Method for producing (hetero)aromatic hydroxylamines

Details Method for producing (hetero)aromatic hydroxylamines Method for producing (hetero)aromatic hydroxylamines

2000-02-29

2001-07-03

Raymond, Richard L. (Department: 1611)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C564S256000, C564S300000, C564S336000

Reexamination Certificate

active

06255489

ABSTRACT:

The present invention relates to a process for the preparation of (hetero)aromatic hydroxylamine derivates of the formula I
where:
R
1
is hydrogen, halogen, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylcarbonyl, C
1
-C
4
-dialkylaminocarbonyl, C
1
-C
4
-alkylcarbonylamino, C
1
-C
4
-alkylcarbonyl-C
1
-C
6
-alkylamino, C
1
-C
4
-alkoxycarbonyl, —CH
2
O —N═C(R
a
)—C(R
b
)═N—O—R
c
, —CH
2
—O—N═C(R
d
)—C
1
-C
4
-alkyl, or a group A-B, where
A is —O—, —CH
2
—, —O—CH
2
—, CH
2
—O—, —CH
2
—O—CO—, —CH═CH—, —CH═N—O—, —CH
2
—O—N═C(R
a
)- or a single bond,
B is phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, furanyl, thienyl, pyrrolyl or C
3
-C
7
-cycloalkyl, where B may be substituted by 1-3 substituents R
i
,
R
i
is hydrogen, halogen, cyano, C-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylcarbonyl, C
1
-C
4
-alkyl-C (R
d
)=N—O—C
1
-C
4
-alkyl, C
1
-C
4
-alkoxycarbonyl, C
1
-C
4
-alkylaminocarbonyl, C
1
-C
4
-dialkylaminocarbonyl, C
1
-C
4
-alkylcarbonylamino, C
1
-C
4
-alkylcarbonyl-C
1
-C
4
-alkylamino or phenyl which itself may be substituted by halogen or C
1
-C
4
-alkyl,
R
a
and R
c
are each hydrogen, halogen, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, cyclopropyl or trifluoromethyl,
R
b
is C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
3
-C
6
-cycloalkyl, phenyl, hetaryl or heterocyclyl,
R
d
independently of one another, are hydrogen, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, or C
2
-C
4
-alkynyl,
R
2
is halogen, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl or C
1
-C
4
-alkoxycarbonyl,
x is N or CH and
n is 0, 1, 2 or 3, it being possible for the radicals R
4
to be different when n is greater than 1,
by hydrogenating a (hetero)aromatic nitro compound of the formula II
where R
1
, X and R
2
have the abovementioned meanings, in the presence of a hydrogenation catalyst.
The literature (DE-A 2,455,238 and DE-A 2,455,887) describes the preparation of phenylhydroxylamines by catalytic reduction of nitroaromatics in the presence of aromatic amines such as pyridine. DE-A 2,357,370 and DE-A 2,327,412 describe a similar process with the aid of heterocyclic amines, such as piperidine. In all these publications, the amine simultaneously acts as a solvent. The yields achievable by these processes are, after appropriate working up and purification, 50-85%; if the reaction is carried out in the presence of pyridine, the yield is slightly higher in individual cases. However, carrying out the reaction in pyridine is not very desirable owing to the more complicated working up (higher boiling point, similar solvent properties to the hydroxylamine) and for cost reasons.
A more suitable process for the preparation of (hetero)aromatic hydroxylamines of the formula I of the present invention is described in DE-A 19,502,700. Here, the reaction is carried out in the presence of special heterocyclic amines, ie. N-alkylmorpholines, which, as in the abovementioned publications, also act as the solvent. Although this process leads to higher product yields, it requires large amounts of alkylmorpholines for complete dissolution of the starting material and, owing to adduct formation of the product with the alkylmorpholine used, complicated working up operations for isolating the product. Since the alkylmorpholines cause considerable problems when carrying out the subsequent stages, their concentration must be greatly reduced by means of distillation and they must be completely removed in an additional extraction step. The high thermal load adversely affects the purity and yield of the hydroxylamines, many of which are unstable.
The recycled hydrogenation catalyst loses activity after a few cycles. The costs associated with the regeneration of the catalyst reduce the cost-efficiency of the process.
Finally, GB-A 1,092,027 discloses a hydrogenation process for the preparation of cyclohexylhydroxylamines in the presence of amines. In addition to the abovementioned heterocyclic amines, cyclohexylamine, an alicyclic amine, is preferably used in this process. The addition of a protic solvent, such as ethanol, leads to a substantially lower yield in the examples described. With respect to the reaction temperature, the amine used and any solvent added, the different type of substrate requires specific conditions (90° C., cyclohexylamine, ethanol), which cannot be applied to hydrogenation of (hetero)aromatic nitro compounds.
It is an object of the present invention to provide a process for the preparation of E-acylated (hetero)aromatic hydroxylamines which does not have the disadvantages described.
We have found that this object is achieved by the process mentioned at the outset, wherein the hydrogenation is carried out in a mixture of an inert, aprotic solvent and an aliphatic amine.
The surprising aspect of this process is that particularly aliphatic amines give good hydrogenation results although the prior art explicitly indicates the use of (hetero)aromatic and heterocyclic amines. Furthermore, when aliphatic amines are used, there is a lower level of adduct formation with the hydroxylamine. A major part of the amine can thus be removed in a gentle manner by distillation or extraction.
Also surprising is that the hydrogenation in the presence of aliphatic amines can be improved by adding a nonpolar, aprotic solvent, in such a way that the formation of undesirable byproducts, such as azoxy compounds, is substantially absent and hence the crude hydrogenation mixture obtained after removing the amine can be used directly in the subsequent stages.
Finally, it was not expected that the hydrogenation catalyst would have substantially longer time-on-stream in the novel process than in the process described and using N-alkylmorpholines.
The novel process is preferably suitable for the preparation of (hetero)aromatic compounds of the formula I, where
R
1
is —CH
2
—O—N═(R
a
)—C(R
b
)═N—O—R
6
, C
1
-C
4
-alkyl-CR
d
═N—O—C
1
-C
4
-alkyl or a group A-B where A, B, R
a
, R
b
, R
c
and R
d
and R
2
, X and n have the meanings stated in claim
1
.
In particular, the novel process can be used to prepare the intermediates, stated in WO 96/01256, for III
a
and crop protection agents IV
a.
in which
R
f
is C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, unsubstituted or substituted, saturated or mono- or diunsaturated heterocyclyl or unsubstituted or substituted aryl or hetaryl,
R
e
is halogen, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio or C
l
-C
4
-alkoxycarbonyl and
m is 0, 1, 2, and R
3
and R
4
have the meanings stated in claim
1
(cf. Tables A and B).
TABLE A
IIIa


No.
R
e
m
R
f
R
3
mp. [° C.], IR [cm
−1]
IIIa.1
—
0
C
6
H
5
COOCH
3
1718, 1600, 1545, 1507,
1481, 1458, 1399, 1359,
1032, 757
IIIa.2
—
0
C
6
H
5
CONHCH
3
1653, 1601, 1545, 1707,
1479, 1454, 1414, 1398,
1355, 755
IIIa.3
—
0
C
6
H
5
COCH
3
1643, 1622, 1601, 1544,
1493, 1480, 1368, 1027,
759, 745
IIIa.4
—
0
C
6
H
5
COC
2
H
5
1619, 1600, 1550, 1495,
1482, 1462, 1454, 1358,
765, 753
IIIa.5
—
0
4-Cl—C
6
H
4
COOCH
3
105
IIIa.6
—
0
4-Cl—C
6
H
4
CONHCH
3
1653, 1546, 1503, 1480,
1455, 1426, 1390, 1357,
1094, 1071
TABLE B
IVa


No.
R
e
m
R
f
R
4
R
3
mp. [° C.], IR [cm
−1
]
IVa.1
5-CH
3
1
4-Cl—C
6
H
4
CH
3
COOCH
3
1738, 1561, 1500, 1456, 1440,
1359, 1094, 1010, 764
IVa.2
4-CF
3
1
cyclohexyl
CH
3
COOCH
3
1743, 1496, 1456, 1441, 1359,
1272, 1262, 1176, 1124, 1029
IVa.3
4-Cl
1
5-Cl-pyridin-2-yl
CH
3
COOCH
3
92
IVa.4
4-H
3
CO
2
C
1
CH
2
C
6
H
5
CH
3
COOCH
3
71
IVa.5
—
0
C
6
H
5
CH
3
CONHCH
3
1675, 1600, 1545, 1508, 1479,
1462, 1399, 1355, 1054, 756
IVa.6
—
0
C
6
H
5
CH
3
COCH
3
1680, 1600, 1545, 1507, 1480,
1456, 1359, 1056, 1032, 758
IVa.7
—
0
C
6
H
5
CH
3
COC
2
H
5
1678, 1600, 1545, 1480, 1456,
1394, 1378, 1358, 1055, 756
IVa.8
—
0
2,4-Cl
2
-phenyl
CH
3
CONHCH

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