U.S. patent application number 10/106390 was filed with the patent office on 2002-12-19 for preparation of n-benzylamines.
Invention is credited to Bartsch, Michael, Siegel, Wolfgang, Winsel, Harald.
Application Number | 20020193636 10/106390 |
Document ID | / |
Family ID | 7680381 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193636 |
Kind Code |
A1 |
Winsel, Harald ; et
al. |
December 19, 2002 |
PREPARATION OF N-BENZYLAMINES
Abstract
N-Benzylamines are prepared by a process in which (i) in a first
step, a benzaldehyde is reacted with a primary amine to give the
imine and (ii) in a second step, the imine is hydrogenated with
hydrogen in the presence of a catalyst containing one or more
metals of groups 8 to 10 of the Periodic Table of the Elements to
give the N-benzylamine, wherein the iminization (i) is carried out
in a water-miscible solvent and the resulting water of reaction is
not removed, and the hydrogenation (ii) is carried out in the imine
solution obtained in the iminization (i) and containing water of
reaction.
Inventors: |
Winsel, Harald;
(Birkenheide, DE) ; Siegel, Wolfgang;
(Limburgerhof, DE) ; Bartsch, Michael; (Neustadt,
DE) |
Correspondence
Address: |
Herbert B. Keil
KEIL & WEINKAUF
1101 Connecticut Ave., N.W.
Washington
DC
20036
US
|
Family ID: |
7680381 |
Appl. No.: |
10/106390 |
Filed: |
March 27, 2002 |
Current U.S.
Class: |
564/398 |
Current CPC
Class: |
C07C 249/02 20130101;
C07C 249/02 20130101; C07C 213/02 20130101; C07C 217/58 20130101;
C07C 251/24 20130101; C07C 211/27 20130101; C07C 213/02 20130101;
C07C 209/52 20130101; C07C 209/52 20130101 |
Class at
Publication: |
564/398 |
International
Class: |
C07C 29/26 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 4, 2001 |
DE |
10116816.0 |
Claims
We claim:
1. A process for the preparation of N-benzylamines, in which (i) in
a first step, a benzaldehyde is reacted with a primary amine to
give the imine and (ii) in a second step, the imine is hydrogenated
with hydrogen in the presence of a catalyst containing one or more
metals of groups 8 to 10 of the Periodic Table of the Elements to
give the N-benzylamine, wherein the iminization (i) is carried out
in a water-miscible solvent and the resulting water of reaction is
not removed, and the hydrogenation (ii) is carried out in the imine
solution obtained in the iminization (i) and containing water of
reaction.
2. A process for the preparation of N-benzylamines of the formula
(I) 10where R.sup.1, R.sup.2, R.sup.3 and R.sup.4, independently of
one another, are each H, halogen or C.sub.1-C.sub.4-alkyl or
C.sub.1-C.sub.4-alkoxy each of which is unsubstituted or mono- or
polysubstituted by halogen, R.sup.5 is H or C.sub.1-C.sub.8-alkyl
and R.sup.6 is H, C.sub.1-C.sub.8-alkyl or C.sub.5-C.sub.12-aryl or
C.sub.5-C.sub.12-cycloalkyl, each of which may be mono- or
polysubstituted by halogen, OH or C.sub.1-C.sub.4-alkyl and/or
C.sub.1-C.sub.4-alkoxy each of which is unsubstituted or mono- or
polysubstituted by halogen, or is C.sub.1-C.sub.4-alkoxy- or
benzyloxy-substituted C.sub.1-C.sub.4-alkyl, in which (i) in a
first step, a benzaldehyde of the formula (II) is reacted with an
amine of the formula (III) 11to give the imine of the formula (IV)
12where R.sup.1-R.sup.6 have the abovementioned meanings, and (ii)
in a second step, the imine of the formula (IV) is hydrogenated
with hydrogen in the presence of a catalyst containing one or more
metals of groups 8 to 10 of the Periodic Table of the Elements to
give the N-benzylamine of the formula (1), wherein the iminization
(i) is carried out in a water-miscible solvent and the resulting
water of reaction is not removed, and the hydrogenation (ii) is
carried out in the imine (IV) solution obtained in the iminization
(i) and containing water of reaction.
3. A process as claimed in claim 1, wherein the water-miscible
solvent is selected from the group consisting of methanol, ethanol,
n-propanol, isopropanol, glycol, tert-butanol, THF, glycol
monoalkyl ethers and glycol dialkyl ethers.
4. A process as claimed in claim 1, wherein the catalyst used is
palladium on active carbon.
5. A process as claimed in claim 2, wherein the aldehyde of the
formula (II) is selected from the group consisting of benzaldehyde,
4-methoxybenzaldehyde, 4-tert-butylbenzaldehyde,
4-methylbenzaldehyde, 4-chlorobenzaldehyde, 4-fluorobenzaldehyde,
3-fluorobenzaldehyde, 3,5-difluorobenzaldehyde,
4-trifluoromethylbenzaldehyde and
3,5-bistrifluoromethylbenzaldehyde.
6. A process as claimed in claim 2, wherein the amine of the
formula (III) is selected from the group consisting of
.alpha.-phenylethylamine, 1-(4-methylphenyl)ethylamine,
2-heptylamine, 1-(4-chlorophenyl)ethylamine- , 1-phenylpropylamine,
2-amino-3,3-dimethylbutane, 1-(1-naphthyl)ethylamin- e,
1,2,3,4-tetrahydronaphthylamine, 1-(4-methoxyphenyl)ethylamine,
aminocyclopentanol, aminocyclohexanol, 1-aminoindane,
1-(2,4-dichlorophenyl)ethylamine, 1-benzyloxy-2-propylamine,
1-(2-naphthyl)ethylamine,
1-(3,5-bistrifluoromethylphenyl)-ethylamine and
1-(4-fluorophenyl)ethylamine.
7. A process as claimed in claim 1, wherein the iminization (i) is
carried out at from 10 to 40.degree. C. and at atmospheric
pressure.
Description
[0001] The invention relates to a process for the preparation of
N-benzylamines.
[0002] It is known that N-benzyl-.alpha.-methylbenzylamine can be
prepared by iminization of benzaldehyde with
.alpha.-methylbenzylamine and subsequent hydrogenation of the imine
formed. Such a process is described by Huckabee et al., Organic
Process Research & Development 4(2000), 594-595. Optically pure
(R)- and (S)-N-benzyl-.alpha.-methylbenzylamine are obtained from
benzaldehyde and (R)- and (S)-.alpha.-phenylethylamine,
respectively, by palladium-catalyzed hydrogenation of
benzylidene(1-phenylethyl)imine formed as an intermediate. The
iminization is carried out in toluene as a solvent, and the
resulting water of reaction is removed by azeotropic
distillation.
[0003] It is an object of the present invention to provide a
simpler process for the preparation of N-benzylamines.
[0004] We have found that this object is achieved by a process for
the preparation of N-benzylamines, in which
[0005] (i) in a first step, a benzaldehyde is reacted with a
primary amine to give the imine and
[0006] (ii) in a second step, the imine is hydrogenated with
hydrogen in the presence of a catalyst containing one or more
metals of groups 8 to 10 of the Periodic Table of the Elements to
give the N-benzylamine,
[0007] wherein the iminization (i) is carried out in a
water-miscible solvent and the resulting water of reaction is not
removed, and the hydrogenation (ii) is carried out in the imine
solution obtained in the iminization (i) and containing water of
reaction.
[0008] Preferred N-benzylamines prepared by the novel process are
those of the formula (I) 1
[0009] where
[0010] R.sup.1, R.sup.2, R.sup.3 and R.sup.4, independently of one
another, are each H, halogen or C.sub.1-C.sub.4-alkyl or
C.sub.1-C.sub.4-alkoxy, each of which is unsubstituted or mono- or
polysubstituted by halogen,
[0011] R.sup.5 is H or C.sub.1-C.sub.8-alkyl and
[0012] R.sup.6 is H, C.sub.1-C.sub.8-alkyl or C.sub.5-C.sub.12-aryl
or C.sub.5-C.sub.12-cycloalkyl, each of which may be mono- or
polysubstituted by halogen, OH or C.sub.1-C.sub.4-alkyl and/or
C.sub.1-C.sub.4-alkoxy, each of which is unsubstituted or mono- or
polysubstituted by halogen, or is C.sub.1-C.sub.4-alkoxy- or
benzyloxy-substituted C.sub.1-C.sub.4-alkyl.
[0013] These are obtained by a procedure in which
[0014] (i) in a first step, a benzaldehyde of the formula (II) is
reacted with an amine of the formula (III) 2
[0015] to give an imine of the formula (IV) 3
[0016] where
[0017] R.sup.1-R.sup.6 have the abovementioned meanings, and
[0018] (ii) in a second step, the imine of the formula (IV) is
hydrogenated with hydrogen in the presence of a catalyst containing
one or more metals of groups 8 to 10 of the Periodic Table of the
Elements to give the N-benzylamine of the formula (I),
[0019] the iminization (i) being carried out in a water-miscible
solvent and the resulting water of reaction not being removed, and
the hydrogenation (ii) being carried out in the imine (IV) solution
solution obtained in the iminization (i) and containing water of
reaction.
[0020] In a first step (i), a benzaldehyde, preferably a
benzaldehyde of the formula (II), is reacted with an amine,
preferably an amine of the formula (III), to give an imine,
preferably of the formula (IV). R.sup.1 to R.sup.4 are, for
example, fluorine, chlorine, bromine, iodine, methyl,
trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl or the corresponding alkoxy radicals. The
benzaldehydes (II) may be up to tetrasubstituted but are preferably
unsubstituted or mono- or disubstituted. Benzaldehydes of the
formula (II) are, for example, benzaldehyde, 4-methoxybenzaldehyde,
4-tert-butylbenzaldehyde, 4-methylbenzaldehyde,
4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 3-fluorobenzaldehyde,
3,5-difluorobenzaldehyde, 4-trifluoromethylbenzaldehyde and
3,5-bistrifluoromethylbenzaldehyde.
[0021] R.sup.5 and R.sup.6 are, for example, methyl, ethyl, propyl,
isopropyl, 1- or 2-butyl, 1-, 2- or 3-pentyl, 1-, 2- or 3-hexyl,
1-, 2-, 3- or 4-heptyl or 1-, 2-, 3- or 4-octyl. R.sup.6 may
furthermore be C.sub.5-C.sub.12-aryl or C.sub.5-C.sub.12-cycloalkyl
which is unsubstituted or mono- or polysubstituted, preferably
mono- or disubstituted, by OH, said halogens or said unsubstituted
or substituted C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy
radicals, e.g. phenyl, naphthyl, tetrahydronaphthyl, indyl,
cyclopentyl or cyclohexyl which is unsubstituted or substituted in
this manner. Amines of the formula (III) are, for example,
.alpha.-phenylethylamine, 1-(4-methylphenyl)ethylamine,
2-heptylamine, 1-(4-chlorophenyl)ethylamine, 1-phenylpropylamine,
2-amino-3,3-dimethylbutane, 1-(1-naphthyl)ethylamine,
1,2,3,4-tetrahydronaphthylamine, 1-(4-methoxyphenyl)-ethylamine,
aminocyclopentanol, aminocyclohexanol, 1-aminoindane,
1-(2,4-dichlorophenyl)ethylamine, 1-benzyloxy-2-aminopropane,
1-benzyloxy-3-aminobutane, 1-(2-naphthyl)ethylamine,
1-(3,5-bistrifluoromethylphenyl)-ethylamine and
1-(4-fluorophenyl)ethylam- ine.
[0022] The iminization (i) is carried out in the homogeneous phase
in a water-miscible solvent. Suitable water-miscible solvents are
methanol, ethanol, n-propanol, isopropanol, glycol, tert-butanol,
THF, glycol monoalkyl ethers or glycol dialkyl ethers, such as
dimethoxyethane. Preferred solvents are methanol, ethanol,
n-propanol and isopropanol, and a particularly preferred solvent is
methanol. Usually, the concentration of the benzaldehyde (II) and
that of the amine (III) together is from 10 to 65% by weight.
[0023] The iminization (i) is preferably carried out at from 10 to
40.degree. C., particularly preferably from 20 to 30.degree. C.,
and preferably at atmospheric pressure. A reaction time of from 0.1
to 5 hours is usually sufficient for the iminization (i).
[0024] Without prior removal of the water of reaction, the imine
formed is hydrogenated, after the iminization, with hydrogen in the
presence of a palladium-containing catalyst in the imine solution
containing the water of reaction. Suitable catalysts contain one or
more metals of groups 8 to 10 of the Periodic Table of the Elements
on any desired conventional inorganic support, such as alumina,
silica, zirconium dioxide, titanium dioxide or carbon. Preferred
catalysts contain platinum, palladium, nickel or rhodium on an
inorganic support, palladium on active carbon being particularly
preferred.
[0025] The hydrogenation (ii) is preferably carried out at from 10
to 40.degree. C., particularly preferably at from 20 to 30.degree.
C., the hydrogen pressure usually being from 0.1 to 25, preferably
from 0.1 to 5, bar. A reaction time of from 1 to 100 hours is
usually sufficient for the hydrogenation.
[0026] The hydrogenation catalyst can be added before or after the
iminization (i). The process can be operated continuously or
batchwise and takes place without racemization when chiral amines
are used.
[0027] As a result of the omission of the azeotropic distillation,
the imine formed as an intermediate is not subjected to thermal
stress. Furthermore, the novel process is easier to carry out than
the process disclosed in the prior art since the process does not
include the azeotropic distillation as an operation.
[0028] The examples which follow illustrate the invention.
EXAMPLES
Example 1
Batchwise Synthesis of N-4-methoxybenzyl-1-phenylethylamine
[0029] 4
[0030] 100 ml of methanol and 100 mmol of 1-phenylethylamine are
initially taken, and 100 mmol of 4-methoxybenzaldehyde are added
dropwise at 24.degree. C. in the course of 15 minutes. Stirring is
effected for 6 hours at 24.degree. C., the completeness of the
iminization is checked by GC, 0.5 g of Pd/C (10% by weight) is
added and the crude mixture is hydrogenated with hydrogen for 5
hours at atmospheric pressure. A sample is taken and the
composition is investigated by GC analysis.
[0031] GC analysis results (in GC percent by area):
1 1-Phenylethylamine 4.7% 4-Methoxybenzaldehyde 0.2%
N-4-Methoxybenzyl-1-phenylethylamine 89.5%
Example 2
Batchwise Synthesis of N-benzyl-1-(4-methylphenyl)ethylamine
[0032] 5
[0033] 100 ml of methanol and 100 mmol of
4-methyl-1-phenylethylamine are initially taken, and 100 mmol of
benzaldehyde are added dropwise at 24.degree. C. in the course of
15 minutes. Stirring is effected for 6 hours at 24.degree. C., the
completeness of the iminization is checked by GC, 0.5 g of Pd/C
(10% by weight) is added and the crude mixture is hydrogenated with
hydrogen for 5 hours at atmospheric pressure. A sample is taken and
the composition is investigated by GC analysis.
[0034] GC analysis results (in GC percent by area):
2 4-Methyl-1-phenylethylamine 5.1% Benzaldehyde 1.3%
N-Benzyl-1-(4-methylphenyl)ethylamine 82.5%
Example 3
Batchwise Synthesis of (R)-N-benzyl-1-phenylethylamine
[0035] 6
[0036] 412 kg of methanol and 375.7 kg of (R)-1-phenylethylamine
(ee=97.1%) are initially taken and 329 kg of benzaldehyde are added
dropwise at 24.degree. C. in the course of 120 minutes. Stirring is
effected for 6 hours at 24.degree. C., the completeness of the
iminization is checked by GC, 6 kg of Pd/C (5% by weight) are added
and the crude mixture is hydrogenated with hydrogen for 24 hours at
atmospheric pressure. The sample is taken and the composition is
investigated by GC analysis.
[0037] GC analysis results (in GC percent by area):
3 (R)-1-Phenylethylamine 0% Benzaldehyde 0.1%
(R)-N-Benzyl-1-phenylethylamine 99.4% ee = 97.1%
Example 4
Batchwise Synthesis of N-benzyl-2-methylhexylamine
[0038] 7
[0039] 100 ml of methanol and 100 mmol of 2-heptylamine are
initially taken and 100 mmol of benzaldehyde are added dropwise at
24.degree. C. in the course of 15 minutes. Stirring is effected for
6 hours at 24.degree. C., the completeness of the iminization is
checked by GC, 0.5 g of Pd/C (10% by weight) is added and the crude
mixture is hydrogenated with hydrogen for 5 hours at atmospheric
pressure. A sample is taken and the composition is investigated by
GC analysis.
[0040] GC analysis results (in GC percent by area):
4 2-Heptylamine 0.6% Benzaldehyde 0.0% N-Benzyl-2-methylhexylamine
97.8%
Example 5
Batchwise Synthesis of N-benzyl-1-naphthylethylamine
[0041] 8
[0042] 100 ml of methanol and 350 mmol of 1-naphthylethylamine are
initially taken and 350 mmol of benzaldehyde are added dropwise at
24.degree. C. in the course of 15 minutes. Stirring is effected for
6 hours at 24.degree. C., the completeness of the iminization is
checked by GC, 0.5 g of Pd/C (10% by weight) is added and the crude
mixture is hydrogenated with hydrogen for 5 hours at atmospheric
pressure. A sample is taken and the composition is investigated by
GC analysis.
[0043] GC analysis results (in GC percent by area):
5 1-Naphthylethylamine 0.6% Benzaldehyde 0.0%
N-Benzyl-1-naphthylethylamine 94.3%
Example 6
Continuous Synthesis of (S)-N-benzyl-1-phenylethylamine
[0044] 9
[0045] 1 185 g of methanol, 605.9 g of (S)-phenylethylamine
(ee=99.2%) and 530.6 g of benzaldehyde are mixed at room
temperature and, after 30 minutes, the resulting imine is
hydrogenated in a fixed-bed tubular reactor at room temperature and
10 bar hydrogen pressure over 144 g of a palladium-containing
hydrogenation catalyst (1% by weight of Pd, 10% by weight of MgO on
Al.sub.2O.sub.3) to give the (S)-N-benzylphenylethylamin- e. A
sample is taken at the reactor exit and the composition is
investigated by GC analysis. Working up is carried out by
distillation.
[0046] GC analysis results (in GC percent by area):
6 (S)-Phenylethylamine 0.1% Benzaldehyde 0%
(S)-N-Benzyl-1-phenylethylamine 98.3% ee = 99.1%
* * * * *