Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-03-23
2002-08-27
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S253000
Reexamination Certificate
active
06441236
ABSTRACT:
The present invention relates to a process for preparing trione bis(oxime ether) derivatives of the formula I
where the substituents have the following meanings:
R
1
,R
3
are each unsubstituted, partially or fully halogenated C
1
-C
6
-alkyl or C
3
-C
6
-cycloalkyl;
R
2
,R
4
are each unsubstituted C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl-, C
2
-C
4
-alkynyl- or phenyl-substituted methyl and
x is oxygen or N—OH.
Furthermore, the invention relates to ketals of the formula III,
bisoxime ether ketals of the formula IV
and bisoxime ether ketones of the formula Ia
which are obtainable by this process.
Bisoxime ether ketones of the formula Ia and bisoxime ether oximes of the formula Ib are interesting intermediates for preparing the crop protection agents known from WO-A 97/15552.
In the prior art, there are only a few documents dedicated to the synthesis of bisoxime or trisoxime derivatives of vicinal triketones. Furthermore, some of the in some cases older documents have inaccurate or erroneous structures (Gazz. Chim. Ital., 67 (1937), 388; Gazz. Chim. Ital., 52 (1922), 289). The structural elucidation of the complex mixtures of substances which are formed, for example, in the reaction of 3-(hydroxyimino)pentane-2,4-dione with hydroxylamine was only possible by modern analytical methods: in addition to the (E,E,E)- and (E,Z,E)-isomers of the pentane-2,3,4-trione trisoxime, cyclized furoxanes and isoxazoles are formed (J. Chem. Soc., Perkin Trans. II (1987), 523). Owing to the cyclic byproducts formed and the wrong regio- and stereochemistry, the substance mixtures obtained by the reaction of triketones and hydroxylamine are not suitable for synthesizing the trione bis(oxime ether) derivatives Ia and Ib.
A targeted synthesis of the bisoxime ether oximes Ib is described in WO 97/15552.
This synthesis sequence has the disadvantage that the central oxime ether function (R
2
O—N═C) is only synthesized in the last step. Since the steric demand of the two substituents at the central carbon atom (R
1
—C═NOR
4
and R
3
—C═NOH) differs only slightly, the oximation does not proceed in a stereoselective manner and, with regard to the bond R
2
O—N, mixtures of isomers are formed which are difficult to separate.
It is an object of the present invention to provide a process which allows the synthesis of compounds of the formulae Ia and Ib in a targeted manner and which additionally affords the desired isomers of these compounds directly, i.e. without an isomer separation.
We have found that this object is achieved by the process mentioned at the outset, which comprises
1) reacting a dione of the formula II,
where the substituents R
1
, R
2
and R
3
are each as defined above with an alcohol or diol in the presence of an acid to give the ketal of the formula III,
where the substituents R
5
and R
6
are each C
1
-C
6
-alkyl, benzyl or C
1
-C
3
-haloalkyl or R
5
and R
6
together with the carbon and the two oxygen atoms of the ketal function form a ring A
where the substituents and the index n have the following meanings:
R
7
,R
8
,R
11
,R
12
are each hydrogen, halogen, C
1
-C
4
-alkyl, C
1
-C
3
-haloalkyl, C
1
-C
4
-alkoxymethyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl or phenyl, where the latter may be substituted by nitro or halogen;
R
9
,R
10
each have one of the meanings given for R
7
, R
8
, R
11
or R
12
and R
9
and R
10
together form an exo-methylene group or a carbonyl group and
n is 0,1 or 2,
2) converting the result ketal III
a) with an alkoxyamine of the formula R
4
O—NH
2
, where R
4
is as defined above, or one of its acid addition salts, or
b) with hydroxylamine or its acid addition salt and subsequent alkylation with an alkylating agent R
4
—L
1
, where R
4
is as defined above and L
1
is a nucleophilically replaceable leaving group, into the bisoxime ether ketal IV,
where the substituents R
1
to R
6
are each as defined above, and
3) hydrolyzing the bisoxime ether ketal IV obtained in this manner in the presence of acid,
a) to give the bisoxime ether ketone Ia,
or
b) aminating it with hydroxylamine or its acid addition salt to give the bisoxime ether oxime Ib,
By the process according to the invention, it is possible to synthesize, in a targeted manner, compounds of the formula Ia or Ib, depending in each case on the design of step 3). A further advantage of the process is the fact that the compounds Ia and Ib are obtained in isomerically pure form with regard to the central oxime ether unit.
A particular embodiment of the process is shown in scheme 1.
By conducting the reaction in a suitable manner, it is possible to obtain preferably the E,E-isomer Ia′ and E,Z,E-isomer Ib′ via the bisoxime ether ketals IV′ (see scheme 1):
in step 1) diols, such as, for example, ethylene glycol, 1,3-propane diol or preferably 2,2-dimethyl-1,3-propanediol are employed which afford the cyclic ketals III.
the oximation step is carried out according to variant 2a). Specifically, the ketal III is reacted with an acid addition salt of the alkoxyamine R
4
O—NH
2
at 20-65° C. and the acid which is released during the reaction is at least partially bound by addition of bases.
in step 3a)/3b), the hydrolysis/aminolysis is started at a pH of from 0.5-1.5 and at 20-400° C.
If, on the other hand, for example dimethyl ketal IIIa ( R
5
, R
6
=methyl), which is hydrolyzed (step 3a) or aminated (step 3b) at temperatures above 40° C., is used as starting material, the fractions of the Z-isomer Ia″ or Ib″ in the reaction mixture generally increase.
The individual process steps are illustrated in more detail below.
1) Ketal Formation
The ketal formation can generally be carried out with C
1
-C
6
-alkanols, such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, n-pentanol, with benzyl alcohol or with C
1
-C
3
-haloalkyl alcohols, such as, for example, 2,2,2-trichloroethanol. Particularly suitable are diols, such as, for example, o-dihydroxybenzene, ethylene glycol (1,2-ethanediol), 1-(2-nitrophenyl)-1,2-ethanediol, hex-5-ene-1,2-diol, 1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 3-bromo-1,2-propanediol, 2-exo-methylene-1,3-propanediol, 2,2-dibromo-1,3-propanediol, 1,4-butanediol, 1,4-dimethoxy-2,3-butanediol. Particularly suitable are sterically demanding diols, such as 1,3-propanediol and 2,2-dimethyl-1,3-propanediol.
The ketal formation is generally carried out in the presence of acids, such as BF
3
×Et
2
O (Lewis acid) or preferably Bronstedt acids, such as sulfuric acid, hydrogen chloride, hydrogen bromide or hydrogen iodide, perchloric acid, orthophosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, p-dodecylbenzenesulfonic acid or camphor sulfonic acid. Preference is given to using p-toluenesulfonic acid or sulfuric acid.
The acid is usually employed in catalytic amounts of from 0.05 to 2 mol % and preferably from 0.5 to 1 mol %, based on the dione II.
The reaction temperature generally depends on the nature of the alcohol employed and is generally 20-150° C. and preferably 60-110° C. When using diols, a temperature of 60-90° C. has been found to be advantageous in many cases.
The water formed during the reaction is usually removed from the reaction mixture. To this end, the methods described in the prior art are employed (see, for example, Organikum, Barth Verlagsgesellschaft, Leipzig).
The water of reaction can, on the one hand, be removed using dehydrating agents, such as, for example, ortho esters. The ortho ester, such as, for example, trimethyl orthoformate, is generally employed in a concentration of from 1 to 1.5 molar equivalents. The reaction time is generally from 0.5 to 3 hours.
On the other hand, it has been found advantageous to remove the water of reaction using entrainers, such as toluene or cyclohexane. The end point of the reaction can be determined easily by the amount of water which is separated off. In some cases, it is advantageous to carry out the reaction at reduced pressure.
The preferred solvent is the alcohol that is required for the ketalization, w
Götz Roland
Grote Thomas
Gypser Andreas
Keil Michael
Mayer Horst
Barts Samuel
Prize Elvis O.
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