U.S. patent application number 09/833211 was filed with the patent office on 2002-01-31 for process for producing trifluoromethylbenzylamines.
Invention is credited to Kume, Takashi, Narizuka, Satoru, Tsukada, Eri.
Application Number | 20020013500 09/833211 |
Document ID | / |
Family ID | 18624756 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013500 |
Kind Code |
A1 |
Narizuka, Satoru ; et
al. |
January 31, 2002 |
Process for producing trifluoromethylbenzylamines
Abstract
The present invention relates to a process for producing a
trifluoromethylbenzylamine represented by the general formula (1),
1 where R.sup.1 represents hydrogen atom, a halogen atom selected
from the group consisting of fluorine, chlorine, bromine and
iodine, or trifluoromethyl group. This process includes the step of
reducing an oxime by hydrogen in an organic solvent in the presence
of a catalyst and ammonia. The oxime is represented by the general
formula (2), 2 where R.sup.1 is defined as above, and R.sup.2
represents hydrogen atom, an alkyl group or an aralkyl group. With
this process, the trifluoromethylbenzylamine can be produced with
high yield.
Inventors: |
Narizuka, Satoru; (Saitama,
JP) ; Tsukada, Eri; (Saitama, JP) ; Kume,
Takashi; (Saitama, JP) |
Correspondence
Address: |
CROWELL & MORING LLP
Intellecual Propety Group
P.O. Box 14300
Washington
DC
20044-4300
US
|
Family ID: |
18624756 |
Appl. No.: |
09/833211 |
Filed: |
April 12, 2001 |
Current U.S.
Class: |
564/385 |
Current CPC
Class: |
C07C 209/40 20130101;
C07C 211/29 20130101; C07C 209/40 20130101 |
Class at
Publication: |
564/385 |
International
Class: |
C07C 29/40 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 13, 2000 |
JP |
2000-112629 |
Claims
What is claimed is:
1. A process for producing a trifluoromethylbenzylamine represented
by the general formula (1), said process comprising reducing an
oxime by hydrogen in an organic solvent in the presence of a
catalyst and ammonia, said oxime being represented by the general
formula (2), 8where R.sup.1 represents hydrogen atom, a halogen
atom selected from the group consisting of fluorine, chlorine,
bromine and iodine, or trifluoromethyl group, 9where R.sup.1 is
defined as above, and R.sup.2 represents hydrogen atom, an alkyl
group or an aralkyl group.
2. A process for producing a trifluoromethylbenzylamine represented
by the general formula (1), said process comprising: (a) reacting a
trifluoromethylbenzaldehyde represented by the general formula (2)
with a hydroxylamine represented by the general formula (3),
thereby obtaining an oxime represented by the general formula (4);
and (b) reducing said oxime by hydrogen in an organic solvent in
the presence of a catalyst and ammonia, thereby producing said
trifluoromethylbenzylamine. 10where R.sup.1 represents hydrogen
atom, a halogen atom selected from the group consisting of
fluorine, chlorine, bromine and iodine, or trifluoromethyl group,
11where R.sup.1 and R.sup.2 are defined as above.
3. A process according to claim 2, wherein said hydroxylamine is
prepared by neutralizing an acid salt of said hydroxylamine with a
base.
4. A process according to claim 3, wherein said base is selected
from the group consisting of pyridine, triethylamine,
N-methylmorpholine, sodium bicarbonate, sodium carbonate, potassium
bicarbonate, potassium carbonate, calcium carbonate, lithium
hydroxide, sodium hydroxide, and potassium hydroxide.
5. A process according to claim 3, wherein a molar ratio of said
base to said acid salt of said hydroxylamine is at least 1.
6. A process according to claim 1, wherein said catalyst is a
heterogeneous catalyst.
7. A process according to claim 6, wherein said heterogeneous
catalyst is an activated carbon carrying thereon palladium.
8. A process according to claim 1, wherein said catalyst is in an
amount of 0.0001 to 1 mol %, based on the number of moles of said
oxime.
9. A process according to claim 1, wherein said reducing is
conducted under a hydrogen pressure of 5 atmospheres or more.
10. A process according to claim 1, wherein said ammonia is in an
amount of 1-10 moles per mol of said oxime.
11. A process for producing a trifluoromethylbenzylamine
represented by the general formula (1), said process comprising:
(a) mixing together a trifluoromethylbenzaldehyde represented by
the general formula (2), an acid salt of a hydroxylamine
represented by the general formula (3), and a base, thereby
obtaining an oxime represented by the general formula (4); and (b)
reducing said oxime by hydrogen in an organic solvent in the
presence of an catalyst and ammonia, thereby producing said
trifluoromethylbenzylamine. 12where R.sup.1 represents hydrogen
atom, a halogen atom selected from the group consisting of
fluorine, chlorine, bromine and iodine, or trifluoromethyl group,
13where R.sup.1 is defined as above, H.sub.2NOR.sup.2 (3) where
R.sup.2 represents hydrogen atom, an alkyl group or an aralkyl
group, 14where R.sup.1 and R.sup.2 are defined as above.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to copending application Ser.
No. 09/532,004, entitled "PROCESS FOR PRODUCING
TRIFLUOROMETHYLBENZYLAMINES", filed on Mar. 21, 2000.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a process for producing
trifluoromethylbenzylamines.
[0003] Trifluoromethylbenzylamines represented by the general
formula (1) are important compounds, for example, as intermediates
for producing medicines and agricultural chemicals. 3
[0004] 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.
[0005] 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
[0006] It is therefore an object of the present invention to
provide a process for producing a trifluoromethylbenzylamine with
high yield.
[0007] According to the present invention, there is provided a
process for producing a trifluoromethylbenzylamine represented by
the general formula (1), 4
[0008] where R.sup.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 oxime is represented by the general
formula (2), 5
[0009] where R.sup.1 is defined as above, and R.sup.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), 6
[0010] where R.sup.1 is defined as above,
H.sub.2NOR.sup.2 (4)
[0011] where R.sup.2 is defined as above.
[0012] 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
[0013] 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.sup.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-trifluoromethylbenzalde- hyde, 3-trifluoromethylbenzaldehyde,
4-trifluoromethylbenzaldehyde,
3-fluoro-4-trifluoromethylbenzaldehyde,
2-fluoro-5-trifluoromethylbenzald- ehyde,
2-chloro-3-trifluoromethylbenzaldehyde,
2-chloro-5-trifluoromethylb- enzaldehyde,
4-chloro-8-trifluoromethylbenzaldehyde,
3,5-bis(trifluoromethyl)benzaldehyde,
2,4-bis(trifluoromethyl)benzaldehyd- e,
2,6-bis(trifluoromethylbenzaldehyde and
2,5-bis(trifluoromethyl)benzald- ehyde.
[0014] As stated above, the hydroxylamine is represented by the
general formula (4) in which R.sup.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.
[0015] 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
hydroxylamine.
[0016] 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.
[0017] The reaction temperature is normally -20 to 150.degree. C.,
and although there are no particular restrictions on this
temperature, the reaction proceeds smoothly even in the vicinity of
room temperature.
[0018] 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 oxide 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.
[0019] 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).
[0020] 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
carbon. Although the amount of the catalyst may vary according to
its type, it is preferably 0.0001-1 mol %, more preferably
0.001-0.1 mol %, based on the number of moles of the oxime.
[0021] Examples of the reaction solvent used in the second step
include alcohols, hydrocarbons, ethers, carboxylic acids, esters,
and amides. Typical examples of these solvents include methanol,
ethanol, benzene, toluene, xylene, ethyl benzene, isopropyl
benzene, tetralin, mesitylene, tetrahydrofuran, diethyl ether,
acetic acid, ethyl acetate and dimethylformamide, and two or more
types of these solvents can be used in combination.
[0022] Hydrogen pressure for conducting catalytic hydrogenation of
the second step may vary according to the solvent type, the
catalyst type and other conditions. Although a pressure within the
range of normal pressure (atmospheric pressure) to about 100
atmospheres can be used, a pressure of 5 atmospheres or more is
used preferably.
[0023] In the second step, although a temperature within the range
of -10.degree. C. to the boiling point of the solvent can be
normally used for the reaction temperature, a temperature of
roughly 0-50.degree. C. is preferable, and the object of the second
step can be sufficiently achieved even at room temperature
(10-30.degree. C.).
[0024] In the second step, ammonia is added to the reaction system
to improve the selectivity of the reaction to obtain the
trifluoromethylbenzylamine represented by the general formula (1).
This ammonia can be added to the reaction system in the form of
liquid ammonia or by dissolving in the reaction solvent. The amount
of this ammonia is not particularly limited, and it is preferably
1-10 moles, more preferably 3-5 moles, to 1 mole of the oxime
represented by the general formula (2).
[0025] After separating the catalyst from the reaction mixture
obtained by the reaction of the second step, the
trifluoromethylbenzylamine represented by the general formula (1)
can be obtained at an extremely high yield by a procedure such as
concentration.
[0026] As shown in the general formula (1), the target compound,
trifluoromethylbenzylamine, has an amino group at the benzyl
position. It is generally known that an amino group at the benzyl
position tends to be eliminated by the occurrence of hydrogenolysis
by catalytic hydrogenation. Therefore, there was also concern over
elimination of the amino group in the target compound of the
present invention as well. However, according to the present
invention, the elimination reaction of the amino group unexpectedly
hardly occurs at all, and the target compound can be obtained both
selectively and at significantly high yield.
[0027] The hydrogenation reaction of the oxime compound of the
second step is believed to go through a reaction intermediate (5)
as shown in the following reaction scheme. 7
[0028] Similar to the oxime represented by the general formula (2),
since this reaction intermediate (5) has one or two trifluoromethyl
groups, which are extremely powerful electron attracting groups, on
the benzene ring, the reaction intermediate (5) is susceptible to
attack by various nucleophiles such as water and the target
compound of the present invention. There was therefore concern over
decreased selectivity for the target compound due to the formation
of benzyl alcohol and secondary amine as by-products. However,
according to the process of the present invention, there is
unexpectedly hardly any formation of reaction by-products such as
addition products, and the target compound represented by the
general formula (1) can be obtained both selectively and at
remarkably high yield.
[0029] Examples of the trifluoromethylbenzylamine represented by
the general formula (1) include 2-trifluoromethylbenzylamine,
3-trifluoromethylbenzylamine, 4-trifluoromethylbenzylamine,
8-fluoro-4-trifluoromethylbenzylamine,
2-fluoro-5-trifluoromethylbenzylam- ine,
2-chloro-3-trifluoromethylbenzylamine,
2-chloro-5-trifluoromethylbenz- ylamine,
4-chloro-3-trifluoromethylbenzylamine, 3,5-bis(trifluoromethyl)be-
nzylamine, 2,4-bis(trifluoromethyl)benzylamine,
2,6-bis(trifluoromethyl)be- nzylamine and
2,5-bis(trifluoromethyl)benzylamine.
[0030] The following nonlimitative examples are illustrative of the
present invention.
EXAMPLE 1
[0031] The first step of the process of the present invention was
conducted as follows. At first, 8.79 g (50.5 mmol) of
4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of
hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol
and 34 ml of water followed by the addition of 2.5 g of sodium
hydroxide and stirring for 1 hour at room temperature. After adding
ether and washing with dilute hydrochloric acid, the reaction
liquid was further washed with saturated brine followed by drying
with mirabilite and concentrating to obtain 9.26 g (48.2 mmol) of
4-trifluoromethylbenzylaldehyde oxime (yield: 95.5%).
EXAMPLE 2
[0032] The second step of the process of the present invention was
conducted as follows. At first, a 100 ml autoclave equipped with an
electromagnetic stirrer was charged with 5.00 g (26 mmol) of
4-trifluoromethylbenzaldehyde oxime, 50 ml of 2M-ammoniacal
methanol solution (containing 100 mmol of ammonia), and 0.25 g of a
catalyst (i.e., a carbon powder (50% wet) carrying thereon 5%
palladium), followed by introduction of hydrogen to have an inside
pressure of 1 MPa. Then, the reaction mixture was stirred, while
the reaction temperature was maintained at 20.degree. C. and while
hydrogen was gradually introduced into the autoclave in a manner to
maintain the total pressure at 1 MPa. After conducting the reaction
for 2 hr, the reaction was stopped, followed by removing the
catalyst by filtration. As a result of analyzing the obtained
reaction liquid by gas chromatography, 4-trifluoromethylbenzylamine
was formed at a yield of 87.6%.
EXAMPLE 3
[0033] Example 2 was repeated except in that 50 ml of 2M-ammoniacal
methanol solution were replaced with 50 ml of 2M-ammoniacal
2-propanol solution (containing 100 mmol of ammonia) and that the
reaction was conducted for 3.5 hr in place of 2 hr. As a result of
analyzing the obtained reaction liquid by gas chromatography,
4-trifluoromethylbenzylam- ine was formed at a yield of 95.0%.
EXAMPLE 4
[0034] The second step of the process of the present invention was
conducted as follows. At first, a 1-liter autoclave equipped with a
mechanical stirrer was charged with 300 g (1.59 mol) of
4-trifluoromethylbenzylaldehyde oxime, 460 g of 2-propanol, and 15
g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon
5% palladium), followed by introduction of 40 g of liquid ammonia
and then introduction of hydrogen to have a pressure of 1 MPa.
Then, the reaction mixture was stirred, while the reaction
temperature was maintained at 20.degree. C. and while hydrogen was
gradually introduced into the autoclave in a manner to maintain the
total pressure at 1 MPa. After conducting the reaction for 4 hr,
the reaction was stopped, followed by removing the catalyst by
filtration. As a result of analyzing the obtained reaction liquid
by gas chromatography, 4-trifluoromethylbenzylamine was formed at a
yield of 92.6%.
EXAMPLE 5
[0035] Example 4 was repeated except in that 460 g of 2-propanol
were replaced with 460 g of toluene and that the reaction was
conducted for 3 hr in place of 4 hr. As a result of analyzing the
obtained reaction liquid by gas chromatography,
4-trifluoromethylbenzylamine was formed at a yield of 97.6%.
EXAMPLE 6
[0036] Example 4 was repeated except in that 460 g of 2-propanol
were replaced with a combination of 368 g of 2-propanol and 92 g of
toluene and that the reaction was conducted for 2 hr in place of 4
hr. As a result of analyzing the obtained reaction liquid by gas
chromatography, 4-trifluoromethylbenzylamine was formed at a yield
of 98.5%.
[0037] The entire disclosure of Japanese Patent Application No.
2000-112629 filed on Apr. 13, 2000, including specification, claims
and summary, is incorporated herein by reference in its
entirety.
* * * * *