Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-04-12
2002-04-23
Barts, Samuel (Department: 1821)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C504S332000
Reexamination Certificate
active
06376712
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing trifluoromethylbenzylamines.
Trifluoromethylbenzylamines represented by the general formula (1) are important compounds, for example, as intermediates for producing medicines and agricultural chemicals.
J. Pharm Sci., 54, 1204 (1965) discloses a process for producing a trifluoromethylbenzylamine by a catalytic reduction of trifluoromethylbenzonitrile in the presence of a catalyst. J Med. Chem., 27, 1111 (1984) discloses a process for producing a trifluoromethylbenzylamine by reducing a trifluoromethylbenzaldehyde oxime using a lithium aluminum hydride.
In the above mentioned conventional processes, since the former process uses a large amount of catalyst while not being satisfactory in terms of yield, and the latter process involves the use of hazardous substances requiring non-aqueous conditions while also not achieving a high yield, both of these processes have not been able to achieve satisfactory results as production processes applied on an industrial scale.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a process for producing a trifluoromethylbenzylamine with high yield.
According to the present invention, there is provided a process for producing a trifluoromethylbenzylamine represented by the general formula (1),
where R
1
represents hydrogen atom, a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, or trifluoromethyl group. This process comprises reducing an oxime by hydrogen in an organic solvent in the presence of a catalyst and ammonia. This oxygen is represented by the general formula (2),
where R
1
is defined as above, and R
2
represents hydrogen atom, an alkyl group or an aralkyl group. This oxime can be obtained by reacting a trifluoromethylbenzaldehyde represented by the general formula (3) with a hydroxylamine represented by the general formula (4),
where R
1
is defined as above,
H
2
NOR
2
(4)
where R
2
is defined as above,
According to the process of the present invention, it becomes possible to produce the trifluoromethylbenzylamine at high yield and high selectivity, while also allowing each reaction step to be carried out under mild conditions. Therefore, this process is very effective in producing the target product in an industrial scale.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The oxime represented by the general formula (2) can be produced by the first step of reacting a trifluoromethylbenzaldehyde represented by the general formula (3) with a hydroxylamine represented by the general formula (4). As stated above, the trifluoromethylbenzaldehyde is represented by the general formula (3) in which R
1
is hydrogen atom, a halogen atom selected from fluorine, chlorine, bromine and iodine, or trifluoromethyl group. Examples of the trifluoromethylbenzaldehyde, represented by the general formula (3), include 2-trifluoromethylbenzaldehyde, 3-trifluoromethylbenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-fluoro-4-trifluoromethylbenzaldehyde, 2-fluoro-5-trifluoromethylbenzaldehyde, 2-chloro-3-trifluoromethylbenzaldehyde, 2-chloro-5-trifluoromethylbenzaldehyde, 4-chloro-3-trifluoromethylbenzaldehyde, 3,5-bis(trifluoromethyl)benzaldehyde, 2,4-bis(trifluoromethyl)benzaldehyde, 2,6-bis(trifluoromethyl)benzaldehyde and 2,5 -bis(trifluoromethyl)benzaldehyde.
As stated above, the hydroxylamine is represented by the general formula (4) in which R
2
is hydrogen atom, an alkyl group or an aralkyl group. Specific examples of the hydroxylamine are alkylhydroxylamines having 1 to 10 carbon atoms, such as hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, O-propylhydroxylamine, O-isopropylhydroxylamine, O-n-butylhydroxylamines, O-isobutylhydroxylamine, O-amylhydroxylamine, O-hexylhydroxylamine, O-heptylhydroxylamine, O-octylhydroxylamine, O-2:ethylhexylhydroxylamine, O-nonylhydroxylamine and O-decylhydroxylamine. Further specific examples of the hydroxylamine are aralkylhydroxylamines such as O-benzylhydroxylamine, O-p-tolylmethylhydroxylamine and O-phenethylhydroxylamine.
In the first step of the process, the hydroxylamine may be an acid salt of hydroxylamine, and this acid salt is formed by a reaction of the hydroxylamine with an acid such as hydrochloric acid, sulfuric acid, or a carboxylic acid. In the case of using an acid salt of the hydroxylamine, a hydroxylamine obtained by neutralizing in advance the acid salt with a base may be used in the first step. Alternatively, an acid salt of the hydroxylamine may be reacted with a trifluoromethylbenzaldehyde represented by the general formula (3) in the presence of a base, resulting in generation of a hydroxylamine, while simultaneously allowing a reaction of this hydroxylamine with the trifluoromethylbenzaldehyde, thereby obtaining an oxime represented by the general formula (2). The base used in the process is preferably the one inert in the hydrogenation. Preferable examples of the base that can be used include organic bases such as pyridine, triethylamine and N-methylmorpholine, and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide. The amount of the base used in the process is preferably at least 1 mole, and more preferably 1 to 10 moles, per mol of an acid salt of the hycdroxylamine.
In the first step of the process, any solvent that is inert in the reaction can be used. Examples of solvents that can be used in the first step include ether-based, alcohol-based, amide-based, nitrile-based, aliphatic hydrocarbon-based, aromatic hydrocarbon-based, amine-based and halogenated hydrocarbon-based solvents. Typical examples of these solvents include tetrahydrofuran, diethyl ether, methanol, ethanol, dimethylformamide, acetonitrile, hexane, benzene, toluene, pyridine, triethylamine, chloroform, methylene chloride and chlorobenzene, and two or more of these solvents can be used in combination.
The reaction temperature is normally −20 to 150° C., and although there are no particular restrictions on this temperature, the reaction proceeds smoothly even in the vicinity of room temperature.
The oxime represented by the general formula (2) is obtained nearly quantitatively from the reaction mixture obtained in the reaction of the first step by procedures such as extraction, liquid separation, concentration, distillation and crystallization. In some cases, the oxime may be able to be used in the next step (second step) while still in the form of the reaction mixture without being isolated. Furthermore, although there are two types of isomers present in the oxime obtained by the first step, that is, the syn form and anti form, the oxime can be used either in the form of a single isomer or as a mixture of both isomers in the second step of the present invention.
Next, the following provides an explanation of the second step of the process in which the trifluoromethylbenzylamine represented by the general formula (1), the final target product, is obtained by reduction of the oxime represented by the general formula (2).
In the second step, the reaction product (oxime) obtained by the first step can be reduced by catalytic hydrogenation. Although both heterogeneous and homogeneous catalysts can be used as the catalyst of the catalytic hydrogenation, heterogeneous catalysts are preferable in consideration of their ease of removal. Thus, metals or metal oxides such as palladium or platinum oxide, or these supported on a carrier such as activated carbon, alumina or diatomaceous earth, can be used. Examples of the catalyst include palladium-loaded activated carbon, palladium hydroxide-loaded activated carbon, palladium-loaded barium sulfate, palladium-loaded calcium carbonate, palladium-loaded strontium carbonate, palladium black, palladium-loaded silica gel, platinum dioxide, platinum-loaded activated carbon, platinum black, Raney nickel, ruthenium-loaded activated carbon and rhodium-loaded activated c
Kume Takashi
Narizuka Satoru
Tsukada Eri
Barts Samuel
Central Glass Company Limited
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