Preparation of N-benzylamines

Details Preparation of N-benzylamines Preparation of N-benzylamines

2002-03-27

2002-11-05

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S386000, C564S389000, C564S391000

Reexamination Certificate

active

06476268

ABSTRACT:

The invention relates to a process for the preparation of N-benzylamines.
It is known that N-benzyl-&agr;-methylbenzylamine can be prepared by iminization of benzaldehyde with &agr;-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-&agr;-methylbenzylamine are obtained from benzaldehyde and (R)- and (S)-&agr;-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.
It is an object of the present invention to provide a simpler process for the preparation of N-benzylamines.
We have found that this object is achieved by 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.
Preferred N-benzylamines prepared by the novel process are those of the formula (I)
where
R
1
, R
2
, R
3
and R
4
, independently of one another, are each H, halogen or C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy, each of which is unsubstituted or mono- or polysubstituted by halogen,
R
5
is H or C
1
-C
8
-alkyl and
R
6
is H, C
1
-C
8
-alkyl or C
5
-C
12
-aryl or C
5
-C
12
-cycloalkyl , each of which may be mono- or polysubstituted by halogen, OH or C
1
-C
4
-alkyl and/or C
1
-C
4
-alkoxy, each of which is unsubstituted or mono- or polysubstituted by halogen, or is C
1
-C
4
-alkoxy- or benzyloxy-substituted C
1
-C
4
-alkyl.
These are obtained by a procedure in which p
1
(i) in a first step, a benzaldehyde of the formula (II) is reacted with an amine of the formula (III)
 to give an imine of the formula (IV)
 where
R
1
-R
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 (I),
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.
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
1
to R
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.
R
5
and R
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
6
may furthermore be C
5
-C
12
-aryl or C
5
-C
12
-cycloalkyl which is unsubstituted or mono- or polysubstituted, preferably mono- or disubstituted, by OH, said halogens or said unsubstituted or substituted C
1
-C
4
-alkyl or C
1
-C
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, &agr;-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)ethylamine.
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.
The iminization (i) is preferably carried out at from 10 to 40° C., particularly preferably from 20 to 30° C., and preferably at atmospheric pressure. A reaction time of from 0.1 to 5 hours is usually sufficient for the iminization (i).
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.
The hydrogenation (ii) is preferably carried out at from 10 to 40° C., particularly preferably at from 20 to 30° 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.
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.
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.


REFERENCES:
Organic Process Research & Development, 2000, 4, 594-595; Huckabee et al.

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