Process and novel intermediates for preparing...

Details Process and novel intermediates for preparing... Process and novel intermediates for preparing...

2002-08-19

2003-12-30

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06670482

ABSTRACT:

The present invention relates to a process for preparing isoxazolin-3-ylacylbenzenes, to novel intermediates and to novel processes for preparing these intermediates.
Isoxazolin-3-ylacylbenzenes are useful compounds which can be employed in the area of crop protection. 2-Alkyl-3-(4,5-dihydro-isoxazol-3-yl)acylbenzenes are described, for example, in WO 98/31681, as herbicidally active compounds.
It is an object of the present invention to provide an alternative process for the preparation of 3-heterocyclyl-substituted benzoyl derivatives described in WO 98/31681. The process described in WO 98/31681 for preparing the 2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes and their precursor (2-alkyl-3-(4,5-dihydroisoxazol-3-yl)bromobenzene derivatives) is not well suited for the preparation of these compounds on a large industrial scale, since the synthesis extends over several steps and the yield of the respective end product is relatively low, based on the starting materials employed in the first step of the synthesis.
We have found that this object is achieved by reducing the number of process steps required for preparing the 3-heterocyclyl-substituted benzoyl derivatives, compared with the process described in WO 98/31681, when the synthesis occurs via selected intermediate compounds. Moreover, the process according to the invention has the advantage that the overall yield of end products of the formula I and also for the intermediates, based on the starting materials employed, is higher than the yield in the processes described in WO 98/31681. In addition, the respective intermediates in the individual process steps can be obtained in good yield. Moreover, some of the individual process steps are advantageous for the industrial preparation of the intermediate compounds since they allow a cost-effective and economical preparation of these compounds. It is furthermore advantageous that the starting materials used are basic chemicals which are easy to prepare and which can be obtained from a number of independent suppliers of basic chemicals, even in relatively large amounts. Altogether, the process according to the invention provides a cost-effective, economical and safe industrial-scale process for preparing herbicidally active compounds of the formula I.
The present invention provides a process for preparing the compounds of the formula I
where:
R
1
is hydrogen, C
1
-C
6
-alkyl,
R
2
is hydrogen, C
1
-C
6
-alkyl,
R
3
, R
4
, R
5
are each hydrogen, C
1
-C
6
-alkyl or R
4
and R
5
together form a bond,
R
6
is a heterocyclic ring,
n is 0, 1 or 2;
which comprises preparing an intermediate of the formula VI,
in which R
1
, R
3
-R
5
are each as defined above.
In subsequent reaction steps, compounds of the formula VI are converted into the corresponding 3-bromo-substituted compounds (bromobenzene derivatives), and the amino group at the phenyl ring is converted into an S(O)
n
R
2
group, preferably sulfonyl group, giving rise to compounds of the formula X:
The compounds of the formula X (3-(4,5-dihydroisoxazol-3-yl)bromobenzenes) are useful intermediates for preparing active compounds of the formula I. In particular, the process according to the invention gives the compounds I in the last reaction step in good yield. The compounds I are suitable, for example, for use as crop protection agents, in particular as herbicides, as described in WO 96/26206 and WO 97/35850.
The present invention particularly preferably provides a process for preparing the compounds of the formula I where R
2
=C
1
-C
6
-alkyl, which comprises preparing an intermediate of the formula VI.
The present invention likewise particularly preferably provides a process for preparing compounds of the formula I where R
2
=hydrogen, comprising the preparation of an intermediate of the formula VI.
Likewise according to the invention, it is possible to prepare compounds of the formula I or the intermediates required for this, in particular compounds of the formula VI or X, in an advantageous manner by combining one or more of the following process steps a)-g), where, with respect to the compounds of the formula I, one process step of the group of process steps a)-f) has to be, involved:
a) reaction of a nitro-o-methylphenyl compound of the formula II
in which the radical R
1
is as defined above, with an organic nitrite R-ONO under action of a base to give the oxime of the formula III
 in which the radical R
1
is as defined above;
b) cyclization of the oxime of the formula III using an alkene of the formula IV
 in which R
3
to R
5
are each as defined in claim 1, in the presence of a base to give the isoxazole of the formula V
 in which R
1
, R
3
to R
5
are each as defined in claim 1;
c) reduction of the nitro group in the presence of a catalyst to give the aniline of the formula VI
 in which R
1
, R
3
to R
5
are each as defined in claim 1;
d) reaction of the aniline of the formula VI with a dialkyl disulfide of the formula VII
R
2
—S—S—R
2
  VII
 in the presence of an organic nitrite R-ONO and, if appropriate, a catalyst to give the thioether of the formula VIII
 in which R
1
to R
5
are each as defined in claim 1;
e) bromination of the thioether of the formula VIII with a brominating agent to give the bromothioether of the formula IX
 in which R
1
to R
5
are each as defined in claim 1;
f) oxidation of the bromothioether of the formula IX with an oxidizing agent to give the isoxazole of the formula X
 where n is the number 1 or 2,
g) if appropriate, reaction of the isoxazoline of the formula X with a compound of the formula R
6
—OH (XI) in the presence of carbon monoxide, a catalyst and a base to give the compounds of the formula I.
The process according to the invention for preparing compounds X comprises essentially one or more of the process steps a)-f) or, in the case of the compounds I, one or more of the process steps a)-g), where a process step from the group of process steps a)-f) has to be involved. Preference is given to reaction sequences which comprise either one of process steps a) or d) or else both steps a) and d).
In all cases, C
1
-C
6
-alkyl and C
1
-C
4
-alkyl are straight-chain or branched alkyl groups having 1-6 and 1-4 carbon atoms, respectively, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl. This applies analogously to the C
1
-C
6
-alkoxy group.
R
1
, R
2
are preferably alkyl groups, in particular methyl, ethyl, isopropyl, n-propyl or n-butyl groups.
R
3
, R
4
and R
5
are preferably hydrogen. R
4
and R
5
together may also represent a bond, resulting in the corresponding isoxazole derivatives. In this case, R
3
is preferably hydrogen.
In the definition of R
6
, “heterocyclic ring” is a saturated, unsaturated or partially unsaturated heterocycle having 1, 2 or 3 oxygen, sulfur or nitrogen atoms. Preference is given to heterocycles having two nitrogen atoms. In particular, R
6
is a pyrazole radical as described in more detail in WO 98/31681. It is preferably a pyrazole attached in the 4-position which may be unsubstituted or substituted by further radicals which are chemically inert under the chosen reaction conditions. Such suitable pyrazole substituents are, for example, the following groups: hydroxyl, oxo, sulfonyloxy, C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy, in particular in the 1-position C
1
-C
4
-alkyl. R
6
is particularly preferably the group 1-alkyl-5-hydroxypyrazol-4-yl, in particular 1-methyl-5-hydroxypyrazol-4-yl; 1-ethyl-5-hydroxypyrazol-4-yl.
The process according to the invention is particularly suitable for preparing the following compounds of the formula I:
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methyl-sulfonylbenzoyl)-5-hydroxypyrazole,
1-ethyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methyl-sulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-ethyl-4-methyl-sulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-propyl-4-methyl-sulfonylbenzoyl)-5-hydroxypyrazole,
1-methyl-4-(3-(4,

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