Radioactive halogen-labeled precursor compounds

Abstract

To provide a radioactive halogen-labeled precursor compound that is highly stable and reactive.SOLUTION: The compound is represented by general formula (II) in the figure. In the formula, R1 and R2 each independently represent an alkyl group having 5-20 carbon atoms, X1 and X2 each independently represent a halogen atom, and R3 represents a monovalent group derived from a sugar.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a radioactive halogen-labeled precursor compound, a compound used in the production of this precursor compound, and a method for producing a radioactive halogen-labeled compound using this precursor compound. [Background technology]

[0002] Labeling reactions with radioactive halogens, such as radioactive fluorine, are often carried out by synthesizing a labeling precursor compound by attaching a leaving group to the halogen-labeling site of the target substrate, and then bonding the radioactive halogen to this labeling precursor compound. In this process, the structure of the leaving group in the labeling precursor compound greatly affects the reactivity of the labeling reaction. Examples of such leaving groups include trifluoromethanesulfonyloxy groups and benzenesulfonyloxy groups.

[0003] Recently, the inventors have developed a radioactive fluorine-labeled precursor compound containing a benzenesulfonyloxy group with a hydrophobic amide tag as a leaving group, and have filed patent applications (Patent Documents 1 and 2). Because this precursor compound contains a hydrophobic moiety, it has the advantage that the target labeled compound can be separated from the unreacted precursor compound by a simple method after the reaction is complete. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2018 / 164043 [Patent Document 2] Japanese Patent Publication No. 2017-52713 [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] In order to efficiently perform a labeling reaction with a radioactive halogen, it is necessary to use a highly reactive labeling precursor compound. On the other hand, even if the reactivity is high, if the labeling precursor compound easily decomposes, the efficiency of the labeling reaction cannot be expected. The present invention has been made under such a technical background, and an object thereof is to provide a radioactive halogen labeling precursor compound having high reactivity and stability.

Means for Solving the Problems

[0006] As a result of intensive studies to solve the above problems, the present inventors have found that a radioactive halogen labeling precursor compound containing a trifluoromethanesulfonyloxy group having a hydrophobic amide tag as a leaving group has high reactivity and stability, and have completed the present invention.

[0007] That is, the present invention provides the following (1) to (17). (1) The following general formula (I)

Chemical formula

[0008] (2) The compound according to (1), wherein R 1 and R 2 in the general formula (I) are alkyl groups having 7 to 11 carbon atoms.

[0009] (3) The compound according to (1) or (2), wherein X 1 and X 2 in the general formula (I) are fluorine atoms or chlorine atoms.

[0010] (4) The following general formula (II)

Chemical formula

[0011] (5) R in general formula (II) 1 and R 2 However, the compounds described in (4) are alkyl groups having 7 to 11 carbon atoms.

[0012] (6) X in general formula (II) 1 and X 2 The compound described in (4) or (5), wherein the compound is a fluorine atom or a chlorine atom.

[0013] (7) A compound according to any one of (4) to (6), wherein L in general formula (A) or (B) is an alkylene group (however, one or more -CH2- groups of the alkylene group may be substituted with -O- or a phenylene group).

[0014] (8) R in general formula (A) or (B) 4The compound is one of the compounds described in (4) to (7), wherein the compound is a 4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl group, a naphthalene-2-yl group, a 2-nitro-1H-imidazole-1-yl group, or an aminocarbonyl group protected with a tert-butoxycarbonyl group.

[0015] (9) The following general formula (IIIa) [ka] [In the formula, X 4 represents a radioactive halogen atom, R 3a This represents a monovalent group derived from a compound to be labeled with a radioactive halogen atom. A method for producing a radioactive halogen-labeled compound represented by the following general formula (IIa) [ka] [In the formula, R 1 and R 2 Each of these independently represents an alkyl group with 5 to 20 carbon atoms, and X 1 and X 2 Each of these independently represents a halogen atom, and R 3a This has the same meaning as above. A method comprising the step of reacting a labeled precursor compound represented by with a radioactive halide ion to obtain a radioactive halogen-labeled compound represented by general formula (IIIa).

[0016] (10) R in general formula (IIa) 1 and R 2 The method described in (9), wherein the alkyl group has 7 to 11 carbon atoms.

[0017] (11) X in general formula (IIa) 1 and X 2 The method according to (9) or (10), wherein the atom is a fluorine atom or a chlorine atom.

[0018] (12) R in general formulas (IIa) and (IIIa) 3aHowever, a monovalent group derived from sugar, a monovalent group derived from peptide, or the following general formula (A) or (B) [ka] [ka] (In the formula, L represents a divalent group that functions as a spacer, R 4 (where * represents an aryl group which may be substituted with a substituent, a heteroaryl group which may be substituted with a substituent, or an aminocarbonyl group which may be protected with a protecting group, and * represents a bonding site.) The method according to any one of (9) to (11), wherein the group is represented by .

[0019] (13) The compound according to (12), wherein L in general formula (A) or (B) is an alkylene group (however, one or more -CH2- groups of the alkylene group may be substituted with -O- or a phenylene group).

[0020] (14) R in general formula (A) or (B) 4 The compound according to (12) or (13), wherein the compound is a 4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl group, a naphthalene-2-yl group, a 2-nitro-1H-imidazole-1-yl group, or an aminocarbonyl group protected with a tert-butoxycarbonyl group.

[0021] (15) X in general formula (IIIa) 4 but, 211 The method described in any of (9) to (14) above.

[0022] (16) Reagent for producing labeled precursor compounds, comprising any of the compounds described in (1) to (3).

[0023] A labeling precursor reagent for radioactive halogen-labeled compounds, comprising any of the compounds described in (17)(4) to (8). [Effects of the Invention]

[0024] This invention provides a novel radioactive halogen-labeled precursor compound. Because this precursor compound exhibits high reactivity and stability, it enables the efficient production of radioactive halogen-labeled compounds. [Brief explanation of the drawing]

[0025] [Figure 1] TLC image of the reaction solution (left lane: standard sample (iodine-substituted C), right lane: reaction solution). [Modes for carrying out the invention]

[0026] The present invention will be described in detail below. In this invention, "halogen atom" refers to, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an astatine atom, and the like.

[0027] In this invention, "radioactive halogen atom" means, for example, 18 F, 75 Br, 76 Br, 77 Br, 82 Br, 123 I, 124 I, 125 I, 131 I, 133 I, 209 At, 210 At, 211 Examples include "at," etc.

[0028] In this invention, "radioactive halide ions" means, for example, 18 F - , 75 Br - , 76 Br - , 77 Br - , 82 Br - , 123 I - , 124 I - , 125 I - , 131 I - , 133I - , 209 At - , 210 At - , 211 At - And so on.

[0029] In the present invention, "alkyl group having 5 to 20 carbon atoms" refers to a linear or branched alkyl group having 5 to 20 carbon atoms, such as pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, and the like.

[0030] In the present invention, "alkyl group having 7 to 11 carbon atoms" refers to a linear or branched alkyl group having 7 to 11 carbon atoms, such as a heptyl group, octyl group, nonyl group, decyl group, undecyl group, etc.

[0031] In the present invention, "aryl group" refers to, for example, a phenyl group, a naphthalene-1-yl group, a naphthalene-2-yl group, and the like.

[0032] In the present invention, "heteroaryl group" refers to, for example, pyridine-2-yl group, pyridine-3-yl group, pyridine-4-yl group, pyrimidine-2-yl group, pyrimidine-4-yl group, pyrimidine-5-yl group, furan-2-yl group, furan-3-yl group, thiophene-2-yl group, thiophene-3-yl group, imidazole-1-yl group, imidazole-2-yl group, imidazole-4-yl group, imidazole-5-yl group, and the like.

[0033] In the present invention, the "protecting group" of an aminocarbonyl group is, for example, tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, allyloxycarbonyl group, trifluoroacetyl group, phthaloyl group, p-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, and the like.

[0034] In general formulas (I), (II), and (IIa), R 1 and R 2 each independently represent an alkyl group having 5 to 20 carbon atoms. R 1 and R 2 may be different groups, but are preferably the same group. R 1 and R 2 may be the above-mentioned groups, but are preferably an alkyl group having 7 to 11 carbon atoms, and more preferably an alkyl group having 7 or 11 carbon atoms.

[0035] In general formulas (I), (II), and (IIa), X 1 and X 2 each independently represent a halogen atom. X 1 and X 2 may be different atoms, but are preferably the same atom. X 1 and X 2 may be any halogen atom, but is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

[0036] In general formula (I), X 3 represents a halogen atom. X 3 may be any halogen atom, but is preferably a fluorine atom.

[0037] In general formula (II), R 3 represents a monovalent group derived from a sugar or a monovalent group derived from a peptide. Here, the "monovalent group derived from a sugar" means, for example, a monovalent group obtained by removing one hydrogen atom in a sugar molecule, and the "monovalent group derived from a peptide" means, for example, a monovalent group obtained by removing one hydrogen atom in a peptide molecule. The hydrogen atom to be removed is, for example, the hydrogen atom in the hydroxy group contained in the sugar and peptide molecules. The types of sugars and peptides are not particularly limited, but those having the property of accumulating in specific organs or tissues (such as cancer tissues) in vivo are preferred.

[0038] R in general formula (II) 3 This is the following general formula (A) or (B) [ka] [ka] It may also represent the base indicated by .

[0039] In general formulas (A) and (B), L represents a divalent group that functions as a spacer. L may be a group having an aromatic ring, as long as it functions as a spacer. An example of L is an alkylene group. However, one or more -CH2- in the alkylene group may be substituted with -O- or a phenylene group. Here, the phenylene group may be an 0-phenylene group, an m-phenylene group, or a p-phenylene group. L may be any of the above-mentioned groups, but preferably it is -CH2-O-, -CH2-O-CH2-, or -CH2-. The number of carbon atoms in the alkylene group is not particularly limited, but preferably it is 1 to 7, and more preferably 1 to 3. Even when -CH2- is substituted with -O- or a phenylene group, the -O- or phenylene group is counted as one carbon atom and included in the "number of carbon atoms in the alkylene group" as described above.

[0040] In general formulas (A) and (B), R 4 R represents an aryl group which may be substituted with a substituent, a heteroaryl group which may be substituted with a substituent, or an aminocarbonyl group which may be protected with a protecting group. Here, the aryl group is not particularly limited, but a phenyl group or a naphthalene-2-yl group is preferred. The heteroaryl group is also not particularly limited, but an imidazole-1-yl group is preferred. The substituent is also not particularly limited, but a nitro group, a 2,3-bis(tert-butoxycarbonyl)guanidinomethyl group, a sulfo group, or a fluorine atom is preferred, and a nitro group or a 2,3-bis(tert-butoxycarbonyl)guanidinomethyl group is more preferred. The protecting group for the aminocarbonyl group is not particularly limited, but a tert-butoxycarbonyl group is preferred. 4It may be the group described above, but preferably it is a 4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl group, a naphthalene-2-yl group, or a 2-nitro-1H-imidazol-1-yl group. Also, R 4 When it is an aminocarbonyl group that may be protected by a protecting group, a functional moiety having an amino group can be easily bonded here. Therefore, when it is desired to bond such a functional moiety, R 4 is preferably an aminocarbonyl group that may be protected by a protecting group, for example, an aminocarbonyl group protected by a tert-butoxycarbonyl group.

[0041] R in the general formulas (IIa) and (IIIa) 3a represents a monovalent group derived from a compound to be labeled with a radioactive halogen atom. Here, the "monovalent group derived from a compound to be labeled with a radioactive halogen atom" means, for example, a monovalent group obtained by removing one hydrogen atom in the molecule of the compound, and the hydrogen atom to be removed is, for example, the hydrogen atom in the hydroxy group contained in the molecule of the compound. The monovalent group derived from a compound to be labeled with a radioactive halogen atom may be any group. Since the compound labeled with a radioactive halogen atom is used as a radiopharmaceutical (for example, a PET reagent), the part other than the radioactive halogen atom of the compound used as a radiopharmaceutical may be used as the monovalent group derived from the compound to be labeled with a radioactive halogen atom. Also, since many such parts other than the radioactive halogen atom have the property of accumulating in specific organs or tissues (such as cancer tissues) in the living body, such parts may be used as the monovalent group derived from the compound to be labeled with a radioactive halogen atom. Furthermore, since many such parts other than the radioactive halogen atom have the property of stabilizing the radioactive halogen atom in the living body (for example, the structure described in International Publication No. 2019 / 151384), such parts may be used as the monovalent group derived from the compound to be labeled with a radioactive halogen atom. Specific examples of the monovalent group derived from a compound to be labeled with a radioactive halogen atom include the groups exemplified as R 3 above.

[0042] X in general formula (IIIa) 4 X represents a radioactive halogen atom. 4 This can be any radioactive halogen atom, but preferably, 18 F, or 211 At, moreover, 211 It is At.

[0043] The compound represented by general formula (I) can be used as a reagent for producing labeled precursor compounds, i.e., as a raw material reagent for producing the compound represented by general formula (II). The reagent for producing labeled precursor compounds usually consists only of the compound represented by general formula (I), but may also contain other substances. The compound represented by general formula (I) can be produced according to the production method described in Example 1, using 2,2-difluoro-2-(fluorosulfonyl)acetic acid and dioctylamine as raw materials, with modifications and changes as necessary.

[0044] Compounds represented by general formula (II) can be used as labeling precursor reagents for radioactive halogen-labeled compounds. Labeling precursor reagents for radioactive halogen-labeled compounds usually consist only of compounds represented by general formula (II), but may also contain other substances. Compounds represented by general formula (II) can be produced, for example, by reacting a compound represented by general formula (I) with a sugar, a peptide, or a compound containing a group represented by general formula (A) or (B).

[0045] Compounds represented by general formula (II) have the following advantages as precursor compounds for radioactive halogen-labeled compounds. 1) It has higher reactivity than conventional precursor compounds (for example, precursor compounds containing a benzenesulfonyloxy group as a leaving group), enabling highly efficient radioactive halogenation. 2) It is more stable, easier to handle, and can be stored than conventional precursor compounds (for example, precursor compounds containing a trifluoromethanesulfonyloxy group as a leaving group). 3) Because it contains a hydrophobic moiety, the target labeled compound can be easily separated from the unreacted precursor compound after the reaction is complete.

[0046] A labeled precursor compound represented by general formula (IIa) can be produced, for example, by reacting a compound represented by general formula (I) with a compound having a hydroxyl group.

[0047] Radioactive halogen-labeled compounds represented by general formula (IIIa) can be produced by reacting a labeled precursor compound represented by general formula (IIa) with a radioactive halide ion. The radioactive halide ion used is not particularly limited, however 18 F - , or 211 At - And more preferably, 211 At - The reaction conditions can be appropriately set depending on the type of precursor compound and radioactive halide ion. A person skilled in the art can easily determine the appropriate reaction temperature, reaction time, and the concentration of each substance. [Examples]

[0048] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0049] [Example 1] Synthesis of halogen-labeled compounds (1) Synthesis of 4-fluorosulfonylbenzoic acid chloride (2) [ka] To a stirred solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1) (1.00 g, 5.62 mmol, 1.00 eq.), PCl5 (1.31 g, 6.29 mmol, 1.12 eq.) was added at room temperature. After stirring at 60°C for 3 hours, the reaction mixture was distilled to obtain 4-fluorosulfonylbenzoic acid chloride (2) (1.03 g, 5.24 mmol, 93%).

[0050] (2) Synthesis of 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonylfluoride (3) [ka] A stirred solution of dioctylamine (4.40 mL, 14.6 mmol, 2.60 eq.) in CH2Cl2 (2.00 mL) was added at 0°C to a solution of 4-fluorosulfonylbenzoate chloride (2) (1.03 g, 5.24 mmol, 93%) in CH2Cl2 (2.50 mL). After stirring at the same temperature for 3 hours, the reaction mixture was poured into Et2O. The residue was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using toluene to obtain 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (3) (534 mg, 1.33 mmol, 24%).

[0051] (3) Synthesis of 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonylfluoride (4) [ka] To a stirred solution of NEt3 (3.52 mL, 25.3 mmol, 3.00 eq.) and didodecylamine (3.58 g, 10.1 mmol, 1.20 eq.) in CH2Cl2 (5.80 mL), a solution of 4-fluorosulfonylbenzoic acid chloride (2) (1.03 g, 5.24 mmol, 93%) was added at -40°C. After stirring at the same temperature for 40 minutes, the reaction mixture was poured into Et2O. The residue was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using toluene to obtain 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (4) (961 mg, 1.87 mmol, 22%).

[0052] (4) Synthesis of (E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (6) [ka] To a stirred solution of 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (3) (164.9 mg, 0.414 mmol, 2.00 eq.) and (2,2-dimethyl-(E)-(5-(4-(2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)-1,3-dioxan-5-yl)methanol (5) (108.3 mg, 0.207 mmol, 1.00 eq.) in CH3CN (0.951 mL), MTBD (89.7 μL, 0.621 mmol, 3.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extracts were washed with brine, dried on MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane:siRNA(80:20) to obtain (E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate(6) (47.4 mg, 0.0524 mmol, 25%).

[0053] (5) Synthesis of (E)-(5-(4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl-2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (7) [ka] To a stirred solution of 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (4) (103.5 mg, 0.202 mmol, 1.60 eq.) and (2,2-dimethyl-(E)-(5-(4-(2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)-1,3-dioxan-5-yl)methanol (5) (66.1 mg, 0.207 mmol, 1.00 eq.) in CH3CN (0.624 mL), MTBD (54.7 μL, 0.379 mmol, 3.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extracts were washed with brine, dried on MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with hexane:siRNA(80:20) to obtain (E)-(5-(4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl-2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate(7) (109.8 mg, 0.108 mmol, 86%).

[0054] (6) Synthesis of 5-iodomethyl-(E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxane (8) [ka] To a stirred solution of (E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (7) (50.6 mg, 0.0497 mmol, 1.00 eq.) in DMF (0.280 mL), potassium iodide (18.3 mg, 0.0995 mmol, 2.00 eq.) was added at 60°C. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured into a 10% Na2SO4 aqueous solution. The aqueous layer was extracted twice with ELISA. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane:SiO(80:20) to obtain 5-iodomethyl-(E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxane(8) (28.3 mg, 0.0447 mmol, 90%).

[0055] (7) Synthesis of 1-(4-(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propoxy)benzyl)guanidine (9) [ka] To a stirred solution of (E)-(5-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (8) (12.0.0 mg.0189 mmol, 1.00 eq.) in ELISA (0.150 mL), 3M HCl (0.150 mL) was added at 60°C. After stirring at the same temperature for 45 minutes, the reaction mixture was poured into MeOH and concentrated under vacuum. The residue was purified by bond elution with water to obtain 1-(4-(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propoxy)benzyl)guanidine (9) (4.9 mg, 0.00120 mmol, 66%).

[0056] (8) Synthesis of (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (11) [ka] To a stirred solution of 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (3) (328 mg, 0.818 mmol, 2.00 eq.) and (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (10) (138 mg, 0.435 mmol, 1.00 eq.) in CH3CN (0.951 mL), MTBD (189 μL, 1.31 mmol, 3.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane:siRNA(80:20) to obtain (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (11) (23.1 mg, 0.0330 mmol, 8%).

[0057] (9) Synthesis of (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (12) [ka] To a stirred solution of 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonylfluoride (4) (103.2 mg, 0.201 mmol, 1.50 eq.) and (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (10) (43.0 mg, 0.134 mmol, 1.00 eq.) in CH3CN (0.624 mL), MTBD (38.7 μL, 0.268 mmol, 2.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using toluene:siRNA (90:10) to obtain (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (12) (84.2 mg, 0.104 mmol, 78%).

[0058] (10) Synthesis of 5-iodomethyl-5-((naphthalene-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane (14) [ka] To a stirred solution of (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)trifluoromethanesulfonate methyl (13) (11.0 mg, 0.0245 mmol, 1.00 eq.) in CH3CN (0.350 mL), potassium iodide (5.20 mg, 0.0310 mmol, 1.30 eq.) was added at room temperature. After stirring at 60°C for 30 minutes, the reaction mixture was poured into a 10% Na2SO3 aqueous solution, and the aqueous layer was extracted twice with ELISA. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with hexane:siRNA(80:20) to obtain 5-iodomethyl-5-((naphthalene-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane(14) (7.8 mg, 0.0180 mmol, 75%).

[0059] (11) Synthesis of (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (16) [ka] To a stirred solution of 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (3) (118 mg, 0.294 mmol, 1.50 eq.) and (2,2-dimethyl-5-((2-nitro-1H-imidazole-1-yl)methyl)-1,3-dioxan-5-yl)methanol (15) (52.6 mg, 0.194 mmol, 1.00 eq.) in CH3CN (0.725 mL), MTBD (56.6 μL, 0.392 mmol, 2.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane:siRNA(80:20) to obtain (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (16) (55.9 mg, 0.0856 mmol, 44%).

[0060] (12) Synthesis of (2,2-dimethyl-5-((naphthalene-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (12) [ka] To a stirred solution of 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonyl fluoride (4) (124 mg, 0.241 mmol, 1.50 eq.) and (2,2-dimethyl-5-((2-nitro-1H-imidazole-1-yl)methyl)-1,3-dioxan-5-yl)methanol (15) (43.7 mg, 0.161 mmol, 1.00 eq.) in CH3CN (0.702 mL), MTBD (46.4 μL, 0.321 mmol, 2.00 eq.) was added at 0°C. After stirring at the same temperature for 20 minutes, the reaction mixture was poured into an aqueous solution of NH4Cl, and the aqueous layer was extracted twice with ELISA. The combined extract was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with toluene:siRNA (90:10) to obtain (2,2-dimethyl-5-((2-nitro-1H-imidazole-1-yl)methyl)-1,3-dioxan-5-yl)methyl 2-(didodecylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (17) (73.3 mg, 0.0958 mmol, 60%).

[0061] (13) Synthesis of 5-iodomethyl-5-((naphthalene-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane (19) [ka] To a stirred solution of (2,2-dimethyl-5-((2-nitro-1H-imidazole-1-yl)methyl)-1,3-dioxan-5-yl)methyl-4-methylbenzenesulfonic acid (18) (48.8 mg, 0.115 mmol, 1.00 eq.) in CH3CN (0.651 mL), potassium iodide (86.0 mg, 0.518 mmol, 4.50 eq.) was added at room temperature. After stirring at 60°C for 30 minutes, the reaction mixture was poured into a 10% Na2SO3 aqueous solution, and the aqueous layer was extracted twice with siRNA. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with hexane:siRNA (50:50) to obtain 5-iodomethyl-5-((naphthalene-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane (19) (24.2 mg, 0.0635 mmol, 55%).

[0062] (14) Synthesis of 2-(iodomethyl)-2-((2-nitro-1H-imidazole-1-yl)methyl)propane-1,3-diol (20) [ka] To a stirred solution of 1-((5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-2-nitro-1H-imidazole (19) (10.0 mg, 0.0262 mmol, 1.00 eq.) in MeOH (0.262 mL), TFA (0.606 μL) was added at 0°C. After stirring at 60°C for 1.5 hours, the reaction mixture was poured into toluene and concentrated under vacuum. The residue was purified by column chromatography on silica gel using chloroform:MeOH (90:10) to obtain 2-(iodomethyl)-2-((2-nitro-1H-imidazole-1-yl)methyl)propan-1,3-diol (20) (8.9 mg, 0.0260 mmol, 99%).

[0063] [Example 2] Synthesis of halogen-labeled precursor compound (1) Synthesis of (5-(benzyl oxmethyl)-2,2-dimethyl-1,3-dioxylan-5-yl)methanol [ka]

[0064] Synthesis of (1-1)4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane Pentaerythritol (10.0 g, 73.4 mmol), 1,1,1-trimethoxyethane (28.7 mL, 220 mmol, 3.00 eq.), and p-toluenesulfonic acid monohydrate (140 mg, 0.734 mmol, 0.01 eq.) were reacted in toluene (36.5 mL) at 0°C for 12 hours. Then, pentaerythritol (10.0 g, 73.4 mmol, 1.00 eq.) was added and the mixture was reacted at 130°C for 3 hours, after which triethylamine (1.0 mL) was added for neutralization. After concentrating the product under reduced pressure, the title compound (4.98 g, 31.1 mmol, 43%) was obtained as white crystals by recrystallization using toluene, diethyl ether, and hexane. [ka] 1 H NMR (400 MHz, CDCl3) δ 4.05 (s, 6H, Hb), 3.46 (s, 2H, Ha,), 1.45 (s, 3H, Hc);

[0065] Synthesis of (1-2)2-(benzyloxymethyl)-2-(hydroxymethyl)propane-1,3-diol Sodium hydride (3.17 g, 132 mmol, 2.12 eq.) was washed with dry hexane, then dry N,N-dimethylsulfuramide (15.5 mL) was added, followed by the addition of a solution of 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane in dry N,N-dimethylsulfuramide (15.5 mL) at 0°C. After stirring at room temperature for 1 hour, benzyl bromide (11.1 mL, 93.7 mmol, 1.50 eq.) was added at 0°C. After reacting at room temperature for 2 hours, methanol (5.0 ml) was added, and the mixture was poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the mixture was dried over magnesium sulfate. The solution, after removing magnesium sulfate by filtration, was concentrated under reduced pressure. The resulting residue was diluted with methanol (100 mL), and camphor sulfonic acid (1.45 g, 6.24 mmol, 0.01 eq.) was added. The mixture was reacted at room temperature for 12 hours. After draining the reaction solution into water, it was washed with hexane / ethyl acetate (9:1), and the target product was extracted from the remaining aqueous layer using ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After removing the magnesium sulfate by filtration, the resulting solution was concentrated to obtain the title compound (7.38 g, 32.6 mmol, 52%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.26-7.36 (m, 5H, H-aromatic), 4.48 (s, 2H, Ha), 3.68 (s, 6H, Hc), 3.47 (s, 2H, Hb), 2.17 (s, 3H, Hd);

[0066] Synthesis of (1-3)(5-(benzyl oxymethyl)-2,2-dimethyl-1,3-dioxyran-5-yl)methanol 2,2-dimethoxypropane (4.8 mL, 38.9 mmol, 1.20 eq.) was added at room temperature to a solution of 2-(benzyloxymethyl)-2-(hydroxymethyl)propane-1,3-diol (7.34 g, 32.4 mmol, 1.0 eq.) and camphor sulfonic acid (7.54 mg, 0.0324 mmol, 0.001 eq.) in N,N-dimethylformamide (16.2 mL). The reaction solution was incubated at 60°C for 40 minutes, then neutralized with triethylamine and poured into water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized over hexane and ethyl acetate to obtain the title compound (6.30 g, 23.6 mmol, 73%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.28-7.38 (m, 5H, H-aromatic), 4.54 (s, 2H, Ha), 3.73 (m, 4H, Hd), 3.68(d, 2H, He, J = 6.0 Hz ), 3.58 (s, 2H, Hc), 2.35 (t, 1H, He, J = 6.0 Hz), 1.41 (d, 6H, Hf, J = 5.6 Hz);

[0067] (2) Synthesis of tert-butyl 2-((5-((benzyloxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)acetate [ka] Sodium hydride (1.75 g, 43.7 mmol, 2.00 eq.) was washed with dry hexane, and then dry N,N-dimethylsulfuramide (16.4 ml) was added. Subsequently, tert-butyl 2-bromoacetate (4.81 mL, 32.8 mmol, 1.50 eq.) was added at 0°C. After reacting at room temperature for 1 hour, the reaction was stopped by adding ethanol, and then the mixture was poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After removing the magnesium sulfate by filtration, the mixture was concentrated under reduced pressure. The resulting residue was diluted with methanol (42 mL), and then potassium carbonate (5.83 g, 42.2 mmol, 2.0 eq.) and water (0.761 mL, 42.2 mmol, 2.0 eq.) were added at 0°C. After reacting at room temperature for 2.5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was diluted in dry N,N-dimethylformamide (60 mL), and then potassium carbonate (11.7 g, 84.5 mmol, 4.0 eq.) and iodomethane (3.96 mL, 63.4 mmol, 3.0 eq.) were added. After reacting at room temperature for 2 hours, the reaction solution was poured into saturated ammonium chloride aqueous solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried using magnesium sulfate. After removing the magnesium sulfate by filtration, the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (2.84 g, 8.39 mmol, 40%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.26-7.36 (m, 5H, H-aromatic), 4.52 (s, 2H, Ha), 4.07(s, 2H, Hd), 3.80 (s, 4H, Hc), 3.73 (s, 3H, Hf), 3.58 (s, 2H, Hb), 3.51 (s, 2H, Hg),1.41 (d, 6H, He, J = 4.4 Hz);

[0068] (3) Synthesis of 2-((5-((hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)acetamide [ka]

[0069] Synthesis of (3-1)2-((5-((benzyloxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)acetamide To a solution of tert-butyl 2-((5-((benzyloxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy) acetate (8.75 g, 25.9 mmol, 1.0 eq.) in methanol (13.5 mL), ammonia (13.5 mL) was added at -30°C. After sealing the tube, the mixture was reacted at room temperature for 12 hours. After opening, the mixture was stirred at room temperature to remove the ammonia, followed by removal of the methanol under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.48 g, 23.1 mmol, 89%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.28-7.38 (m, 5H, H-aromatic), 6.77 (br, 1H, NH), 5.35 (br, 1H, NH), 4.51 (s, 2H, Ha), 3.94 (s, 2H, Hd), 3.74 (m, 4H, Hc), 3.60 (s, 2H, Hb), 3.48 (s, 2H, Hg), 1.41 (d, 6H, He, J = 6.4 Hz);

[0070] Synthesis of (3-2)2-((5-((hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)acetamide To a suspension of Pd / C (6.93 g, 0.3 g / mmol, 10%) in tetrahydrofuran (348 mL), 2-((5-((benzyloxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)acetamide (7.48 g, 23.1 mmol, 1.0 eq.) was added. The reaction vessel was placed under atmospheric pressure and a hydrogen atmosphere, and the reaction was carried out at room temperature for 2 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.13 g, 17.7 mmol, 76%). [ka] 1 H NMR (400 MHz, CDCl3) δ 6.76 (br, 1H, NH), 5.41 (br, 1H, NH), 4.01 (s, 2H, Hd), 3.74 (m, 4H, Hc), 3.70 (d, 2H, Ha, J = 5.2 Hz ), 3.64 (s, 2H, Hb), 1.42 (d, 6H, He, J = 6.4 Hz);

[0071] (4) Synthesis of (5-((2-(bis(tert-butoxycarbonyl)amino)-2-oxoethyl)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate [ka]

[0072] Synthesis of (4-1)(5-((2-amino-2-oxaethoxy)methyl)-2,2-dimethyl-1,3-oxiran-5-yl)methyl 2-(didioctylamino)-1,1-difluoro-2-oxaethane-1-sulfonate To a 1.0 mL dry acetonitrile solution of 2-((5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxylan-5-yl)methoxy)acetamide (100 mg, 429 μmol, 1.0 eq.), 124 μL, 857 μmol, 2.0 eq. and a 1.0 mL dry acetonitrile solution of 2-(dioctylamino)-1,1-difluoro-2-oxaethane-1-sulfonylfluoride (258 mg, 643 μmol, 1.5 eq.) were added at 0°C. After reacting under ice cooling for 1.5 hours, the reaction solution was poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, and then dried over magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography to obtain the title compound (63.5 mg, 103 μmol, 24%). [ka] 1 H NMR (400 MHz, CDCl3) δ 6.71 (br, 1H, NH), 5.49 (br, 1H, NH), 4.61 (s, 2H, Hd), 4.00 (s, 2H, Ha), 3.75 (m, 4H, Hc), 3.57 (s, 2H, Hb ), 3.36 (m, 4H, Hg), 1.42 (d, 6H, He, J = 2.5 Hz), 1.27 (m, 24H, Hh), 0.881(m, 6H, Hi); 19 F NMR (400 MHz, CDCl3) δ -98.0 (s, 2F, F-1)

[0073] Synthesis of (4-2)(5-((2-(bis(tert-butoxycarbonyl)amino)-2-oxoethyl)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (5-((2-amino-2-oxaethoxy)methyl)-2,2-dimethyl-1,3-oxiran-5-yl)methyl 2-(didioctylamino)-1,1-difluoro-2-oxaethane-1-sulfonate (40 mg, 65 μmol, 1.0 eq.) was mixed with a 30% 1,4-dioxane solution of di-tert-butyl dicarbonate (110 μL, 160 μmol, 2.5 eq.) and N,N-dimethylaminopyridine (7.9 mg, 65 μmol, 1.0 eq.) at 0°C. After reacting at room temperature for two hours, the mixture was poured into a mixture of ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The filtrate, after removing magnesium sulfate by filtration, was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (47 mg, 58 μmol, 89%). [ka] 1 H NMR (400 MHz, CDCl3) δ 4.70 (s, 2H, Hd), 4.52 (s, 2H, Ha), 3.81 (m, 4H, Hc), 3.53 (s, 2H, Hb ), 3.39 (m, 4H, Hg), 1.53 (s, 18H, Hf ), 1.41 (d, 6H, He, J = 4.5 Hz), 1.27 (m, 24H, Hh), 0.881(m, 6H, Hi); 19 F NMR (400 MHz, CDCl3) δ -98.1 (s, 2F, F-1)

[0074] (5) Synthesis of (2R,3R)-5,7-dimethoxy-8-((N-methylamino)methyl)-2-(3,4,5-trimethoxyphenyl)chroman-3-ol [ka]

[0075] Synthesis of (5-1)(2R,3R)-5,7-dimethoxy-2-(3,4,5-triphenoxyphenyl)chroman-3-yl 3,4,5-trimethoxybenzoate (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxy)chroman-3-yl 3,4,5-trihydroxybenzoate (5.00 g, 10.9 mmol, 1.0 eq.) was dissolved in dried N,N,-dimethylformamide (50 mL) and potassium carbonate (18.1 g, 131 mmol, 12.0 eq.) and iodomethane (6.79 mL, 109 mmol, 10.0 eq.) were added at 0°C. After reacting at room temperature for 12 hours, the mixture was poured into a mixture of ethyl acetate and saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The resulting organic layer was dried over magnesium sulfate, and the magnesium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.28 g, 925 mmol, 85%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.18 (s, 2H, Hd), 6.70 (s, 2h, Hb), 6.23 (d, 1H, H-6, J =2.4Hz), 6.12 (d, 1H, H-8, J =2.0Hz), 5.67 (br, 1H, H-3), 5.09 (s, 1H, H-2), 3.86-3.70 (m, 24H, H-Me), 3.05 (d, 2H, H-4, J = 3.6Hz);

[0076] Synthesis of (5-2)(2R,3R)-8-formyl-5,7-dimethoxy-2-(3,4,5-trimethoxy)chroman-3-nyl 3,4,5-trimethoxybenzoate To 4.28 mL of dried N,N,-dimethylformamide, phosphoryl chloride (180 μL, 1.93 mmol, 1.1 eq.) was added at 0°C. After reacting at room temperature for 30 minutes, a solution of (2R,3R)-5,7-dimethoxy-2-(3,4,5-triphenoxyphenyl)chroman-3-yl 3,4,5-trimethoxybenzoate (1.00 g, 1.75 mmol, 1.0 eq.) in dried N,N-dimethylformamide was added at 0°C. After stirring for a further 2 hours at room temperature, the reaction solution was poured into sodium bicarbonate solution and ethyl acetate at 0°C. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The filtrate, after removing magnesium sulfate by filtration, was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (788 mg, 1.29 mmol, 73%). [ka] 1 H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H, H-CHO), 7.11 (s, 2H, Hd), 6.86 (s, 2H, Hb), 6.10 (s, 1H, H-6), 5.73 (br, 1H, H-3), 5.24 (s, 1H, H-2), 3.94-3.70 (m, 24H, H-Me), 3.08 (m, 2H, H-4);

[0077] Synthesis of (5-3)(2R,3R)-5,7-dimethoxy-8-((N-methylamino)methyl)-2-(3,4,5-trimethoxyphenyl)chroman-3-ol (2R,3R)-8-formyl-5,7-dimethoxy-2-(3,4,5-trimethoxy)chroman-3-nyl 3,4,5-trimethoxybenzoate (1.00 g, 1.67 mmol) was reacted in 40% aqueous methylamine solution (20 mL, 0.24 mol) at room temperature for 24 hours. The reaction solution was poured into a mixture of methylene chloride and water, and the organic layer was washed with water. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in ethanol (7.0 mL), and then sodium borohydride (316 mg, 8.53 mmol, 5.0 eq.) was added at 0°C. After reacting at room temperature for 24 hours, the mixture was poured into methylene chloride and water. The aqueous layer was extracted with methylene chloride, and then the organic layer was extracted with 1 M hydrochloric acid. The aqueous layer was adjusted to pH 9 using sodium bicarbonate and potassium carbonate, and then extracted with dichloromethane. The resulting organic layer was filtered over magnesium sulfate and concentrated under reduced pressure to obtain the title compound (390 mg, 931 μmol, 56%). [ka] 1 H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H, H-CHO), 6.78 (s, 2h, Hb), 6.12 (s, 1H, H-6), 4.94 (s, 1H, H-2), 4.28 (br, 1H, H-3), 3.90-3.84 (m, 24H, H-Me), 3.00 (d, 2H, Ha, J = 3.0 Hz), 2.89 (m, 2H, H-4), 2.39 (s, 3H, H-NHMe);

[0078] (6) Synthesis of 3,4,5-tris(methoxymethyl)benzoic acid [ka]

[0079] (6-1) Synthesis of methyl 3,4,5-tris(methoxymethyl)benzoate Diisopropylethylamine (7.1 mL, 40.7 mmol, 7.5 eq.) and chloro(methoxy)methane (1.86 mL, 24.4 mmol, 4.5 eq.) were added to a 54 mL solution of methyl 3,4,5-trihydroxybenzoate (1.00 g, 5.43 mmol, 1.0 eq.) in dichloromethane at 0°C. After reacting at room temperature for 2 hours, the mixture was poured into saturated ammonium chloride aqueous solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. The filtrate, after removing magnesium sulfate by filtration, was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.64 g, 5.21 mmol, 96%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 2H, Hb), 5.25 (s, 4H, Hc), 5.22 (s, 2H, Hd), 3.89 (s, 3H, Ha), 3.61 (s, 3H, Hf), 3.51 (s, 6H, He);

[0080] (6-2) Synthesis of 3,4,5-tris(methoxymethyl)benzoic acid To a methanol solution (3.2 mL) of methyl 3,4,5-tris(methoxymethyl)benzoate (2-34) (623 mg, 1.97 mmol, 1.0 eq.), potassium carbonate (544 mg, 3.94 mmol, 2.0 eq.) and water (3.2 mL) were added at room temperature. After reacting at 70°C for 2 hours, the reaction solution was poured into ammonium chloride, 1 M hydrochloric acid, and ethyl acetate. The aqueous layer was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and dried over magnesium sulfate. The resulting residue was recrystallized using chloroform and hexane to obtain the title compound (518 mg, 1.71 mmol, 87%). [ka] 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H, Hb), 5.26 (s, 4H, Hc), 5.24 (s, 2H, Hd), 3.58 (s, 3H, Hf), 3.52 (s, 6H, He);

[0081] (7)(2R,3R)-8-((2-((5-((((2-(N,N-dioctylamino)-1,1-difluorolo-2-oxoethyl)sulfonyl)oxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-N-methylacetamide)methyl)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl Synthesis of 3,4,5-tris(methoxymethyl)benzoate [ka]

[0082] Synthesis of (7-1)(5-((2-((((2R,3R)-3-hydroxy-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-8-yl)methyl)(N-methylamino)-2-oxoethyl)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(N,N-dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (5-((2-(bis(tert-butoxycarbonyl)amino)-2-oxoethyl)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(N,N-dioctylamino)-1,1-fluoro-2-oxoethane-1-sulfonate (40 mg, 48 μmol, 1.0 eq.) was added to a dry dichloromethane solution (1.0 mL) with (2R,3R)-5,7-dimethoxy-8-((N-methylamino)methyl)-2-(3,4,5-trimethoxy)chroman-3-ol (24 mg, 58 μmol, 1.2 eq.) and N,N-dimethylaminopyridine (5.9 mg, 48 μmol, 1.0 eq.) at 0°C. After reacting at room temperature for 2 hours, the mixture was poured into ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After filtering off the magnesium sulfate, the mixture was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (19.3 mg, 19.0 μmol, 40%). [ka] 1 H NMR (400 MHz, CDCl3) δ 6.75, 6.69 (s, 2H, HB), 6.15, 6.14 (s, 1H, H-6), 4.97,4.95 (s, 1H, H-2), 4.70, 4.68 (s, 2H, Hd), 4.34 (s, 2H, Ha), 4.24 (br, 1H, H-3), 4.12 (m, 4H, Hc), 3.92-3.82 (m, 15H, H-Me), 3.82 (m, 2H, HA), 3.76-3.71 (m, 3H, H-NMe- ), 3.41 (s, 2H, Hb ), 3.41-3.34 (m, 4H, Hg), 3.02-2.87 (m, 2H, H-4), 2.79 (s, 3H, H-NHMe), 1.40 (d, 6H, He, J = 3.5 Hz), 1.27- 1.24(m, 24H, Hh), 0.883 - 0.856 (m, 6H, Hi); 19 F NMR (400 MHz, CDCl3) δ -98.1 (s, 2F, F-1)

[0083] (7-2)(2R,3R)-8-((2-((5-((((2-(N,N-dioctylamino)-1,1-difluorolo-2-oxoethyl)sulfonyl)oxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-N-methylacetamide)methyl)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-3-yl synthesis of 3,4,5-tris(methoxymethyl)benzoate (5-((2-((((2R,3R)-3-hydroxy-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)chroman-8-yl)methyl)(N-methylamino)-2-oxoethyl)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl 2-(N,N-dioctylamino)-1,1-difluoro-2-oxoethane-1-sulfonate (23 mg, 23 μmol, 1.0 eq.) in a dry dichloromethane solution (1.0 mL), to which 3,4,5-tris(methoxymethyl)benzoic acid (10 mg, 34 μmol, 1.5 eq.) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (21 mg, 45 μmol, 2.0 eq.) are added. N,N,-dimethylaminopyridine (2.8 mg, 23 μmol, 1.0 eq.) was added at 0°C. After stirring for 15 minutes at room temperature, the reaction solution was poured into saturated ammonium chloride aqueous solution and ethyl acetate. After extracting the aqueous layer with ethyl acetate, the organic layer was washed with saturated brine and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the mixture was concentrated under reduced pressure. The title compound was obtained by purifying the resulting residue by silica gel column chromatography (14.7 mg, 17 μmol, 50%). [ka] 1H NMR (400 MHz, CDCl3) δ 7.37,7.35 (s, 2H, HD), 6.71,6.67 (s, 2H, HB), 6.13 (s, 1H, H-6), 5.61, 5.64 (br, 1H, H-3), 5.20~5.11(m, 6H, Hj,k), 5.05 (s, 1H, H-2), 4.71, 4.67 (s, 2H, Hd), 4.51~4.34(m, 4H, Hc), 3.84 ~3.74 (m,19H,Ha,A,Me), 3.56 (s, 3H, Hm), 3.44 (s, 6H, Hl), 3.42 (s, 2H, Hb), 3.40-3.34 (m, 4H, Hg), 3.06-3.00 (m, 2H, H-4), 2.86 (s, 3H, H-NHMe), 1.40 (d, 6H, He, J = 4.0 Hz), 1.28- 1.24(m, 24H, Hh), 0.921 - 0.854 (m, 6H, Hi); 19 F NMR (400 MHz, CDCl3) δ -98.1 (s, 2F, F-1)

[0084] [Example 3] 211 Reactivity and stability at At labeling Astatine-211 211 At) uses a cyclotron to irradiate stable isotopes of bismuth with an alpha beam. 209 Bi(α,2n) 211 It was produced by the nuclear reaction of At. 211 At was isolated by distillation using a 20% oxygen / nitrogen gas mixture as a carrier gas, heated in a furnace at 850°C, and then recovered by washing the downstream capture tube with a solvent of the choice. 211 The At solution was concentrated using the method described below and used for labeling.

[0085] (1) Using carbonates 211 Concentration of At solution In previous studies, it was recovered using methanol. 211By adding 72.4 μmol of sodium, potassium, cesium, and other bicarbonates and carbonates to 100 μL of At solution, 211 It was confirmed that the solvent could be removed with nitrogen gas while minimizing the volatilization of At. In this study, potassium carbonate and cesium carbonate were dissolved in methanol, and 3.6 μmol of the carbonate was prepared in liquid form. 211 It was mixed with At solution. Then, a venting needle connected to activated carbon was attached, and the solvent was removed with nitrogen gas. The vial before and after solvent removal 211 We measured the radioactivity of At. 211 The At survival rate was calculated. The results are shown in Table 1. [Table 1]

[0086] (2) A labeled precursor having a novel leaving group 211 At sign Table 1, bottom row: Two liquid carbonates, 3.6 μmol each, concentrated under specific conditions. 211 After removing the solvent from At, labeled precursors A and B (2.2 μmol / 100 μL) dissolved in anhydrous acetonitrile were added and thoroughly mixed using a vortex mixer. The labeled precursors were reacted at room temperature and 60°C. 211 The generation rate of the At-labeled compound (C) was determined by TLC. 1 μL of the reaction solution was spotted onto the TLC plate at different time points, and after 2 minutes, the solution was developed with hexane:ethyl acetate in a 4:1 ratio. The generation rate of C was measured by autoradiography. The results are shown in Table 2. Furthermore, to confirm that the precursor was less damaged when using B than when using A, the change in the TLC spot when exposed to 254 nm UV light was observed (Figure 1). [ka] [Table 2]

[0087] The leaving group (CDf8) of the newly developed labeled precursor B was designed to have a lower acidity than triflate, the leaving group of A, but higher acidity than tosyl (acidity pKa: triflate = -14, tosyl = 0.7). Therefore, labeled precursor B is expected to be more reactive than precursors with a tosyl group and more moderately stable than precursors with a triflate group. In this study, TLC analysis confirmed that the At labeling of labeled precursor B proceeded sufficiently. Furthermore, while numerous spots were observed on the TLC over time in A, which has a triflate group, indicating decomposition (Figure 1 top), it was revealed that precursor B suffered less damage (Figure 1 bottom). [Industrial applicability]

[0088] Since radioactive halogen-labeled compounds can be used in pharmaceuticals, the present invention is applicable to industrial fields related to pharmaceuticals.

Claims

1. The following general formula (I) 【Chemistry 1】 [In the formula, R １ and R ２ each independently represents an alkyl group having 5 to 20 carbon atoms, and X １ and X ２ each independently represents a halogen atom; X ３ represents a halogen atom. A compound represented by the formula:

2. R in general formula (I) １ and R ２ is an alkyl group having 7 to 11 carbon atoms.

3. X in general formula (I) １ and X ２ The compound according to claim 1 or 2, wherein is a fluorine atom or a chlorine atom.

4. The following general formula (II) 【Chemistry 2】 [In the formula, R １ and R ２ each independently represents an alkyl group having 5 to 20 carbon atoms, and X １ and X ２ each independently represents a halogen atom; R ３ is a monovalent group derived from a sugar, a monovalent group derived from a peptide, or a group represented by the following general formula (A) or (B): 【Transformation 3】 【Chemistry 4】 (wherein L represents a divalent group that functions as a spacer, R ４ represents an aryl group which may be substituted with a substituent, a heteroaryl group which may be substituted with a substituent, or an aminocarbonyl group which may be protected with a protecting group, and * represents a binding site. represents a group represented by the following formula: A compound represented by the formula:

5. R in general formula (II) １ and R ２ is an alkyl group having 7 to 11 carbon atoms.

6. X in general formula (II) １ and X ２ The compound according to claim 4 or 5, wherein is a fluorine atom or a chlorine atom.

7. In the general formula (A) or (B), L is an alkylene group (provided that the alkylene group has one or more —CH ２ 7. The compound according to claim 4, wherein - may be substituted with -O- or a phenylene group.

8. R in general formula (A) or (B) ４ is a 4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl group, a naphthalen-2-yl group, a 2-nitro-1H-imidazol-1-yl group, or an aminocarbonyl group protected with a tert-butoxycarbonyl group.

9. The following general formula (IIIa) 【Transformation 5】 [In the formula, X ４ represents a radioactive halogen atom, R ３ａ represents a monovalent group derived from a compound to be labeled with a radioactive halogen atom. The present invention relates to a method for producing a radioactive halogen-labeled compound represented by the following general formula (IIa): 【Transformation 6】 [In the formula, R １ and R ２ each independently represents an alkyl group having 5 to 20 carbon atoms, and X １ and X ２ each independently represents a halogen atom; R ３ａ has the same meaning as above.] with a radioactive halide ion to obtain a radioactive halogen-labeled compound represented by general formula (IIIa).

10. R in general formula (IIa) １ and R ２ The method according to claim 9, wherein is an alkyl group having 7 to 11 carbon atoms.

11. X in general formula (IIa) １ and X ２ The method according to claim 9 or 10, wherein is a fluorine atom or a chlorine atom.

12. R in general formulas (IIa) and (IIIa) ３ａ is a monovalent group derived from a sugar, a monovalent group derived from a peptide, or a group represented by the following general formula (A) or (B): 【Transformation 7】 【Transformation 8】 (wherein L represents a divalent group that functions as a spacer, R ４ represents an aryl group which may be substituted with a substituent, a heteroaryl group which may be substituted with a substituent, or an aminocarbonyl group which may be protected with a protecting group, and * represents a binding site. The method according to any one of claims 9 to 11, wherein the group is

13. In the general formula (A) or (B), L is an alkylene group (provided that the alkylene group has one or more —CH ２ The compound according to claim 12, wherein - may be substituted with -O- or a phenylene group.

14. R in general formula (A) or (B) ４ is an aminocarbonyl group protected with a 4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl group, a naphthalen-2-yl group, a 2-nitro-1H-imidazol-1-yl group, or a tert-butoxycarbonyl group.

15. X in general formula (IIIa) ４ but, ２１１ 15. The method according to any one of claims 9 to 14, wherein At.

16. A reagent for producing a labeled precursor compound, comprising the compound according to any one of claims 1 to 3.

17. A labeled precursor reagent for a radioactive halogen-labeled compound, comprising the compound according to any one of claims 4 to 8.