WO2020085238A1 - Salt of radioactive fluorine-labeled precursor compound - Google Patents

Abstract

In order to improve the stability of a precursor compound of a radioactive fluorine-labeled compound, the present invention provides a stabilized composition which contains, as a main component, a salt of a compound represented by formula (2). (In the formula, X₁ represents a hydrogen atom or a halogen atom; X₂ represents a fluorine atom or a nitrile group; and R₁ represents a substituted or unsubstituted alkylsulfonyloxy group or a substituted or unsubstituted arylsulfonyloxy group.) By converting a compound represented by formula (2) into a salt, the compound represented by formula (2) is stabilized and is able to be stored for a long period of time.

Description

Radioactive fluorine labeled precursor compound salt

The present invention relates to a salt of a labeled precursor compound of 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound, which is a compound having CYP11B2 selective binding property.

The 2- (3-pyridinyl) -1H-benzimidazole derivative compound is known to have high selectivity for CYP11B2 (Patent Document 1). For example, Non-patent Document 1 reports that ¹⁸ F-CDP2230, which is a 2- (3-pyridinyl) -1H-benzimidazole derivative compound, visualized a primary aldosterone-producing tumor with PET (Patent Document 1). . Further, a 2- (3-pyridinyl) -1H-benzimidazole derivative compound is also expected as a non-invasive diagnostic imaging agent for heart disease (Patent Document 2).

Furthermore, the applicant has the ability to selectively inhibit CYP11B2 even with respect to 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compounds, which are not disclosed in Patent Documents 1 and 2. Has been applied for a patent (Patent Documents 3 and 4).

International Publication No. 2015/199205 International Publication No. 2017/213247 Japanese Patent Application 2017-253837 Japanese Patent Application 2018-089920

However, the labeling precursor compounds of the radioactive fluorine-labeled compounds described in Patent Documents 3 and 4 have a problem that the purity gradually decreases when stored in a neat (solvent-free) state. It became clear by the knowledge.

The present invention has been made in view of the above circumstances, and improves the stability of a radioactive fluorine-labeled precursor compound of a 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound. The purpose is to

The present inventors have conducted extensive studies in order to achieve the above object, and as a result, found that the compound represented by the following formula (2) can be stably stored by inducing it into a salt, and completed the present invention. Came to do.

That is, one aspect of the present invention is a stabilized composition of a labeling precursor compound of a radioactive fluorine-labeled compound, wherein the radioactive fluorine-labeled compound is a compound represented by the following formula (1) or a salt thereof, The present invention provides a stabilized composition of a labeled precursor compound, wherein the precursor compound contains a salt of the compound represented by the following formula (2) as a main component.

In formula (1), X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom.

In formula (2), X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, R ₁ represents a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. Indicates.

According to still another aspect of the present invention, there is provided a method for preserving a labeled precursor compound for a radiofluorine-labeled compound, wherein the radiofluorine-labeled compound is a compound represented by the above formula (1) or a salt thereof, A method for storing a labeled precursor compound of a radioactive fluorine-labeled compound, which comprises storing the labeled precursor compound as a salt, wherein the labeled precursor compound is a compound represented by the above formula (2).

According to another aspect of the present invention, there is provided a method for producing a labeling precursor compound for a radiofluorine-labeled compound, wherein the radiofluorine-labeled compound is a compound represented by the above formula (1) or a salt thereof. A method for producing a labeled precursor compound for a radioactive fluorine compound, which comprises preparing the labeled precursor compound as a salt, wherein the precursor compound is a compound represented by the above formula (2).

Further, according to still another aspect of the present invention, the compound represented by the formula (2) or a salt thereof derived from the stabilized composition of the present invention is subjected to radiofluorination reaction as a labeled precursor compound. There is provided a method for producing a radioactive fluorine-labeled compound or a salt thereof, which comprises a step of obtaining a radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof.

According to still another aspect of the present invention, there is provided a container containing the above-mentioned stabilizing composition of the present invention.

According to the present invention, a compound represented by the above formula (2), which is a radioactive fluorine-labeled precursor compound of a 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound, is converted into a salt. Since it is stored in the form, the stability can be improved.

5 is a graph showing the results (30 ° C., with argon sealed) obtained in Reference Example 1, Example 1 and Example 2 for comparison. 3 is a graph showing the results (−25 ° C., with argon sealed) obtained in Reference Example 1, Example 1 and Example 2 for comparison.

In the present invention, the “halogen atom” is at least one selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Further, in the present invention, the “salt” may be any one that is pharmaceutically acceptable, and examples thereof include inorganic acid salts and organic acid salts. Of these, from the viewpoint of storage stability, a sulfate is preferable as the inorganic acid salt, a sulfonate is preferable as the organic acid salt, and a substituted or unsubstituted alkyl sulfonate and a substituted or unsubstituted aryl sulfonate are more preferable. preferable. As the substituted or unsubstituted alkyl sulfonate, methane sulfonic acid (mesyl acid) salt, ethane sulfonate, propane sulfonate, butane sulfonate, trifluoromethane sulfonate, pentafluoroethane sulfonate, heptafluoro Examples thereof include propane sulfonate and nonafluorobutane sulfonate. Examples of the substituted or unsubstituted aryl sulfonate include benzene sulfonic acid (besyl acid) salt, p-toluene sulfonic acid (tosylic acid) salt, p-nitrobenzene sulfonate, and trinitrobenzene sulfonate. A salt in which the same ion as the sulfonate ion generated when the substituent R ₁ of the formula (2) is eliminated by radiofluorination is used as a counter ion is more preferable.

In the present invention, the “radioactive fluorine atom” is a radioactive isotope of fluorine, and preferably ¹⁸ F can be used.

From the viewpoint of increasing the binding property of the radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof to CYP11B2, in the above formulas (1) and (2), when X ₁ is a hydrogen atom, X ₂ Is preferably a fluorine atom. From the same viewpoint, in the formulas (1) and (2), when X ₁ is a halogen atom, X ₂ is preferably a fluorine atom or a nitrile group. From the same viewpoint, in the above formulas (1) and (2), when X ₁ is a fluorine atom, X ₂ is preferably a fluorine atom or a nitrile group.

Preferred examples of the compound represented by the above formula (1) include three compounds represented by the following chemical formulas.

From the same viewpoint, among the compounds represented by the above formula (2), preferable compounds include the following compounds 201, 202 and 203.

In the compound represented by the above formula (2), the substituted or unsubstituted alkylsulfonyloxy group represented by R ₁ is preferably a substituted or unsubstituted alkylsulfonyloxy group having 1 to 12 carbon atoms. In the substituted alkylsulfonyloxy group, the hydrogen atom of the alkyl chain may be replaced with a halogen atom, preferably the fluorine atom. In the compound represented by the above formula (2), the substituted or unsubstituted arylsulfonyloxy group represented by R ₁ is preferably a substituted or unsubstituted benzenesulfonyloxy group, more preferably a substituted benzenesulfonyloxy group. is there. The substituted arylsulfonyloxy group preferably has a hydrogen atom on the aryl ring substituted with an alkyl group having 1 to 12 carbon atoms or a nitro group. Preferred specific examples of the substituted or unsubstituted alkylsulfonyloxy group and the substituted or unsubstituted arylsulfonyloxy group include methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group and trifluoromethane. A sulfonyloxy group is mentioned. In the compound represented by the above formula (2), R ₁ is preferably a substituted or unsubstituted arylsulfonyloxy group, and particularly preferably a p-toluenesulfonyloxy group. Similarly, among the compounds represented by the above formula (2), more preferably the compounds 201, 202 and 203 _{R 1} is p- toluenesulfonyloxy group, said _{R 1} is p- toluenesulfonyloxy group Compound 201 is particularly preferred.

Subsequently, a method for preparing the stabilized composition of the present invention will be described below. The compound (free form) represented by the above formula (2) can be synthesized, for example, according to the following scheme 1. In Scheme 1 below, X ₁ represents a hydrogen atom or a halogen atom, and X ₂ represents a fluorine atom or a nitrile group.

By mixing the compound (free form) represented by the above formula (2) with an inorganic acid or an organic acid, the basic group and the inorganic acid or organic acid in the compound represented by the above formula (2) are mixed. An acid-base reaction with an acidic group can occur to form a salt.

Here, as the inorganic acid or the organic acid, an acid corresponding to the above-mentioned salt can be used. For example, sulfuric acid is used when forming a sulfate, and sulfonic acid is used when forming a sulfonate. The inorganic acid or the organic acid can be used in a neat state, in a state of being dissolved in a solvent, or in a state of forming a salt. After isolation and purification of the compound (free form) represented by the above formula (2) or in a solvent containing the compound (free form) represented by the above formula (2), an inorganic acid or an organic acid is added. The reaction may be carried out, and it is preferable to react the compound (free form) represented by the above formula (2) with an inorganic acid or an organic acid in a solvent, more preferably with stirring. Any solvent may be used as long as it can dissolve the free form of the compound represented by the above formula (2) and the inorganic acid or organic acid, and examples thereof include alcohols having 1 to 4 carbon atoms (eg, methanol, ethanol, n- Propanol, isopropanol, n-butanol, t-butanol, etc.), acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, acetone are used.
As an example, there is a method of subjecting the compound 11 of the above scheme 1 tosylation reaction, and then subjecting the free form purified by a chromatography method, a recrystallization method or the like to a salt forming reaction without leaving the solvent in a neat state. To be For example, the salt-forming reaction may be carried out by adding the inorganic acid or the organic acid to the free form fraction purified by the chromatography method as it is or after appropriately concentrating it. By doing so, the decomposition of the free form can be reduced and the salt can be obtained in good yield.
When the reaction is carried out under stirring, the stirring time may be sufficient for the mixture to become a uniform solution or suspension. Further, the above reaction may be carried out at room temperature or while heating. When heating, it is preferable to use a block heater, a water bath, an oil bath or the like to heat to 30 to 40 ° C.

When a solvent is used for the acid-base reaction, the salt of the compound represented by the above formula (2) can be obtained by evaporating the solvent. After the acid-base reaction, the solvent may be filtered before being evaporated to remove insoluble impurities. The filtration may be carried out in an air atmosphere or an atmosphere of an inert gas such as nitrogen gas or argon gas. When natural filtration or suction filtration is difficult due to the properties of the mixture, a solvent may be added to the filter to dissolve the residue and evaporate the solvent.
The residue thus obtained constitutes the stabilized composition of the present invention and contains the salt of the compound represented by the above formula (2) as a main component. The stabilized composition of the present invention may be solid or amorphous. Specific examples of the solid include powders, granules, emulsions, pastes and the like, but the solid is not limited thereto as long as the decomposition of the salt of the compound represented by the formula (2) is suppressed.

The salt of the compound represented by the above formula (2) and the stabilized composition of the present invention containing the salt as a main component can be stored in a container, preferably sealed. The container for housing the composition may be made of glass or plastic. Further, the container may be filled with an inert gas (nitrogen, argon, etc.) as appropriate.

The storage temperature of the salt of the compound represented by the above formula (2) and the stabilizing composition of the present invention is not particularly limited, but the upper limit is 50 ° C. or lower, preferably 40 ° C. or lower, More preferably, it is 30 ° C. or lower. The lower limit is not particularly limited, but may be −200 ° C. or higher, preferably −100 ° C. or higher, more preferably 0 ° C. or higher. Particularly, in the case of an organic acid salt, it can be stably stored even at a refrigeration temperature or higher (10 ° C. or higher).

The lower limit of the storage period of the salt of the compound represented by the above formula (2) and the stabilized composition of the present invention is 1 week or longer, preferably 2 weeks or longer, and more preferably 1 month or longer. The upper limit is preferably 5 years or less, more preferably 3 years or less, and even more preferably 2 years or less.

When the stabilized composition of the present invention contains the labeled precursor compound of the radioactive fluorine-labeled compound represented by the above formula (2) in the form of a salt, its decomposition is suppressed. In particular, an OH compound in which R _{1 of the} compound represented by the above formula (2) is substituted with a hydroxy group, and a compound in which R _{1 of the} compound represented by the above formula (2) is substituted with a chloro group Generation of a certain Cl body and a dimer of the compound represented by the following formula (3) is reduced.

The stabilized composition of the present invention may contain a salt of the compound represented by the above formula (2) as its main component and one or more other components as secondary components. Examples of the main subcomponent include the OH form, the Cl form, and the dimer. The stabilizing composition of the present invention may contain at least one of these subcomponents, but preferably contains substantially no subcomponents other than these subcomponents. Here, "substantially free" means that the target component is undetected in the method for quantifying the content of each component, or the content is below the detection limit. .

The composition of the present invention is appropriately contained in the above container and stored at the above storage temperature for the above storage period to contain the salt of the compound represented by the formula (2) as the main component. The amount can be maintained at 90% or more, preferably 95% or more, more preferably 98% or more in the peak area ratio on the chromatogram by the high performance liquid chromatography method. Further, the content of the OH form is preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, still more preferably 0.1% in the peak area ratio on the chromatogram by the high performance liquid chromatography method. You can keep: In addition, the content of Cl is preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, still more preferably 0.1% in terms of the peak area ratio on the chromatogram by the high performance liquid chromatography method. You can keep: Further, the content of the dimer of the compound represented by the formula (3) in the peak area ratio on the chromatogram by the high performance liquid chromatography method is preferably 30% or less, more preferably 10% or less, and further preferably It becomes possible to maintain it at 5% or less, and even more preferably at 1% or less. The conditions of this high performance liquid chromatography method are shown below.

Sample dissolution solvent: Methanol Sample concentration: 0.2 mg / mL
Injection volume: 10 μL
Detector: UV-visible absorptiometer (measurement wavelength: 293 nm)
Column: (filler) phenylhexyl group-modified silica gel, (size) 4.6 x 150 mm
Column temperature: 40 ° C
Mobile phase: A mixed solvent of 60 vol% of mobile phase A (10 mmol / L ammonium hydrogen carbonate aqueous solution) and 40 vol% of mobile phase B (methanol) was added over 55 minutes to 40 vol% of mobile phase A and 60 vol% of mobile phase B Use as a mixed solvent.
Retention time of OH body: about 7 minutes Retention time of Cl body: about 14 minutes Retention time of main component: about 24 minutes Retention time of dimer: about 41 minutes

The stabilized composition of the present invention may be subjected to a radiofluorination reaction as it is, or may be subjected to a radiofluorination reaction after being dissolved in a solvent.

The preferred radiofluorination reaction includes a nucleophilic substitution reaction of the compound represented by the above formula (2) to the group represented by R ₁ using a radiofluoride ion, and the radiofluoride ion is used. The nucleophilic substitution reaction is preferably carried out in the presence of a base such as an alkali metal carbonate (for example, sodium carbonate or potassium carbonate) or tetraalkylammonium.

The radiofluorination reaction is preferably carried out in the presence of a phase transfer catalyst, and examples of the phase transfer catalyst include 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8. 8] -hexacosane (trade name: Cryptofix 222) or the like can be used.

The radioactive fluorination reaction is preferably carried out by heating, more preferably at the boiling point of the organic solvent or higher, and for example, the lower limit is preferably 50 ° C. or higher, 70 ° C. or higher, 90 ° C. or higher, and the upper limit is 200 ° C. Hereinafter, it is preferable to carry out at 180 ° C. or lower and 150 ° C. or lower.

When the radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof is used as a drug, after the radioactive fluorination reaction, unreacted radioactive fluorine and insoluble impurities are filled with a membrane filter or various fillers. It is desirable to purify by a column, HPLC or the like.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these contents.

In the examples, the molecular structure of each compound was identified by ¹ H-NMR spectrum. As the NMR apparatus, AVANCEIII (manufactured by Bruker) having a resonance frequency of 500 MHz) was used, tetramethylsilane (TMS) was used as an internal standard, and the TMS resonance was set to 0.00 ppm. All chemical shifts are in ppm on the delta scale (δ), and for fine splitting of the signal, abbreviations (s: singlet, d: doublet, t: triplet, dd: double doublet, dt: double triplet, m: Multiplet, bs: broad singlet, q: quintet).
Hereinafter, “room temperature” in the examples is 25 ° C.
In the synthesis examples of each compound, each step in the compound synthesis was repeated as necessary to secure a necessary amount when used as an intermediate or the like in another synthesis.

(Production Example 1) Synthesis of compound 201 (free form) According to the following scheme 2, compound 201 (free form) was synthesized.

Synthesis of 2- (tert-butyldiphenylsilyloxy) ethylamine (Compound 6) 2-Aminoethanol (Compound 5) (2.2 mL, 40.0 mmol) was dissolved in dichloromethane (100 mL), then at room temperature, tert. -Butyldiphenylsilyl chloride (15.6 mL, 60.0 mmol) and imidazole (5.44 g, 80.0 mmol) were added, and the mixture was stirred overnight at room temperature under an argon gas atmosphere. After completion of the reaction, water was added under ice cooling, and the mixture was extracted 3 times with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (eluent: ethyl acetate → ethyl acetate / methanol = 10/1 → 5/1). , 2- (tert-butyldiphenylsilyloxy) ethylamine (Compound 6) (12.2 g, 40.7 mmol) was obtained.
Compound 6 ¹ H-NMR (solvent: deuterated chloroform): δ7.67-7.65 (m, 4H), 7.44-7.36 (m, 6H), 3.70 (t, J = 5. 3Hz, 2H), 2.84 (t, J = 5.3Hz, 2H), 2.79 (bs, 2H), 3.08 (bs, 2H), 1.07 (s, 9H).

Synthesis of N- (5-fluoro-2-nitrophenyl) -2- (tert-butyldiphenylsilyloxy) ethylamine (Compound 7) 2,4-Difluoronitrobenzene (Compound 1) (66.9 μL, 0.606 mmol) After being dissolved in dichloromethane (2.0 mL), potassium carbonate (420.5 mg, 3.04 mmol) and 2- (tert-butyldiphenylsilyloxy) ethylamine (Compound 6) ( 546.7 mg, 1,83 mmol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added at room temperature, and the mixture was extracted 3 times with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 20/1 → 10/1) to give N- ( 5-Fluoro-2-nitrophenyl) -2- (tert-butyldiphenylsilyloxy) ethylamine (Compound 7) (286.9 mg, 0.654 mmol) was obtained.
¹ H-NMR (solvent: deuterated chloroform) of Compound 7: δ8.51 (bs, 1H), 8.22 (dd, J = 9.5, 6.2 Hz, 1H), 7.67-7.65 ( m, 4H), 7.43-7.36 (m, 6H), 6.43 (dd, J = 11.5, 2.6Hz, 1H), 6.37-6.33 (m, 1H), 3.90 (t, J = 5.4 Hz, 2H), 3.47 (q, J = 5.4 Hz, 2H), 1.07 (s, 9H).

Synthesis of 3-fluoro-N- [2- (tert-butyldiphenylsilyloxy) ethyl] -1,6-phenylenediamine (Compound 8) N- (5-Fluoro-2-nitrophenyl) -2- (tert- Butyldiphenylsilyloxy) ethylamine (Compound 7) (286.9 mg, 0.654 mmol) was dissolved in methanol (3.0 mL), and then 10% palladium carbon (11.2 mg) was added under an argon gas atmosphere. . Subsequently, the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere. After completion of the reaction, the mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 20/1 → 5/1) to give 3-fluoro. There was obtained -N- [2- (tert-butyldiphenylsilyloxy) ethyl] -1,6-phenylenediamine (Compound 8) (122.4 mg, 0.300 mmol).
¹ H-NMR (solvent: deuterated chloroform) of Compound 8: δ7.67 (dd, J = 6.0, 1.3 Hz, 4H), 7.43-7.41 (m, 2H), 7.39- 7.36 (m, 4H), 6.62 (dd, J = 8.3, 5.7 Hz, 1H), 6.34-6.28 (m, 2H), 4.16 (bs, 1H), 3.91 (t, J = 5.4 Hz, 2H), 3.21 (q, J = 5.2 Hz, 2H), 3.08 (bs, 2H), 1.07 (s, 9H).

Synthesis of 5- {6-fluoro-1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridin-3-methanol (Compound 9) 5-hydroxymethyl-3-pyridinecarboxaldehyde (40.8 mg, 0.298 mol) was dissolved in N, N'-dimethylformamide (0.5 mL), and then cooled under ice-cooling with 3-fluoro-N- [2- (tert-butyldiphenylsilyloxy) ethyl]. -1,6-Phenylenediamine (Compound 8) (122.4 mg, 0.300 mol) and Oxone (registered trademark) monopersulfate compound (221.3 mg, 0.360 mmol) were added, and the mixture was heated to room temperature under an argon gas atmosphere. And stirred for 30 minutes. After completion of the reaction, a saturated sodium thiosulfate aqueous solution and a saturated sodium hydrogen carbonate aqueous solution were added under ice cooling, and the mixture was extracted 3 times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane / methanol = 10/5/1). , 5- {6-fluoro-1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridin-3-methanol (Compound 9) (131.3 mg, 0.250 mmol) was obtained. It was
¹ H-NMR (solvent: deuterated chloroform) of Compound 9: δ8.96 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.12 (t, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.8, 4.8 Hz, 1H), 7.38-7.36 (m, 6H), 7.29-7.28 (m 4H), 7.09-7.05 (m, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H), 4.76 (d, J = 5.8 Hz, 2H) 4.40 (t, J = 5.7 Hz, 2H), 3.94 (t, J = 5.7 Hz, 2H), 0.89 (s, 9H).

Synthesis of 6-fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] -1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazole (Compound 10) 5- {6 -Fluoro-1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazol-2-yl} pyridin-3-methanol (Compound 9) (131.3 mg, 0.250 mmol) in dichloromethane (2.5 mL) After being dissolved in water, triethylamine (104.4 μL, 0.750 mmol) and p-toluenesulfonic acid anhydride (163.0 mg, 0.500 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes in an argon gas atmosphere. Stir for minutes. After completion of the reaction, water was added and the mixture was extracted 3 times with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude product. Imidazole (85.0 mg, 1.25 mmol) was dissolved in N, N'-dimethylformamide (0.2 mL) and then ice-cooled. After adding triethylamine (174.1 μL, 1.25 mmol), the crude product obtained above was dissolved in N, N′-dimethylformamide (0.8 mL) and added, and the mixture was added at room temperature under an argon gas atmosphere for 4 hours. It was stirred. After the reaction was completed, water was added and the mixture was extracted 3 times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol = 30/1 → 20/1 → 10/1). 6-Fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] -1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazole (Compound 10) (128.1 mg , 0.222 mmol) was obtained.
¹ H-NMR (solvent: deuterated chloroform) of Compound 10: δ 9.06 (d, J = 2.2z, 1H), 8.55 (d, J = 2.2 Hz, 1H), 7.92 (t, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.8, 4.8 Hz, 1H), 7.55 (s, 1H), 7.40-7.35 (m, 6H), 7.29-7.27 (m, 4H), 7.09-7.05 (m, 2H), 6.90-6.86 (m, 2H), 5.13 (s, 2H), 4. 34 (t, J = 5.5 Hz, 2H), 3.94 (t, J = 5.5 Hz, 2H), 0.89 (s, 9H).

Synthesis of 2- {6-fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazol-1-yl} ethanol (Compound 11) 6-fluoro-2- [5- (imidazole 1-ylmethyl) pyridin-3-yl] -1- [2- (tert-butyldiphenylsilyloxy) ethyl] benzimidazole (Compound 10) (128.1 mg, 0.222 mmol) in tetrahydrofuran (2.0 mL) After dissolution, tetrabutylammonium fluoride (0.33 mL, tetrahydrofuran solution, about 1M, 0.33 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes under an argon gas atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20/1 → 10/1 → 5/1) to give 2- {. 6-Fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazol-1-yl} ethanol (Compound 11) (25.8 mg, 0.0765 mmol) was obtained.
Compound ^{1 1} H-NMR (solvent: deuterated chloroform): δ 9.07 (d, J = 2.2 Hz, 1 H), 8.64 (d, J = 2.2 Hz, 1 H), 7.87 (t, J = 2.2 Hz, 1H), 7.73 (dd, J = 8.9, 4.8 Hz, 1H), 7.62 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H) ), 7.13 (s, 1H), 7.12 (dt, J = 10.3, 2.4 Hz, 1H), 6.98 (t, J = 1.3 Hz, 1H), 5.27 (s , 2H), 4.21 (t, J = 5.7Hz, 2H), 3.99 (t, J = 5.7Hz, 2H), 2.44 (bs, 1H).

Synthesis of 6-chloro-5-fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] -1- [2- (p-toluenesulfonyloxy) ethyl] benzimidazole (Compound 201) 2 -{6-Fluoro-2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazol-1-yl} ethanol (Compound 11) (2.00 g, 5.93 mmol) in tetrahydrofuran (10. 64 g), 1M aqueous sodium hydroxide solution (16.7 g) and p-toluenesulfonyl chloride (1.70 g) were added at 10 ° C., and the mixture was stirred for 2 hours.
After completion of the reaction, 5% by weight aqueous sodium hydrogen carbonate solution (25.26 g) was added under ice cooling, the mixture was stirred for 5 minutes, and then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed 3 times with a 20 wt% sodium chloride aqueous solution, and the obtained ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, purification was carried out by amino silica gel chromatography (eluent: ethyl acetate / methanol = 100/1 → 50/1), and main fractions containing the target substance were collected.
The obtained main distillate fraction was concentrated under reduced pressure at 30 ° C. or lower to about 20 mL, activated carbon (trade name: purified Shirasagi, 0.1 g) was added, washed with ethyl acetate (10 mL), and stirred at room temperature for 30 minutes. Then, the mixture was filtered through Celite and then concentrated under reduced pressure to obtain a free form of compound 201.
¹ H-NMR (solvent: deuterated methanol) of compound 201: δ8.82 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.02 (t, J = 2.1 Hz, 1H), 7.90 (s, 1H), 7.62 (dd, J = 8.8, 4.7 Hz, 1H), 7.28 (dd, J = 6.4, 1) .8 Hz, 3 H), 7.21 (dd, J = 8.9, 2.4 Hz, 1 H), 7.13-7.10 (m, 1 H), 7.06 (t, J = 2.3 Hz, 3H), 5.46 (s, 2H), 4.49 (t, J = 5.9Hz, 2H), 4.25 (t, J = 5.9Hz, 2H), 2.32 (s, 3H). .

(Reference example 1)
Using a collection vial (for 5 mL) as a storage container, the compound 201 (free form) (5 mg) obtained in Production Example 1 was powdered at -60 ° C, -25 ° C, frozen (0 ° C), and refrigerated (4 C.) or 30.degree. C. and stored with or without argon sealing. Samples were taken after 72 hours, 114 hours, 256 hours or 400 hours and analyzed for purity by HPLC. The HPLC conditions are as shown below.

<HPLC conditions>
Sample dissolution solvent: methanol Sample concentration: powder sample; 1.0 mg / mL, solution sample; 0.2 mg / mL
Injection volume: 10 μL
Detector: UV-visible absorptiometer (measurement wavelength: 293 nm)
Column: XBridge Phenyl 3.5 μm, 4.6 × 150 mm, manufactured by Nippon Waters Co., Ltd. Column temperature: Constant temperature around 40 ° C. Mobile phase A: 10 mmol / L ammonium hydrogen carbonate solution mobile phase B: Transfer of methanol mobile phase for liquid chromatography : Flow rate controlled by concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1: 1.0 mL / min
Area measurement range: 45 minutes Re-equilibration time: 10 minutes Retention time of compound 201: Approximately 24 minutes

The results are shown in Table 2. The storage results at 30 ° C. (with argon sealed) and −25 ° C. (with argon sealed) are shown in FIGS. 1 and 2, respectively.

From the results in Table 2, it can be seen that the area percentage of HPLC of Compound 201 (free form) tends to decrease as the storage temperature rises. Particularly, at a storage temperature of 30 ° C., the amount of Compound 201 is 72 hours later. The surface 100% value of (free body) decreased to about half.

(Example 1)
In the synthesis of the compound 201 of Production Example 1, the same procedure as in Production Example 1 was performed up to the step of obtaining a main fraction containing Compound 201 (free form) by amino silica gel chromatography. The obtained main distillate fraction was concentrated under reduced pressure at 30 ° C. or lower to about 20 mL. A sulfuric acid salt of compound 201 was obtained by adding a solution of sulfuric acid (0.44 g, 1.5 equivalents) in ethyl acetate to the concentrated solution, stirring the mixture for 1 hour, and then filtering.
The sulfate salt of compound 201 (5 mg) was stored under the same conditions as in Reference Example 1. Samples were taken after 48 hours, 184 hours, 328 hours or 400 hours and analyzed by HPLC for purity. The HPLC conditions are the same as in Reference Example 1. The results are shown in Table 3. The results of storage at 30 ° C. (with argon sealed) and −25 ° C. (with argon sealed) are shown in FIGS. 1 and 2, respectively.

From the results of Table 3, it was found that the stability was improved as compared with Table 2. When stored at 30 ° C., the area 100% value gradually decreased. Moreover, when the molecular weights of main impurities were confirmed by LC / MS, it was found that the tosyl group was replaced with a sulfate group.
Next, in order to confirm the number of equivalents of sulfuric acid in the sulfate salt of compound 201, potentiometric titration was carried out using the obtained sulfate salt of compound 201 and 0.1N NaOH aqueous solution. It was found to be sulfate.

(Example 2)
In the synthesis of the compound 201 of Production Example 1, the same procedure as in Production Example 1 was performed up to the step of obtaining a main fraction containing Compound 201 (free form) by amino silica gel chromatography. The obtained main distillate fraction was concentrated under reduced pressure at 30 ° C. or lower to about 20 mL. The concentrate was added to a solution of p-toluenesulfonic acid monohydrate (2.26 g, 4 equivalents) in ethyl acetate, stirred for 1 hour, and then filtered to obtain a tosylate salt of Compound 201.
The tosylate salt of compound 201 (5 mg) was stored under the same conditions as in Reference Example 1. Samples were taken after 48 hours, 192 hours, 360 hours or 450 hours and analyzed for purity by HPLC. The HPLC conditions are the same as in Reference Example 1. The results are shown in Table 4. The results of storage at 30 ° C. (with argon sealed) and −25 ° C. (with argon sealed) are shown in FIGS. 1 and 2, respectively.

From the results of Table 4, it was found that the stability was improved under any storage condition compared to Table 2.

From the results of FIGS. 1 and 2, at both 30 ° C. and −25 ° C., the decrease in purity was reduced as compared with the case where the compound 101 was stored in the free form.
Next, in order to confirm the number of equivalents of tosylic acid in the tosylate salt of Compound 201, the obtained tosylate salt of Compound 201 was analyzed by NMR. The tosylate salt may be a tritosylate salt. It turned out that it is highly effective.
By storing in the form of salts such as sulfates and tosylate salts, reduction in purity can be reduced even from room temperature conditions of 30 ° C. to freezing conditions of −25 ° C. Among them, storage in the form of tosylate salts is possible. It turned out to be particularly effective.

This application claims the priority right based on Japanese Patent Application No. 2018-200389 filed on October 24, 2018, and incorporates all the disclosure thereof.

Claims (11)

1. A stabilized composition of a labeling precursor compound of a radioactive fluorine-labeled compound, comprising:
   The radioactive fluorine-labeled compound is a compound represented by the following formula (1) or a salt thereof,
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom. ]
   The labeled precursor compound contains a salt of a compound represented by the following formula (2) as a main component,
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and R ₁ represents a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. . ]
   A stabilized composition of the labeled precursor compound.
2. The stabilizing composition according to claim 1, wherein in the formula (2), R ₁ is a substituted or unsubstituted arylsulfonyloxy group.
3. The stabilized composition according to claim 1 or 2, wherein the salt of the labeled precursor compound represented by the formula (2) is a salt derived from an organic acid.
4. The stabilized composition according to claim 3, wherein the organic acid is a substituted or unsubstituted aryl sulfonic acid.
5. A method for storing a labeled precursor compound of a radioactive fluorine-labeled compound, comprising:
   The radioactive fluorine-labeled compound is a compound represented by the following formula (1) or a salt thereof,
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom. ]
   The labeled precursor compound is a compound represented by the following formula (2),
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and R ₁ represents a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. . ]
   A method for storing a labeled precursor compound of a radioactive fluorine-labeled compound, which comprises storing the labeled precursor compound as a salt.
6. A method for producing a labeling precursor compound for a radioactive fluorine-labeled compound, wherein the radioactive fluorine-labeled compound is a compound represented by the following formula (1) or a salt thereof,
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and X ₃ represents a radioactive fluorine atom. ]
   The labeled precursor compound is a compound represented by the following formula (2),
   

   

   
   [In the formula, X ₁ represents a hydrogen atom or a halogen atom, X ₂ represents a fluorine atom or a nitrile group, and R ₁ represents a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. . ]
   A method for producing a labeled precursor compound for a radiofluorine-labeled compound, which comprises preparing the labeled precursor compound as a salt.
7. The method for producing a labeled precursor compound for a radioactive fluorine-labeled compound according to claim 6, wherein R ₁ in the formula (2) is a substituted or unsubstituted arylsulfonyloxy group.
8. The method for producing a labeled precursor compound of a radioactive fluorine-labeled compound according to claim 6 or 7, wherein the salt of the labeled precursor compound represented by the formula (2) is a salt derived from an organic acid.
9. The method for producing a labeled precursor compound of a radioactive fluorine-labeled compound according to any one of claims 6 to 8, wherein the organic acid is a substituted or unsubstituted aryl sulfonic acid.
10. The compound represented by the formula (2) or a salt thereof derived from the stabilized composition according to any one of claims 1 to 4 is subjected to a radiofluorination reaction as a labeling precursor compound, and the compound represented by the formula (1) ) The method for producing a radioactive fluorine-labeled compound or a salt thereof, which comprises the step of obtaining a radioactive fluorine-labeled compound or a salt thereof.
11. A container containing the stabilizing composition according to any one of claims 1 to 4.

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