JP2011020944A - Method for producing positron-releasing source compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a high-purity positron-releasing source compound. <P>SOLUTION: The method for producing the positron-releasing source compound (I) [wherein, R<SP>1</SP>is a group containing a positron-releasing element] includes a step for obtaining a trialkyltin compound (III) from a halogen compound (II) [in the formulas, R<SP>2</SP>is a protective group activating an -OCO<SB>2</SB>- group; Hal is halogen; R<SP>3</SP>to R<SP>5</SP>are each independently 1-8C alkyl], and a step for obtaining a nonane carbonate compound (IV) [wherein, R<SP>2</SP>to R<SP>5</SP>represent the same meanings as above] from the trialkyltin compound (III). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing a positron emitter compound.

  In recent years, with the development of medicine, cognitive impairment has attracted attention in addition to common diseases. Dementia includes familial Alzheimer's disease in addition to aging as in Alzheimer-type senile dementia. Some have both genetic and acquired factors, such as schizophrenia.

  Alzheimer's disease has been pointed out to be related to nicotine because of the low incidence of smokers. In particular, recent studies have revealed that α7, one of the subtypes of nicotine acetylcholinesterase receptor in the brain, is associated with Alzheimer's disease. The relationship between α7 and other cognitive dysfunctions such as memory impairment, schizophrenia, hyperactivity disorder, and Parkinson's disease has been investigated.

  Therefore, a ligand for α7 has been searched as a therapeutic agent for cognitive impairment. For example, Patent Document 1 discloses a compound that is a ligand for α7 and is useful for treatment of diseases related to nicotinic receptor dysfunction.

  By the way, the present inventors have been conducting research on diagnosing brain disease by positron tomography using a compound that binds to α7 as a positron emission source. However, there are at least 12 subtypes in the nicotinic receptor, and many compounds that are considered to be selective ligands of α7 bind to other subtypes, and are accurate. It has been difficult to search for positron emitting source compounds that can be diagnosed. However, as disclosed in Patent Document 2, it has been found that the compound described in Patent Document 1 is suitable as a positron emission source for positron tomography.

Special table 2002-540208 gazette JP 2007-217370 A

  As described above, the present inventors have synthesized a compound having a positron-releasing ability to the compound described in Patent Document 1, and have developed a positron tomography method using the compound. The present inventors have synthesized a positron-emitting source compound from the above bromine-substituted compound according to the following scheme.

[Wherein R represents a group containing a positron emitting element]

  Moreover, the raw material compound of the said scheme, ie, the compound of patent document 1, was synthesize | combined by the following scheme.

  However, when a positron emitting source compound is synthesized as in the above scheme, it is very difficult to completely separate the unreacted bromo substituent from the tributyltin substituent due to the similarity in chemical structure. Such a bromo-substituted product is also mixed into the target compound, a positron-emitting compound. As a result, when positron emission tomography is performed using the positron emission source compound synthesized by the above scheme, the bromo-substituted product also binds to α7, so the amount of positron emission source compound that binds to α7 is reduced and sensitivity is lowered. There was a risk.

  The present invention has been made paying attention to the above-described circumstances, and an object of the present invention is to provide a method capable of producing a positron emission source compound with higher purity.

  The inventors of the present invention have made extensive studies to solve the above problems. As a result, if a trialkyltin group for introducing a substituent having a positron emission ability is previously introduced and then 1,4-diazabicyclo [3.2.2] nonane is reacted, The present invention was completed by discovering that the chemical structure of the target compound, the positron-emitting source compound, and its precursor compound are greatly different, so that purification becomes easier and a positron-emitting source compound with higher purity can be obtained.

  A method for producing a positron emission source compound according to the present invention is a method for producing a positron emission source compound represented by the following general formula (I):

[Wherein R ¹ represents a C _1-6 alkyl group containing a positron emitting element or a halogen atom]
Obtaining a trialkyltin compound (III) from the halogen compound (II);

[Wherein R ² represents a protecting group for activating the —OCO ₂ — group; Hal represents a halogen atom; R ^{3 to} R ⁵ each independently represents a C _1-8 alkyl group]
And a step of obtaining a nonane carbonate compound (IV) from the trialkyltin compound (III);

[Wherein R ^{2 to} R ⁵ are as defined above]
It is characterized by including.

  In the present invention, the “halogen atom” refers to any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, but from the viewpoint of reactivity, the fluorine atom is excluded from Hal and Hal ′.

The “C _1-6 alkyl group” refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. The “C _1-8 alkyl group” refers to a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, and examples thereof include heptyl and octyl in addition to the above. .

In the method of the present invention, R ² is preferably a group obtained by removing a hydroxyl group from any one of nitrophenol, N-hydroxysuccinimide and pentafluorophenol. These protecting groups are stable in the reaction according to the present invention, do not adversely affect the reaction, and can be easily exchanged with 1,4-diazabicyclo [3.2.2] nonane.

In the process of the present invention, each butyl and R ³ to R ^5, also, the _{^{R 1 - 11 CH 3, -}} 76 Br or - ¹²³ is preferably either a I.

  The positron-emitting source compound produced by the method of the present invention has less impurities and higher purity than those obtained by the conventional method. Therefore, by using the positron emission source compound produced by the method of the present invention, a more sensitive positron tomography method becomes possible. Therefore, the present invention is very useful industrially as enabling accurate positron tomography.

  As described above, the method for producing a positron emission source compound according to the present invention comprises a step of obtaining a trialkyltin compound (III) from a halogen compound (II), and a nonanecarbonate compound (IV) from a trialkyltin compound (III). A obtaining step. Hereinafter, the method of the present invention will be described in the order of execution.

1. Synthesis of Halogen Compound (II) Halogen compound (II), which is a raw material compound of the present invention, can be easily synthesized by the following scheme.

[Wherein R ² and Hal are as defined above; Hal ′ represents a halogen atom, which may be the same as or different from Hal]

  Compound (V) may be a commercially available compound or can be easily synthesized from a commercially available compound by methods known to those skilled in the art.

R ² is --OCO ₂ - a protecting group of the group, and --OCO ₂ - A which enhance the activity of the group, --OCO ₂ - group and 1,4-diazabicyclo [3.2.2] and nonane A thing that improves reactivity. Examples of such a group include a group obtained by removing a hydroxyl group from any one of nitrophenol, N-hydroxysuccinimide, and pentafluorophenol.

  Since compound (VI) has a relatively simple chemical structure, it may be used if it is commercially available, or may be synthesized from commercially available compounds by methods known to those skilled in the art. .

  In general, the reaction may be performed by reacting compound (V) and compound (VI) in a solvent in the presence of a base. Preferably, it is preferable to add the more reactive compound (V) in the solution of the compound (VI).

  As the solvent, an anhydrous organic solvent is preferably used in order to suppress decomposition of the compound (V). For example, halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; amides such as dimethylformamide and dimethylacetamide; mixed solvents thereof, which have been dried in advance Can be mentioned.

  As the base, those that can be dissolved in the organic solvent are suitable. For example, an organic base such as pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, diazabicycloundecene can be used.

  The concentration of the compound (V) and the compound (VI) in the reaction mixture may be adjusted as appropriate, and can be, for example, about 20 mg / mL or more and 100 mg / mL or less, respectively. In addition, when one of the compound (V) or the compound (VI) is expensive or there is a situation where it is necessary to synthesize without a commercially available product, the amount of one used can be less than the other. However, they are usually used in equimolar or nearly equimolar amounts. The amount of the base used may be equimolar or approximately equimolar with respect to compound (V) and compound (VI).

  The reaction temperature may be adjusted as appropriate, but in order to suppress the decomposition of the compound (V), it is preferably about −10 ° C. or more and 10 ° C. or less when the compound (VI) is dropped. In order to suppress the rapid progress of the reaction, it is also a preferable aspect to add a solution of the compound (VI) dropwise. After the addition of compound (VI), the reaction may be further advanced at about 0 ° C. or more and 10 ° C. or less.

  The reaction time may be appropriately adjusted. Specifically, the reaction time can be determined until the disappearance of the raw material compound is confirmed by chromatography or the like, or can be determined by a preliminary experiment or the like. Usually, after addition of compound (VI), it can be about 30 minutes or more and about 5 hours or less.

  After completion of the reaction, normal post-treatment may be performed. For example, after the solvent is distilled off under reduced pressure, it is diluted with an organic solvent that is not miscible with water, such as ethyl acetate or chloroform, and then washed with water or saturated saline. Next, the organic phase is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate and then concentrated. The target compound may be further purified by recrystallization or the like.

2. Synthesis of Trialkyltin Compound (III) Next, the trialkyltin compound (III) is produced from the halogen compound (II). More specifically, bistrialkyltin is reacted with halogen compound (II) in a solvent in the presence of tetrakistriphenylphosphine palladium (0) to replace the halogen group of halogen compound (II) with a trialkyltin group. .

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; amides such as dimethylformamide and dimethylacetamide; aromatic hydrocarbons such as toluene; A mixed solvent which has been dried in advance can be used.

  Since general bistrialkyltin is commercially available, it is preferable to use an excess amount of bistrialkyltin with respect to the halogen compound (II). Usually, about 1.5 times mol or more and 3 times mol or less are used with respect to a halogen compound. Tetrakistriphenylphosphine palladium (0) is sufficient in a catalytic amount of about 0.05 to 0.2 times mol of the halogen compound (II).

  The concentration of the halogen compound (II) and bistrialkyltin in the reaction mixture can be adjusted as appropriate, but usually 1 mg / mL or more, 20 mg / mL or less, 0.01 mL / mL or more, 0.1 mL / mL, respectively. It can be about mL or less.

  The reaction temperature may be appropriately adjusted. For example, the reaction temperature may be 30 ° C. or higher and 150 ° C. or lower, and may be heated to reflux. In addition, the reaction time may be determined as appropriate, but it can usually be about 1 hour or more and 10 hours or less.

  After completion of the reaction, normal post-treatment may be performed. For example, after the solvent and the like are distilled off under reduced pressure, the residue may be purified by silica gel column chromatography or the like.

3. Synthesis of nonane carbonate compound (IV) Next, a trialkyltin compound (III) and 1,4-diazabicyclo [3.2.2] nonane are reacted in a solvent in the presence of a base to give nonane carbonate compound (IV). To manufacture.

  Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; amides such as dimethylformamide and dimethylacetamide; A dried product can be used.

  As the base, those that can be dissolved in the organic solvent are suitable. For example, an organic base such as pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, diazabicycloundecene can be used. In order to accelerate the reaction, a catalytic amount of imidazole or the like may be added.

  What is necessary is just to adjust suitably the quantity of compound (III) and nonane compound in a reaction liquid mixture. For example, both may be used in an equimolar or substantially equimolar amount, but in some cases, one may be used in an amount of about 1.05 to 2.0 times the other.

  The concentrations of compound (III) and nonane compound in the reaction mixture may be adjusted as appropriate, but the reaction can be carried out at a relatively high concentration. For example, the concentration of compound (III) can be about 100 mg / mL to about 400 mg / mL and the nonane compound concentration can be about 10 mg / mL to about 50 mg / mL. Further, the base may be used in the same mole as the compound (III) or nonane compound.

  The reaction temperature may be adjusted as appropriate, and can be, for example, 10 ° C or higher and 50 ° C or lower. In addition, the reaction time may be determined as appropriate, but it can usually be about 1 hour or more and 10 hours or less.

  After completion of the reaction, normal post-treatment may be performed. For example, after the solvent and the like are distilled off under reduced pressure, the residue may be purified by silica gel column chromatography or the like.

  After completion of the reaction, normal post-treatment may be performed. For example, the reaction mixture is diluted with an organic solvent immiscible with water, such as ethyl acetate or chloroform, and washed with water, saturated saline, or the like. Next, the organic phase is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate and then concentrated. The target compound may be further purified by chromatography such as recrystallization. In addition, since nonane carbonate compound (IV) which is a target compound is different in structure and physical properties from trialkyltin compound (III) and 1,4-diazabicyclo [3.2.2] nonane which are raw material compounds, Separation from these starting compounds is easy and can be obtained with high purity.

4). Synthesis of Positron Release Source Compound (I) The positron emission source compound (I) is obtained by substituting the trialkyltin group of the nonane carbonate compound (IV) obtained above with a group having an element having a positron emission ability. Can be manufactured.

¹¹ C, ¹⁸ F, ⁷⁶ Br and ¹²³ I can be exemplified as an element having a positron emission ability. Accordingly, examples of R ¹ containing an element having a positron emission ability include [ ¹¹ C] C _1-6 alkyl group, and ¹⁸ F, ⁷⁶ Br, and ¹²³ I.

As a reagent for introducing R ¹ , a [ ¹¹ C] C _1-6 alkyl halide, ¹⁸ F ⁻ , ⁷⁶ Br ⁻ , ¹²³ I ⁻ may be used.

Specifically, the positron emission source compound (I) can be produced according to the method described in Patent Document 2 (Japanese Patent Application Laid-Open No. 2007-217370). That is, for example, in order to produce a positron emission source compound in which R ¹ is ¹¹ CH ₃ , ¹¹ CO ₂ is obtained by irradiating a target corresponding to a positron emission element with a positron accelerated by a cyclotron. A positron emission source compound can be produced by reducing the ¹¹ CO ₂ with, for example, a microlab and then reacting with hydroiodic acid to form ¹¹ CH ₃ I to react with the nonane carbonate compound (IV).

  The nonane carbonate compound (IV) obtained by the method of the present invention is less contaminated with impurities such as intermediate compounds and has high purity. As a result, the purity of the positron emission source compound obtained by the method of the present invention is also increased. Therefore, if positron emission tomography is performed using the positron emission source compound produced by the method of the present invention, measurement with higher sensitivity becomes possible.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

Example 1-1 4-Bromophenyl 4-nitrophenyl carbonate To a mixed solvent consisting of anhydrous tetrahydrofuran (60 mL) and anhydrous dichloromethane (24 mL), 4-bromophenol (5 g, 28.9 mmol) and pyridine (2.29 g, 28. 9 mmol) was added and dissolved. After cooling the solution, an anhydrous tetrahydrofuran solution (24 mL) of p-nitrophenyl ester of chloroformate (5.83 g, 28.9 mmol) was added at −2 to 3 ° C. Further, the reaction mixture was stirred at 3 ° C. for 1 hour to promote the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized using ethyl acetate to obtain the target compound (yield: 7.26 g, yield: 74%).
¹ H-NMR (CDCl ₃ ) δ 8.36-8.30 (m, 2H), 7.59-7.54 (m, 2H), 7.51-7.45 (m, 2H), 7.21-7.15 (m, 2H)

Example 1-2 4-Nitrophenyl 4- (tributylstannyl) phenyl carbonate 4-Bromophenyl 4-nitrophenyl carbonate (1 g, 2.96 mmol) obtained in Example 1-1 was converted to anhydrous 1,4- Dissolved in dioxane (100 mL). Tetrakistriphenylphosphine palladium (0) (381 mg, 0.33 mmol) and bistributyltin (3.28 mL, 6.51 mmol) were added to the solution. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 90/10) to obtain a crude target compound (yield: 500 mg). Without further purification, proceeded to the next step.

Example 1-3 4- (Tributylstannyl) phenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate To a mixed solvent consisting of anhydrous dichloromethane (576 μL) and anhydrous dimethylformamide (576 μL), 1 , 4-diazabicyclo [3.2.2] nonane (38.5 g, 0.31 mmol) and the crude 4-nitrophenyl 4- (tributylstannyl) phenyl carbonate (256 mg, 0) obtained in Example 1-2 above. .34 mmol) was dissolved. To the solution, imidazole (4.24 mg, 0.06 mmol) and triethylamine (43.5 μL, 0.31 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours to promote the reaction. After completion of the reaction, the reaction mixture was diluted with chloroform. The obtained diluted solution was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using NH silica (eluent: n-heptane / ethyl acetate = 3/2). Further, purification by gel permeation chromatography (eluent: chloroform) using GPC columns (JAIGEL-1H and JAIGEL-2H, each φ20 × 600 mm) gave the target compound (yield: 40.1 mg, Example 1- 2—Yield through Example 1-3: 4.9%).
¹ H-NMR (CDCl ₃ ) δ 7.56-7.31 (m, 2H, aromatic), 7.14-6.91 (m, 2H, aromatic), 4.51-4.24 (m, 1H), 3.30-2.90 (m, 6H), 2.24-1.94 (m, 2H), 1.88-0.75 (m, 27H)

Claims (4)

A method for producing a positron emission source compound represented by the following general formula (I):
[Wherein R ¹ represents a C _1-6 alkyl group containing a positron emitting element or a halogen atom]
Obtaining a trialkyltin compound (III) from the halogen compound (II);
[Wherein R ² represents a protecting group for activating the —OCO ₂ — group; Hal represents a halogen atom; R ^{3 to} R ⁵ each independently represents a C _1-8 alkyl group]
And a step of obtaining a nonane carbonate compound (IV) from the trialkyltin compound (III);
[Wherein R ^{2 to} R ⁵ are as defined above]
The manufacturing method characterized by including. The production method according to claim 1, wherein R ² is a group obtained by removing a hydroxyl group from any one of nitrophenol, N-hydroxysuccinimide, and pentafluorophenol. R < ³ > -R < ⁵ > is a butyl group, respectively, The manufacturing method of Claim 1 or 2. R ¹ is - ¹¹ CH _3, - ⁷⁶ Br or - ¹²³ A process according to claim 1 is any one of I.