WO2017090354A1 - Aromatic compound [11c]-methylation method - Google Patents
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- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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Definitions
- the present invention relates to a method for bonding a [ 11 C] methyl group (that is, a methyl group labeled with 11 C) to an aromatic carbon of an aromatic compound.
- aromatic carbon can be [ 11 C] methylated very rapidly, and therefore, a PET drug labeled with [ 11 C] having a short half-life can be suitably produced.
- PET Positron emission tomography
- a tracer labeled with a short-lived radionuclide such as 11 C or 18 F is used.
- the tracer labeled with 11 C has many advantages as described below. (1) Since the carbon atom which exists in all the organic compounds is utilized, the applicable range is very wide. (2) 11 C precursor becomes 11 CH 3 for the synthesis of labeled tracer by I, 11 CO, 11 CO 2, such as compounds, preparation has been well established, the purified precursor It can be obtained stably. (3) Since the tracer containing 11 C has a short half-life (20.4 minutes), many trial experiments and clinical studies for basic research can be conducted in one day.
- 11 C nuclides which can be produced by cyclotron ultratrace; a (tens of hundreds nmol level 12 value considering the incorporation of C), and ultra-dilute 11 C nuclides, special of a large excess of the labeled substrate Must be reacted under conditions. For this reason, there is a special difficulty that does not need to be considered in a normal chemical reaction, such as the amount of adsorption to the container must be taken into account.
- the conventional methylation method by cross-coupling with organotin compounds and organoboron compounds using palladium complexes makes it difficult or impossible to synthesize organotin compounds and organoboron compounds as reaction substrates. There were cases where it was not. Moreover, even if it could be synthesized, it was unstable and sometimes decomposed in a short time. Furthermore, it may be necessary to use an additive suitable for the reaction, and there is a problem that the reaction system becomes complicated and purification becomes difficult.
- the present invention has been made in view of the above-described conventional situation, and it is easy to synthesize a reaction substrate as a raw material, and can be used as a method for producing a [ 11 C] -labeled tracer for PET. Providing a methylation method is a problem to be solved.
- the present inventors have studied a cross-coupling reaction with [ 11 C] -labeled methyl group using a compound that can be easily synthesized as a reaction substrate instead of an organotin compound or an organoboron compound. It was. As a result, a novel reaction that has not been known so far is to prepare an aromatic palladium complex from an aromatic halogen or aromatic triflate as a reaction substrate, and to react this aromatic palladium complex with a methylpalladium complex. And the manufacturing method of the present invention was completed.
- the method for methylating an aromatic compound of the present invention includes: A first palladium complex forming step of adding [ 11 C] -labeled methyl iodide to an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand are dissolved to form a [ 11 C] methyl palladium complex; , In an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand are dissolved, an aromatic halogen (where halogen is I or Br, a triflate group, 2 Or aromatic triflate (provided that I, Br, and two or more triflate functional groups are not bonded) A second palladium complex forming step of forming an aromatic palladium complex, The [ 11 C] methylpalladium complex solution prepared in the first palladium complex formation step and the aromatic palladium complex solution prepared in the second palladium complex formation step are mixed
- the phosphine ligand refers to a compound having three organic substituents bonded to a trivalent phosphorus atom and further having an unshared electron pair.
- Organic substituents are preferably bulky, and specifically, those having a cone angle of 180 degrees or more as a bulkiness index are preferred.
- the applicable range of the aromatic halogen and aromatic triflate as a substrate is extremely wide, and the aromatic halogen and aromatic triflate have an alkyl group, an alkenyl group, an alkynyl group,
- the present invention can be applied even when a substituent such as an aryl group, amino group, hydroxyl group, amide group, formyl group, oxo group, or oxycarbonyl group is bonded.
- a substituent such as an aryl group, amino group, hydroxyl group, amide group, formyl group, oxo group, or oxycarbonyl group is bonded.
- compounds in which two or more halogen or triflate groups are substituted are not applicable.
- each substituent reacts with a palladium complex to produce two or more aromatic palladium complexes that are intermediates, resulting in a plurality of final products. It is.
- aromatic halogen a halogenated phenyl which may have a substituent can be used. The inventors have confirmed that methylation can be performed quickly and in good yield using a halogenated phenyl which may have a substituent.
- [11 C] demethyl bromide celecoxib by methyl iodide) (vertical axis: radiation intensity and the horizontal axis: time).
- Is a HPLC chart in the case of performing Example 4 i.e. [11 C] [11 C] methylation reaction of 4-iodo-L-phenylalanine by methyl iodide) (vertical axis: radiation intensity and the horizontal axis: time) .
- It is an HPLC chart of the case of performing the Example 5 [11 C] methylation reaction i.e. [11 C] UCB-J by methyl iodide) (vertical axis: radiation intensity and the horizontal axis: time).
- [ 11 C] -labeled methyl iodide is contained in an aprotic polar solvent in which a zerovalent palladium complex and a phosphine ligand are dissolved.
- an aromatic halogen (where halogen is I or Br) in an aprotic polar solvent of a zerovalent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand.
- the zero-valent palladium complex used in the first palladium complex-forming step and the second palladium complex-forming step is not particularly limited.
- a palladium zero-valent complex obtained by reducing Pd (OAc) 2 , Pd 2 ( dba) 3 etc. can be used.
- a phosphine ligand refers to a compound in which three organic substituents are bonded to a trivalent phosphorus atom and further has an unshared electron pair.
- trialkylphosphine such as trimethylphosphine, trioctylphosphine, tributylphosphine, dimethyloctylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, trixylylphosphine, trimesitylphosphine, tris (tetramethyl).
- Phenyl) phosphine diphenyl-p-chlorophenylphosphine, tris (p-methoxyphenyl) phosphine, diphenylethylphosphine, dimethylphenylphosphine, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane, dioctyloctane Xylphosphine, dibutylbutoxyphosphine, diphenylphenoxyphosphine, ditritolyloxyphosphine, dixylylsilyloxyphosphine, di Phenylethoxyphosphine, diethylphenoxyphosphine, octyldioctoxyphosphine, butylbutoxyphosphine, phenyldiphenoxyphosphine, tolylditolyloxyphosphine, xylyldixyloxyphosphin
- phosphine ligand used in the first palladium complex forming step a phosphine ligand having two or more aromatic substituents bonded to a phosphorus atom is preferable, and o-tolylphosphine is particularly preferable.
- the phosphine ligand used in the second palladium complex forming step is preferably a bulky phosphine ligand having a high electron density and easily forming a coordination unsaturated palladium complex. This is because in the second palladium complex formation step, an oxidative addition reaction must be caused with an aromatic halogen or aromatic trifre having low reactivity.
- N-heterocyclic carbene ligand can be used as the ligand used in the second palladium complex formation step.
- the N-heterocyclic carbene ligand refers to a ligand composed of a cyclic carbene species sandwiched between two adjacent nitrogen atoms.
- Examples of the aprotic polar solvent used in the first palladium complex forming step and the second palladium complex forming step include formamide solvents such as N, N-dimethylformamide and N, N-diethylformamide, N, N— Acetamide solvents such as dimethylacetamide and N, N-diethylacetamide, pyrrolidone solvents such as N-methyl-2-pyrrolidone and N-vinyl-2-pyrrolidone, sulfoxide solvents such as dimethyl sulfoxide and diethyl sulfoxide, hexamethylphospho Luamide, ⁇ -butyrolactone, etc. can be used.
- a formamide solvent, an acetamide solvent, and a pyrrolidone polar solvent are preferable.
- ⁇ Reaction mechanism of methylation method of aromatic compound of the present invention In a conventional methylation method using a methyl palladium complex, an organic tin compound is used as a reaction substrate (see, for example, Patent Document 1) or an organic boron compound is used (see, for example, Patent Document 2).
- carbon substituted with a boron group or a tin group is characterized by having an anionic charge under appropriate reaction conditions.
- a methyl group having a cationic property derived from methyl iodide has a cationic property derived from an aromatic halogen or an aromatic triflate under the use of an appropriate palladium complex.
- a trinuclear trans-methyl-Pd II iodide A and a tri-coordinate trans-phenyl-Pd II iodide B are used to form a binuclear intermediate ( C1 or C2) is generated.
- this binuclear intermediate (a) intermolecular exchange between phenyl and iodine ligands, or (b) intermolecular exchange between methyl and iodine ligands was performed.
- (Methyl) (phenyl) Pd II (D) and Pd II I 2 are formed.
- cis (methyl) (phenyl) Pd II (D) the methyl ligand and the phenyl ligand undergo reductive elimination to produce toluene.
- a coordination-unsaturated trans-type three-coordination complex is formed as an intermediate, and this is a cis-type that is easily reductively eliminated by organic group exchange. It is presumed that the reaction proceeds easily by becoming a three-coordination complex. For this reason, in addition to palladium complexes and reaction substrates, special additives such as acids and bases are added, as in the conventional methylation method by cross-coupling with organotin compounds and organoboron compounds using palladium complexes. Even without this, methylation can be carried out rapidly.
- iodobenzene (10.7 ⁇ L, 100 ⁇ mol), Pd 2 (dba) 3 (45 mg, 50 ⁇ mol), and Ligand (200 ⁇ mol) were weighed into a screw-tube test tube in an argon atmosphere, and a solvent ( 500 ⁇ L) was added and stirred at 60 ° C. for 1 hour.
- Pd 2 (dba) 3 4 mg, 5.0 ⁇ mol
- P (o-tolyl) 3 6.1 mg, 20 ⁇ mol
- CH 3 I (12.5 ⁇ L / 0.8 M 10 ⁇ mol) was weighed, and a solvent (500 ⁇ L) was further added, followed by stirring at room temperature for 1 minute.
- N-heterocyclic carbene ligand 3 When N-heterocyclic carbene ligand 3 was used (see entries 3 to 5), the desired toluene was obtained in a yield of 9 to 23%. It was also found that when tri-1-naphthylphosphine was used as the ligand (entry 6), toluene was obtained in a high yield of 99%. Even when the reaction time in entry 2 was shortened to 1 minute, it was confirmed that the target toluene was obtained in a 66% yield. Therefore, it was found that the methylation reaction of the present invention has a very high reaction rate even when the yield is low, and can be sufficiently used as a method for [ 11 C] methylation of aromatic compounds.
- Phenyl triflate can be easily synthesized from hydroxybenzene. Therefore, methylation was carried out under the same conditions as in entry 2 except that phenyltriflate, which can be easily prepared from hydroxybenzene, was used as a substrate instead of iodobenzene. As a result, it was found that the desired toluene was obtained with a yield of 67%.
- Example 1 In Example 1, [ 11 C] methylation reaction of iodobenzene with [ 11 C] methyl iodide was performed. 11 C nuclei were produced from a 14 N (p, ⁇ ) 11 C nuclear reaction using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. [ 11 C] methyl iodide was synthesized by converting 11 CO 2 ⁇ 11 CH 3 OH ⁇ 11 CH 3 I in this order using 11 CO 2 gas as a starting material, using a dedicated labeling synthesizer.
- [ 11 C] methyl iodide was blown into an NMP solution (100 ⁇ L) of Pd 2 (dba) 3 (1.8 mg, 1.9 ⁇ mol) and P (o-tolyl) 3 (2.4 mg, 7.8 ⁇ mol). Then, separately prepared solution ⁇ Iodobenzene (1.1 ⁇ L, 10 ⁇ mol), Pd 2 (dba) 3 (4.6 mg, 5 ⁇ mol), Tri-1-naphthylphosphine (8.2 mg, 20 ⁇ mol) was weighed and NMP (200 ⁇ L ), And a solution stirred at 60 ° C. for 1 hour was added, and the reaction was performed at 90 ° C. for 4 minutes.
- the HPLC analysis yield of the target [ 11 C] toluene was 36% (see FIG. 2).
- the HPLC analysis yield is an analysis by HPLC with a radiation detector and represents the peak area of [ 11 C] toluene as a ratio to the total peak area (the same applies hereinafter).
- Example 2 [ 11 C] methylation reaction was carried out under the same conditions except that benzene bromide was used in place of benzene iodide in Example 1. As a result, as shown in FIG. 3, the production of the desired [ 11 C] toluene was observed, and the HPLC analysis yield was 61%.
- Example 3 [ 11 C] methylation reaction of demethyl celecoxib bromide with [ 11 C] methyl iodide was performed. [ 11 C] methyl iodide was blown into an NMP solution (150 ⁇ L) of Pd 2 (dba) 3 (1.8 mg, 1.9 ⁇ mol) and P (o-tolyl) 3 (2.4 mg, 7.8 ⁇ mol).
- Example 4 In Example 4, [ 11 C] methylation reaction of 4-iodo-L-phenylalanine with [ 11 C] methyl iodide was performed. [ 11 C] methyl iodide was blown into an NMP solution (250 uL) of Pd 2 (dba) 3 (1.0 mg, 1 ⁇ mol) and P (o-tolyl) 3 (1.4 mg, 4.6 ⁇ mol).
- Example 5 synaptic vesicle glycoprotein 2A (SV2A ) and coupling approximately 10 UCB-J that is known to be GBq.
- [11 C] 11 by using methyl iodide present in synaptic vesicles C- Labeled. Details are shown below. [ 11 C] methyl iodide was blown into an NMP solution (250 ⁇ L) of Pd 2 (dba) 3 (1.0 mg, 1.0 ⁇ mol) and P (o-tolyl) 3 (1.4 mg, 4.6 ⁇ mol).
- various aromatic halides or various aromatic triflates can be rapidly [ 11 C] methylated, and thus can be used for the production of PET drugs.
Abstract
[Problem] To provide an aromatic compound methylation method, in which a reaction substrate that serves as a raw material can be synthesized easily, and which can be employed as a method for producing a [11C]-labeled tracer for PET use.
[Solution] In a first palladium complex formation step, [11C]-labeled methyl iodide is added to an aprotic polar solvent having a 0-valent palladium complex and a phosphine ligand dissolved therein to form a [11C]-methyl palladium complex. In a second palladium complex formation step, an aromatic halogen (wherein the halogen is I or Br) or an aromatic triflate is added to an aprotic polar solvent having a 0-valent palladium complex and a phosphine ligand or an N-heterocyclic carbene ligand dissolved therein to form an aromatic palladium complex. The solution containing the [11C]-methyl palladium complex is mixed with the solution containing the aromatic palladium complex to cause the bonding of a [11C]-methyl group to an aromatic substituent.
Description
本発明は芳香族化合物の芳香族炭素に[11C]メチル基（すなわち11Cで標識化されたメチル基）を結合させる方法に関する。本発明によれば、極めて迅速に芳香族炭素を[11C]メチル化することができるため、半減期の短い[11C]で標識されたPET薬剤を好適に製造することができる。
The present invention relates to a method for bonding a [ 11 C] methyl group (that is, a methyl group labeled with 11 C) to an aromatic carbon of an aromatic compound. According to the present invention, aromatic carbon can be [ 11 C] methylated very rapidly, and therefore, a PET drug labeled with [ 11 C] having a short half-life can be suitably produced.
陽電子放射断層画像撮影法（PET）は、理・工・薬・医が連携した一気通貫型研究であり、創薬においては、薬剤の体内動態イメージング法として活用され始めている。PETにおいてキーとなるテクノロジーは、生物活性化合物の陽電子放出核種での標識化であり、優れたPET薬剤の創製がPET分子イメージング研究の成否の鍵となる。
Positron emission tomography (PET) is an all-in-one research collaboration between science, engineering, medicine, and medicine, and is beginning to be used as a drug pharmacokinetic imaging method in drug discovery. The key technology in PET is the labeling of bioactive compounds with positron emitting nuclides, and the creation of excellent PET drugs is the key to the success of PET molecular imaging research.
ＰＥＴ法では、短寿命放射核種である11C、18Fなどで標識されたトレーサーが用いられる。この中でも、11Cで標識されたトレーサーは、次に述べるように、多くの長所を有している。
（１）全ての有機化合物中に存在している炭素原子を利用しているため、適用範囲が極めて広い。
（２）11Cで標識されたトレーサーを合成するための前駆体となる11CH3I、11CO、11CO2といった化合物は、調製法が充分に確立されており、精製された前駆体を安定的に入手することができる。
（３）11C含有トレーサーは半減期が短い（20.4分）ため、一日に多くの基礎的研究のための試行実験や臨床研究の実施を行うことができる。また、合成終了後に生じる放射性核種で標識化された副生成物の処理等に関しても、適切な遮蔽をして時間減衰させればよいので、特別な注意を払う必要がない。このため、11Cで標識されたトレーサーは、ＰＥＴ法における最も優れたトレーサーであるということができる。 In the PET method, a tracer labeled with a short-lived radionuclide such as 11 C or 18 F is used. Among them, the tracer labeled with 11 C has many advantages as described below.
(1) Since the carbon atom which exists in all the organic compounds is utilized, the applicable range is very wide.
(2) 11 C precursor becomes 11 CH 3 for the synthesis of labeled tracer by I, 11 CO, 11 CO 2, such as compounds, preparation has been well established, the purified precursor It can be obtained stably.
(3) Since the tracer containing 11 C has a short half-life (20.4 minutes), many trial experiments and clinical studies for basic research can be conducted in one day. Also, with respect to the treatment of by-products labeled with radionuclides generated after the completion of synthesis, it is only necessary to attenuate the time by appropriate shielding, so that no special attention is required. Therefore, it can be said that the tracer labeled with 11 C is the most excellent tracer in the PET method.
（１）全ての有機化合物中に存在している炭素原子を利用しているため、適用範囲が極めて広い。
（２）11Cで標識されたトレーサーを合成するための前駆体となる11CH3I、11CO、11CO2といった化合物は、調製法が充分に確立されており、精製された前駆体を安定的に入手することができる。
（３）11C含有トレーサーは半減期が短い（20.4分）ため、一日に多くの基礎的研究のための試行実験や臨床研究の実施を行うことができる。また、合成終了後に生じる放射性核種で標識化された副生成物の処理等に関しても、適切な遮蔽をして時間減衰させればよいので、特別な注意を払う必要がない。このため、11Cで標識されたトレーサーは、ＰＥＴ法における最も優れたトレーサーであるということができる。 In the PET method, a tracer labeled with a short-lived radionuclide such as 11 C or 18 F is used. Among them, the tracer labeled with 11 C has many advantages as described below.
(1) Since the carbon atom which exists in all the organic compounds is utilized, the applicable range is very wide.
(2) 11 C precursor becomes 11 CH 3 for the synthesis of labeled tracer by I, 11 CO, 11 CO 2, such as compounds, preparation has been well established, the purified precursor It can be obtained stably.
(3) Since the tracer containing 11 C has a short half-life (20.4 minutes), many trial experiments and clinical studies for basic research can be conducted in one day. Also, with respect to the treatment of by-products labeled with radionuclides generated after the completion of synthesis, it is only necessary to attenuate the time by appropriate shielding, so that no special attention is required. Therefore, it can be said that the tracer labeled with 11 C is the most excellent tracer in the PET method.
しかし、11Cの半減期は約20分と極めて短いため、反応開始から生成物を精製して投与するまで、なるべく40分以内に行うことが理想である。このため、トレーサーの合成反応は極めて短時間で完了しなければならないという問題がある。
また、サイクロトロンで製造できる11C核種は超微量（数十から数百nmolレベル；12Cの混入を考慮した値）であり、超希薄な11C核種と、大過剰の被標識基質という特殊な条件下で反応させなければならない。このため、容器への吸着量等も考慮しなければならない等、通常の化学反応では考慮しなくてもよいような特殊な困難性が存在する。 However, since the half-life of 11 C is as short as about 20 minutes, it is ideal to carry out the reaction within 40 minutes from the start of the reaction until the product is purified and administered. For this reason, there is a problem that the synthesis reaction of the tracer must be completed in a very short time.
Further, 11 C nuclides which can be produced by cyclotron ultratrace; a (tens of hundreds nmol level 12 value considering the incorporation of C), and ultra-dilute 11 C nuclides, special of a large excess of the labeled substrate Must be reacted under conditions. For this reason, there is a special difficulty that does not need to be considered in a normal chemical reaction, such as the amount of adsorption to the container must be taken into account.
また、サイクロトロンで製造できる11C核種は超微量（数十から数百nmolレベル；12Cの混入を考慮した値）であり、超希薄な11C核種と、大過剰の被標識基質という特殊な条件下で反応させなければならない。このため、容器への吸着量等も考慮しなければならない等、通常の化学反応では考慮しなくてもよいような特殊な困難性が存在する。 However, since the half-life of 11 C is as short as about 20 minutes, it is ideal to carry out the reaction within 40 minutes from the start of the reaction until the product is purified and administered. For this reason, there is a problem that the synthesis reaction of the tracer must be completed in a very short time.
Further, 11 C nuclides which can be produced by cyclotron ultratrace; a (tens of hundreds nmol level 12 value considering the incorporation of C), and ultra-dilute 11 C nuclides, special of a large excess of the labeled substrate Must be reacted under conditions. For this reason, there is a special difficulty that does not need to be considered in a normal chemical reaction, such as the amount of adsorption to the container must be taken into account.
本発明者らは、こうしたPET用の11C含有トレーサーを製造する方法として、０価のパラジウム錯体とホスフィン配位子存在下において[11C]標識ヨウ化メチルを用いて[11C]メチルパラジウム錯体とし、この[11C]メチルパラジウム錯体と有機スズ化合物や有機ホウ素化合物とをクロスカップリングさせる[11C]標識メチル化方法を開発している(特許文献１，２、非特許文献１～４)。
As a method for producing such 11 C-containing tracer for PET, the present inventors have used [ 11 C] methyl palladium in the presence of a zero-valent palladium complex and a phosphine ligand using [ 11 C] -labeled methyl iodide. A [ 11 C] -labeled methylation method in which this [ 11 C] methyl palladium complex is cross-coupled with an organotin compound or an organoboron compound as a complex has been developed ( Patent Documents 1 and 2, Non-Patent Documents 1 to 4).
しかし、上記従来のパラジウム錯体を用いた有機スズ化合物や有機ホウ素化合物とのクロスカップリングによるメチル化方法では、反応基質となる有機スズ化合物や有機ホウ素化合物の合成が困難であったり、合成ができなかったりする場合があった。また、例え合成できても、不安定であり、短時間で分解する場合もあった。さらには、反応に適した添加剤を使用することが必要な場合もあり、反応系が複雑になって、精製が困難になるという問題もあった。
本発明は、上記従来の実情に鑑みてなされたものであり、原料となる反応基質の合成が容易であり、PET用の[11C]標識トレーサーの製造方法として利用が可能な、芳香族化合物のメチル化方法を提供することを解決すべき課題としている。 However, the conventional methylation method by cross-coupling with organotin compounds and organoboron compounds using palladium complexes makes it difficult or impossible to synthesize organotin compounds and organoboron compounds as reaction substrates. There were cases where it was not. Moreover, even if it could be synthesized, it was unstable and sometimes decomposed in a short time. Furthermore, it may be necessary to use an additive suitable for the reaction, and there is a problem that the reaction system becomes complicated and purification becomes difficult.
The present invention has been made in view of the above-described conventional situation, and it is easy to synthesize a reaction substrate as a raw material, and can be used as a method for producing a [ 11 C] -labeled tracer for PET. Providing a methylation method is a problem to be solved.
本発明は、上記従来の実情に鑑みてなされたものであり、原料となる反応基質の合成が容易であり、PET用の[11C]標識トレーサーの製造方法として利用が可能な、芳香族化合物のメチル化方法を提供することを解決すべき課題としている。 However, the conventional methylation method by cross-coupling with organotin compounds and organoboron compounds using palladium complexes makes it difficult or impossible to synthesize organotin compounds and organoboron compounds as reaction substrates. There were cases where it was not. Moreover, even if it could be synthesized, it was unstable and sometimes decomposed in a short time. Furthermore, it may be necessary to use an additive suitable for the reaction, and there is a problem that the reaction system becomes complicated and purification becomes difficult.
The present invention has been made in view of the above-described conventional situation, and it is easy to synthesize a reaction substrate as a raw material, and can be used as a method for producing a [ 11 C] -labeled tracer for PET. Providing a methylation method is a problem to be solved.
本発明者らは上記課題を解決するため、有機スズ化合物や有機ホウ素化合物に替えて、合成が容易な化合物を反応基質とした[11C]標識メチル基とのクロスカップリング反応について研究を行った。その結果、反応基質として芳香族ハロゲンや芳香族トリフレートから芳香族パラジウム錯体を調製し、さらにこの芳香族パラジウム錯体とメチルパラジウム錯体とを反応させるという、従来には知られていなかった新規な反応を見出し、本発明の製造方法を完成した。
In order to solve the above problems, the present inventors have studied a cross-coupling reaction with [ 11 C] -labeled methyl group using a compound that can be easily synthesized as a reaction substrate instead of an organotin compound or an organoboron compound. It was. As a result, a novel reaction that has not been known so far is to prepare an aromatic palladium complex from an aromatic halogen or aromatic triflate as a reaction substrate, and to react this aromatic palladium complex with a methylpalladium complex. And the manufacturing method of the present invention was completed.
すなわち、本発明の芳香族化合物のメチル化方法は、
０価のパラジウム錯体とホスフィン配位子とが溶解した非プロトン性極性溶媒中に[11C]標識ヨウ化メチルを加えて[11C]メチルパラジウム錯体を形成させる第１のパラジウム錯体形成工程と、
０価のパラジウム錯体と、ホスフィン配位子又はＮ-ヘテロサイクリックカルベン配位子とが溶解した非プロトン性極性溶媒に芳香族ハロゲン（ただし、ハロゲンはＩ又はＢｒであり、トリフレート基や２つ以上のハロゲン元素が結合していないことを要件とする）又は芳香族トリフレート（ただし、Ｉ、Ｂｒ、及び２つ以上のトリフレート官能基が結合していないことを要件とする）を加えて芳香族パラジウム錯体を形成させる第２のパラジウム錯体形成工程と、
前記第１のパラジウム錯体形成工程で調製した前記[11C]メチルパラジウム錯体の溶液と、前記第２のパラジウム錯体形成工程で調製した前記芳香族パラジウム錯体の溶液と、を混合して芳香族置換基に[11C]メチル基を結合させるカップリング工程と、を備えることを特徴とする。 That is, the method for methylating an aromatic compound of the present invention includes:
A first palladium complex forming step of adding [ 11 C] -labeled methyl iodide to an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand are dissolved to form a [ 11 C] methyl palladium complex; ,
In an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand are dissolved, an aromatic halogen (where halogen is I or Br, a triflate group, 2 Or aromatic triflate (provided that I, Br, and two or more triflate functional groups are not bonded) A second palladium complex forming step of forming an aromatic palladium complex,
The [ 11 C] methylpalladium complex solution prepared in the first palladium complex formation step and the aromatic palladium complex solution prepared in the second palladium complex formation step are mixed to perform aromatic substitution. And a coupling step of bonding a [ 11 C] methyl group to the group.
０価のパラジウム錯体とホスフィン配位子とが溶解した非プロトン性極性溶媒中に[11C]標識ヨウ化メチルを加えて[11C]メチルパラジウム錯体を形成させる第１のパラジウム錯体形成工程と、
０価のパラジウム錯体と、ホスフィン配位子又はＮ-ヘテロサイクリックカルベン配位子とが溶解した非プロトン性極性溶媒に芳香族ハロゲン（ただし、ハロゲンはＩ又はＢｒであり、トリフレート基や２つ以上のハロゲン元素が結合していないことを要件とする）又は芳香族トリフレート（ただし、Ｉ、Ｂｒ、及び２つ以上のトリフレート官能基が結合していないことを要件とする）を加えて芳香族パラジウム錯体を形成させる第２のパラジウム錯体形成工程と、
前記第１のパラジウム錯体形成工程で調製した前記[11C]メチルパラジウム錯体の溶液と、前記第２のパラジウム錯体形成工程で調製した前記芳香族パラジウム錯体の溶液と、を混合して芳香族置換基に[11C]メチル基を結合させるカップリング工程と、を備えることを特徴とする。 That is, the method for methylating an aromatic compound of the present invention includes:
A first palladium complex forming step of adding [ 11 C] -labeled methyl iodide to an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand are dissolved to form a [ 11 C] methyl palladium complex; ,
In an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand are dissolved, an aromatic halogen (where halogen is I or Br, a triflate group, 2 Or aromatic triflate (provided that I, Br, and two or more triflate functional groups are not bonded) A second palladium complex forming step of forming an aromatic palladium complex,
The [ 11 C] methylpalladium complex solution prepared in the first palladium complex formation step and the aromatic palladium complex solution prepared in the second palladium complex formation step are mixed to perform aromatic substitution. And a coupling step of bonding a [ 11 C] methyl group to the group.
ここで、ホスフィン配位子とは、３価のリン原子に有機置換基が３つ結合しており、さらに非共有電子対を有する化合物をいう。有機置換基は嵩高いものが好ましく、具体的には嵩高さ指標となる円錐角が１８０度以上のものが好ましい。
Here, the phosphine ligand refers to a compound having three organic substituents bonded to a trivalent phosphorus atom and further having an unshared electron pair. Organic substituents are preferably bulky, and specifically, those having a cone angle of 180 degrees or more as a bulkiness index are preferred.
本発明の[11C]メチル化方法において、基質となる芳香族ハロゲン及び芳香族トリフレートの適用範囲は極めて広範囲であり、芳香族ハロゲン及び芳香族トリフレートにアルキル基、アルケニル基、アルキニル基、アリール基、アミノ基、水酸基、アミド基、ホルミル基、オキソ基期、オキシカルボニル基等の置換基が結合していても適用できる。ただし、ハロゲンやトリフレート基が２つ以上置換している化合物は適用できない。ハロゲンやトリフレートが２つ以上置換していると、それぞれの置換基がパラジウム錯体と反応し中間体となる芳香族パラジウム錯体が２種以上生じ、結果として複数の最終生成物が生じてしまうからである。
芳香族ハロゲンとして、置換基を有してもよいハロゲン化フェニルを用いることができる。発明者らは、置換基を有してもよいハロゲン化フェニルを用いて、迅速かつ良い収率でメチル化を行うことができることを確認している。 In the [ 11 C] methylation method of the present invention, the applicable range of the aromatic halogen and aromatic triflate as a substrate is extremely wide, and the aromatic halogen and aromatic triflate have an alkyl group, an alkenyl group, an alkynyl group, The present invention can be applied even when a substituent such as an aryl group, amino group, hydroxyl group, amide group, formyl group, oxo group, or oxycarbonyl group is bonded. However, compounds in which two or more halogen or triflate groups are substituted are not applicable. If two or more halogens or triflates are substituted, each substituent reacts with a palladium complex to produce two or more aromatic palladium complexes that are intermediates, resulting in a plurality of final products. It is.
As the aromatic halogen, a halogenated phenyl which may have a substituent can be used. The inventors have confirmed that methylation can be performed quickly and in good yield using a halogenated phenyl which may have a substituent.
芳香族ハロゲンとして、置換基を有してもよいハロゲン化フェニルを用いることができる。発明者らは、置換基を有してもよいハロゲン化フェニルを用いて、迅速かつ良い収率でメチル化を行うことができることを確認している。 In the [ 11 C] methylation method of the present invention, the applicable range of the aromatic halogen and aromatic triflate as a substrate is extremely wide, and the aromatic halogen and aromatic triflate have an alkyl group, an alkenyl group, an alkynyl group, The present invention can be applied even when a substituent such as an aryl group, amino group, hydroxyl group, amide group, formyl group, oxo group, or oxycarbonyl group is bonded. However, compounds in which two or more halogen or triflate groups are substituted are not applicable. If two or more halogens or triflates are substituted, each substituent reacts with a palladium complex to produce two or more aromatic palladium complexes that are intermediates, resulting in a plurality of final products. It is.
As the aromatic halogen, a halogenated phenyl which may have a substituent can be used. The inventors have confirmed that methylation can be performed quickly and in good yield using a halogenated phenyl which may have a substituent.
本発明の芳香族化合物のメチル化方法では、第１のパラジウム錯体形成工程として、０価のパラジウム錯体とホスフィン配位子とが溶解した非プロトン性極性溶媒中に[11C]標識ヨウ化メチルを加え、[11C]メチル基がパラジウムに結合した[11C]メチルパラジウム錯体の溶液とする。一方、第２のパラジウム錯体形成工程として、０価のパラジウム錯体とホスフィン配位子又はＮ-ヘテロサイクリックカルベン配位子の非プロトン性極性溶媒中に芳香族ハロゲン（ただし、ハロゲンはＩ又はＢｒ）又は芳香族トリフレートを加えて芳香族置換基がパラジウムに結合した芳香族パラジウム錯体の溶液とする。こうして得られた[11C]メチルパラジウム錯体の溶液と芳香族パラジウム錯体の溶液とを混合して[11C]メチル化芳香族化合物とする。
In the method for methylating an aromatic compound of the present invention, as the first palladium complex formation step, [ 11 C] -labeled methyl iodide is contained in an aprotic polar solvent in which a zerovalent palladium complex and a phosphine ligand are dissolved. To obtain a solution of [ 11 C] methyl palladium complex in which [ 11 C] methyl group is bonded to palladium. On the other hand, in the second palladium complex formation step, an aromatic halogen (where halogen is I or Br) in an aprotic polar solvent of a zerovalent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand. ) Or an aromatic triflate to obtain a solution of an aromatic palladium complex in which an aromatic substituent is bonded to palladium. The solution of [ 11 C] methylpalladium complex thus obtained and the solution of aromatic palladium complex are mixed to obtain a [ 11 C] methylated aromatic compound.
第１のパラジウム錯体形成工程及び第２のパラジウム錯体形成工程において用いる０価のパラジウム錯体としては特に限定はなく、例えばPd(OAc)2を還元して得られるパラジウム０価錯体や、Pd2(dba)3等を用いることができる。
また、本明細書において、ホスフィン配位子とは３価のリン原子に有機置換基が３つ結合しており、さらに非共有電子対を有する化合物をいう。具体的には、例えばトリメチルホスフィン、トリオクチルホスフィン、トリブチルホスフィン、ジメチルオクチルホスフィン等のトリアルキルホスフィンや、トリ（o-トリル）ホスフィン、トリシクロヘキシルホスフィン、トリキシリルホスフィン、トリメシチルホスフィン、トリス（テトラメチルフェニル）ホスフィン、ジフェニル-ｐ-クロロフェニルホスフィン、トリス（ｐ-メトキシフェニル）ホスフィン、ジフェニルエチルホスフィン、ジメチルフェニルホスフィン、ビス（ジフェニルホスフィノ）メタン、１，２-ビス（ジフェニルホスフィノ）エタン、ジオクチルオクトキシホスフィン、ジブチルブトキシホスフィン、ジフェニルフェノキシホスフィン、ジトリルトリルオキシホスフィン、ジキシリルキシリルオキシホスフィン、ジフェニルエトキシホスフィン、ジエチルフェノキシホスフィン、オクチルジオクトキシホスフィン、ブチルブトキシホスフィン、フェニルジフェノキシホスフィン、トリルジトリルオキシホスフィン、キシリルジキシリルオキシホスフィン、フェニルジエトキシホスフィン、エチルジフェノキシホスフィン、トリオクチルホスファイト、トリブチルホスファイト、ジメチルオクチルホスファイト、トリシクロヘキシルホスファイト、トリフェニルホスファイト、トリトリルホスファイト、トリキシリルホスファイト、ジフェニルエチルホスファイト、ジメチルフェニルホスファイト、1,3-ビス（ジフェニルホスフィノ）プロパン(dppp) 、 (2-ビフェニルイル)ジシクロヘキシルホスフィン、トリ-（１-ナフチル）ホスフィン等が挙げられる。
第１のパラジウム錯体形成工程で用いるホスフィン配位子としては、リン原子に芳香族置換基が２つ以上結合したホスフィンリガンドが好ましく、特にo-トリルホスフィンが好ましい。
また、第２のパラジウム錯体形成工程で用いるホスフィン配位子としては、電子密度が高くて、配位不飽和パラジウム錯体を形成し易い嵩高いホスフィン配位子が好ましい。なぜならば、第２のパラジウム錯体形成工程では、反応性の低い芳香族ハロゲンや芳香族トリフレーと酸化的付加反応を起こさせなければならないからである。具体的には、例えば、1,3-ビス（ジフェニルホスフィノ）プロパン(dppp) 、 (2-ビフェニルイル)ジシクロヘキシルホスフィン、トリ-（１-ナフチル）ホスフィン、トリ（o-トリル）ホスフィン等を用いることができる。さらに、第２のパラジウム錯体形成工程で用いる配位子としては、Ｎ-ヘテロサイクリックカルベン配位子を用いることができる。ここで、Ｎ-ヘテロサイクリックカルベン配位子とは、隣接する２つの窒素原子に挟まれた環状カルベン種からなる配位子をいう。 The zero-valent palladium complex used in the first palladium complex-forming step and the second palladium complex-forming step is not particularly limited. For example, a palladium zero-valent complex obtained by reducing Pd (OAc) 2 , Pd 2 ( dba) 3 etc. can be used.
In this specification, a phosphine ligand refers to a compound in which three organic substituents are bonded to a trivalent phosphorus atom and further has an unshared electron pair. Specifically, for example, trialkylphosphine such as trimethylphosphine, trioctylphosphine, tributylphosphine, dimethyloctylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, trixylylphosphine, trimesitylphosphine, tris (tetramethyl). Phenyl) phosphine, diphenyl-p-chlorophenylphosphine, tris (p-methoxyphenyl) phosphine, diphenylethylphosphine, dimethylphenylphosphine, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane, dioctyloctane Xylphosphine, dibutylbutoxyphosphine, diphenylphenoxyphosphine, ditritolyloxyphosphine, dixylylsilyloxyphosphine, di Phenylethoxyphosphine, diethylphenoxyphosphine, octyldioctoxyphosphine, butylbutoxyphosphine, phenyldiphenoxyphosphine, tolylditolyloxyphosphine, xylyldixyloxyphosphine, phenyldiethoxyphosphine, ethyldiphenoxyphosphine, trioctylphosphite , Tributyl phosphite, dimethyloctyl phosphite, tricyclohexyl phosphite, triphenyl phosphite, tolyl phosphite, trixyl phosphite, diphenylethyl phosphite, dimethylphenyl phosphite, 1,3-bis (diphenylphosphino) Examples include propane (dppp), (2-biphenylyl) dicyclohexylphosphine, and tri- (1-naphthyl) phosphine.
As the phosphine ligand used in the first palladium complex forming step, a phosphine ligand having two or more aromatic substituents bonded to a phosphorus atom is preferable, and o-tolylphosphine is particularly preferable.
The phosphine ligand used in the second palladium complex forming step is preferably a bulky phosphine ligand having a high electron density and easily forming a coordination unsaturated palladium complex. This is because in the second palladium complex formation step, an oxidative addition reaction must be caused with an aromatic halogen or aromatic trifre having low reactivity. Specifically, for example, 1,3-bis (diphenylphosphino) propane (dppp), (2-biphenylyl) dicyclohexylphosphine, tri- (1-naphthyl) phosphine, tri (o-tolyl) phosphine, etc. are used. be able to. Furthermore, an N-heterocyclic carbene ligand can be used as the ligand used in the second palladium complex formation step. Here, the N-heterocyclic carbene ligand refers to a ligand composed of a cyclic carbene species sandwiched between two adjacent nitrogen atoms.
また、本明細書において、ホスフィン配位子とは３価のリン原子に有機置換基が３つ結合しており、さらに非共有電子対を有する化合物をいう。具体的には、例えばトリメチルホスフィン、トリオクチルホスフィン、トリブチルホスフィン、ジメチルオクチルホスフィン等のトリアルキルホスフィンや、トリ（o-トリル）ホスフィン、トリシクロヘキシルホスフィン、トリキシリルホスフィン、トリメシチルホスフィン、トリス（テトラメチルフェニル）ホスフィン、ジフェニル-ｐ-クロロフェニルホスフィン、トリス（ｐ-メトキシフェニル）ホスフィン、ジフェニルエチルホスフィン、ジメチルフェニルホスフィン、ビス（ジフェニルホスフィノ）メタン、１，２-ビス（ジフェニルホスフィノ）エタン、ジオクチルオクトキシホスフィン、ジブチルブトキシホスフィン、ジフェニルフェノキシホスフィン、ジトリルトリルオキシホスフィン、ジキシリルキシリルオキシホスフィン、ジフェニルエトキシホスフィン、ジエチルフェノキシホスフィン、オクチルジオクトキシホスフィン、ブチルブトキシホスフィン、フェニルジフェノキシホスフィン、トリルジトリルオキシホスフィン、キシリルジキシリルオキシホスフィン、フェニルジエトキシホスフィン、エチルジフェノキシホスフィン、トリオクチルホスファイト、トリブチルホスファイト、ジメチルオクチルホスファイト、トリシクロヘキシルホスファイト、トリフェニルホスファイト、トリトリルホスファイト、トリキシリルホスファイト、ジフェニルエチルホスファイト、ジメチルフェニルホスファイト、1,3-ビス（ジフェニルホスフィノ）プロパン(dppp) 、 (2-ビフェニルイル)ジシクロヘキシルホスフィン、トリ-（１-ナフチル）ホスフィン等が挙げられる。
第１のパラジウム錯体形成工程で用いるホスフィン配位子としては、リン原子に芳香族置換基が２つ以上結合したホスフィンリガンドが好ましく、特にo-トリルホスフィンが好ましい。
また、第２のパラジウム錯体形成工程で用いるホスフィン配位子としては、電子密度が高くて、配位不飽和パラジウム錯体を形成し易い嵩高いホスフィン配位子が好ましい。なぜならば、第２のパラジウム錯体形成工程では、反応性の低い芳香族ハロゲンや芳香族トリフレーと酸化的付加反応を起こさせなければならないからである。具体的には、例えば、1,3-ビス（ジフェニルホスフィノ）プロパン(dppp) 、 (2-ビフェニルイル)ジシクロヘキシルホスフィン、トリ-（１-ナフチル）ホスフィン、トリ（o-トリル）ホスフィン等を用いることができる。さらに、第２のパラジウム錯体形成工程で用いる配位子としては、Ｎ-ヘテロサイクリックカルベン配位子を用いることができる。ここで、Ｎ-ヘテロサイクリックカルベン配位子とは、隣接する２つの窒素原子に挟まれた環状カルベン種からなる配位子をいう。 The zero-valent palladium complex used in the first palladium complex-forming step and the second palladium complex-forming step is not particularly limited. For example, a palladium zero-valent complex obtained by reducing Pd (OAc) 2 , Pd 2 ( dba) 3 etc. can be used.
In this specification, a phosphine ligand refers to a compound in which three organic substituents are bonded to a trivalent phosphorus atom and further has an unshared electron pair. Specifically, for example, trialkylphosphine such as trimethylphosphine, trioctylphosphine, tributylphosphine, dimethyloctylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, trixylylphosphine, trimesitylphosphine, tris (tetramethyl). Phenyl) phosphine, diphenyl-p-chlorophenylphosphine, tris (p-methoxyphenyl) phosphine, diphenylethylphosphine, dimethylphenylphosphine, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane, dioctyloctane Xylphosphine, dibutylbutoxyphosphine, diphenylphenoxyphosphine, ditritolyloxyphosphine, dixylylsilyloxyphosphine, di Phenylethoxyphosphine, diethylphenoxyphosphine, octyldioctoxyphosphine, butylbutoxyphosphine, phenyldiphenoxyphosphine, tolylditolyloxyphosphine, xylyldixyloxyphosphine, phenyldiethoxyphosphine, ethyldiphenoxyphosphine, trioctylphosphite , Tributyl phosphite, dimethyloctyl phosphite, tricyclohexyl phosphite, triphenyl phosphite, tolyl phosphite, trixyl phosphite, diphenylethyl phosphite, dimethylphenyl phosphite, 1,3-bis (diphenylphosphino) Examples include propane (dppp), (2-biphenylyl) dicyclohexylphosphine, and tri- (1-naphthyl) phosphine.
As the phosphine ligand used in the first palladium complex forming step, a phosphine ligand having two or more aromatic substituents bonded to a phosphorus atom is preferable, and o-tolylphosphine is particularly preferable.
The phosphine ligand used in the second palladium complex forming step is preferably a bulky phosphine ligand having a high electron density and easily forming a coordination unsaturated palladium complex. This is because in the second palladium complex formation step, an oxidative addition reaction must be caused with an aromatic halogen or aromatic trifre having low reactivity. Specifically, for example, 1,3-bis (diphenylphosphino) propane (dppp), (2-biphenylyl) dicyclohexylphosphine, tri- (1-naphthyl) phosphine, tri (o-tolyl) phosphine, etc. are used. be able to. Furthermore, an N-heterocyclic carbene ligand can be used as the ligand used in the second palladium complex formation step. Here, the N-heterocyclic carbene ligand refers to a ligand composed of a cyclic carbene species sandwiched between two adjacent nitrogen atoms.
また、第１のパラジウム錯体形成工程及び第２のパラジウム錯体形成工程において用いる非プロトン性極性溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジエチルホルムアミドなどのホルムアミド系溶媒、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ，Ｎ－ジエチルアセトアミドなどのアセトアミド系溶媒、Ｎ－メチル－２－ピロリドン、Ｎ－ビニル－２－ピロリドンなどのピロリドン系溶媒、ジメチルスルホキシド、ジエチルスルホキシドなどのスルホキシド系溶媒、ヘキサメチルホスホルアミド、γ－ブチロラクトン等を用いることができる。これらの中でも、ホルムアミド系溶媒、アセトアミド系溶媒、ピロリドン系極性溶媒が好ましい。
Examples of the aprotic polar solvent used in the first palladium complex forming step and the second palladium complex forming step include formamide solvents such as N, N-dimethylformamide and N, N-diethylformamide, N, N— Acetamide solvents such as dimethylacetamide and N, N-diethylacetamide, pyrrolidone solvents such as N-methyl-2-pyrrolidone and N-vinyl-2-pyrrolidone, sulfoxide solvents such as dimethyl sulfoxide and diethyl sulfoxide, hexamethylphospho Luamide, γ-butyrolactone, etc. can be used. Among these, a formamide solvent, an acetamide solvent, and a pyrrolidone polar solvent are preferable.
＜本発明の芳香族化合物のメチル化方法の反応機構＞
従来のメチルパラジウム錯体を用いたメチル化方法では、反応基質として有機スズ化合物を用いたり(例えば特許文献１参照)や、有機ホウ素化合物を用いたりしている（例えば特許文献２参照）。特に、ホウ素基やスズ基が置換した炭素は、適切な反応条件の下では、アニオン性の電荷を持つことが特徴である。
これに対して、本発明のメチル化方法では、適切なパラジウム錯体の使用下に、ヨウ化メチル由来のカチオン性を帯びたメチル基が、芳香族ハロゲンや芳香族トリフレート由来のカチオン性を帯びた芳香族官能基に結合するという、従来の有機化学の常識に反するような、全く新規な化学反応を利用するものである。発明者らは、このような特異な反応が起こる理由について、次のように推測している。以下、[11C] CH3Iとハロゲン化フェニル（あるいはベンゼントリフレート）とのカップリングを例に挙げて説明する。 <Reaction mechanism of methylation method of aromatic compound of the present invention>
In a conventional methylation method using a methyl palladium complex, an organic tin compound is used as a reaction substrate (see, for example, Patent Document 1) or an organic boron compound is used (see, for example, Patent Document 2). In particular, carbon substituted with a boron group or a tin group is characterized by having an anionic charge under appropriate reaction conditions.
On the other hand, in the methylation method of the present invention, a methyl group having a cationic property derived from methyl iodide has a cationic property derived from an aromatic halogen or an aromatic triflate under the use of an appropriate palladium complex. It uses a completely new chemical reaction, which is contrary to the conventional common sense of organic chemistry, such as bonding to an aromatic functional group. The inventors presume the reason why such a unique reaction occurs as follows. Hereinafter, the coupling between [ 11 C] CH 3 I and halogenated phenyl (or benzene triflate) will be described as an example.
従来のメチルパラジウム錯体を用いたメチル化方法では、反応基質として有機スズ化合物を用いたり(例えば特許文献１参照)や、有機ホウ素化合物を用いたりしている（例えば特許文献２参照）。特に、ホウ素基やスズ基が置換した炭素は、適切な反応条件の下では、アニオン性の電荷を持つことが特徴である。
これに対して、本発明のメチル化方法では、適切なパラジウム錯体の使用下に、ヨウ化メチル由来のカチオン性を帯びたメチル基が、芳香族ハロゲンや芳香族トリフレート由来のカチオン性を帯びた芳香族官能基に結合するという、従来の有機化学の常識に反するような、全く新規な化学反応を利用するものである。発明者らは、このような特異な反応が起こる理由について、次のように推測している。以下、[11C] CH3Iとハロゲン化フェニル（あるいはベンゼントリフレート）とのカップリングを例に挙げて説明する。 <Reaction mechanism of methylation method of aromatic compound of the present invention>
In a conventional methylation method using a methyl palladium complex, an organic tin compound is used as a reaction substrate (see, for example, Patent Document 1) or an organic boron compound is used (see, for example, Patent Document 2). In particular, carbon substituted with a boron group or a tin group is characterized by having an anionic charge under appropriate reaction conditions.
On the other hand, in the methylation method of the present invention, a methyl group having a cationic property derived from methyl iodide has a cationic property derived from an aromatic halogen or an aromatic triflate under the use of an appropriate palladium complex. It uses a completely new chemical reaction, which is contrary to the conventional common sense of organic chemistry, such as bonding to an aromatic functional group. The inventors presume the reason why such a unique reaction occurs as follows. Hereinafter, the coupling between [ 11 C] CH 3 I and halogenated phenyl (or benzene triflate) will be described as an example.
まず、第1段階として、図１の（１）式に示すように、CH3Iが０価のパラジウム錯体と酸化的付加反応を起こし、三配位トランス-メチル-PdIIヨウ化物Aとなる。他方、（２）式に示すように、ハロゲン化フェニルも０価のパラジウム錯体と酸化的付加反応を起こし、三配位トランス-フェニル-PdIIヨウ化物Bとなる。（１）式や（２）式において四配位錯体ではなく、配位不飽和な三配位錯体（unsaturated tri-coordinated）となるのは、ホスフィン配位子の嵩高さによるものである。さらに、（３）式に示すように、三配位トランス-メチル-PdIIヨウ化物Aと、三配位トランス-フェニル-PdIIヨウ化物Bとから、二核性中間体（binuclear intermediate）（C1又はC2）が生成する。この二核性中間体において、(a)フェニル配位子とヨウ素配位子の分子間交換、あるいは(b)メチル配位子とヨウ素配位子の分子間交換が行われ、その結果、シス（メチル）（フェニル）PdII（D）及びPdIII2が生成する。 最後に、シス（メチル）（フェニル）PdII（D）においてメチル配位子とフェニル配位子とが、還元的脱離をしてトルエンが生成する。
First, as shown in FIG. 1 (1), as the first step, CH 3 I undergoes an oxidative addition reaction with a zerovalent palladium complex to form a tricoordinate trans-methyl-Pd II iodide A. . On the other hand, as shown in the formula (2), phenyl halide also undergoes an oxidative addition reaction with a zero-valent palladium complex to become a three-coordinate trans-phenyl-Pd II iodide B. In the formulas (1) and (2), it is not a tetracoordinate complex but an unsaturated tri-coordinated because of the bulkiness of the phosphine ligand. Furthermore, as shown in the formula (3), a trinuclear trans-methyl-Pd II iodide A and a tri-coordinate trans-phenyl-Pd II iodide B are used to form a binuclear intermediate ( C1 or C2) is generated. In this binuclear intermediate, (a) intermolecular exchange between phenyl and iodine ligands, or (b) intermolecular exchange between methyl and iodine ligands was performed. (Methyl) (phenyl) Pd II (D) and Pd II I 2 are formed. Finally, in cis (methyl) (phenyl) Pd II (D), the methyl ligand and the phenyl ligand undergo reductive elimination to produce toluene.
以上のように、本発明の芳香族化合物のメチル化方法では、中間体として配位不飽和なトランス型の三配位錯体が形成され、これが有機基交換によって還元的脱離が容易なシス型の三配位錯体となることによって、反応が容易に進行するものと推定される。このため、従来の、パラジウム錯体を用いた有機スズ化合物や有機ホウ素化合物とのクロスカップリングによるメチル化方法のように、パラジウム錯体及び反応基質以外に、酸や塩基等、特別な添加剤を添加しなくても、迅速にメチル化を行うことができる。
As described above, in the method for methylating an aromatic compound of the present invention, a coordination-unsaturated trans-type three-coordination complex is formed as an intermediate, and this is a cis-type that is easily reductively eliminated by organic group exchange. It is presumed that the reaction proceeds easily by becoming a three-coordination complex. For this reason, in addition to palladium complexes and reaction substrates, special additives such as acids and bases are added, as in the conventional methylation method by cross-coupling with organotin compounds and organoboron compounds using palladium complexes. Even without this, methylation can be carried out rapidly.
＜実施例＞
以下、本発明を具体化した実施例について述べる。なお、使用した溶媒について以下の略号を用いることがある。
dba : dibenzylideneacetone
NMP : N-methyl-2-pyrrolidone
DMSO : Dimethyl sulfoxide <Example>
Embodiments embodying the present invention will be described below. The following abbreviations may be used for the solvents used.
dba: dibenzylideneacetone
NMP: N-methyl-2-pyrrolidone
DMSO: Dimethyl sulfoxide
以下、本発明を具体化した実施例について述べる。なお、使用した溶媒について以下の略号を用いることがある。
dba : dibenzylideneacetone
NMP : N-methyl-2-pyrrolidone
DMSO : Dimethyl sulfoxide <Example>
Embodiments embodying the present invention will be described below. The following abbreviations may be used for the solvents used.
dba: dibenzylideneacetone
NMP: N-methyl-2-pyrrolidone
DMSO: Dimethyl sulfoxide
（ヨウ化メチルによるヨードベンゼンのメチル化反応）
本発明のメチル化反応を行うにあたり、まずは非放射性条件下、ヨウ化メチルとヨードベンゼンを用いたモデル反応を設定し、反応温度を100℃、反応時間5分として反応条件の検討を行った。反応は、エントリー１～６の６種類の条件で行った（下記表１参照）。反応生成物の分析は、ガスクロマトグラフ(GC)を用いて行った。目的物のトルエンの収率は、ノナンを内部標準物質としてヨウ化メチルの使用量を基準として算出した。なお、本発明者らは、有機スズや有機ホウ素化合物を用いた[11C]メチル化法において、Pd2(dba)3/4P(o-tolyl)3を含む溶液はガス状の[11C]ヨウ化メチルに対して非常に高い捕獲力と反応性を示すことを見出している（特許文献１、２）。そこで、この反応条件を基盤として、アルゴン雰囲気下、ネジ口試験管にヨードベンゼン（10.7μL, 100μmol）、Pd2(dba)3 (45 mg, 50μmol)、Ligand (200μmol)をはかりとり、溶媒(500μL)を加え、60℃で１時間撹拌した。また、別途にネジ口試験管にPd2(dba)3 (4.6 mg, 5.0μmol)、P(o-tolyl)3 (6.1 mg, 20 μmol)、CH3I(12.5μL /0.8 M 溶媒溶液を10 μmol)をはかりとり、さらに溶媒(500μL)を加え室温で１分間撹拌した。続いて、前者の反応溶液を後者の反応溶液へ移送し、その後100℃で5分間撹拌した。反応後すぐに冷却し、内部標準としてn-ノナン(50μL /0.1M 溶媒溶液を5μmol)を加えた反応液をシリカゲルのショートカラムにのせ、酢酸エチルで溶出したのちGC分析を行った。結果を表１に示す。
・ガスクロマトグラフィー分析条件
水素炎イオン化検出器（FID検出器）付き
島津製GC-2014 : キャピラリーカラムGL-Science社製InertCap1 (長さ30 m, 内径0.25 mm)
キャリアガス: ヘリウム 流速64.0 mL/min, 線速度25.0 cm/sec
試料導入部及び検出器の温度: 210℃カラム温度:初期温度40℃、最終温度200℃。7分目から23分目まで5℃/分で昇温し、23分目から28分目まで15℃/分で昇温。
保持時間：トルエン（6.3 min） (Methylation of iodobenzene with methyl iodide)
In carrying out the methylation reaction of the present invention, first, a model reaction using methyl iodide and iodobenzene was set under non-radioactive conditions, and the reaction conditions were examined at a reaction temperature of 100 ° C. and a reaction time of 5 minutes. The reaction was performed under the six conditions ofentries 1 to 6 (see Table 1 below). The analysis of the reaction product was performed using a gas chromatograph (GC). The yield of the target toluene was calculated based on the amount of methyl iodide used with nonane as an internal standard substance. In the [ 11 C] methylation method using organotin or an organoboron compound, the inventors of the present invention used a solution containing Pd 2 (dba) 3 / 4P (o-tolyl) 3 as a gaseous [ 11 C It has been found that it has a very high trapping power and reactivity with methyl iodide (Patent Documents 1 and 2). Therefore, based on these reaction conditions, iodobenzene (10.7 μL, 100 μmol), Pd 2 (dba) 3 (45 mg, 50 μmol), and Ligand (200 μmol) were weighed into a screw-tube test tube in an argon atmosphere, and a solvent ( 500 μL) was added and stirred at 60 ° C. for 1 hour. Separately, Pd 2 (dba) 3 (4.6 mg, 5.0 μmol), P (o-tolyl) 3 (6.1 mg, 20 μmol), CH 3 I (12.5 μL / 0.8 M 10 μmol) was weighed, and a solvent (500 μL) was further added, followed by stirring at room temperature for 1 minute. Subsequently, the former reaction solution was transferred to the latter reaction solution, and then stirred at 100 ° C. for 5 minutes. The reaction solution was cooled immediately after the reaction, and added with n-nonane (5 μmol of 50 μL / 0.1M solvent solution) as an internal standard, placed on a silica gel short column, eluted with ethyl acetate, and then subjected to GC analysis. The results are shown in Table 1.
Gas chromatography analysis conditions Shimadzu GC-2014 with flame ionization detector (FID detector): Capillary column GL-Science InertCap1 (length 30 m, inner diameter 0.25 mm)
Carrier gas: Helium flow rate 64.0 mL / min, linear velocity 25.0 cm / sec
Sample introduction part and detector temperature: 210 ° C. Column temperature: initial temperature 40 ° C., final temperature 200 ° C. The temperature was raised at 5 ° C / min from the 7th minute to the 23rd minute, and raised at 15 ° C / min from the 23rd minute to the 28th minute.
Retention time: Toluene (6.3 min)
本発明のメチル化反応を行うにあたり、まずは非放射性条件下、ヨウ化メチルとヨードベンゼンを用いたモデル反応を設定し、反応温度を100℃、反応時間5分として反応条件の検討を行った。反応は、エントリー１～６の６種類の条件で行った（下記表１参照）。反応生成物の分析は、ガスクロマトグラフ(GC)を用いて行った。目的物のトルエンの収率は、ノナンを内部標準物質としてヨウ化メチルの使用量を基準として算出した。なお、本発明者らは、有機スズや有機ホウ素化合物を用いた[11C]メチル化法において、Pd2(dba)3/4P(o-tolyl)3を含む溶液はガス状の[11C]ヨウ化メチルに対して非常に高い捕獲力と反応性を示すことを見出している（特許文献１、２）。そこで、この反応条件を基盤として、アルゴン雰囲気下、ネジ口試験管にヨードベンゼン（10.7μL, 100μmol）、Pd2(dba)3 (45 mg, 50μmol)、Ligand (200μmol)をはかりとり、溶媒(500μL)を加え、60℃で１時間撹拌した。また、別途にネジ口試験管にPd2(dba)3 (4.6 mg, 5.0μmol)、P(o-tolyl)3 (6.1 mg, 20 μmol)、CH3I(12.5μL /0.8 M 溶媒溶液を10 μmol)をはかりとり、さらに溶媒(500μL)を加え室温で１分間撹拌した。続いて、前者の反応溶液を後者の反応溶液へ移送し、その後100℃で5分間撹拌した。反応後すぐに冷却し、内部標準としてn-ノナン(50μL /0.1M 溶媒溶液を5μmol)を加えた反応液をシリカゲルのショートカラムにのせ、酢酸エチルで溶出したのちGC分析を行った。結果を表１に示す。
・ガスクロマトグラフィー分析条件
水素炎イオン化検出器（FID検出器）付き
島津製GC-2014 : キャピラリーカラムGL-Science社製InertCap1 (長さ30 m, 内径0.25 mm)
キャリアガス: ヘリウム 流速64.0 mL/min, 線速度25.0 cm/sec
試料導入部及び検出器の温度: 210℃カラム温度:初期温度40℃、最終温度200℃。7分目から23分目まで5℃/分で昇温し、23分目から28分目まで15℃/分で昇温。
保持時間：トルエン（6.3 min） (Methylation of iodobenzene with methyl iodide)
In carrying out the methylation reaction of the present invention, first, a model reaction using methyl iodide and iodobenzene was set under non-radioactive conditions, and the reaction conditions were examined at a reaction temperature of 100 ° C. and a reaction time of 5 minutes. The reaction was performed under the six conditions of
Gas chromatography analysis conditions Shimadzu GC-2014 with flame ionization detector (FID detector): Capillary column GL-Science InertCap1 (length 30 m, inner diameter 0.25 mm)
Carrier gas: Helium flow rate 64.0 mL / min, linear velocity 25.0 cm / sec
Sample introduction part and detector temperature: 210 ° C. Column temperature: initial temperature 40 ° C., final temperature 200 ° C. The temperature was raised at 5 ° C / min from the 7th minute to the 23rd minute, and raised at 15 ° C / min from the 23rd minute to the 28th minute.
Retention time: Toluene (6.3 min)
Pd(0)錯体としてPd(PPh3)4を用いてヨードベンゼンからフェニルパラジウム錯体を調製して反応を行った場合、DMSO溶媒では65%の収率で目的のトルエンが生成することが分かった（エントリー１）。また、NMP溶媒を用いた時の収率は同様の63％であった（エントリー２）。さらに、Pd2(dba)3の使用下に、二座の配位子の1,3-ビス（ジフェニルホスフィノ）プロパン(dppp) 1やBuchwald配位子である(2-ビフェニルイル)ジシクロヘキシルホスフィン2、やＮ-ヘテロサイクリックカルベン配位子3を用いたところ（エントリー３～５参照）、目的のトルエンが9～23%の収率で得られた。また、配位子にトリ-1-ナフチルホスフィンを用いた場合（エントリー６）、トルエンが99％という高収率で得られることが分かった。なお、エントリー２における反応時間５分間を１分間に短縮した場合であっても、目的のトルエンは66%収率で得られることを確認した。したがって、本発明のメチル化反応は、例え収率が低い場合であっても反応速度は極めて速く、芳香族化合物の[11C]メチル化方法として充分利用できることが分かった。
It was found that when a palladium palladium complex was prepared from iodobenzene using Pd (PPh 3 ) 4 as the Pd (0) complex and reacted, DMSO solvent produced the desired toluene in 65% yield. (Entry 1). The yield when using NMP solvent was the same 63% (entry 2). Furthermore, with the use of Pd 2 (dba) 3 , the bidentate ligand 1,3-bis (diphenylphosphino) propane (dppp) 1 and the Buchwald ligand (2-biphenylyl) dicyclohexylphosphine 2. When N-heterocyclic carbene ligand 3 was used (see entries 3 to 5), the desired toluene was obtained in a yield of 9 to 23%. It was also found that when tri-1-naphthylphosphine was used as the ligand (entry 6), toluene was obtained in a high yield of 99%. Even when the reaction time in entry 2 was shortened to 1 minute, it was confirmed that the target toluene was obtained in a 66% yield. Therefore, it was found that the methylation reaction of the present invention has a very high reaction rate even when the yield is low, and can be sufficiently used as a method for [ 11 C] methylation of aromatic compounds.
次に、表１のエントリー６において、ヨードベンゼンの使用量を半分の50μmolに減らし、比較的温和な60℃で反応を行った時、目的のトルエンは92%の高収率で得られることが分かった。
Next, in entry 6 of Table 1, when the reaction is carried out at a relatively mild 60 ° C. with the amount of iodobenzene used being reduced to 50 μmol, the target toluene can be obtained in a high yield of 92%. I understood.
フェニルトリフレートはヒドロキシベンゼンから容易に合成可能である。そこで、ヨードベンゼンの代わりに、ヒドロキシベンゼンから容易に調製できるフェニルトリフレートを基質とし、その他の条件はエントリー２と同様としてメチル化を行った。その結果、目的のトルエンが67%の収率で得られることが分かった。
Phenyl triflate can be easily synthesized from hydroxybenzene. Therefore, methylation was carried out under the same conditions as in entry 2 except that phenyltriflate, which can be easily prepared from hydroxybenzene, was used as a substrate instead of iodobenzene. As a result, it was found that the desired toluene was obtained with a yield of 67%.
（実施例１）
実施例１では[11C]ヨウ化メチルによるヨードベンゼンの[11C]メチル化反応を行った。11C核の製造は住友重機械工業社製サイクロトロンCYPRIS HM-12S を使用し14N(p,α)11Cの核反応より製造した。[11C]ヨウ化メチルの合成は専用の標識用合成装置を用いて、11CO2ガスを出発物質として11CO2→11CH3OH→11CH3Iの順に変換して合成した。Pd2(dba)3 (1.8 mg,1.9μmol)、P(o-tolyl)3 (2.4 mg,7.8μmol)、のNMP溶液（100μL）に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液｛ヨードベンゼン（1.1μL,10μmol）、Pd2(dba)3 (4.6 mg, 5μmol)、Tri-1-naphthylphosphine (8.2 mg, 20μmol)をはかりとり、NMP(200μL)を加え、60 ℃で１時間撹拌した溶液を添加し、90 ℃、4分間反応を行った。反応終了後アセトニトリルを1 mL加えて、フィルターに通した。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行った。その結果、目的の[11C]トルエンのHPLC分析収率は36%であった（図２参照）。ここで、HPLC分析収率とは、放射線検出器付きHPLCにて分析し[11C]トルエンのピーク面積を全ピーク面積との比で表したものである（以下同様）。
HPLC分取条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 60 : 40
Flow rate : 1.0 mL / min
Retention time : desired compound ([11C]Toluene) 5.5 min Example 1
In Example 1, [ 11 C] methylation reaction of iodobenzene with [ 11 C] methyl iodide was performed. 11 C nuclei were produced from a 14 N (p, α) 11 C nuclear reaction using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. [ 11 C] methyl iodide was synthesized by converting 11 CO 2 → 11 CH 3 OH → 11 CH 3 I in this order using 11 CO 2 gas as a starting material, using a dedicated labeling synthesizer. [ 11 C] methyl iodide was blown into an NMP solution (100 μL) of Pd 2 (dba) 3 (1.8 mg, 1.9 μmol) and P (o-tolyl) 3 (2.4 mg, 7.8 μmol). Then, separately prepared solution {Iodobenzene (1.1 μL, 10 μmol), Pd 2 (dba) 3 (4.6 mg, 5 μmol), Tri-1-naphthylphosphine (8.2 mg, 20 μmol) was weighed and NMP (200 μL ), And a solution stirred at 60 ° C. for 1 hour was added, and the reaction was performed at 90 ° C. for 4 minutes. After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC. As a result, the HPLC analysis yield of the target [ 11 C] toluene was 36% (see FIG. 2). Here, the HPLC analysis yield is an analysis by HPLC with a radiation detector and represents the peak area of [ 11 C] toluene as a ratio to the total peak area (the same applies hereinafter).
HPLC preparative conditions
Column: COSMOSIL 5-C 18 AR-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 60: 40
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] Toluene) 5.5 min
実施例１では[11C]ヨウ化メチルによるヨードベンゼンの[11C]メチル化反応を行った。11C核の製造は住友重機械工業社製サイクロトロンCYPRIS HM-12S を使用し14N(p,α)11Cの核反応より製造した。[11C]ヨウ化メチルの合成は専用の標識用合成装置を用いて、11CO2ガスを出発物質として11CO2→11CH3OH→11CH3Iの順に変換して合成した。Pd2(dba)3 (1.8 mg,1.9μmol)、P(o-tolyl)3 (2.4 mg,7.8μmol)、のNMP溶液（100μL）に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液｛ヨードベンゼン（1.1μL,10μmol）、Pd2(dba)3 (4.6 mg, 5μmol)、Tri-1-naphthylphosphine (8.2 mg, 20μmol)をはかりとり、NMP(200μL)を加え、60 ℃で１時間撹拌した溶液を添加し、90 ℃、4分間反応を行った。反応終了後アセトニトリルを1 mL加えて、フィルターに通した。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行った。その結果、目的の[11C]トルエンのHPLC分析収率は36%であった（図２参照）。ここで、HPLC分析収率とは、放射線検出器付きHPLCにて分析し[11C]トルエンのピーク面積を全ピーク面積との比で表したものである（以下同様）。
HPLC分取条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 60 : 40
Flow rate : 1.0 mL / min
Retention time : desired compound ([11C]Toluene) 5.5 min Example 1
In Example 1, [ 11 C] methylation reaction of iodobenzene with [ 11 C] methyl iodide was performed. 11 C nuclei were produced from a 14 N (p, α) 11 C nuclear reaction using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. [ 11 C] methyl iodide was synthesized by converting 11 CO 2 → 11 CH 3 OH → 11 CH 3 I in this order using 11 CO 2 gas as a starting material, using a dedicated labeling synthesizer. [ 11 C] methyl iodide was blown into an NMP solution (100 μL) of Pd 2 (dba) 3 (1.8 mg, 1.9 μmol) and P (o-tolyl) 3 (2.4 mg, 7.8 μmol). Then, separately prepared solution {Iodobenzene (1.1 μL, 10 μmol), Pd 2 (dba) 3 (4.6 mg, 5 μmol), Tri-1-naphthylphosphine (8.2 mg, 20 μmol) was weighed and NMP (200 μL ), And a solution stirred at 60 ° C. for 1 hour was added, and the reaction was performed at 90 ° C. for 4 minutes. After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC. As a result, the HPLC analysis yield of the target [ 11 C] toluene was 36% (see FIG. 2). Here, the HPLC analysis yield is an analysis by HPLC with a radiation detector and represents the peak area of [ 11 C] toluene as a ratio to the total peak area (the same applies hereinafter).
HPLC preparative conditions
Column: COSMOSIL 5-C 18 AR-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 60: 40
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] Toluene) 5.5 min
（実施例２）
実施例２では実施例１におけるヨウ化ベンゼンの替りに臭化ベンゼンを用い、その他については同様の条件で[11C]メチル化反応を行った。その結果、図３に示すように目的の[11C]トルエンの生成が観測され、そのHPLC分析収率は61%であった。 (Example 2)
In Example 2, [ 11 C] methylation reaction was carried out under the same conditions except that benzene bromide was used in place of benzene iodide in Example 1. As a result, as shown in FIG. 3, the production of the desired [ 11 C] toluene was observed, and the HPLC analysis yield was 61%.
実施例２では実施例１におけるヨウ化ベンゼンの替りに臭化ベンゼンを用い、その他については同様の条件で[11C]メチル化反応を行った。その結果、図３に示すように目的の[11C]トルエンの生成が観測され、そのHPLC分析収率は61%であった。 (Example 2)
In Example 2, [ 11 C] methylation reaction was carried out under the same conditions except that benzene bromide was used in place of benzene iodide in Example 1. As a result, as shown in FIG. 3, the production of the desired [ 11 C] toluene was observed, and the HPLC analysis yield was 61%.
（実施例３）
実施例３では[11C]ヨウ化メチルによるデメチル臭化セレコキシブの[11C]メチル化反応を行った。
Pd2(dba)3 (1.8 mg, 1.9μmol)、P(o-tolyl)3 (2.4 mg, 7.8μmol)、のNMP溶液（150μL）に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液｛ブロモ前駆体（4.5 mg, 10μmol）、Pd2(dba)3 (4.6 mg, 5μmol)、Tri-1-naphthylphosphine (8.2 mg, 20μmol)をはかりとりNMP(500μL)を加え、60 ℃で１時間撹拌した溶液｝を添加し、90 ℃、4分間反応を行った。反応終了後アセトニトリルを1 mL加えて、フィルターに通した。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行った。その結果、図４に示すように、目的の[11C]セレコキシブのHPLC分析収率80%で得られた。
HPLC分取条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 60 : 40
Flow rate : 1.0 mL / min
Retention time : desired compound ([11C]セレコキシブ) 5.4 min
また、同様の条件により、30 GBqの[11C]ヨウ化メチルを用いて生体投与を目的とした[11C]セレコキシブ溶液を調製した。その結果、1 GBqの[11C]セレコキシブの投与溶液を調製する事が出来た。
一般的にラットに投与する場合には0.02 GBq、サルやヒトへの投与では0.2 GBqが必要であると知られており、本実施例により、目的の[11C]セレコキシブを生体投与の十分量である1 GBq合成可能であることが確認できた。 (Example 3)
In Example 3, [ 11 C] methylation reaction of demethyl celecoxib bromide with [ 11 C] methyl iodide was performed.
[ 11 C] methyl iodide was blown into an NMP solution (150 μL) of Pd 2 (dba) 3 (1.8 mg, 1.9 μmol) and P (o-tolyl) 3 (2.4 mg, 7.8 μmol). Then, separately prepared solution {Bromo precursor (4.5 mg, 10 μmol), Pd 2 (dba) 3 (4.6 mg, 5 μmol), Tri-1-naphthylphosphine (8.2 mg, 20 μmol) are weighed and NMP (500 μL ), And a solution stirred at 60 ° C. for 1 hour} was added, followed by reaction at 90 ° C. for 4 minutes. After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC. As a result, as shown in FIG. 4, the desired [ 11 C] celecoxib was obtained with an HPLC analysis yield of 80%.
HPLC preparative conditions
Column: COSMOSIL 5-C 18 AR-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 60: 40
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] Celecoxib) 5.4 min
In addition, under the same conditions, a [ 11 C] celecoxib solution intended for biological administration was prepared using 30 GBq of [ 11 C] methyl iodide. As a result, an administration solution of 1 GBq [ 11 C] celecoxib could be prepared.
It is generally known that 0.02 GBq is necessary when administered to rats, and 0.2 GBq is necessary when administered to monkeys and humans. According to this example, the target [ 11 C] celecoxib is sufficient for in vivo administration. It was confirmed that 1 GBq can be synthesized.
実施例３では[11C]ヨウ化メチルによるデメチル臭化セレコキシブの[11C]メチル化反応を行った。
Pd2(dba)3 (1.8 mg, 1.9μmol)、P(o-tolyl)3 (2.4 mg, 7.8μmol)、のNMP溶液（150μL）に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液｛ブロモ前駆体（4.5 mg, 10μmol）、Pd2(dba)3 (4.6 mg, 5μmol)、Tri-1-naphthylphosphine (8.2 mg, 20μmol)をはかりとりNMP(500μL)を加え、60 ℃で１時間撹拌した溶液｝を添加し、90 ℃、4分間反応を行った。反応終了後アセトニトリルを1 mL加えて、フィルターに通した。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行った。その結果、図４に示すように、目的の[11C]セレコキシブのHPLC分析収率80%で得られた。
HPLC分取条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 60 : 40
Flow rate : 1.0 mL / min
Retention time : desired compound ([11C]セレコキシブ) 5.4 min
また、同様の条件により、30 GBqの[11C]ヨウ化メチルを用いて生体投与を目的とした[11C]セレコキシブ溶液を調製した。その結果、1 GBqの[11C]セレコキシブの投与溶液を調製する事が出来た。
一般的にラットに投与する場合には0.02 GBq、サルやヒトへの投与では0.2 GBqが必要であると知られており、本実施例により、目的の[11C]セレコキシブを生体投与の十分量である1 GBq合成可能であることが確認できた。 (Example 3)
In Example 3, [ 11 C] methylation reaction of demethyl celecoxib bromide with [ 11 C] methyl iodide was performed.
[ 11 C] methyl iodide was blown into an NMP solution (150 μL) of Pd 2 (dba) 3 (1.8 mg, 1.9 μmol) and P (o-tolyl) 3 (2.4 mg, 7.8 μmol). Then, separately prepared solution {Bromo precursor (4.5 mg, 10 μmol), Pd 2 (dba) 3 (4.6 mg, 5 μmol), Tri-1-naphthylphosphine (8.2 mg, 20 μmol) are weighed and NMP (500 μL ), And a solution stirred at 60 ° C. for 1 hour} was added, followed by reaction at 90 ° C. for 4 minutes. After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC. As a result, as shown in FIG. 4, the desired [ 11 C] celecoxib was obtained with an HPLC analysis yield of 80%.
HPLC preparative conditions
Column: COSMOSIL 5-C 18 AR-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 60: 40
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] Celecoxib) 5.4 min
In addition, under the same conditions, a [ 11 C] celecoxib solution intended for biological administration was prepared using 30 GBq of [ 11 C] methyl iodide. As a result, an administration solution of 1 GBq [ 11 C] celecoxib could be prepared.
It is generally known that 0.02 GBq is necessary when administered to rats, and 0.2 GBq is necessary when administered to monkeys and humans. According to this example, the target [ 11 C] celecoxib is sufficient for in vivo administration. It was confirmed that 1 GBq can be synthesized.
（実施例４）
実施例４では[11C]ヨウ化メチルによる4-iodo-L-phenylalanineの[11C]メチル化反応を行った。
Pd2(dba)3 (1.0 mg, 1 μmol)、P(o-tolyl)3(1.4 mg, 4.6 μmol)のNMP溶液(250uL)に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液{4-iodo-L-phenylalanine（1.45 mg, 5 μmol）Pd2(dba)3 (2.75 mg, 3 μmol)、Tri-1-naphthylphosphine (4.94 mg, 12 μmol)をはかりとり、これに上述のNMP溶液(200 μL)を加え、60 °Cで１時間撹拌した溶液}を添加し、90 °C、４分間反応を行った。
反応終了後、アセトニトリルを1 mL 加えて、フィルターに通した。この混合溶液から0.1 mL を抜き取って、RI検出-HPLCにて分析を行った。
その結果、図５に示すように、目的の[11C]tolylalanineがHPLC分析収率20%で得られた。
HPLC分析条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 5 : 95
Flow rate : 1.0 mL/min
Retention time : desired compound ([11C]tolylalanine) 5.9 min Example 4
In Example 4, [ 11 C] methylation reaction of 4-iodo-L-phenylalanine with [ 11 C] methyl iodide was performed.
[ 11 C] methyl iodide was blown into an NMP solution (250 uL) of Pd 2 (dba) 3 (1.0 mg, 1 μmol) and P (o-tolyl) 3 (1.4 mg, 4.6 μmol). Then prepared solutions {4-iodo-L-phenylalanine (1.45 mg, 5 μmol) Pd 2 (dba) 3 (2.75 mg, 3 μmol), Tri-1-naphthylphosphine (4.94 mg, 12 μmol) The above NMP solution (200 μL) was added thereto, and the solution stirred at 60 ° C. for 1 hour} was added thereto, and the reaction was performed at 90 ° C. for 4 minutes.
After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC.
As a result, as shown in FIG. 5, the desired [ 11 C] tolylalanine was obtained with a HPLC analysis yield of 20%.
HPLC analysis conditions Column: COSMOSIL 5-C18 AR-II 4.6 × 150 mm
Eluent: CH3CN: H 2 O = 5: 95
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] tolylalanine) 5.9 min
実施例４では[11C]ヨウ化メチルによる4-iodo-L-phenylalanineの[11C]メチル化反応を行った。
Pd2(dba)3 (1.0 mg, 1 μmol)、P(o-tolyl)3(1.4 mg, 4.6 μmol)のNMP溶液(250uL)に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液{4-iodo-L-phenylalanine（1.45 mg, 5 μmol）Pd2(dba)3 (2.75 mg, 3 μmol)、Tri-1-naphthylphosphine (4.94 mg, 12 μmol)をはかりとり、これに上述のNMP溶液(200 μL)を加え、60 °Cで１時間撹拌した溶液}を添加し、90 °C、４分間反応を行った。
反応終了後、アセトニトリルを1 mL 加えて、フィルターに通した。この混合溶液から0.1 mL を抜き取って、RI検出-HPLCにて分析を行った。
その結果、図５に示すように、目的の[11C]tolylalanineがHPLC分析収率20%で得られた。
HPLC分析条件
Column : COSMOSIL 5-C18 AR-II 4.6×150 mm
Eluent : CH3CN : H2O = 5 : 95
Flow rate : 1.0 mL/min
Retention time : desired compound ([11C]tolylalanine) 5.9 min Example 4
In Example 4, [ 11 C] methylation reaction of 4-iodo-L-phenylalanine with [ 11 C] methyl iodide was performed.
[ 11 C] methyl iodide was blown into an NMP solution (250 uL) of Pd 2 (dba) 3 (1.0 mg, 1 μmol) and P (o-tolyl) 3 (1.4 mg, 4.6 μmol). Then prepared solutions {4-iodo-L-phenylalanine (1.45 mg, 5 μmol) Pd 2 (dba) 3 (2.75 mg, 3 μmol), Tri-1-naphthylphosphine (4.94 mg, 12 μmol) The above NMP solution (200 μL) was added thereto, and the solution stirred at 60 ° C. for 1 hour} was added thereto, and the reaction was performed at 90 ° C. for 4 minutes.
After completion of the reaction, 1 mL of acetonitrile was added and passed through a filter. 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC.
As a result, as shown in FIG. 5, the desired [ 11 C] tolylalanine was obtained with a HPLC analysis yield of 20%.
HPLC analysis conditions Column: COSMOSIL 5-C18 AR-II 4.6 × 150 mm
Eluent: CH3CN: H 2 O = 5: 95
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] tolylalanine) 5.9 min
（実施例５）
実施例５では、シナプス小胞に存在するsynaptic vesicle glycoprotein 2A (SV2A) と結合することが知られているUCB-Jを約10 GBq.の[11C]ヨウ化メチルを用いることで11C-標識化した。以下に詳細を示す。
Pd2(dba)3 (1.0 mg, 1.0 μmol)、P(o-tolyl)3 (1.4 mg, 4.6 μmol)のNMP溶液(250 μL)に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液（Br標識前駆体（1.92 mg, 5 μmol）、Pd2(dba)3 (2.2 mg, 2.5 μmol)、Tri-1-naphthylphosphine (4.12 mg, 10 μmol)）をはかりとり、前述のNMP溶液(250 μL)を加え、60 °Cで１時間撹拌した溶液}を添加し、90 °C、４分間反応を行った。反応終了後、CH3CN : 水 = 1 : 1の溶液を500 mL 加えて、フィルターに通した後、逆相カラムクロマトグラフィーを使用し目的物を精製した結果、182 MBq.を有する[11C]UCB-Jを単離することができた（図６上側チャート）。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行い、放射化学純度99％、化学純度99%であることを確認した（図６下側チャート）。
HPLC分離条件
Column : COSMOSIL 5-C18 MS-II 10×250 mm
Eluent : CH3CN : H2O = 45 : 55
Flow rate : 6.0 mL/min
Retention time : desired compound ([11C]UCB-J) 12.3 min
HPLC分析条件
Column : COSMOSIL 5-C18 MS-II 4.6×150 mm
Eluent : CH3CN : H2O = 40 : 60
Flow rate : 1.0 mL/min
Retention time : desired compound ([11C]UCB-J) 5.0 min (Example 5)
In Example 5, synaptic vesicle glycoprotein 2A (SV2A ) and coupling approximately 10 UCB-J that is known to be GBq. Of [11 C] 11 by using methyl iodide present in synaptic vesicles C- Labeled. Details are shown below.
[ 11 C] methyl iodide was blown into an NMP solution (250 μL) of Pd 2 (dba) 3 (1.0 mg, 1.0 μmol) and P (o-tolyl) 3 (1.4 mg, 4.6 μmol). Then, separately prepared solutions (Br-labeled precursor (1.92 mg, 5 μmol), Pd 2 (dba) 3 (2.2 mg, 2.5 μmol), Tri-1-naphthylphosphine (4.12 mg, 10 μmol)) The NMP solution (250 μL) described above was added, and the solution stirred at 60 ° C. for 1 hour} was added, followed by reaction at 90 ° C. for 4 minutes. After completion of the reaction, CH 3 CN: water = 1:. 1 solution was added 500 mL, passed through a filter, the result of purification of the desired product using reverse phase column chromatography, 182 MBq having [11 C ] UCB-J could be isolated (upper chart in FIG. 6). 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC to confirm that the radiochemical purity was 99% and the chemical purity was 99% (lower chart in FIG. 6).
HPLC separation conditions
Column: COSMOSIL 5-C18 MS-II 10 × 250 mm
Eluent: CH 3 CN: H 2 O = 45: 55
Flow rate: 6.0 mL / min
Retention time: desired compound ([ 11 C] UCB-J) 12.3 min
HPLC analysis conditions
Column: COSMOSIL 5-C18 MS-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 40: 60
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] UCB-J) 5.0 min
実施例５では、シナプス小胞に存在するsynaptic vesicle glycoprotein 2A (SV2A) と結合することが知られているUCB-Jを約10 GBq.の[11C]ヨウ化メチルを用いることで11C-標識化した。以下に詳細を示す。
Pd2(dba)3 (1.0 mg, 1.0 μmol)、P(o-tolyl)3 (1.4 mg, 4.6 μmol)のNMP溶液(250 μL)に[11C]ヨウ化メチルを吹き込んだ。その後、別途調製しておいた溶液（Br標識前駆体（1.92 mg, 5 μmol）、Pd2(dba)3 (2.2 mg, 2.5 μmol)、Tri-1-naphthylphosphine (4.12 mg, 10 μmol)）をはかりとり、前述のNMP溶液(250 μL)を加え、60 °Cで１時間撹拌した溶液}を添加し、90 °C、４分間反応を行った。反応終了後、CH3CN : 水 = 1 : 1の溶液を500 mL 加えて、フィルターに通した後、逆相カラムクロマトグラフィーを使用し目的物を精製した結果、182 MBq.を有する[11C]UCB-Jを単離することができた（図６上側チャート）。この混合溶液から0.1 mLを抜き取って、RI検出-HPLCにて分析を行い、放射化学純度99％、化学純度99%であることを確認した（図６下側チャート）。
HPLC分離条件
Column : COSMOSIL 5-C18 MS-II 10×250 mm
Eluent : CH3CN : H2O = 45 : 55
Flow rate : 6.0 mL/min
Retention time : desired compound ([11C]UCB-J) 12.3 min
HPLC分析条件
Column : COSMOSIL 5-C18 MS-II 4.6×150 mm
Eluent : CH3CN : H2O = 40 : 60
Flow rate : 1.0 mL/min
Retention time : desired compound ([11C]UCB-J) 5.0 min (Example 5)
In Example 5, synaptic vesicle glycoprotein 2A (SV2A ) and coupling approximately 10 UCB-J that is known to be GBq. Of [11 C] 11 by using methyl iodide present in synaptic vesicles C- Labeled. Details are shown below.
[ 11 C] methyl iodide was blown into an NMP solution (250 μL) of Pd 2 (dba) 3 (1.0 mg, 1.0 μmol) and P (o-tolyl) 3 (1.4 mg, 4.6 μmol). Then, separately prepared solutions (Br-labeled precursor (1.92 mg, 5 μmol), Pd 2 (dba) 3 (2.2 mg, 2.5 μmol), Tri-1-naphthylphosphine (4.12 mg, 10 μmol)) The NMP solution (250 μL) described above was added, and the solution stirred at 60 ° C. for 1 hour} was added, followed by reaction at 90 ° C. for 4 minutes. After completion of the reaction, CH 3 CN: water = 1:. 1 solution was added 500 mL, passed through a filter, the result of purification of the desired product using reverse phase column chromatography, 182 MBq having [11 C ] UCB-J could be isolated (upper chart in FIG. 6). 0.1 mL was extracted from this mixed solution and analyzed by RI detection-HPLC to confirm that the radiochemical purity was 99% and the chemical purity was 99% (lower chart in FIG. 6).
HPLC separation conditions
Column: COSMOSIL 5-C18 MS-
Eluent: CH 3 CN: H 2 O = 45: 55
Flow rate: 6.0 mL / min
Retention time: desired compound ([ 11 C] UCB-J) 12.3 min
HPLC analysis conditions
Column: COSMOSIL 5-C18 MS-II 4.6 × 150 mm
Eluent: CH 3 CN: H 2 O = 40: 60
Flow rate: 1.0 mL / min
Retention time: desired compound ([ 11 C] UCB-J) 5.0 min
この発明は上記発明の実施の態様及び実施例の説明に何ら限定されるものではない。特許請求の範囲を逸脱せず、当業者が容易に想到できる範囲で種々の変形態様もこの発明に含まれる。
The present invention is not limited to the description of the embodiments and examples of the above invention. Various modifications are also included in the present invention as long as those skilled in the art can easily conceive without departing from the scope of the claims.
本発明の製造方法によれば、様々な芳香族ハロゲン化物あるいは様々な芳香族トリフレートを迅速に[11C]メチル化することができるため、PET薬剤の製造に利用することができる。
According to the production method of the present invention, various aromatic halides or various aromatic triflates can be rapidly [ 11 C] methylated, and thus can be used for the production of PET drugs.
Claims (3)
- ０価のパラジウム錯体とホスフィン配位子とが溶解した非プロトン性極性溶媒中に[11C]標識ヨウ化メチルを加えて[11C]メチルパラジウム錯体を形成させる第１のパラジウム錯体形成工程と、
０価のパラジウム錯体と、ホスフィン配位子又はＮ-ヘテロサイクリックカルベン配位子とが溶解した非プロトン性極性溶媒に芳香族ハロゲン（ただし、ハロゲンはＩ又はＢｒであり、トリフレート基や２つ以上のハロゲン元素が結合していないことを要件とする）又は芳香族トリフレート（ただし、Ｉ、Ｂｒ、及び２つ以上のトリフレート官能基が結合していないことを要件とする）を加えて芳香族パラジウム錯体を形成させる第２のパラジウム錯体形成工程と、
前記第１のパラジウム錯体形成工程で調製した前記[11C]メチルパラジウム錯体の溶液と、前記第２のパラジウム錯体形成工程で調製した前記芳香族パラジウム錯体の溶液とを混合して芳香族置換基に[11C]メチル基を結合させるカップリング工程を備える芳香族化合物の[11C]メチル化方法。 A first palladium complex forming step of adding [ 11 C] -labeled methyl iodide to an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand are dissolved to form a [ 11 C] methyl palladium complex; ,
In an aprotic polar solvent in which a zero-valent palladium complex and a phosphine ligand or N-heterocyclic carbene ligand are dissolved, an aromatic halogen (where halogen is I or Br, a triflate group, 2 Or aromatic triflate (provided that I, Br, and two or more triflate functional groups are not bonded) A second palladium complex forming step of forming an aromatic palladium complex,
The [ 11 C] methylpalladium complex solution prepared in the first palladium complex forming step and the aromatic palladium complex solution prepared in the second palladium complex forming step are mixed to prepare an aromatic substituent. [11 C] methylation of aromatic compounds comprising a coupling step of coupling the [11 C] methyl group. - 前記芳香族ハロゲンは置換基を有してもよいハロゲン化フェニルである請求項１に記載の芳香族化合物の[11C]メチル化方法。 The method for [ 11 C] methylation of an aromatic compound according to claim 1, wherein the aromatic halogen is a halogenated phenyl which may have a substituent.
- 前記芳香族トリフレートは置換基を有してもよいベンゼントリフレートである請求項１又は２に記載の芳香族化合物の[11C]メチル化方法。 The method for [ 11 C] methylation of an aromatic compound according to claim 1 or 2, wherein the aromatic triflate is an optionally substituted benzene triflate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56135426A (en) * | 1978-10-30 | 1981-10-22 | Union Carbide Corp | Coupling of arylmonochloride and heteroarylmonochloride |
| JPH01250328A (en) * | 1987-12-02 | 1989-10-05 | Mitsubishi Kasei Corp | Method for dimerizing aromatic halogen compound |
| WO2008023780A1 (en) * | 2006-08-25 | 2008-02-28 | Gifu University | Method of rapid methylation, kit for preparing pet tracer and method of producing pet tracer |
| WO2010074272A1 (en) * | 2008-12-26 | 2010-07-01 | 国立大学法人岐阜大学 | Method for rapidly methylating heteroaromatic ring aryl and method for producing pet tracer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56135426A (en) * | 1978-10-30 | 1981-10-22 | Union Carbide Corp | Coupling of arylmonochloride and heteroarylmonochloride |
| JPH01250328A (en) * | 1987-12-02 | 1989-10-05 | Mitsubishi Kasei Corp | Method for dimerizing aromatic halogen compound |
| WO2008023780A1 (en) * | 2006-08-25 | 2008-02-28 | Gifu University | Method of rapid methylation, kit for preparing pet tracer and method of producing pet tracer |
| WO2010074272A1 (en) * | 2008-12-26 | 2010-07-01 | 国立大学法人岐阜大学 | Method for rapidly methylating heteroaromatic ring aryl and method for producing pet tracer |
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