Process for producing halogenated benzene compound

Details Process for producing halogenated benzene compound Process for producing halogenated benzene compound

2000-06-30

2001-10-23

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C564S442000, C568S937000

Reexamination Certificate

active

06307045

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing a halogenated benzene compound, the process comprising the step of reacting in a solvent an organometallic compound with a halide ion (X
−
), under light irradiation conditions in the presence of a semiconductor catalyst with a photocatalytic activity, particularly to a process useful for producing a halogenated benzene compound labeled with a radioactive halogen.
2. Description of the Related Art
Halogenated benzene compounds have an important role as various biologically active substances typified by drugs and agrochemicals and as intermediates for their synthesis. Further, compounds including a radioactive halogen in their molecules have extremely valuable as a radioactive tracer which is used for elucidating in-vivo behavior of drugs and the like in the course of their development, or as in-vivo or in-vitro diagnostic or therapeutic drugs for clinical diagnosis or therapy. Among the compounds including a radioactive halogen in their molecules to be used for these purposes, N-isopropylamphetamine hydrochloride labeled with iodine-123 is used as an in-vivo diagnostic drug for brain functions, 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid is used as that for heart diseases, and an iodohippuric acid sodium salt is used as that for kidney and urinary tract diseases, for example.
In recent years, a labeling method utilizing the exchange of a metal such as tin, silicon and germanium with a halogen has been widely used as a technique for producing such compounds including a radioactive halogen in their molecules because products with high specific radioactivities can be obtained in high position selectivities. However, since raw materials to be used for labeling are generally available with stability in the form of halide ions, the above method requires complicated operations, for example, of conducting the reaction in the presence of an oxidizing agent (sometimes, in large excess) such as hypochlorite, chloramine T (N-chloro-4-methylbenzenesulfonamide sodium salt), Iodo-Gen™ (1,3,4,6-tetrachloro-3&agr;,6&agr;-diphenylglycoluril), Iodo-beads™ (N-chloro-benzenesulfonamide (sodium salt) derivatized, uniform, nonporous, polystyrene beads), hydrogen peroxide and NBS (1-Bromosuccinimide), and of removing the remaining oxidizing agent by, for example, adding a reducing agent at the completion of the reaction.
Further, in the above method, the compound to be labeled is exposed to oxidizing conditions. Therefore, it is difficult to apply the method when the compound to be labeled is unstable in such conditions.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a widely-applicable process for producing halogenated compounds, the process being useful for the production of compounds possessing a halogen, particularly a radioactive halogen, in their molecules.
Under such circumstances, the present inventors have studied intensively, and have found a process for producing a halogenated benzene compound represented by the general formula [II]:
wherein X, n, m, A and Q have the same meanings as those defined below, the process comprising the step of reacting in a solvent an organometallic compound represented by the general formula [I]:
wherein M represents an R
1
3
Sn group, an R
1
3
Si group, an R
1
3
Ge group, an (R
2
CO
2
)Hg group, a ClHg group or an (R
3
O)
2
B group wherein each R
1
independently represents a C1-C8 alkyl group, R
2
represents a C1-C3 alkyl group or a C1-C3 haloalkyl group, R
3
represents a hydrogen atom or a C1-C3 alkyl group, n represents an integer of from 0 to 4, m represents an integer of from 0 to 1, each A independently represents a fluorine atom, a nitro group, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxy group or a C2-C8 acyloxy group, and Q represents an organic residue, with a halide ion represented by the general formula X− wherein X represents a halogen atom including each isotope thereof, under light irradiation conditions in the presence of a semiconductor catalyst with a photocatalytic activity (hereinafter, the process is referred to as the process of the present invention).
In the process of the present invention, the reaction can be conducted under mild conditions without the whole reaction system being exposed to oxidative conditions. Since the process uses the halide ion as the source of the halogen atom to be introduce, it is suitable particularly for the production of labeled compounds which should be synthesized in high purities and in high specific radioactivities from small amounts of radioactive raw materials for the halogenation which have restricted chemical forms.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step.
DETAILED DESCRIPTION OF THE INVENTION
The semiconductor catalysts with the photocatalytic activity to be used in the process of the present invention are semiconductor catalysts which are solid catalysts with the property that electrons in a valence band of the catalysts are excited by light. Most of the catalysts are metal oxides or metal sulfides. Specific examples of them include titanium oxide (TiO
2
), strontium titanate (SrTiO
3
), tungsten oxide (WO
3
), bismuth oxide (Bi
2
O
3
), zirconium oxide (ZrO
2
), stannum oxide (SnO
2
), zinc oxide (ZnO) and zinc sulfide (ZnS). The semiconductor catalyst with the photocatalytic activity may have any form as long as its solid surface can receive light during its use. For example, powder, granule and ones supported on carriers by coating are available. Further, commercially available ones may also be employed.
The amount, in molar ratio, of the semiconductor catalyst is preferably not less than that of the halide ion (X
−
). When the concentration of the halide ion in a solution is low, the amount of the semiconductor catalyst is preferably excessive.
The light to be used in the process of the present invention may be any one which has a wavelength at which the light can excite electrons of the semiconductor catalyst. For example, when titanium oxide (TiO
2
), strontium titanate (SrTiO
3
) or tungsten oxide (WO
3
) is used, any light with wavelengths shorter than 388 nm may be applied. A black light, a mercury lamp, a xenon lamp and the like can be employed as a light source.
Examples of the halide ion (X
−
) to be used in the process of the present invention include an iodide ion (I
−
), a bromide ion (Br
−
) and a chloride ion (Cl
−
). The halide ion is used in the form of its salt of a metal such as an alkali metal or of a quaternary ammonium such as tetrabutylammonium. Examples of such salts include sodium iodide (NaI), potassium iodide (KI), sodium bromide (NaBr), potassium bromide (KBr), sodium chloride (NaCl) and potassium chloride (KCl). Furthermore, the halide ion also includes ions of isotopes of the halogen. The isotopes may be radioactive isotopes. Examples of such isotopes include iodines-123, 125, 128 and 131, bromines-75, 76, 77, 80 and 82, and chlorines-36 and 38.
The reaction in the process of the present invention is conducted in a solvent. The solvent to be used may be any one in which the organometallic compound [I], which is one of the raw materials, can be dissolved with stability and

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