JPH08290054A - Separation of aromatic fluoro-component and chloro-component - Google Patents

Abstract

PURPOSE: To separate and purify a fluoro-component having a structure wherein a chloro-group of a chloro-component obtained by fluorinating a chloro- component of an aromatic hydrocarbon compd. having an electron withdrawing substituent is substituted with a fluoro-group from a large amt. of a raw material chloro-component. CONSTITUTION: Liquid chromatography using an alkali eluent as a moving phase and a long chain alkylated carrier as a solid phase is adapted.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for purifying a butyrophenone derivative psychotropic drug which is a ligand of D2 receptor subtype in the brain and a synthetic intermediate thereof, a specific solid phase carrier applied to the purification method, and the purification method. Positron tomography diagnosis (P- 18) comprising a fluorine-18-labeled aromatic hydrocarbon compound having an electron-withdrawing substituent obtained by applying the method
The present invention also relates to a diagnostic agent for ET), but also to a technique that can be applied when synthesizing a fluorine-18-labeled compound to be developed in the future from a chloro precursor.

[0002]

2. Description of the Related Art Fluorine has almost the same van der Waals radius as a hydrogen atom and has a mimetic effect with a hydrogen atom, and many studies have been conducted on its application to the biomedical field (" Chemistry "Tomoya Kitazume Kodansha," Study of Fluorine "Shinnosuke Matsuura, Todai Press and" Compound of Fluorine "Nobuo Ishikawa, Kodansha). Successful examples include nucleic acids, pitamine, arachidonic acid,
Peptides, amino acids, sugars, synthetic new quinolone antibacterial agents, beta-lactam antibiotics, artificial blood, pesticides, ceramic products, etc. (“Fluorine pharmacy” by Yoshiro Kobayashi)
Hirokawa Shoten). One successful example thereof is a fluoro derivative of a butyrophenone psychotropic drug having an alkylphenyl ketone structure, which is a ligand of the D2 receptor subtype in the brain. The butyrophenone derivative psychotropic drug is a drug having both morphine-like analgesic properties and phenothiazine-like neuroleptic properties discovered during research related to meperidine, and is widely used mainly as a therapeutic drug for schizophrenia and epilepsy. There are dozens of derivatives,
These synthetic techniques have already been studied in detail and have been known for a long time [Shansen, Journal of Medical and Pharmaceutical Chemistry (J
anssen, J.Med.pharm.chem.) 1, 281 (1959)].

The following compounds are listed as typical butyrophenone derivatives.

Embedded image In the formula, Q is a group

[Chemical 4] Indicates.

In recent years, positron emission tomography (PET) using a compound labeled with a positron decay radionuclide has rapidly become popular as one of non-invasive tomography diagnostic techniques [Raven Press (19
86), Positron Emission Tomography (Positr
on Emission Tomography), Em Leighich (1985),
"Brain Function and Positron CT" Keiichi Matsuura Shujunsha (198
6)].

Among them, the functional tests of the brain by PET, the determination of the lesion site, and the diagnosis are the main fields of application, and a butyrophenone derivative psychotropic drug which is a ligand of the D2 receptor subtype in the brain considered to be usable there. Labeled with a positron radionuclide of is a group of labeled drugs that has received the most attention in PET technology.

Among them, the labeling method using ¹¹ C nuclide has been already established and is relatively popular (“positron CT”, written by Yukio Tateno, Institute of Medicine (1983)). But ¹¹
The half-life of C nuclide is very short ( ¹¹ C: 20 minutes), PET
Even if an ¹¹ C-labeled compound is manufactured and used in a facility equipped with an apparatus, there are severe time restrictions.

On the other hand, since fluorine 18 in the positron-decaying radionuclide has a relatively long half-life ( ¹⁸ F: 110 minutes), it can be transported and has a substantially high specific activity. ⁺ Line energy is small (Emax = 0.6Me
V), the in-vivo range is 2 mm ( ¹¹ C: Emax = 1 MeV, in-vivo range 4 mm, ¹³ N: Emax = 1.2 MeV, in-vivo range 5 mm, ¹⁵ O: Emax = 1.7 MeV, in-vivo range It is as short as 9 mm), and this point has characteristics such as becoming effective with the spread of high-resolution (resolution 4 mm) positron cameras in the future.

Further, many fluoro compounds useful as physiologically active compounds are known, and their safety and physiological actions have been investigated [Positron Emission Tomography and Autoradiography (Positron
Emission Tomography and Autoradiography) Chapter 9, Em Phelps]. Therefore, attention has been paid to labeling with ¹⁸ F [Fluorine-18 labeling of Radiopharmaceuticals.
Radiopharmaceuticals), Kilborne National Academic Press (1990)] The following methods have been published as typical production methods.

(1) Using a diazonium salt as a precursor,
Fluorination in one step [CS Kook, M.F.Reed, G.A.Digence, Journal of Nuclea Medicine (J.Nuc.Med.)
5, 533 (1975)].

(2) A method for obtaining an ¹⁸ F-butyrophenone derivative psychotropic drug by an exchange reaction with [ ¹⁸ F] fluoride by using a usual ¹⁹ F-butyrophenone derivative psychotropic drug itself as a precursor [S-Faroxad, M. Dixik, Journal of Rabeled Compounds
And Radio Pharmaceuticals (J. Labelled
Comp.Radiol.) 22, 721 (1985)].

(3) Nitrobenzonitrile or trimethylammoniobenzonitrile was used as a starting material, and [18]
Fluorinating ¹⁸ F with F] fluoride to synthesize [ ¹⁸ F] fluorobenzonitrile, which was then reacted with cyclopropyllithium to produce cyclopropyl-4- [18
F] fluorophenyl ketone, which is subjected to a ring-opening reaction with hydrochloric acid to give [18 F] fluoro-4-chlorobutyrophenone, which is then coupled with an amine derivative to obtain a desired labeled compound [C. Jay S.
Faller, A. P. Wolf, C. C., M. Jay Adam, Journal of Rabeled Compounds and Radio Pharmaceuticals (J.
Labeled Comp. Radiol.) 26, 386 (1989)].

(4) A method in which a nitro derivative of a butyrophenone derivative psychotropic drug is used as a precursor, and this is exchange-fluorinated with [18F] fluoride to obtain the desired labeled product in one step.

(5) A method of obtaining a desired labeled product by exchange fluorination in the same manner as in (4), using a chloro derivative of a butyrophenone derivative psychotropic drug as a precursor.

However, each of these manufacturing methods has the following drawbacks. That is, in the method (1), the diazonium salt used as the precursor is unstable and the yield of fluorination is low, which is not practical. (2)
The method of utilizing the psychotropic drug itself of ¹⁹ F-butyrophenone derivative is a large amount of cold body (ie ¹⁹ F) which is a carrier.
The purity of the labeled body is remarkably poor due to the coexistence of (body). (3)
The method using nitrobenzonitrile as a starting material has a sufficient yield, but since it is a multi-step (four-step) reaction operation, the automatic synthesizer becomes complicated and the operation requires skill, so it is not a practical method. I can not say.

Furthermore, the method of the one-step exchange reaction of the nitro or chloro precursors of (4) and (5) with [18F] fluoride is advantageous from the viewpoint of the number of steps, but this method is produced from a small accelerator. Since the amount of fluorine that is generated is extremely small, the amount of the fluorine body obtained by the reaction is very small (1/50 to 1/1000) compared to the raw material nitro body or chloro body. It is difficult to separate from a large amount of nitro or chloro compounds that are close to each other, and so far we have only studied reaction conditions,
The production method as a whole including the purification method has not been completed, and a high-purity product has not been obtained.

As a result of research on this problem, some of the inventors of the present invention have established a technique for separating and purifying a fluoro form and a nitro form for a method by a one-step exchange reaction of a nitro precursor with a fluoride. 6-157097 was carried out, but the separation and purification of the chloro precursor and the fluoro body was unsolved.

[0017]

DISCLOSURE OF THE INVENTION In the one-step fluorine labeling method using a chloro body as a precursor, the present inventors have found the importance of separating and purifying a minute amount of a fluoro body contained in a product. I paid attention. In other words, the development of this separation and purification technology is the key to the method for producing the ¹⁸ F fluorinated butyrophenone type brain D2 receptor subtype ligand using a chloro body as a precursor. If a method that can be generally applied can be found, it is possible to use these P because the chloro form is generally more stable and easily available than the nitro form.
Comparable to the development of a new synthetic method for ET diagnostic agents, it can provide highly pure novel [18F] aromatic compounds that never existed before, and is extremely useful for practical application of many novel PET diagnostic agents. It brings useful technological advances.

[0018]

[Means for Solving the Problems] In order to solve the above problems, the present inventors investigated various conditions by liquid chromatography using high performance liquid chromatography, and found that there are carriers and solvents used for the chromatography. In a specific combination, it was found that it was possible to elute a fluoro-substituted butyrophenone-based ligand, which was not seen in the prior art, in front of its precursor chloro form, but as a result of further studies, it was found that Not only separation and purification of substituted butyrophenone-based ligands, but also separation and purification of aromatic hydrocarbon compounds having a wide range of electron-withdrawing substituents and chloro groups from aromatic hydrocarbon compounds in which the chloro groups are replaced by fluoro groups. The present invention has been completed, and the present invention has been completed.

That is, the present invention has a structure in which the chloro group of the chloro compound obtained by fluorinating an aromatic hydrocarbon compound (chloro compound) having an electron-withdrawing substituent and a chloro group is replaced with a fluoro group. Compound (fluoro form)
Is a long-chain alkylated solid-phase carrier for separating the chlorinated form by liquid chromatography using an alkaline eluent. In separating a fluoro body from a mixture of an aromatic hydrocarbon compound having an electron-withdrawing substituent and a chloro group (chloro body) and a compound having a structure in which the chloro group of the chloro body is replaced with a fluoro group (fluoro body), A method for separating a fluoro form and a chloro form, which comprises applying an alkaline (pH ≧ 8) eluent as a mobile phase and liquid chromatography using a long-chain alkylated carrier as a solid phase. In addition, a positron emission tomography diagnosis (PE) using as an active ingredient a fluorine-18-labeled aromatic hydrocarbon compound having an electron-withdrawing substituent obtained by applying the above-mentioned fractionation method.
T) diagnostic agent. Is.

In the present invention, as the electron-withdrawing substituent, a cyano group, an aldehyde group, a halogeno group, a nitro group,
A cycloalkylcarbonyl group or a formula,

Embedded image (In the formula, X represents a group which may have a substituent and is formed by removing a hydrogen atom bonded to the ring-constituting nitrogen atom from a saturated nitrogen-containing heterocyclic compound. A is an optionally branched lower group. Represents an alkylene group) and X is 1
-Pyrrolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl, 1-piperazinyl, 1-indolinyl, 4-morpholinyl, N-heterocyclic group containing 1 or 2 nitrogen atoms such as 1-piperidinyl as a ring-constituting atom, These are substituents, for example, lower alkylamino groups such as hydroxy group, amino and methylamino, acylamino groups such as acetylamino, lower alkoxy groups such as methoxy, halogen atoms such as chlorine atom, acyl groups such as acetyl, oxo group,
Lower alkyl group such as methyl group, cycloalkyl group such as cyclohexyl group, aryl group such as phenyl group, and further pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, benzimidazolinyl, benzimidazolyl And so on. Further, among these substituents, the aryl group and the nitrogen-containing heterocyclic group may further have the above substituents, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, an oxo group, a phenyl group and the like. Further, X may have a substituent by a spiro bond, and examples thereof include spiro.
[Imidazolidine-piperidin] yl, spiro [cyclohexane-piperidin] yl and the like can be mentioned.

Further, as an example of X, a general formula

[Chemical 6] There are also compounds that can be represented by the formula, in which R ₁ , R ₂ , R
₃ and R ₄ are each a hydrogen, a hydroxy group, a halogen atom or an alkyl group, an alkoxy group or a phenyl group which may be substituted with a hydroxy group, an amino group which may have a substituent, a cyclic amino group or a cyclic imino. Represents an optionally substituted aminocarbonyl group, R ₁ and R ₂ may together form a cyclic group, and the alkyl group may be a group selected from methyl, ethyl and propyl, and may be substituted. The phenyl group which may be present is a group selected from methoxyphenyl, methylphenyl, ethylphenyl, chlorophenyl, fluorophenyl and bromophenyl, and the cyclic group which may have a substituent is piperidino, piperazino, 2-oxobenzimidazo. Lysinyl, 3-methyl-2-oxobenzimidazole, 3-ethyl-2-oxobenzii Dazorijiniru, 3-fluoro-ethyl-2-oxo-benz imidazolidinyl and 1-phenyl-4-imidazolidinone-5,5-ylidene, 1
-Phenyl-3-methyl-4-imidazolidinone-5,
Spiro-bonded cyclic groups such as 5-ylidene, 1-phenyl-3-ethyl-4-imidazolidinone-5,5-ylidene, 1-phenyl-3-fluoroethyl-4-imidazolidinone-5,5-ylidene Can be a group selected from

Also, the formula

[Chemical 7] Examples of the optionally branched lower alkylene group for A include alkylene having 2 to 4 carbon atoms such as ethylene, propylene, butylene, isopropylene and isobutylene. In addition, examples of cycloalkyl of the cycloalkylcarbonyl group include cyclopropyl.

The mixture of the fluoro-form of the alkylphenyl ketone compound and a large amount of chloro-form to which the separation / purification of the present invention is applied is a trace amount of fluoro-form produced by fluorinating the chloro-form as a precursor. And a reaction mixture in which a large excess of chloro form coexists. According to the present invention, the fluoro body is eluted from the mixture containing such a large amount of the chloro body and a small amount of the fluoro body in advance of the chloro body, and therefore, the influence of tailing on the elution of the large amount of the chloro body is caused. It is possible to collect the fluoro body as pure as possible without receiving the fluorocarbons.

As mentioned above, one of the main objects of the present invention is to separate the fluoro compound of interest from the reaction product obtained by the fluorination reaction of the chloro precursor with fluoride by (high-performance) liquid chromatography. Regarding
A particularly advantageous reaction product is obtained by the following reaction formula.

Embedded image (In the formula, Z represents an electron-withdrawing substituent, and X and A have the same meanings as described above.)

For example, particularly specific fluoro compounds to be separated include altanserine, orthofluorophenylalanine, metafluorophenylalanine, parafluorophenylalanine, fluoroacetophenone, fluorobenzonitrile, 4,4'-difluorodiphenylketone and 4- Fluorophenyl cyclopropyl ketone, orthofluorobenzaldehyde, metafluorobenzaldehyde, parafluorobenzaldehyde, orthofluorobenzonitrile, metafluorobenzonitrile, parafluorobenzonitrile, 4-methoxy-5-fluorobenzaldehyde, 2,2- Dimethyl-5-fluoroindanone, 2,2-dimethyl-6-fluoroindanone, 2,2-dimethyl-5-fluoroindandione,
4-fluoro-1-methylsulfonylbenzene, 4-fluoro-1-methylsulfinylbenzene and the like can be mentioned.

In the present invention, liquid chromatography can be carried out as follows. That is, 1) A long-chain alkylated carrier is used as a solid phase carrier in chromatography, and HPLC is carried out using an alkaline aqueous solution as an eluent. 2) The long-chain alkylated carrier has 1 to 18 carbon atoms.
Among them, those having a long-chain alkyl group (for example, octyl group, octadecyl group) are mentioned, and among them, octadecylated ones are preferable. Examples of the alkylated carrier include silica gel and a polymer carrier, and the polymer carrier is preferable.

The alkaline aqueous solution that can be used in the separation / purification of the present invention is not limited, but has a pH of 8 or more,
Phosphate buffer solution, borate buffer solution, triethylamine aqueous solution and sodium hydroxide aqueous solution having a pH of 10 or more are preferred, and phosphate buffer solution and sodium hydroxide aqueous solution are preferred. Examples of the mobile phase that can be used in the present invention include those obtained by mixing these alkaline aqueous solutions with an organic solvent such as acetonitrile.

According to the present invention, the separation degree α of the fluoro body from the chloro body is 0.9 or less, that is, the fluoro body can be eluted before the chloro body which may exist in a large amount as compared with the fluoro body. This separation situation provides the following advantages. Under normal conditions, that is, under acidic and neutral conditions, the fluoro-form elutes after a large amount of the chloro-form, and due to the tailing phenomenon peculiar to liquid chromatography, the chloro-form is contaminated in the eluate fraction of the fluoro-form and is produced. Although the purity of the body is lowered, according to the present invention, the fluoro body can be eluted before the chloro body, and such a phenomenon can be avoided.

Expressed as the degree of separation α, the value of α is 0.8 to 1.0 under acidic and neutral conditions, but is 0.9 or less and 0.8 to 0 under the conditions of the present invention. .4, and the retention time of the chloro form was set to 100%, and the fraction of the target fluoro form was eluted at a time of 10% or more before, and when the elution of the fraction of the fluoro form was almost completed, Elution begins,
There will be no chloro contamination in the target fluoro fraction. The effects of the present invention are shown in Table 1 below.

[0030]

[Table 1]

As described above, it is clear from the degree of separation that a high-purity fluoro body can be recovered, and therefore the present invention can provide a highly pure labeled drug which is important for positron emission tomography. . According to the present invention
The diagnostic agent for PET containing an [18F] aromatic compound as an active ingredient does not substantially contain the chloro form of the raw material corresponding to the active ingredient. The diagnostic agent for PET of the present invention is preferably in the form of an injection, and the active ingredient is 0.1 to 100 mCi, preferably 0.5 to 20 mC, although it varies depending on the application form.
i, more preferably 1 to 10 mCi, and 0.1 to 10 mCi
It can be adjusted about once / time. These diagnostic agents may include diluents such as ethanol and water, additives such as Triton X, potassium iodide, phosphoric acid, hydrochloric acid, sodium hydroxide, polysorbate 80 and the like.

Furthermore, the present invention can also provide an [18F] aromatic compound as a synthetic intermediate for the above-mentioned [18F] PET diagnostic agent. Examples will be given below, but the present invention is not limited to these examples.

[0033]

【Example】

Example 1 1- [4- (4-chlorophenyl) -4-oxobutyl]-
Synthesis of haloperidol from 4- (4-chlorophenyl) -4-hydroxypiperidine (a chloroprecursor of haloperidol, hereinafter referred to as chlorhaloperidol) by a trace amount of fluoride and separation and purification of haloperidol A 50% hydrofluoric acid aqueous solution for semiconductors (Morita Chemical Co., Ltd.) was diluted to 2 mM with distilled water to obtain 10 μl of tetrabutylammonium hydroxide (Wako Pure Chemical Industries) 10 mg.
After addition to dryness under reduced pressure, 1 ml of acetonitrile (manufactured by Wako Pure Chemical Industries, the same applies below) was added to the residue under an argon stream and stirred at 80 ° C for 5 minutes and then dried under reduced pressure, and 1 ml of acetonitrile was added and stirred at 80 ° C for 5 minutes. After that, it was dried under reduced pressure. To this, 2 mg of chlorohaloperidol was added to anhydrous dimethyl sulfoxide (DMS).
O) (manufactured by Aldrich, the same applies below) was added to a solution dissolved in 500 μl. The reaction flask was replaced with argon and nitrogen gas and placed in a glove box whose humidity was suppressed to 15% or less.
Heated to 0 ° C for 10 minutes. Next, the reaction solution was directly subjected to HPLC (conditions: HPLC column, Showa Denko Asahipak
φ 2.1 cm x 15 cm, eluent acetonitrile: 10 mM
Phosphate buffer pH 11.4 = 50: 50). The generated haloperidol is chlorhaloperidol (retention time rt
= 92 minutes) (rt = 52 minutes) before elution (resolution α =
0.46). Haloperidol corresponding to a yield of 13 nmol was found. The product was confirmed to have the same retention time as the internal standard method, that is, the standard haloperidol (manufactured by Aldrich), and the chromatogram was the same when the standard was added.
It was carried out by increasing the amount added and collecting. The yield was calculated from a calibration curve prepared separately.

Example 2 8- [4- (4-chlorophenyl) -4-oxobutyl]-
Example 1 Synthesis of spiperone from 1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one (a chlor precursor of spiperone, hereinafter referred to as chlorspiperone) with a trace amount of fluoride and separation and purification of spiperone. Cryptand [2.2.2] (manufactured by Merck & Co., Inc.,
The same shall apply hereinafter) 15 mg, potassium carbonate 30 μg, potassium oxalate 2 mg were dissolved, and then acetonitrile 1 was added under an argon stream.
ml was added and the mixture was dried under reduced pressure with stirring at 80 ° C. for 5 minutes, 1 ml of acetonitrile was further added, and the mixture was stirred at 80 ° C. for 5 minutes and dried under reduced pressure.
To this was added 500 μl of anhydrous dimethyl sulfoxide (DMSO) in which 2 mg of chlorspiperone was dissolved. The reaction flask was replaced with argon and nitrogen gas, placed in a glove box whose humidity was kept at 15% or less, and the contents were heated to 80 ° C. for 20 minutes in this mixed gas stream. Next, the reaction solution was directly subjected to HPLC (conditions: HPLC column Asahipak φ2.1 cm × 25 cm, eluent acetonitrile: 10 mM sodium hydroxide aqueous solution = 50: 5).
0). The generated spiperone (rt = 22.3 minutes) was eluted before the starting material chlorspiperone (retention time rt = 39.0 minutes). A spiperone corresponding to a yield of 9 nmol was found. The product was confirmed by having the same retention time as that of the standard spiperone (manufactured by Eisai Co., Ltd.), the same chromatogram when the standard was added, and the amount of addition being increased to be collected. The yield was calculated from a calibration curve prepared separately.

Example 3 Synthesis of p-fluorophenylcyclopropylketone from p-chlorophenylcyclopropylketone by fluoride and separation and purification of p-fluorophenylcyclopropylketone Aqueous hydrofluoric acid solution obtained in the same manner as in Example 1. After dissolving 15 mg of cryptand [2.2.2], 30 μg of potassium carbonate and 2 mg of potassium oxalate in 10 μl of a 2 mM solution, 1 ml of acetonitrile was added under a stream of argon and the mixture was dried under reduced pressure with stirring at 80 ° C. for 5 minutes, and further 1 ml of acetonitrile was added. 80 ℃
After stirring for 5 minutes, the mixture was dried under reduced pressure. To this was added 500 μl of anhydrous dimethyl sulfoxide (DMSO) in which 10 mg of p-chlorophenyl cyclopropyl ketone was dissolved. The reaction flask was replaced with argon and nitrogen gas, and the contents were heated to 80 ° C. for 20 minutes in this mixed gas stream. Next, the reaction solution was directly subjected to HPLC (conditions: HPLC column A
sahipak φ21.5mm × 15cm eluent acetonitrile: 1
0 mM phosphate buffer pH 11.4 = 45: 55). Generated p
-Fluorophenyl cyclopropyl ketone is
-Prior to chlorophenyl cyclopropyl ketone p-
It was eluted at the elution position of fluorophenyl cyclopropyl ketone.

Example 4 From chlorhaloperidol with [18F] fluoride
Synthesis of [18F] haloperidol and Separation and Purification of [18F] Haloperidol 18F Hydrofluoric acid aqueous solution obtained by nuclear reaction by proton irradiation with a perfect synchronous accelerator (Sumitomo Heavy Industries, Ltd.) targeting [18O] heavy water as a fluoride source (2.4
g), 15 mg of cryptand [2.2.2], 30 μg of potassium carbonate and 2 mg of potassium oxalate were added to the mixture to dryness under reduced pressure, and 1 ml of acetonitrile was added under an argon stream to give 80.
After stirring at ℃ for 5 minutes, dry to dryness under reduced pressure and add acetonitrile 1
ml was added and the mixture was stirred at 80 ° C. for 5 minutes and then dried under reduced pressure. Anhydrous DMSO 500 in which 2 mg of chlorhaloperidol was dissolved
μl was added and the reaction temperature was heated to 110 ° C. for 5 minutes. next,
The reaction solution was directly subjected to HPLC (conditions: HPLC column Asahipak φ 4.6 cm × 15 cm eluent acetonitrile: 10 mM phosphate buffer pH 11.4 = 50: 50). The produced [18 F] haloperidol was obtained with radioactivity at the elution position of haloperidol prior to the starting material chlorhaloperidol. Yield 22%, radiochemical purity 99%,
Chemical purity 99%.

Example 5 Synthesis of [18F] p-fluorobenzaldehyde from p-chlorobenzaldehyde by [18F] fluoride and separation and purification of p-fluorobenzaldehyde 18F hydrofluoric acid obtained in the same manner as in Example 4 After dissolving 15 mg of cryptand [2.2.2], 30 μg of potassium carbonate, and 2 mg of potassium oxalate in 2.4 g of an aqueous solution, 1 ml of acetonitrile was added under a stream of argon, and the mixture was dried under reduced pressure with stirring at 80 ° C. for 5 minutes, and further acetonitrile was added. 1 ml was added and the mixture was stirred at 80 ° C. for 5 minutes and then dried under reduced pressure. Anhydrous dimethyl sulfoxide (D) in which 5 mg of p-chlorobenzaldehyde was dissolved
500 μl of MSO) was added and heated to 80 ° C. for 20 minutes. Next, the reaction solution was directly subjected to HPLC (conditions: HPLC column Asahipak φ 4.6 cm × 15 cm eluent acetonitrile: 10 mM phosphate buffer pH 11.4 = 50: 50).
The produced [18 F] p-fluorobenzaldehyde was obtained with radioactivity at the elution position of p-fluorobenzaldehyde prior to the raw material p-chlorobenzaldehyde. Yield 28%, radiochemical purity 99%, chemical purity 99
%.

Example 6 Synthesis of [18F] p-fluorobenzonitrile from p-chlorobenzonitrile by [18F] fluoride and [1]
Separation and Purification of 8F] p-Fluorobenzonitrile In 2.4 g of 18F hydrofluoric acid aqueous solution obtained in the same manner as in Example 4, 15 mg of cryptand [2.2.2], 30 μg of potassium carbonate and 2 mg of potassium oxalate were dissolved. After that, 1 ml of acetonitrile was added under an argon stream, and the mixture was dried under reduced pressure with stirring at 80 ° C. for 5 minutes. Further, 1 ml of acetonitrile was added, stirred for 5 minutes at 80 ° C., and dried under reduced pressure. Anhydrous dimethyl sulfoxide (DM) in which 5 mg of p-chlorobenzonitrile was dissolved
SO) (500 μl) was added, and the mixture was heated to 80 ° C. for 20 minutes. Then, the reaction solution was directly subjected to HPLC (conditions: HPLC column Asahipak φ 4.6 cm × 15 cm eluent acetonitrile: 10 mM phosphate buffer pH 11.4 = 50: 5).
0). The produced [18 F] p-fluorobenzonitrile was obtained with radioactivity at the elution position of p-fluorobenzonitrile prior to the raw material p-chlorobenzonitrile. Yield 20%, radiochemical purity 99%, chemical purity 90%.

Example 7 From [18F] fluoride from p-dichlorobenzene
Synthesis of [18F] p-fluorochlorobenzene and [18
Separation and purification of F] p-fluorochlorobenzene 2.4 g of hydrofluoric acid aqueous solution obtained in the same manner as in Example 4.
Then, 15 mg of cryptand [2.2.2], 3 potassium carbonate
After dissolving 0 μg and 2 mg of potassium oxalate, 1 ml of acetonitrile was added in a stream of argon, and the mixture was dried under reduced pressure with stirring at 80 ° C. for 5 minutes. Further, 1 ml of acetonitrile was added, stirred for 5 minutes at 80 ° C., and dried under reduced pressure. Anhydrous dimethyl sulfoxide (DMSO) 500 in which 5 mg of p-dichlorobenzene was dissolved
μl was added and heated to 80 ° C. for 20 minutes. Next, the reaction solution was directly subjected to HPLC (condition: HPLC column Asahi).
pakφ4.6cm × 15cm eluent acetonitrile: 10m
M phosphate buffer pH 11.4 = 50: 50). Generated
[18 F] p-fluorochlorobenzene was obtained with radioactivity at the elution position of p-fluorochlorobenzene prior to the starting material p-dichlorobenzene. Yield 5%, radiochemical purity 99%, chemical purity 99%.

Example 8 Preparation of PET diagnostic agent containing [18F] haloperidol as an active ingredient 10 ml of the [18F] haloperidol solution obtained in Example 4
To the mixture were added 10 mg of potassium iodide, 150 μl of polysorbate 80 and ethanol, 0.1 ml of a 1N aqueous solution of phosphoric acid was added to neutralize, and the mixture was filtered through a 0.22 μm filter. Pyrogen test using a Toxinometer (Wako Pure Chemical Industries), endotoxin value 0.2E
It was confirmed to be U / ml or less and used as an injection preparation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 25/13 C07C 45/79 45/79 47/55 47/55 49/807 49/807 253 / 34 253/34 255/50 255/50 C07D 211/44 C07D 211/44 211/62 211/62 211/74 211/74 401/04 235 401/04 235 471/10 103 103471/10 103 C07C 45/63 // C07C 45/63 A61K 49/02 C

Claims (11)

[Claims] 1. A compound having a structure in which the chloro group of the chloro compound obtained by fluorinating an aromatic hydrocarbon compound (chloro compound) having an electron-withdrawing substituent and a chloro group is replaced by a fluoro group (fluoro compound) ) Is a long-chain alkylated solid-phase carrier for separating a) from a chloro body by liquid chromatography using an alkaline eluent. 2. The carrier of claim 1, wherein the long chain alkylated solid phase carrier is a long chain alkylated silica gel or polymer. 3. The carrier according to claim 2, wherein the long-chain alkylated silica gel or polymer is octadecylated or octylated. 4. A mixture of an aromatic hydrocarbon compound having an electron-withdrawing substituent and a chloro group (chloro form) and a compound having a structure in which the chloro group of the chloro form is replaced by a fluoro group (fluoro form) to a fluoro form. A method for separating a fluoro form and a chloro form, which comprises applying an alkaline (pH ≧ 8) eluent as a mobile phase and a long-chain alkylated carrier as a solid phase for the separation. 5. The electron-withdrawing substituent is a cyano group, an aldehyde group, a halogeno group, a cycloalkylcarbonyl group or a compound represented by the formula: (In the formula, X represents a group which may have a substituent and is formed by removing a hydrogen atom bonded to the ring-constituting nitrogen atom from a saturated nitrogen-containing heterocyclic compound. A may be branched. A lower alkylene group). 6. X is of the formula: (In the formula, R ₁ , R ₂ , R ₃ and R ₄ each have a hydrogen atom, a hydroxy group, a halogeno group or an alkyl group, an alkoxy group, a phenyl group which may be substituted with a hydroxy group, and a substituent group. Represents an optionally substituted amino group, a cyclic amino group or a cyclic imino group, and an optionally substituted aminocarbonyl group, and R ₁ and R ₂ may together form a cyclic group, and in that case, as a constituent atom The method according to claim 5, which is a heterocyclic group represented by the formula (1) containing a nitrogen atom. 7. In formulas (1), (2) and (3),
The group represented by R ₁ , R ₂ , R ₃ or R ₄ is a group selected from methyl, ethyl and propyl as the alkyl group, the optionally substituted phenyl group is a methoxyphenyl group,
A group selected from a methylphenyl group, an ethylphenyl group, a chlorophenyl group, a fluorophenyl group, a trifluoromethylphenyl group and a bromophenyl group, and a cyclic amino group which may have a substituent is a piperidino group, a piperazino group, 2 -Oxobenzimidazolidinyl group, 3-methyl-2-oxobenzimidazolidinyl group, 3-ethyl-
The 2-oxobenzimidazolidinyl group, the 3-fluoroethyl-2-oxobenzimidazolidinyl group, and the heterocyclic group represented by the formula (1) are 1-phenyl-1,3,8.
-Triazaspiro [4,5] decan-4-one-8-yl, 3-methyl-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one-8-yl, and 3
The method according to claim 6, which is a group selected from -fluoroethyl-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one-8-yl. 8. The method according to claim 4, wherein the alkaline eluent as a mobile phase has a phosphate buffer solution, a borate buffer solution, a carbonate buffer solution, an aqueous amine solution or an aqueous alkali hydroxide solution as its constituent element. . 9. The alkali hydroxide component of an aqueous alkali hydroxide solution, wherein the amine component of the aqueous amine solution is at least one amine selected from triethylamine, diethylmethylamine, ethyldimethylamine, methylpiperidine, ethylpiperidine, or a mixture thereof. 9. The method of claim 8 wherein is one or more alkali metal hydroxides selected from sodium hydroxide, lithium hydroxide, potassium hydroxide. 10. The fluorine atom of the fluoro group is an unstable isotope fluorine 18 atom which is a positron decay nuclide.
the method of. 11. A diagnostic agent for positron emission tomography diagnosis (PET) comprising a fluorine-18-labeled aromatic hydrocarbon compound obtained by the method of claim 10 as an active ingredient.