Formula 1 is interpreted to include its isomers or pharmaceutically acceptable salts.

[0070] According to one example of the present invention, when n is 0, the compound represented by Formula 1 may be a phosphate derivative compound, for example,

[0071] (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate disodium,

[0072] (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromene-7-nyl phosphate,

[0073] (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dimethyl phosphate,

[0074] (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diethyl phosphate,

[0075] (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl dipivoxyl phosphate and

[0076] It may be selected from the group consisting of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl diisopropoxyl phosphate, but is not limited thereto.

[0078] According to one example of the present invention, when n is 1, the compound represented by Formula 1 may be a phosphonate derivative compound, for example,

[0079] (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl diethylphosphonate,

[0080] (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl dihydrophosphonate disodium,

[0081] (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl phosphonate,

[0082] (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl dipivoxyl phosphonate, and

[0083] It may be selected from the group consisting of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl diisoproxyl phosphonate, but is not limited thereto.

[0085] Hereinafter, a method for preparing a phosphate or phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl represented by Formula 1 of the present invention will be described.

[0087] Method for preparing a phosphate derivative of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl >

[0088] According to one embodiment of the present invention, a method for preparing a phosphate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl represented by the following chemical formula 1 can be provided, comprising the following steps a) to c).

[0089] [Chemical Formula 1]

[0090]

[0091] (In the above chemical formula 1, n is 0, and R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of ).

[0092] a) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound by mixing a phosphoryl halogenated compound and a base with a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound;

[0093] b) a step of mixing an acidic aqueous solution or a C1-C4 alkyl alcohol with the above (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound to prepare a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound or a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound; and

[0094] c) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound prepared in step b); may be included,

[0095] The above step c) may be one selected from the following steps c-1) and c-2).

[0096] c-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step b) above,

[0097] c-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound prepared in step b) above with a metal base.

[0099] In step a), a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[3,2-g]d-halogenated phosphate compound can be prepared by mixing a phosphoryl halogenated compound and a base with the (S)-7-hydroxy-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[7-nyl]d-halogenated phosphate compound prepared in step a) can be isolated or not, and the process can proceed continuously to the next step.

[0100] The starting material for the synthesis reaction in step a) is '(S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one compound', represented by the following chemical formula 2.

[0101] [Chemical Formula 2]

[0102]

[0103] According to one example of the present invention, the '(S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalophosphate compound' synthesized by mixing a compound represented by Formula 2 (starting material), a halogenated phosphoryl compound, and a base in step a) may include, for example, a compound represented by Formula 3 below.

[0104] [Chemical Formula 3]

[0105]

[0106] In the above chemical formula 3, X can be a halogen and each independently be one of fluorine (F), bromine (Br), and chlorine (Cl). In this case, the two Xs present in chemical formula 3 may be the same or different from each other, and preferably may be the same.

[0107] According to one example of the present invention, the halogenated phosphoryl compound in step a) may include one or more of phosphoryl chloride (POCl3), phosphoryl bromide (POBr3), and phosphoryl fluoride (POF3). Among these, one or more of phosphoryl chloride (POCl3) and phosphoryl bromide (POBr3) may be used for ease of removal and good economic efficiency. More preferably, it may be phosphoryl chloride (POCl3). Such halogenated phosphoryl compound may be used in an amount of 1 to 5 moles per 1 mole of the compound of Formula 1, and more preferably in an amount of 2 to 4 moles.

[0108] According to one example of the present invention, the base used in the reaction in step a) may include one or more of trimethylamine, triethylamine, tributylamine, dimethylaminotoluene, diisopropylethylamine, and pyridine. Among these, one or more of triethylamine and pyridine may be used in terms of being easy to remove while increasing reaction efficiency.

[0109] According to one example of the present invention, in step a), the reaction may be carried out by mixing an organic solvent in addition to a compound represented by Formula 2 (starting material), a halogenated phosphoryl compound, and a base. The organic solvent may include an inert solvent such as a halogenated carbon compound or an aromatic carbon compound. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, toluene, and xylene. Among these, one or more of dichloromethane and chloroform may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0110] According to one example of the present invention, step a) of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound can be performed, for example, at -5 to 40°C for 2 to 24 hours, preferably at 0 to 30°C for 1 to 12 hours, and more preferably at 5 to 25°C for 2 to 6 hours.

[0112] Next, as step b), an acidic aqueous solution or an alkyl alcohol can be mixed with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound, which is the result obtained in step a), to prepare the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate or (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound. At this time, the product of formula 3 obtained in step a) can be used in an isolated or unisolated state, for example, in an unisolated state.

[0113] According to one example of the present invention, in step b), a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound can be prepared, wherein step b) can be performed at 10 to 110°C for 30 minutes to 36 hours, preferably at 20 to 100°C for 12 to 24 hours, and more preferably at 30 to 50°C for 1 to 6 hours.

[0114] According to one example of the present invention, in order to prepare the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound in step b), the reaction may proceed by mixing with an acidic aqueous solution together with the compound represented by Formula 3.

[0115] According to one example of the present invention, the acidic aqueous solution may include a solution in which an organic acid or an inorganic acid is dissolved in purified water. For example, it may include one or more of organic acids such as phosphoric acid, fumaric acid, lactic acid, citric acid, malic acid, butyric acid, formic acid, and acetic acid, or inorganic acids such as hydrochloric acid (HCl), nitric acid (HNO3), phosphoric acid (H3PO4), sulfuric acid (H2SO4), boric acid (H3BO3), hydrofluoric acid (HF), hydrobrominated acid (HBr), and carbonic acid (H₂CO₃). Among these, one or more of acetic acid and hydrochloric acid can be used in terms of being economical and increasing reaction efficiency, and can be used at a concentration of 0 to 50% (w / w), preferably 0 to 25% (w / w), and more preferably 5 to 10% (w / w).

[0116] According to one example of the present invention, in step b), a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound can be prepared, wherein step b) can be carried out by mixing the compound represented by Formula 3 with an alkyl alcohol. The reaction can be performed at 10 to 110°C for 30 minutes to 36 hours, preferably at 20 to 100°C for 1 hour to 24 hours, and more preferably at 40 to 90°C for 1 hour to 12 hours.

[0117] According to one example of the present invention, when preparing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound in step b), the reaction can be carried out by mixing the compound represented by Formula 2, which is the starting material, with an alkyl alcohol without isolating it after the end of step a).

[0118] According to one example of the present invention, the alkyl alcohol is an alcohol having C1 to C4, preferably including one or more of methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, 2-butyl alcohol, and 3-butyl alcohol, and preferably including one or more of methyl alcohol, ethyl alcohol, propyl alcohol, and butyl alcohol.

[0119] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate, or (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound may be represented by the following chemical formula 4.

[0120] [Chemical Formula 4]

[0121]

[0122] In the above chemical formula 4, R3 and R4 may be identical or different from each other, and each is independently one of H and C1~C4 alkyl, for example, R3 and R4 may be identical.

[0124] Next, as step c), a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate derivative compound can be performed using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound prepared in step b).

[0125] According to one example of the present invention, the product of step c), '(S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate derivative compound', may be one of '(S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound' or 'metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound'.

[0126] According to one example of the present invention, step c) may be one selected from the following steps c-1) and c-2), and by step c-1) a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound may be prepared, and by step c-2) a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound may be prepared.

[0127] c-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step b) above,

[0128] c-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound prepared in step b) above with a metal base.

[0129] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step c-1) can be prepared by mixing a base with a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate with a compound represented by the above formula 4 (wherein R3 and R4 in formula 4 are both hydrogen).

[0130] According to one example of the present invention, step c-1) can be performed at 30 to 100°C for 30 minutes to 48 hours, preferably at 20 to 100°C for 1 hour to 36 hours, and more preferably at 40 to 90°C for 6 hours to 24 hours.

[0131] According to one example of the present invention, the haloalkyl (C1-C4) ester or haloalkyl (C1-C4) carbonate of step c-1) may include, for example, one or more of chloromethyl pivalate, chloroisobutyl propionate, 1-acetoxyethyl bromide, 1-chloroethyl cyclohexyl carbonate, and chloromethyl isopropyl carbonate, and preferably one or more of chloromethyl pivalate and chloromethyl isopropyl carbonate.

[0132] According to one example of the present invention, the base used in the reaction in step c-1) may include one or more of trimethylamine, triethylamine, tributylamine, dimethylaminotoluene, diisopropylethylamine, and pyridine. Among these, one or more of triethylamine and pyridine may be used in terms of being easy to remove while increasing reaction efficiency.

[0133] According to one example of the present invention, in step c-1), an organic solvent may be mixed to proceed with the reaction. The organic solvent may include an inert solvent such as an amide-based or urea-based solvent. For example, the amide-based solvent may include one or more of N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), hexamethylphosphamide (HMPA), and N,N,N',N'-tetramethylurea (TMU), or mixtures thereof. Among these, one or more of N-methyl-2-pyrrolidone (NMP) and N,N-dimethylformamide (DMF) may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0134] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step c-1) can be represented by the following chemical formula 5.

[0135] [Chemical Formula 5]

[0136]

[0137] In the above chemical formula 5, R5 and R6 are each the same or different and are each independently selected from CH2OCOC(CH3), CH2OCO2CH(CH3)2, CHCH(CH3)2OCOCH2CH3, CH(CH3)OCOCH3, and CHCH3OCO2CH(CH2)5, for example, R5 and R6 may be the same.

[0138] Meanwhile, according to one example of the present invention, the metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromene-7-nyl phosphate compound prepared in step c-2) is prepared by mixing a metal base with a compound represented by the above formula 4 (wherein R3 and R4 in formula 4 are both hydrogen), and preferably, purified water may be mixed together.

[0139] According to one example of the present invention, step c-2) can be performed at -5 to 30°C for 30 minutes to 36 hours, preferably at 0 to 30°C for 1 hour to 24 hours, and more preferably at 15 to 25°C for 2 hours to 12 hours.

[0140] According to one example of the present invention, in step c-2), the reaction may proceed by mixing an organic solvent. The organic solvent may include one or more of inert solvents such as halogenated carbon compounds and aromatic carbon compounds, ketones, and alkyl alcohols. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol, ethyl alcohol, propanol, isopropanol, butanol, 2-butanol, and 3-butanol. Among these, one or more of acetone and methyl alcohol may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0141] According to one example of the present invention, in step c-2), the reaction may proceed by mixing purified water with the compound. Purified water may be mixed with the organic solvent in an amount of 0 to 100% (v / v), preferably 0 to 5% (v / v), and more preferably 0 to 10% (v / v).

[0142] According to one example of the present invention, the metal base of step c-2) may include one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium methoxyoxide, potassium hydroxide, potassium carbonate, calcium hydroxide, calcium carbonate, and calcium acetate, and preferably may include one or more of sodium carbonate, sodium methoxyoxide, and calcium acetate, and, for example, 0.5 to 2.5 moles may be mixed per 1 mole of the compound represented by Formula 4 (wherein R3 and R4 in Formula 4 are both hydrogen). Preferably, 0.8 to 2.0 moles may be mixed.

[0144] Method for preparing phosphonate derivative compounds of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl >

[0145] According to another aspect of the present invention, a method for preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diethylphosphonate compound represented by the following chemical formula 1 can be provided, comprising the following steps a') to c').

[0146] [Chemical Formula 1]

[0147]

[0148] (In the above chemical formula 1, n is 1, and R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of )

[0149] a') A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nylmethyl diethylphosphonate compound by mixing a base with a diethylphosphonate compound having a leaving functional group on a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nylmethyl diethylphosphonate compound;

[0150] b') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diethyl phosphonate compound by mixing the above (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound with an alkyl (C1-C2) silyl halide compound; and

[0151] c') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate compound prepared in step b'); may be included,

[0152] The above step c') may be one selected from the following steps c'-1) and c'-2).

[0153] c'-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diester phosphonate compound prepared in step b'),

[0154] c'-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound prepared in step b') above with a metal base.

[0156] In step a'), a compound represented by Chemical Formula 2, a diethyl phosphonate compound having a good leaving functional group, and a base are mixed as starting materials, and (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl diethyl phosphonate compound can be prepared by step a').

[0157] According to one example of the present invention, a diethyl phosphonate compound having a good leaving functional group can be represented by the following chemical formula 6.

[0158] [Chemical Formula 6]

[0159]

[0160] In the above chemical formula 6, R7 may be one of halogen, OSO2C6H5CH3 and OSO2CH3, and the halogen may be one of fluorine (F), bromine (Br) and chlorine (Cl).

[0161] According to one example of the present invention, the compound represented by the formula 6 may be one of diethyl(fluoromethyl)phosphonate, diethyl(chloromethyl)phosphonate, diethyl(iodomethyl)phosphonate, diethyl(methanesulfonyloxymethyl)phosphonate, and diethyl(4-methylbenzenesulfonyloxymethyl)phosphonate, and preferably one of diethyl(methanesulfonyloxymethyl)phosphonate and diethyl(4-methylbenzenesulfonyloxymethyl)phosphonate.

[0162] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl diethylphosphonate compound prepared in step a') may comprise a compound represented by the following chemical formula 7.

[0163] [Chemical Formula 7]

[0164]

[0165] According to one example of the present invention, step a') may proceed with the reaction by mixing an organic solvent with the compound. The organic solvent may include one or more of inert solvents such as halogenated carbon compounds and aromatic carbon compounds, ketones, and alkyl alcohols. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol, ethyl alcohol, propanol, isopropanol, butanol, 2-butanol, and 3-butanol. Among these, one or more of dichloromethane and tetrahydrofuran may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0166] According to one example of the present invention, the base used in the step (=step a') of preparing a compound of Formula 7 may include one or more of sodium hydride, sodium methoxylide, sodium ethoxylide, tertiary sodium butyl hydride, potassium methoxylide, potassium ethoxylide, tertiary potassium butyl hydride, and tertiary magnesium butyl hydride. Preferably, it may include one or more of sodium hydride, sodium methoxylide, sodium ethoxylide, tertiary sodium butyl hydride, and tertiary magnesium butyl hydride, and more preferably, it may include one or more of tertiary sodium butyl hydride and tertiary magnesium butyl hydride.

[0167] According to one example of the present invention, step a') can be performed at -5 to 30°C for 30 minutes to 48 hours, preferably at 0 to 30°C for 1 hour to 36 hours, and more preferably at 15 to 25°C for 2 hours to 24 hours.

[0169] Next, in step b'), the compound of Formula 7, which is the product obtained in step a'), can be mixed with and reacted with an alkyl (C1-C2) silyl halide compound to produce (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl dihydrophosphonate compound.

[0170] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl dihydrophosphonate compound prepared in step b') may comprise a compound represented by the following chemical formula 8.

[0171] [Chemical Formula 8]

[0172]

[0173] According to one example of the present invention, step b') can be performed at -5 to 60°C for 30 minutes to 36 hours, preferably at 0 to 40°C for 1 hour to 24 hours, and more preferably at 15 to 25°C for 2 hours to 12 hours.

[0174] According to one example of the present invention, in step b'), an organic solvent may be mixed together, and the organic solvent in step b') may include an inert solvent such as a halogenated carbon compound and an aromatic carbon compound. For example, the organic solvent may include one or more of carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, toluene, and xylene. Among these, one or more of dichloromethane and tetrahydrofuran may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0175] According to one example of the present invention, the alkyl (C1-C2) silyl halogenated compound may include one or more of trimethylsilyl chloride, trimethylsilyl bromide, and trimethylsilyl trifluoromethanesulfonate, and preferably may include one or more of trimethylsilyl chloride and trimethylsilyl bromide.

[0177] Subsequently, as step c'), a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate derivative compound can be performed.

[0178] According to one example of the present invention, the product of step c'), '(S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl phosphonate derivative compound', may be one of '(S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diester phosphonate compound' or 'metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound'.

[0179] According to one example of the present invention, step c') may be one selected from the following steps c'-1) and c'-2), and by step c'-1), a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[7-nyl]methyl diester phosphonate compound may be prepared, and by step c'-2), a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[7-nyl]methyl dihydrophosphonate compound may be prepared.

[0180] c'-1) A step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl diester phosphonate compound prepared in step b'),

[0181] c'-2) A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound prepared in step b') above with a metal base.

[0182] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl diester phosphonate compound prepared in step c'-1) can be prepared by mixing a compound represented by the chemical formula 8 with a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base.

[0183] According to one example of the present invention, the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl diester phosphonate compound prepared in step c'-1) may comprise a compound represented by the following chemical formula 9.

[0184] [Chemical Formula 9]

[0185]

[0186] In the above chemical formula 9, R8 and R9 is one that is identical or different from each other and is independently selected from CH2OCOC(CH3), CH2OCO2CH(CH3)2, CHCH(CH3)2OCOCH2CH3, CH(CH3)OCOCH3, and CHCH3OCO2CH(CH2)5.

[0187] According to one example of the present invention, step c'-1) can be performed at 30 to 100°C for 30 minutes to 48 hours, preferably at 20 to 100°C for 1 hour to 36 hours, and more preferably at 40 to 90°C for 6 hours to 24 hours.

[0188] According to one example of the present invention, the haloalkyl (C1-C4) ester or haloalkyl (C1-C4) carbonate of step c'-1) may preferably comprise one or more of chloromethyl pivalate, chloroisobutyl propionate, 1-acetoxyethyl bromide, 1-chloroethyl cyclohexyl carbonate, and chloromethyl isopropyl carbonate, and preferably chloromethyl pivalate and chloromethyl isopropyl carbonate, and one or more of these may be used.

[0189] According to one example of the present invention, the base used in the reaction in step c'-1) may include one or more of trimethylamine, triethylamine, tributylamine, dimethylaminotoluene, diisopropylethylamine, and pyridine. Among these, one or more of triethylamine and pyridine may be used in terms of ease of removal and increased reaction efficiency.

[0190] According to one example of the present invention, the reaction may proceed by mixing an organic solvent with the compound in step c'-1). The organic solvent in step c'-1) may include an inert solvent such as an amide-based or urea-based solvent. For example, the amide-based solvent may include one or more of N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), hexamethylphosphamide (HMPA), and N,N,N',N'-tetramethylurea (TMU), or mixtures thereof. Among these, one or more of N-methyl-2-pyrrolidone (NMP) and N,N-dimethylformamide (DMF) may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0191] Meanwhile, according to one example of the present invention, the metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nylmethyl dihydrophosphonate compound (also referred to as the 'metal salt phosphonate compound') prepared in step c'-2) can be prepared by mixing a metal base with the compound represented by formula 8 (R1=H) prepared in step b').

[0192] According to one example of the present invention, step c'-2) can be performed at -5 to 30°C for 30 minutes to 36 hours, preferably at 0 to 30°C for 1 hour to 24 hours, and more preferably at 15 to 25°C for 2 hours to 12 hours.

[0193] According to one example of the present invention, in step c'-2), the reaction may proceed by mixing an organic solvent with the compound. The organic solvent in step c'-2) may include inert solvents such as halogenated carbon compounds and aromatic carbon compounds, ketones, and alkyl alcohols. For example, the organic solvent in step c'-2) may include one or more of carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol, ethyl alcohol, propanol, isopropanol, butanol, 2-butanol, and 3-butanol. Among these, one or more of acetone and methyl alcohol may be used in terms of facilitating the removal of the organic solvent while increasing reaction efficiency.

[0194] According to one example of the present invention, step c'-2) may proceed with the reaction by mixing purified water with the compound. The purified water may be mixed in an amount of 0 to 100% (v / v) with respect to the organic solvent. Preferably, 0 to 50% (v / v), and more preferably 0 to 10% (v / v) may be mixed.

[0195] According to one example of the present invention, the metal base of step c'-2) may include sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium methoxyoxide, potassium hydroxide, potassium carbonate, calcium hydroxide, calcium carbonate, and calcium acetate, and preferably one or more of sodium carbonate, sodium methoxyoxide, and calcium acetate may be used.

[0196] According to one example of the present invention, in step c'-2), 0.5 to 2.1 moles can be mixed for 1 mole of the compound represented by Formula 8, and preferably 0.8 to 2.0 moles can be mixed.

[0198] The present invention will be explained in more detail below through embodiments according to the present invention and comparative examples not according to the present invention, but the scope of the present invention is not limited by the embodiments presented below.

[0200] Example 1 Preparation of (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl Dihydrophosphate

[0201] 8.0 ml of pyridine was added to a solution of 12.3 g of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one (decasinol) dissolved in 60 ml of dichloromethane, and after cooling to 5°C, 9.4 ml of phosphoryl chloride was slowly added dropwise. The temperature was slowly raised to 25°C and stirred for 4 hours. After confirming the completion of the reaction, 60 ml of purified water was added dropwise. The mixture was stirred for 10 minutes, and phase separation was performed. 20 ml of 5% hydrochloric acid solution was added to the organic layer, and the mixture was stirred at 40°C for 2 hours. After cooling to room temperature, the pH was adjusted to 8–9 with an aqueous saturated sodium bicarbonate solution, and phase separation was performed. 20 ml of dichloromethane was added to the aqueous layer, and after stirring for 10 minutes, phase separation was performed. After acidifying the aqueous layer to a pH of 3–4 with concentrated hydrochloric acid, 30 ml of tetrahydrofuran was added and stirred for 10 minutes. The layers were separated, 30 ml of tetrahydrofuran was added to the aqueous layer, and stirred for 10 minutes. The layers were separated, the organic layers were combined, dried with anhydrous magnesium sulfate, and then subjected to vacuum evaporation to obtain a foamy phase. Recrystallization with acetone and ethyl acetate yielded 13.3 g (81%) of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl dihydrophosphate.

[0202] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.82 (d, 1H), 7.33 (s, 1H), 6.64 (s, 1H), 6.18 (d, 1H), 4.30 - 4.24 (m, 1H), 3.08 - 2.94 (m, 2H), 1.29 (s, 3H). 1.26 (s, 3H).

[0204] Example 2Preparation of Disodium (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl Phosphate

[0205] 0.23 g of sodium hydroxide was added to a solution in which 1.0 g of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate was dissolved in 10 ml of methanol, and the mixture was stirred at 25°C for 12 hours. The resulting solid was filtered, the filtrate was washed with acetone, and then dried under reduced pressure at 50°C to obtain 1.01 g (91%) of disodium (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate, a white solid.

[0206] 1 H NMR (500 MHz, DO) δ 7.85 - 7.70 (m, 1H), 7.32 (d, 1H), 6.67 - 6.56 (m, 1H), 6.15 (dt, 1H), 4.20 (dt, 1H), 3.20 - 2.98 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H).

[0208] Example 3 Preparation of Disodium (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl Phosphate

[0209] 1.36 ml of a 25% sodium methoxyoxide methanol solution was added to a solution in which 1.0 g of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate was dissolved in 10 ml of methanol, and the mixture was stirred at 25°C for 12 hours. Activated carbon was added to the reaction mixture and stirred for 10 minutes, after which the mixture was filtered. The filtrate was washed with methanol, and the filtrate was evaporated under reduced pressure to obtain the residue. Acetone was added to the residue and stirred at 25°C for 1 hour, after which the resulting solid was filtered. After washing the filtrate with acetone, it was dried under reduced pressure at 50°C to obtain 1.07 g (97%) of disodium (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl phosphate, a yellowish solid.

[0210] 1 H NMR (500 MHz, DO) δ 7.85 - 7.70 (m, 1H), 7.32 (d, 1H), 6.67 - 6.56 (m, 1H), 6.16 (dt, 1H), 4.20 (dt, 1H), 3.20 - 2.99 (m, 2H), 1.39 (s, 3H), 1.32 (s, 3H).

[0212] Example 4 Preparation of (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl Dimethyl Phosphate

[0213] 1.25 ml of pyridine was added to a solution of 2.0 g of (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-2-one (decasinol) dissolved in 10 ml of dichloromethane, and after cooling to 5°C, 1.5 ml of phosphoryl chloride was slowly added dropwise. The temperature was slowly raised to 25°C and stirred for 4 hours. 5 ml of methanol was added to this solution and heated under reflux for 8 hours. After cooling to room temperature and removing the solvent by vacuum evaporation, 10 ml of ethyl acetate was added to the residue. The organic layer was washed with purified water, 0.1 N aqueous hydrochloric acid solution, and purified water, dried with anhydrous magnesium sulfate, and then the solvent was removed by vacuum evaporation to obtain a yellow oil phase. 2.5 g (90%) of yellowish oily (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dimethyl phosphate was obtained by purification with a silica gel column.

[0214] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.92 (dd, 1H), 7.52 (s, 1H), 6.79 (s, 1H), 6.26 (d, 1H), 4.61 (dt, 1H), 3.68 (d, 3H), 3.56 (d, 3H), 3.24 (ddd, 1H), 3.01 (dd, 1H), 1.39 (s, 3H), 1.29 (s, 3H).

[0216] Example 5. Preparation of (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]cromen-7-nyl Diethyl Phosphate

[0217] Example 3 In the same way, 5 ml of anhydrous ethanol was added instead of methanol and reacted to obtain 2.9 g (94%) of yellowish oily (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diethyl phosphate.

[0218] 1 ¹H NMR (500 MHz, DMSO- D6) δ 7.92 (dd, 1H), 7.51 (s, 1H), 6.78 (s, 1H), 6.26 (d, 1H), 4.61 - 4.55 (m, 1H), 4.03 (dq, 2H), 3.94 - 3.89 (m, 2H), 3.23 (ddd, 1H), 3.01 (dd, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.23 (td, 3H), 1.15 (td, 3H).

[0220] Example 6 Preparation of (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl dipivoxyl phosphate

[0221] To a solution in which 1.0 g of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate was dissolved in 10 ml of N,N-dimethylformamide, 0.93 g of triethylamine and 2.35 g of chloromethyl isopropyl carbonate were added, and the mixture was stirred at 60°C for 20 hours. After cooling to room temperature, 50 ml of purified water and 20 ml of ethyl acetate were added, and the mixture was stirred for 10 minutes. The layers were separated, the organic layer was washed with purified water, and then dried with anhydrous magnesium sulfate. The solvent was removed by vacuum evaporation to obtain a colorless oil phase. This oil phase was purified with a silica gel column to obtain 0.55 g (31%) of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dipivoxyl phosphate.

[0222] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.94 (dd, 1H), 7.50 (s, 1H), 6.77 (s, 1H), 6.27 (d, 1H), 5.66 - 5.50 (m, 4H), 4.72 - 4.66 (m, 1H), 3.26 (ddd, 1H), 3.02 (dd, 1H), 1.38 (s, 3H), 1.28 (s, 3H), 1.13 (s, 9H), 1.08 (s, 9H).

[0224] Example 7 Preparation of (S)-8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl Diisoproxyl Phosphate

[0225] In the same manner as in Example 5, 2.32 g of chloromethyl pivaleate was added instead of chloromethyl isopropyl carbonate and reacted to obtain a yellowish oil phase, which was purified by a silica gel column to obtain 0.28 g (16%) of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diisopropoxyl phosphate.

[0226] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.94 (d, 1H), 7.49 (s, 1H), 6.79 (s, 1H), 6.28 (d, 1H), 5.61 (d, 2H), 5.58 - 5.52 (m, 2H), 4.80 (dp, 2H), 4.69 (dt, 1H), 3.25 (ddd, 1H), 3.01 (dd, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.23 (ddd, 12H).

[0228] Example 8 Preparation of (S)-((8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]cromen-7-nyl)oxy)methyl diethylphosphonate

[0229] A solution of 19.1 g of tertiary sodium butyl sulfate suspended in 50 ml of tetrahydrofuran was cooled to 5°C, and a solution of 24.6 g of decursinol dissolved in 150 ml of tetrahydrofuran was slowly added dropwise. The temperature was slowly raised to room temperature, and 45.10 g of diethoxyphosphorylmethyl-4-methylbenzenesulfonate was added, followed by stirring at the same temperature for 24 hours. The solvent was removed by vacuum evaporation, and 200 ml of ethyl acetate and 200 ml of purified water were added to the residue. After stirring for 20 minutes, the layers were separated. The organic layer was washed with purified water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and then the solvent was removed by vacuum evaporation to obtain a pale yellow oil phase. This oil phase was purified with a silica gel column to obtain 13.8 g (35%) of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl diethylphosphonate.

[0230] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.94 (d, 1H), 7.45 (s, 1H), 6.73 (s, 1H), 6.25 (d, 1H), 4.04 - 3.93 (m, 5H), 3.87 (dd, 1H), 3.71 (dd, 1H), 3.08 (ddd, 1H), 2.93 (dd, 1H), 1.32 (s, 3H), 1.29 (s, 3H), 1.18 (t, 3H), 1.14 (t, 3H).

[0232] Example 9 Preparation of (S)-((8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl)oxy)methyl dihydrophosphonate

[0233] 10.6 g of trimethylsilyl bromide was added to a solution in which 8 g of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl diethyl phosphate was dissolved in 40 ml of dichloromethane, and the mixture was stirred at room temperature for 5 hours. After removing the solvent by vacuum evaporation, 40 ml of methanol was added to the residue and stirred for 5 hours. The methanol was removed again by vacuum evaporation, 40 ml of ethyl acetate was added, and the mixture was stirred for 10 minutes. The solvent was then removed by vacuum evaporation to obtain a brown oil phase. 4.64 g (68%) of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl dihydrophosphate, a white solid, was obtained by treatment with acetone.

[0234] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.77 (d, 1H), 7.31 (s, 1H), 6.60 (s, 1H), 6.12 (d, 1H), 3.63 (s, 2H), 3.46 (s, 1H), 3.04 (d, 1H), 2.82 (d, 1H), 1.28 (s, 6H).

[0236] Example 10 Preparation of disodium (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methylphosphonate

[0237] 0.8 g of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate was dissolved in 10 ml of methanol, to which 0.24 g of sodium carbonate was added and stirred at 25°C. 3 to 5 drops of purified water were added to this mixed solution and stirred at 25°C for 12 hours. The resulting solid was filtered, and the filtrate was washed with acetone and dried under reduced pressure at 50°C to obtain 0.82 g (91%) of disodium (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methylphosphonate, a white solid.

[0238] 1 H NMR (500 MHz, DO) δ 7.73 (d, 1H), 7.26 (s, 1H), 6.57 (s, 1H), 6.15 (d, 1H), 3.73 (t, 1H), 3.65 (dd, 1H), 3.50 (dd, 1H), 3.01 (t, 2H), 1.44 (s, 3H), 1.31 (s, 3H).

[0240] Example 11 . Preparation of (S)-((8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl)oxy)methyl dipivoxyl phosphonate

[0241] To a solution in which 1.0 g of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl dihydrophosphonate was dissolved in 10 ml of N,N-dimethylformamide, 0.89 g of triethylamine and 2.24 g of chloromethyl isopropyl carbonate were added, and the mixture was stirred at 60°C for 20 hours. After cooling to room temperature, 50 ml of purified water and 20 ml of ethyl acetate were added, and the mixture was stirred for 10 minutes. The layers were separated, the organic layer was washed with purified water, and then dried with anhydrous magnesium sulfate. The solvent was removed by vacuum evaporation to obtain a colorless oil phase. This oil phase was purified with a silica gel column to obtain 0.34 g (20%) of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dipivoxyl phosphonate.

[0242] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.94 (d, 1H), 7.45 (s, 1H), 6.72 (s, 1H), 6.25 (d, 1H), 5.63 - 5.52 (m, 4H), 4.06 (dd, 2H), 3.73 (t, 1H), 3.11 - 3.04 (m, 1H), 2.93 - 2.86 (m, 1H), 1.31 (s, 3H), 1.28 (s, 3H), 1.14 (s, 9H), 1.12 (s, 9H).

[0244] Example 12 Preparation of (S)-((8,8-Dimethoxy-2-oxo-7,8-Dihydro-2H,6H-Pyrano[3,2-g]chromen-7-nyl)oxy)methyl diisoproxyl phosphonate

[0245] 2.01 g of chloromethyl pivaleat was added instead of chloromethyl isopropyl carbonate in the same manner as in Example 9 and reacted to obtain a yellowish oil phase, which was purified by a silica gel column to obtain 0.26 g (15.6%) of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diisopropoxyl phosphate.

[0246] 1 ¹H NMR (500 MHz, DMSO- D 6) δ 7.94 (d, 1H), 7.45 (s, 1H), 6.73 (s, 1H), 6.25 (d, 1H), 5.64 - 5.51 (m, 4H), 4.85 - 4.75 (m, 2H), 4.17 - 4.01 (m, 2H), 3.72 (dd, 1H), 3.09 (ddd, 1H), 2.89 (s, 1H), 1.29 (d, 6H), 1.25 - 1.20 (m, 12H).

[0248] Example 13 . Solubility experiment

[0249] Experiments were conducted to compare the water solubility (mg / ml, 25 ± 2 ℃, 24h) of the novel compounds prepared in Examples 1, 2, 9, and 10, as well as decursin and decursinol (control drugs), and the specific experimental method is as follows.

[0250] 5 ml of distilled water was added to a 10 ml vial, and the novel compounds prepared in Examples 1 to 10 and the control compounds (decursin, decursinol) were added until suspended. The vial was then sealed with a lid and stirred at 100 rpm using a magnetic bar in a water bath at 25 ± 2 ℃ for 24 hours. Each sample was filtered through a 0.45 µm filter, and the solubility (mg / ml) was measured using HPLC.

[0251] Solubility (mg / ml) Deckersin Deckersinol Example 1 Example 2 Example 9 Example 10 insoluble 0.10 6.94 2.93 110.93 113.83

[0252] Therefore, it can be confirmed that the novel compound of the present invention has high potential as a prodrug by significantly improving the physical and chemical properties of the drug, thereby acting very favorably on the absorption and release of the drug.

[0254] Although the embodiments of this specification have been described in greater detail above, this specification is not necessarily limited to these embodiments and may be modified in various ways within the scope of the technical spirit of this specification. Accordingly, the embodiments disclosed in this specification are intended to explain, not limit, the technical spirit of this specification, and the scope of the technical spirit of this specification is not limited by these embodiments. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of protection of this specification shall be interpreted by the claims, and all technical spirits within an equivalent scope shall be interpreted as being included within the scope of rights of this specification.

Claims

Claim 1 A phosphate or phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl represented by the following chemical formula 1, or a salt thereof, [Chemical Formula 1] In the above chemical formula 1, n is an integer of 0 or 1, R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, or a C1-C4 alkyl carbonate, and the salt is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ It is one of ). Claim 2 In claim 1, where n is 0, the phosphate derivative compound represented by Formula 1 is (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate disodium, (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate, (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dimethyl phosphate, (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diethyl A compound selected from the group consisting of phosphate, (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dipivoxyl phosphate and (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diisopropoxyl phosphate. Claim 3 In claim 1, where n is 1, the phosphonate derivative compound represented by Formula 1 is (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl)oxy)methyl diethylphosphonate, (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl)oxy)methyl dihydrophosphonate disodium, (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl)oxy)methylphosphonate, A compound selected from the group consisting of (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl dipivoxyl phosphonate and (S)-((8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl)oxy)methyl diisoproxyl phosphonate. Claim 4 A method for preparing a phosphate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl represented by the following chemical formula 1, [Chemical Formula 1] (In the above chemical formula 1, n is 0, and R1 and R2 are identical or different from each other and are independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ (one of ) a) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound by mixing a phosphoryl halogenated compound and a base with a (S)-7-hydroxy-8,8-dimethoxy-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound; b) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihalogenated phosphate compound by mixing an acidic aqueous solution or a C1-C4 alkyl alcohol with the above (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate compound or a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dialkyl phosphate compound; and c) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl dihydrophosphate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphate compound prepared in step b);A manufacturing method comprising, wherein step c) is one selected from the following steps c-1) and c-2): c-1) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step b); c-2) the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl diester phosphate compound prepared in step b). A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl dihydrophosphate compound by mixing a metal base with a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl phosphate compound.; Claim 5 A method for preparing a phosphonate derivative compound of (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-7-nyl represented by the following chemical formula 1, [Chemical Formula 1] (In the above chemical formula 1, n is 1, and R1 and R2 are the same or different from each other, and each is independently selected from hydrogen (H), a C1-C4 alkyl group, a C1-C4 alkyl ester, a C1-C4 alkyl carbonate, and a metal ion, and the metal ion is a sodium ion (Na + ), calcium ions (Ca 2+ ) and magnesium (Mg 2+ (one of the following) a') a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[3,2-g]methyl diethyl phosphonate compound by mixing a base with a diethyl phosphonate compound having a leaving functional group on a (S)-7-hydroxy-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[7-nyl]methyl diethyl phosphonate compound; b') mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[7-nyl]methyl diethyl phosphonate compound with an alkyl (C1~C2)silyl halide compound (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl methyl dihydrophosphonate compound; and c') a step of preparing (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl methyl dihydrophosphonate compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphonate derivative compound using the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromen-7-nyl phosphonate compound prepared in step b');A manufacturing method comprising, wherein step c') is one selected from the following steps c'-1) and c'-2): c'-1) a step of preparing a (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[3,2-g]cromeno[7-nyl]methyl diester phosphonate compound by mixing a haloalkyl (C1-C4) ester or a haloalkyl (C1-C4) carbonate and a base with the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[7-nyl]methyl diester phosphonate compound prepared in step b'); c'-2) the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno[7-nyl]methyl diester phosphonate compound prepared in step b'). A step of preparing a metal salt (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound by mixing the (S)-8,8-dimethoxy-2-oxo-7,8-dihydro-2H,6H-pyrano[3,2-g]cromeno-7-nyl methyl dihydrophosphonate compound with a metal base.; Claim 6 A method for manufacturing, wherein the halogenated phosphoryl compound of step a) is phosphoryl chloride (POCl3) in claim 4. Claim 7 A method of preparation according to claim 4, wherein the acidic aqueous solution of step b) is an aqueous hydrochloric acid (HCl) solution. Claim 8 A method for manufacturing according to claim 4, wherein the C1-C4 alkyl alcohol of step b) is methanol or ethanol. Claim 9 A method for manufacturing according to claim 4, wherein the haloalkyl (C1-C4) ester in step c-1) is chloromethyl pivalate and the haloalkyl (C1-C4) carbonate is chloromethyl isopropyl carbonate. Claim 10 A method for manufacturing, wherein, in claim 5, the diethyl phosphonate compound having the leaving functional group of step a') is diethyl(4-methylbenzenesulfonyloxymethyl)phosphonate. Claim 11 A method for manufacturing, wherein the base of step a') is one of sodium hydride, sodium methoxylide, sodium ethoxylide, tertiary sodium butylhydrogen, potassium hydride, potassium methoxylide, potassium ethoxylide, tertiary potassium butylide, and tertiary magnesium butylide. Claim 12 A method for manufacturing, wherein the alkyl (C1-C2)silyl halogenated compound in step b') is trimethylsilyl bromide (TMSBr). Claim 13 A method of preparation according to claim 5, wherein the haloalkyl (C1-C4) ester in step c'-1) is chloromethyl pivalate and the haloalkyl (C1-C4) carbonate is chloromethyl isopropyl carbonate. Claim 14 A method of manufacturing according to claim 4 or 5, wherein the metal base is one of sodium hydroxide, sodium carbonate, and sodium methoxyoxide.

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