A simple method for concentrating astatine.

Abstract

For the purpose of producing astatine-211 free from chloride ions with high yield, an astatine-211 production method is provided, the method being characterized by comprising: (1) a step for irradiating bismuth with an α ray to produce astatine-211; (2) a step for heating the astatine-211 produced in step (1) to vaporize the astatine-211; (3) a step for cooling the astatine-211 vaporized in step (2) and collecting the astatine-211 with a volatile and polar solvent to produce an astatine-211 solution; (4) a step for adding a weak acid salt to the astatine-211 solution produced in step (3) to produce an astatine-211 solution containing the weak acid salt; and (5) a step for removing the solvent from the astatine-211 solution containing the weak acid salt which is produced in step (4).

Description

[Technical Field]

[0001] The present invention relates to a method for producing astatine-211, and a method for producing an astatine-211 labeled compound using the astatine-211 produced by this method. [Background technology]

[0002] Astatine is a halogen element and is thought to have chemical properties similar to those of iodine. Astatine exists in several isotopes, but none are stable; all are radioactive. Astatine-211 is one such isotope and has recently attracted attention because it can be used in RI internal therapy to selectively destroy cancer cells.

[0003] Wet separation and dry separation are known methods for producing astatine-211. However, due to problems with wet separation, such as the introduction of impurities, dry separation is currently the mainstream. In the dry separation method, astatine-211 is produced by sequentially carrying out the following steps: 1) irradiating bismuth with α-particles to generate astatine-211; 2) heating and vaporizing the generated astatine-211; 3) cooling the vaporized astatine-211 and recovering it with a solvent; and 4) removing the solvent. It has long been pointed out that astatine is highly volatile and therefore dissipates with the solvent during solvent removal. However, the use of chloroform as a solvent prevents astatine-211 from dissipating (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] E. Aneheim et al., Sci Rep. 2019 Nov 4;9(1):15900 Summary of the Invention [Problem to be solved by the invention]

[0005] As described above, using chloroform as a solvent prevents astatine-211 from scattering and allows for a high recovery rate. However, when chloroform is used as a solvent, chloride ions liberated from chloroform are contaminated with astatine-211, albeit in trace amounts. These contaminated chloride ions are not a significant problem if the labeling reaction with astatine-211 is an electrophilic substitution reaction. However, if the labeling reaction is a nucleophilic substitution reaction, the chloride ions react with the labeling precursor instead of astatine-211, creating a major problem.

[0006] The present invention has been made under such circumstances, and aims to provide a means for preventing the scattering of astatine-211 when removing the solvent from an astatine-211 solution without using chloroform. [Means for solving the problem]

[0007] As a result of extensive research to solve the above problems, the inventors discovered that astatine-211 can be prevented from scattering without using chloroform by recovering astatine-211 using a solvent that does not contain chlorine atoms, such as alcohol, adding carbonate or bicarbonate to the resulting astatine solution, and then removing the solvent, thereby completing the present invention.

[0008] That is, the present invention provides the following [1] to

[12] . [1] A method for producing astatine-211, comprising the following steps (1) to (5): (1) a step of irradiating bismuth with α-particles to generate astatine-211; (2) heating and vaporizing the astatine-211 produced in step (1); (3) cooling the astatine-211 vaporized in step (2) and recovering it with a volatile and polar solvent to obtain an astatine-211 solution; (4) adding a weak acid salt to the astatine-211 solution obtained in step (3) to obtain an astatine-211 solution containing the weak acid salt; (5) A step of removing the solvent from the astatine-211 solution containing the weak acid salt obtained in step (4).

[0009] [2] The method for producing astatine-211 according to [1], wherein the weak acid salt is a carbonate or a bicarbonate.

[0010] [3] The method for producing astatine-211 according to [1], wherein the weak acid salt is an alkali metal carbonate or an alkali metal bicarbonate.

[0011] [4] The method for producing astatine-211 according to [1], wherein the weak acid salt is NaHCO3, Na2CO3, KHCO3, K2CO3, CsHCO3, or Cs2CO3.

[0012] [5] A method for producing astatine-211 according to any one of [1] to [4], characterized in that the volatile and polar solvent is methanol, ethanol, 2-propanol, or acetonitrile.

[0013] [6] A method for producing an astatine-211 labeled compound by reacting astatine-211 produced by the method for producing astatine-211 according to any one of [1] to [5] with a labeled precursor compound, wherein the reaction is a nucleophilic substitution reaction.

[0014] [7] The method for producing an astatine-211 labeled compound according to [6], wherein the labeled precursor compound is a compound having an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group, and the astatine-211 labeled compound is a compound in which the alkylsulfonyloxy group, the haloalkylsulfonyloxy group, or the arylsulfonyloxy group in the labeled precursor compound is substituted with astatine-211.

[0015] [8] The method for producing an astatine-211 labeled compound according to [6], wherein the labeled precursor compound is a compound having a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and the astatine-211 labeled compound is a compound in which the p-toluenesulfonyloxy group or the trifluoromethanesulfonyloxy group in the labeled precursor compound is substituted with astatine-211.

[0016] [9] A method for producing an astatine-211 labeled compound by reacting astatine-211 produced by the method for producing astatine-211 according to any one of [1] to [5] with a labeled precursor compound, wherein the reaction is an electrophilic substitution reaction.

[0017]

[10] The method for producing an astatine-211 labeled compound according to [9], wherein the electrophilic substitution reaction is an aromatic electrophilic substitution reaction.

[0018]

[11] The method for producing an astatine-211 labeled compound according to [9] or

[10] , characterized in that the labeled precursor compound is a compound having a trialkylsilyl group or a trialkylstannyl group, and the astatine-211 labeled compound is a compound in which the trialkylsilyl group or the trialkylstannyl group in the labeled precursor compound is substituted with astatine-211.

[0019]

[12] The method for producing an astatine-211 labeled compound according to [9] or

[10] , wherein the labeled precursor compound is a compound having a trimethylsilyl group or a tributylstannyl group, and the astatine-211 labeled compound is a compound in which the trimethylsilyl group or the tributylstannyl group in the labeled precursor compound is substituted with astatine-211.

[0020] This specification includes the contents disclosed in the specification and / or drawings of Japanese Patent Application No. 2020-081819, which is a priority document of this application. [Effects of the Invention]

[0021] The present invention provides a novel method for producing astatine-211. The production method of the present invention makes it possible to produce astatine-211 free from chloride ion contamination in high yield. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will be described in detail below. (A) Method for producing astatine-211 The method for producing astatine-211 of the present invention is characterized by comprising the following steps (1) to (5).

[0023] In step (1), bismuth is irradiated with α-particles to produce astatine-211. The irradiation of bismuth with alpha rays can be carried out using an accelerator. 209 Bi(α,2n) 211 A nuclear reaction of At occurs, which produces astatine-211.

[0024] In step (2), the astatine-211 produced in step (1) is heated and vaporized. Astatine-211 can be heated in a furnace. The temperature in the furnace is not particularly limited as long as it is a temperature at which astatine-211 can be vaporized, but is preferably 600 to 900°C, and more preferably 800 to 900°C.

[0025] In step (3), the astatine-211 vaporized in step (2) is cooled and recovered with a volatile and polar solvent to obtain an astatine-211 solution.

[0026] The method for cooling astatine-211 is not particularly limited, and examples include a method in which astatine-211 vaporized in a furnace is sent to a tube (cold trap) placed in a tank filled with a low-temperature liquid using a carrier gas. The carrier gas may be one commonly used in dry separation methods for astatine-211, such as helium or a mixture of nitrogen and oxygen. The liquid used in the cold trap may also be one commonly used in dry separation methods for astatine-211, such as liquid nitrogen or ethanol containing dry ice.

[0027] The method for recovering astatine-211 using a solvent is not particularly limited. For example, when astatine-211 is cooled using a cold trap as described above, a method of passing a solvent through the tube of the cold trap can be mentioned.

[0028] The solvent to be used is not particularly limited as long as it is volatile and polar. For example, methanol, ethanol, 2-propanol, or acetonitrile can be used. Among these, methanol is preferred because it has a low boiling point and is easily volatile.

[0029] The solvent preferably does not contain water, because the astatine-211 labeling reaction may be carried out under anhydrous conditions (for example, the astatine-211 labeling reaction of formula (I)-1 or formula (I)-2 described below is carried out under anhydrous conditions), and water is difficult to volatilize and may remain and adversely affect the reaction.

[0030] In addition, it is preferable that the solvent does not contain halogen atoms in its molecule, because if a solvent containing halogen atoms is used, the halide ions liberated from the solvent may adversely affect the reaction between astatine-211 and the labeled precursor compound.

[0031] In step (4), a weak acid salt is added to the astatine-211 solution obtained in step (3) to obtain an astatine-211 solution containing the weak acid salt.

[0032] Examples of weak acid salts that can be used include carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, and acetates. Of these, carbonates and bicarbonates are preferred. This is because the carbonate ions and bicarbonate ions contained in carbonates and bicarbonates evaporate as CO2 or HO, making them easily removable. The carbonates and bicarbonates are preferably salts of alkali metals, such as NaHCO3, Na2CO3, KHCO3, K2CO3, CsHCO3, and Cs2CO3.

[0033] The concentration of the weak acid salt in the astatine-211 solution is not particularly limited as long as it is a concentration that can prevent the scattering of astatine-211, but it is preferably 0.2 to 2.0M, more preferably 0.3 to 1.5M, and even more preferably 0.5 to 1.0M.

[0034] In step (5), the solvent is removed from the astatine-211 solution containing the weak acid salt obtained in step (4). The method for removing the solvent is preferably one that does not easily cause astatine-211 to scatter, and for example, a method of removing the solvent by blowing nitrogen gas can be mentioned.

[0035] (B) First Method for Producing Astatine-211 Labeled Compound The first method for producing an astatine-211-labeled compound of the present invention is a method for producing an astatine-211-labeled compound by reacting astatine-211 produced by the above-mentioned method for producing astatine-211 of the present invention (hereinafter referred to as "astatine-211 of the present invention") with a labeled precursor compound, wherein the reaction is a nucleophilic substitution reaction.

[0036] Astatine-211 recovered with a solvent such as alcohol is in the anionic state ( 211 At -) is presumed to exist. Therefore, the astatine-211 of the present invention acts as a nucleophile in a nucleophilic substitution reaction, reacts with various labeled precursor compounds, and generates an astatine-211 labeled compound.

[0037] The labeled precursor compound to be used is not particularly limited, but a compound having a leaving group for the nucleophilic substitution reaction of astatine-211 is preferred. The leaving group is not particularly limited, and examples thereof include an alkylsulfonyloxy group such as a methanesulfonyloxy group, a haloalkylsulfonyloxy group such as a trifluoromethanesulfonyloxy group, or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group. Preferred leaving groups include a trifluoromethanesulfonyloxy group or a p-toluenesulfonyloxy group. In addition, recently, compounds for stabilizing astatine-211 in vivo have been reported (WO2019 / 151384). The labeled precursor compound used in the present invention may be one that generates such a compound by reacting with astatine-211. For example, the compounds represented by the following formula (I)-1 or formula (I)-2 generate an astatine-211-containing compound stable in vivo (a compound represented by formula (II) described later) by reacting with astatine-211, so these compounds may be used as the labeled precursor compound.

Chemical formula

Chemical formula

[0038] The temperature, time, and solvent used in the reaction between the astatine-211 of the present invention and a labeled precursor compound can be determined depending on the reaction. For example, when reacting the astatine-211 of the present invention with a compound represented by formula (I)-1, the reaction temperature can be 50 to 150°C, preferably 80 to 120°C, the reaction time can be 10 to 60 minutes, preferably 20 to 40 minutes, and acetonitrile can be used as the solvent. Furthermore, when reacting the astatine-211 of the present invention with a compound represented by formula (I)-2, the reaction temperature can be 10 to 30°C, preferably 15 to 25°C, the reaction time can be 10 to 60 minutes, preferably 20 to 40 minutes, and acetonitrile can be used as the solvent.

[0039] (C) Second Method for Producing Astatine-211 Labeled Compounds The second method for producing an astatine-211-labeled compound of the present invention is a method for producing an astatine-211-labeled compound by reacting the astatine-211 of the present invention with a labeled precursor compound, wherein the reaction is an electrophilic substitution reaction.

[0040] The electrophilic substitution reaction is not particularly limited, but is preferably an aromatic electrophilic substitution reaction in which a leaving group on an aromatic ring is substituted with astatine-211.

[0041] The labeled precursor compound to be used is not particularly limited, but compounds having a leaving group that can be easily replaced by astatine-211, such as a trialkylsilyl group or a trialkylstannyl group, are preferred. Examples of trialkylsilyl groups include trimethylsilyl, triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, and tri-n-butylsilyl groups. Of these, the trimethylsilyl group (-SiMe3) is preferred. Examples of trialkylstannyl groups include trimethylstannyl, triethylstannyl, tripropylstannyl, and tributylstannyl groups. Of these, the tributylstannyl group (-SnBu3) is preferred. Recently, astatine-211-metaastatobenzylguanidine has attracted attention as an alpha-ray cancer treatment drug. Therefore, meta-trimethylsilylbenzylguanidine, a precursor of this compound, may be used as the labeled precursor compound. [Example]

[0042] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Example 1 211 Measurement of At survival rate Astatine-211( 211 At) is generated by irradiating a stable isotope of bismuth with an alpha beam using a cyclotron. 209 Bi(α,2n) 211 It was produced by the nuclear reaction of At with bismuth after irradiation. 211 At was isolated by distillation in a furnace at 850 °C (using a mixture of nitrogen and oxygen as the carrier gas), and the downstream trapping tube was washed with a solvent of choice. 211 The At solution was concentrated in the following manner.

[0043] 72.4 μmol of bicarbonate and carbonate salts of sodium, potassium, cesium, etc. were placed in a vial and collected with methanol. 211 100 μL of At solution was added and mixed well. 211The At solution was mixed with bicarbonate or carbonate within 60 minutes after recovery. Then, an aeration needle connected to activated carbon was attached, and the solvent was removed with nitrogen gas. The 211 radioactivity of At was measured before and after solvent removal, 211 and the At residual rate was determined (Table 1).

Table 1

[0044] As shown in Table 1, in all cases where any salt was added, the 211 At residual rate increased significantly compared to the case without adding salt.

[0045] 〔Example 2〕 211 Measurement of the production rate of the At-labeled compound 211 After removing the solvent from the At solution, the following labeling precursor (I)-1 or (I)-2 (21.3 μmol / 300 μL) dissolved in anhydrous acetonitrile was added and mixed well with a vortex mixer. The labeling precursor (I)-1 was allowed to act at 100 °C and the labeling precursor (I)-2 was allowed to act at room temperature for 30 minutes, 211 and the production rate of the At-labeled compound was determined by TLC (Table 2). Thin layer chromatography was performed on a 0.2 mm E. Merck silica gel plate (60F-254), visualized by an imaging plate (IP) system, and calculated by setting an ROI on the spot of the labeled product (II) (Rf 0.4). The developing solvent was hexane:ethyl acetate = 4:1, the IP used was BAS IP SR 2025 E, the exposure time was 2 hours, the IP reader was CD 35 Bio (Elysia-Raytest, Straubenhardt, Germany), and the analysis software was Aida Image Analyzer v.5.1 (Elysia-Raytest, Straubenhardt, Germany).

Chemical formula

Table 2

[0046] As shown in Table 2, the production rate varied depending on the type of salt used. For labeled precursor (I)-1, the production rate was high when CsHCO3 was used, and for labeled precursor (I)-2, the production rate was high when K2CO3 was used.

[0047] Example 3: Labeled precursor and 211 Synthesis of At-labeled compound analogues (iodine derivatives) The labeled precursor (I)-1 ((2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl(4-methyl)benzenesulfonate) and the labeled precursor (I)-2 (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl trifluoromethanesulfonate) were synthesized. 211 To demonstrate that At-labeled compound (I)-2 can be synthesized, 211 Instead of At, we synthesized a compound labeled with iodine (5-iodomethyl-5-((naphthalen-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane), which has similar chemical properties.

[0048] (1)General information NMR spectra were obtained using a Bruker AVANCE III HD 400 (400 MHz for 1 H, 100 MHz for 13 C, 373 Hz for 19 The chemical shifts were recorded on a 1000 ppm F instrument. The chemical shifts were determined by the signal of the internal tetramethylsilane in CDCl3 solution (δ 0 ppm for 1 NMR spectral data are reported in parts per million (ppm) relative to 1H. 1 H), DMSO-d6 (2.50 ppm for 1 H), CD3OD-d4 (3.31 ppm for 1 H), CD3CN-d4 (3.31 ppm for 1H), or chloroform-d (77.16 ppm for 13 C), C6H5CF3(-63.24 ppm for 19 Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; and J, coupling constant in Hertz.

[0049] IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR spectrophotometer. Only the most intense and / or structurally significant absorptions are shown in cm -1 This will be reported as IR data.

[0050] All reactions were monitored by thin-layer chromatography (TLC) on 0.2 mm E. Merck silica gel plates (60F-254) using UV light and visualized with p-anisaldehyde solution, cerium sulfate, ethanolic ninhydrin, I2-SiO2, or 10% ethanolic phosphomolybdic acid. Column chromatography was performed on Merck silica gel 60 (0.063-0.200 mm).

[0051] ESI-TOF mass spectra were measured on a Waters LCT Premier® XE. HRMS (ESI-TOF) was calibrated with leucine enkephalin (SIGMA) as an internal standard.

[0052] Gel permeation chromatography (GPC) for quantitative analysis was performed on a Japan Analytical Industry Model LC 605 (recycling preparative HPLC) using a Japan Analytical Industry Model RI-5 refractive index detector and a Japan Analytical Industry Model 310 ultraviolet detector equipped with a polystyrene gel column (JAIGEL-1H, 20 mm x 600 mm) and chloroform as the solvent (3.5 mL / min).

[0053] Analytical HPLC was performed on an SSC-3461 pump equipped with an SSC-5410 UV detector and a Waters 2475 fluorescence detector.

[0054] A Glass Contour solvent purification system was used to obtain dry THF, toluene, MeCN, and CH2Cl2. DMF was dried over activated molecular sieves 4A.

[0055] (2) Synthesis of (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (2-29) [ka] (2-1) Synthesis of 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2,2,2]-octane (2-26) To a stirred solution of pentaerythritol (2-4) (10.3 g, 73.4 mmol, 1.00 eq.) in toluene (29.5 mL), p-toluenesulfonic acid monohydrate (130.2 mg, 0.734 mmol, 0.0100 eq.) and trimethyl orthoacetate (30.3 mL, 220 mmol, 3.00 eq.) were added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was evaporated in vacuo. The residue was used in the next reaction without further purification.

[0056] To a stirred solution of the residue in toluene (40.5 mL) was added pentaerythritol (2-4) (10.1 g, 73.4 mmol, 1.00 eq.) at room temperature. After stirring at 130 °C for 11 h, the reaction mixture was neutralized with NEt and evaporated in vacuo. The residue was recrystallized from toluene / EtO to give 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2,2,2]-octane (2-26) as white crystals (7.17 g, 44.8 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 4.04 (s, 6H, Hb), 3.47 (d, 2H, Ha, J = 3.2 Hz), 1.47 (s, 3H, Hc); 13 C NMR (100 MHz, CDCl3) δ 108.6, 69.4, 69.0, 61.3, 35.7, 23.5, 23.4; FT-IR (neat) 3648, 3006, 2952, 2882, 1716, 1541, 1507, 1158, 1038, 870 (cm -1 ) [ka] References 2-26: O. Linnenberg, A. Kondinski, C. Stocker, KY Monakhov* Dalton Trans., 2017, 46, 15636-15640

[0057] (2-2) Synthesis of (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (2-29) To a stirred solution of 60% sodium hydride (3.02 g, 74.9 mmol, 1.20 eq.) in DMF (16.5 mL), washed three times with dry hexane, was added a solution of 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2,2,2]-octane (2-26) (10.0 g, 62.4 mmol, 1.00 eq.) in DMF (34.2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Next, a solution of 2-(bromomethyl)naphthalene (13.8 g, 62.4 mmol, 1.00 eq.) in DMF (21.2 mL) was added to the reaction mixture at 0 °C. After stirring at room temperature for 3 h, EtOH and water were added to the stirred solution with cooling. The aqueous layer was extracted twice with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification.

[0058] To a stirred solution of the residue in MeOH (100 mL) was added 3.0 M HCl (10.0 mL) at room temperature. After stirring at 40 °C for 14 h, the reaction mixture was evaporated in vacuo. The residue was used in the next reaction without further purification.

[0059] To a stirred solution of the residue in DMF (27.2 mL) were added CSA (15.6 mg, 0.065 mmol, 0.0012 eq.) and 2,2-dimethoxypropane (8.00 mL, 65.2 mmol, 1.20 eq.) at room temperature. After stirring at 60 °C for 13 h, the reaction mixture was neutralized with NEt3 and poured into H2O. The aqueous layer was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane:ethyl acetate (50:50) and recrystallized from hexane / EtOAc to give (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (2-29) (4.70 g, 14.9 mmol, 24%). 1 1H NMR (400 MHz, CDCl3) δ 7.86 - 7.80 (m, 3H, H-aromatic), 7.74 (s, 1H, H-aromatic), 7.50 - 7.40 (m 3H, H-aromatic), 4.68 (s, 2H, H-f), 3.75 (s, 2H, H-c), 3.74 (s, 2H, H-c), 3.69 (d, 2H, H-b, J = 5.8 Hz), 3.59 (s, 2H, H-e), 2.45 (t, 1H, H-a, J = 5.3 Hz), 1.41 (s, 3H, H-d), 1.39 (s, 3H, H-d); 1313C NMR (100 MHz, CDCl3) δ 135.4, 133.3, 133.2, 128.5, 128.0, 127.8, 126.7, 126.3, 126.1, 125.6, 98.6, 74.0, 72.3, 65.1, 63.0, 39.1, 24.2, 23.5; FT-IR (neat) 3446, 2990, 2870, 1372, 1200, 1081, 1050, 827, 752, 420 (cm -1 )

Chem.

[0060] (3)(2,2-Dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl (4-methyl)benzenesulfonate (2-16) and Synthesis of 2,2-Dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl trifluoromethanesulfonate (2-18)

Chem.

[0061] (3-2) Synthesis of 2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl trifluoromethanesulfonate (2-18) To a stirred solution of (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methanol (2-29) (50.0 mg, 0.172 mmol, 1.00 eq.) in CHCl (0.860 mL) was added 2,6-lutidine (60.0 μL, 0.344 mmol, 2.00 eq.) and trifluoromethanesulfonic anhydride (40.0 μL, 0.206 mmol, 1.20 eq.) at 0 °C. After stirring at 0 °C for 0.5 h, the reaction mixture was poured into saturated aqueous NHCl solution. The aqueous layer was extracted twice with EtOAc. The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with hexane: EtOAc (80:20) to give (2,2-dimethyl-5-((naphthalen-2-ylmethoxy)methyl)-1,3-dioxan-5-yl)methyl trifluoromethanesulfonate (2-18) (68.0 mg, 0.152 mmol, 88%). 11H NMR (400 MHz, CDCl3) δ 7.85-7.81 (m, 3H, aromatic), 7.72 (s, 1H, aromatic), 7.51-7.39 (m, 3H, aromatic), 4.77 (s, 2H, H-a), 4.64 (s, 2H, H-e), 3.79 (d, 2H, J = 12.4 Hz, H-c), 3.71 (d, 2H, J = 12.4 Hz, H-c) 3.37 (s, 2H, H-b) 1.39 (s, 6H, H-d); 13 13C NMR (100 MHz, CDCl3) δ 135.1, 133.3, 133.2, 128.5, 128.0, 127.9, 126.7, 126.4, 126.2, 125.7, 99.0, 75.8, 73.9, 68.4, 62.1, 39.2, 26.5, 20.9; 19 19F NMR (373 MHz, CDCl3) δ -75.2; FT-IR (neat) 2993, 2872, 1415, 1374, 1246, 1203, 1146, 1087, 941, 824, 617, 477 (cm -1 )

Chem.

[0062] (4) Synthesis of 5-iodomethyl-5-((naphthalen-2-ylmethoxy)methyl)-2,2,-dimethyl-1,3-dioxane (2-17)

Chem.

Chemical Structure

[0063] Example 4 211 Measurement of the production rate of At-labeled compounds 2 Under the following two reaction conditions 211 At-labeled metaastatobenzylguanidine ( 211 The labeling synthesis of At-MABG was carried out. 0.5 mg of K2CO3 was dissolved in 90.9 μL of MeOH. 211 The At solution was placed in a reaction vessel, a vent needle connected to activated charcoal was attached, and the solvent was removed with nitrogen gas. Condition (1): 50 μL of trifluoroacetic acid (TFA) containing 0.4 mg of N-chlorosuccinimide (NCS) and 50 μL of TFA containing 0.1 mg of the labeled precursor meta-trimethylsilylbenzylguanidine (MTMSBG) were added, or condition (2): 50 μL of TFA and 50 μL of TFA containing 0.1 mg of the precursor MTMSBG were added. The mixture was heated at 70 °C for 10 min. After heating at 70 °C for 10 min, a vent needle connected to activated charcoal was attached, and the TFA was removed by blowing nitrogen gas through the mixture. The reaction product was dissolved in 0.5 mL of distilled water and passed through a Sep-Pak tC18 Light (dual column) column pre-activated with 3 mL of ethanol (EtOH) and 6 mL of water for injection. The fractions were collected in vials and measured for radioactivity (Table 3). The MABG purity of each fraction was also measured using HPLC (Table 4).

[0064] MTMSBG was purchased from ABX, and Shimadzu Prominence was used for HPLC, SPD-M20A (Shimadzu) for UV detection, and GABI STAR (Raytest) for radioactivity analysis. The analytical conditions are shown below. 211 The elution time of At-MABG is 8.2 minutes. Column: Triart C18 Plus 250 x 4.6 mm (YMC), Mobile phase: MeCN-0.1% TFA (gradient program) Time(min): 0 20 20.5 25.5 MeCN(%) : 30 70 100 100 Flow rate: 1 mL / min, column temperature: 25 °C, detector: UV detector (220 nm)

Chem.

Table 3

[0065] From Table 3, 211 The radiochemical yield after At concentration was 67.3% when NCS was present (collecting product vials 2 - 6), and 75.1% when NCS was absent (collecting product vials 2 - 5). Regardless of the presence or absence of the oxidizing agent NCS 211 The labeled synthesis of At - MABG was successfully achieved with good yield.

Table 4

[0066] From Table 4, the radiochemical purity was 97.7% when NCS was present (collecting product vials 2 - 6), and 95.5% when NCS was absent (collecting product vials 2 - 5). Regardless of the presence or absence of the oxidizing agent NCS, the 211 radiochemical purity of At - MABG was high.

[0067] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Industrial Applicability

[0068] Since the present invention relates to a method for producing astatine - 211, it is applicable in the industrial field of manufacturing pharmaceuticals using astatine - 211, etc.

Claims

1. A method for producing astatine-211, characterized by comprising the following steps (1) to (5): (1) irradiating bismuth with α-rays to generate astatine-211; (2) heating the astatine-211 generated in step (1) to vaporize it; (3) cooling the astatine-211 vaporized in step (2) and recovering it with a volatile and polar solvent to obtain an astatine-211 solution; (4) adding a carbonate or bicarbonate to the astatine-211 solution obtained in step (3) to obtain an astatine-211 solution containing the carbonate or bicarbonate; (5) removing the solvent from the astatine-211 solution containing the carbonate or bicarbonate obtained in step (4).

2. The method for producing astatine-211 according to claim 1, wherein the carbonate or bicarbonate is a carbonate of an alkali metal or a bicarbonate of an alkali metal.

3. The carbonate or bicarbonate is NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , CsHCO 3 , or Cs 2 CO 3 , and the method for producing astatine-211 according to claim 1, characterized in that it is as described above.

4. The method for producing astatine-211 according to any one of claims 1 to 3, wherein the volatile and polar solvent is methanol, ethanol, 2-propanol, or acetonitrile.

5. A method for producing an astatine-211 labeled compound by reacting astatine-211 produced by the method for producing astatine-211 according to any one of claims 1 to 4 with a labeling precursor compound, wherein the reaction is a nucleophilic substitution reaction.

6. The method for producing an astatine-211 labeled compound according to claim 5, wherein the labeling precursor compound is a compound having an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group, and the astatine-211 labeled compound is a compound in which the alkylsulfonyloxy group, haloalkylsulfonyloxy group, or arylsulfonyloxy group in the labeling precursor compound is substituted with astatine-211.

7. The method for producing an astatine-211 labeled compound according to claim 5, wherein the labeling precursor compound is a compound having a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and the astatine-211 labeled compound is a compound in which the p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group in the labeling precursor compound is substituted with astatine-211. **Claim 8**: A method for producing an astatine-211 labeled compound, comprising reacting astatine-211 produced by the method for producing astatine-211 according to any one of Claims 1 to 4 with a labeling precursor compound, wherein the reaction is an electrophilic substitution reaction. **Claim 9** The method for producing an astatine-211 labeled compound according to Claim 8, wherein the electrophilic substitution reaction is an aromatic electrophilic substitution reaction. **Claim 10** The method for producing an astatine-211 labeled compound according to Claim 8 or 9, wherein the labeling precursor compound is a compound having a trialkylsilyl group or a trialkylstannyl group, and the astatine-211 labeled compound is a compound in which the trialkylsilyl group or the trialkylstannyl group in the labeling precursor compound is substituted with astatine-211. **Claim 11** The method for producing an astatine-211 labeled compound according to Claim 8 or 9, wherein the labeling precursor compound is a compound having a trimethylsilyl group or a tributylstannyl group, and the astatine-211 labeled compound is a compound in which the trimethylsilyl group or the tributylstannyl group in the labeling precursor compound is substituted with astatine-211.

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