MXPA01003146A - Method for preparing trion-bis(oxime ether) derivatives andrion-mono and trion-bis(oxime ether) derivatives obtained therewith - Google Patents

Abstract

The present invention relates to a method for the production of trion-bis(oxime ether) derivatives of formula (I), wherein the substituents have the following meaning:R1, R3 represent unsubstituted, partially or totally halogenated C1-C6-alkyl or C3-C6-cycloalkyl;R2, R4 represent C1-C4-alkyl or a methyl substituted by C2-C4-alkenyl, C2-C4-alkinyl or phenyl and X represents oxygen or N-OH. The invention also relates to the intermediate products obtained with said method.

Description

PROCESS FOR PREPARING TRIONA BIS DERIVATIVES (OXIMA ETHER) AND DERIVATIVES OF TRIONA MONO- AND TRIQNABIS (ETHER OXIMA), OBTAINED BY THE SAME The present invention relates to a process for preparing trione bis (ether oxime) derivatives of the formula I wherein the substituents have the following meanings R 1, R 3 are each C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl unsubstituted or partially halogenated; R2, R4 are each C4-C4 alkyl or unsubstituted C2-C4 alkenyl, C2-C4 alkynyl or substituted phenyl-methyl and X is oxygen or N-OH. In addition, the invention relates to ketals of the formula III, ketals of bioxime ether of the formula IV, and ketones bioxime ether of the formula la, which are obtainable by this process. The bioxime ether ketones of the formula oxime and oximes of formula Ib are interesting intermediates for preparing the culture 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 tricetones. In addition, certain cases of older documents have inaccurate or erroneous structures (Gazz. Chim. Ital., 61_ (1937), 388; Gazz Chim. Ital., 52 (1922), 289). The structural elucidation of the more complex mixtures of the substrates that were 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 (E, E, E) - and (E, Z, E) -isomers of penta-2, 3-4-trione trisoxime, cyclized furoxanes and isoxazoles were formed (J. Chem. Soc, Perkin Trans. II (1987), 523. Because the cyclic by-products formed and the erroneous regio- and stereochemistry, the substance mixtures obtained by the reaction of tricetones and hydroxylamine are not suitable for synthesizing the bis (ether oxime) trione la and Ib derivatives. of the oximes of bisoxime Ib are described in WO 97/15552.

Ib This synthesis sequence has the disadvantage that the function of central oxime ether (R20-N = C) is only sintered in the last stage. Since the steric demand for two substituents on the central carbon atom (R1-C = NOR4 and R3-C = NOH) differs only slightly, oximation does not proceed in the stereoselective manner, with respect to the binding of R20-N, mixtures of isomers are formed, which are difficult to separate. It is an object of the present invention to provide a process that allows the synthesis of the compounds of the formula la and Ib in the objected form and which additionally supplies the desired isomers of these compounds directly, ie, without an isomer separation. It has been found that this object is achieved by the processes mentioned at the beginning, which comprises 1) reacting a dione of the formula II, when the substituents R1, R2 and R3 are each as defined above with an alcohol or diol in the presence of an acid to give the ketal of the formula III, wherein the substituents R5 and R6 are each C? -C6 alkyl, benzyl or haloalkyl of C? -C3 or R5 and R6 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: R7, R8, R11, R12 are each hydrogen, halogen, C] .- C4 alkyl, C1-C3 haloalkyl, C? -C alkoxymethyl, C2 alkenyl -C4, C2-C4 alkynyl or phenyl, where the latter can be substituted by nitrogen or halogen; R9, R10 each has one of the meanings given for R7, R8, R11 or R12 and R9 and R10 together form an exo-methylene group or carbonyl group and n is 0, 1 or 2, 2) converting the resulting ketal III a) with an alkoxyamine of the formula R0-NH2, wherein R4 is as defined above, or one of its acid addition salts, or b) with a hydroxylamine or its acid addition salts and subsequent alkylation with an alkylating agent R4-Lx , where R4 is as defined above and L1 is a nucleophilically replaceable leaving group, in cetal ether bioxima IV, wherein the substituents R1 to R6 are each as defined above, and 3) hydrolyze the IV ether bioxide ketal obtained in this way in the presence of acid, a) produce the ketone bioxime ether, b) amine with hydroxylamine or its acid addition salt to produce the oxime bioxime ether Ib, The process according to the invention is possible to synthesize, in the manner objected, the compounds of the formula la or Ib, depending in each case on the design of stage 3). An additional advantage of the process is the fact that the compounds la and Ib are obtained in isomerically pure form with respect to the central oxime ether unit. A particular mode of the process is shown in scheme 1. Scheme 1 By conducting the reaction in a suitable manner, it is possible to obtain preferably the E, E-isomer la 'and E, Z, E-isomer Ib, by means of the ketals of bioxime ether IV (see scheme 1): Step 1) Diols, such as, for example, ethylene glycol, 1,3-propanol diol or preferably 2,2-dimethyl-1,3-propanediol are employed to provide the cyclic ketals III. - the oximation stage is carried out according to variant 2a). Specifically, ketal III reacts with the acid addition salt of the alkoxyamine R40-NH2 at 20-65 ° C and the acid that is released during the reaction is at least partially bound by the addition of bases. in step 3a) / 3b), the hydrolysis / aminolysis begins with a pH from 0.5-1.5 and at 20-40 ° C. If, in another way, for example dimethyl ketal Illa (R5, R6 = methyl), which is hydrolyzed (stage 3a) or aminated (step 3b) at temperatures of about 40 ° C, is used as the starting material, the fractions of the Z-isomer "or Ib" in the reaction mixture generally increases. the "Ib" The individual process steps are illustrated in more detail in the following 1) Cetal Formation The ketal formation can generally be carried out with C? -C6 alkanols, such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, n-pentanol, with benzyl alcohol or with C1-C3 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-dimethoxy-2,3-butanediol. Particularly suitable are the sterically demanded diols, such as 1,3-propanediol and 2,2-dimethyl-1,3-propanediol. Ketal formation is generally carried out in the presence of acids, such as BF3 x Et20 (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 camphorsulfonic acid. Preferably it is given to use p-toluenesulfonic acid or sulfuric acid. The acid is generally employed in catalytic amounts from 0.05 to 2 mol% and preferably from 0.5 to 1 mol%, based on 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 diols are used, 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. In this term, the methods described in the prior art are employed (see, for example, Oganikum, Barth Verlagagesellschaft, Leipziq). The reaction water may, otherwise, be removed using dehydration 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. Otherwise, advantages have been found to remove the water of reaction using separating agents, such as toluene or cyclohexane. The end point of the reaction can be easily determined by the amount of water that is separated. In some cases, it is advantageous to carry out the reaction under reduced pressure. The preferred solvent is the alcohol that was required by the ketalization, which is in this case generally employed in excess. Good results were obtained using, for example, equivalents of 1-10 molar diol. The ketalization is carried out by removing water in the presence of a separating agent, the amount of diol can generally be reduced to 1-3 molar equivalents. Suitable solvents are further hydrocarbons, such as, for example, toluene or cyclohexane, halogenated hydrocarbons, such as chlorobenzene or methylene chloride, amides, such as dimethylphomamide, and ethers, such as diethyl ether or dioxane. The reaction mixtures were made, for example, by extracting with a non-polar solvent, such as an ether, halogenated hydrocarbon, in particular, a hydrocarbon, such as cyclohexane. After the aqueous phase has been separated, the organic phase can generally be used directly in the subsequent oximation step. In many cases, it is not yet necessary to change the solvent. The diones of the formula II are known from the literature or can be prepared by methods known from the literature [see, Indian J. Chem. B, (1991) 749-753; - Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. -Transí.) 28, (1979) 121-128; EP-A 416 857]. In particular, diones II can be prepared by the process illustrated in more detail in the following. The 1,3-diketones of the formula V R3 V,? "Are converted by nitrozation into compounds of formula VI, wherein the substituents R1 and R3 in formula V and VI are as defined in claim 1. Nitrozation is usually effected using sodium nitrite in the presence of a carboxylic acid or mineral acid. Acetic acid, hydrochloric acid and in particular sulfuric acid are particularly suitable. In general, nitrozation is carried out from 10 to 60 ° C and in particular from 10 to 20 ° C. In general, nitrozation is carried out at a pH from 2 to 6 and in particular at a pH from 4 to 5. The following process variants are found to be particularly advantageous: i) the 1,3-diketone V is initially charged in aqueous sodium nitrite solution. The acid is then added dropwise at a pH from 4 to 5; ii) the 1,3-diketone V is initially charged in water and the acid and the aqueous sodium nitrite solution are simultaneously dosed at a pH from 4 to 5. Furthermore, it is advantageous to add an organic solvent in which compound VI is soluble , at the beginning or at the end of the reaction. The resulting solutions can be used directly for the subsequent alkylation step. An intermediate isolation of the thermally and hydrolytically unstable V compound can thus be avoided. In certain cases it may be more advantageous to replace the solvent used for the extraction of VI by a solvent that is more suitable for alkylation. Solvents which are particularly suitable for extraction are aprotic, if the partially water miscible solvents are suitable, for example, halogenated hydrocarbons, for example halogenated hydrocarbons, such as methylene chloride, carboxylic esters, such as ethyl acetate, or ethers, such as methyl tert-butyl ether. The alkylation of VI to diones II can be effected, for example, in alcohols, such as methanol, halogenated hydrocarbon, such as methylene chloride, carboxylic esters such as ethyl acetate, or ethers, such as methyl tert-butyl ether . Ketones, such as acetone, and amides, such as dimethylformamide or N-methylpyrrolidone, are particularly suitable. Suitable alkylating agents are, for example, alkyl halides, tosylates and dialkyl sulfate, dialkyl sulfates of the formula VII (R20) 2S02 VII in which the substituent R2 is as defined in claim 1 are particularly suitable. The alkylation is usually effected in the presence of bases, such as alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkoximides or tertiary amides of alkali metal or alkaline earth metal. The reaction temperature is generally from -20 to 100 ° C and preferably from -10 to 35 ° C and in particular from 0 to 25 ° C. Usually, the solvent and the base are initially charged, and the compound VI and the alkylating agent are then measured simultaneously or successively. 2) Oximation III IV IVa 2a) The alkoxyamine R 40 -NH 2 is also used in the form of an acid addition salt or as a free base, where the latter can be liberated from the salt by the addition of a strong base. Preference is given to using the acid addition salts of the alkoxyamine. All customary acids are suitable for the preparation of the acid addition salts. Of the above, only a few Examples are given: carboxylic acids, such as acetic acid or propionic acid, dicarboxylic acids, such as oxalic acid or succinic acid, mineral acids, such as phosphoric acid or carbonic acid, and in particular hydrochloric acid or sulfuric acid. If the acid addition salts of the alkoxyamine are employed, it is generally advantageous to add a base to bind the acid that is released during the reaction. In many cases, a pH from 2 to 5 and in particular from 3 to 4 has been found to be advantageous for the oximation. In general, 1 to 2.5 equivalent molars are added. Suitable bases are, in particular, pyridines, trialkylamines, sodium hydroxide, sodium acetate and sodium methoxide. If sodium acetate is used, it is customary to add glacial acetic acid. Conversely, this is of course only possible to employ the alkoxyamine as the free base and to use one of the aforementioned acids to establish the aforementioned pH range. The "suitable solvents are, for example, the solvents described in the preceding step." Only suitable carboxylic acids are, such as acetic acid, ethers, such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, or otherwise water mixtures. / pyridine Particularly suitable are alcohols, such as methanol, ethanol, n-propanol or isopropanol It has also been found to be of greater advantage to use the solvent used in the ketalization, or the solvent mixture which is present after the preparation of the ketals III, for the oximation stage, too.If appropriate, it may be convenient to add other solvents to the mixture.So steps 1) and 2) can be carried out as a one-point variant.The reaction temperature is generally from - 20 to 150 ° C and preferably from 0 to 100 ° C and in particular from 20 to 65 ° C 2b) The process described under 2a) can only be carried out in 2 stages, first by reacting the ketal I II with hydroxylamine or its acid addition salts and subsequent alkylation with R4-Li. With respect to the way the reaction is carried out, the statements made in the above apply. The reaction mixture is preferably carried out as described in the process of the preceding step, by extractive methods. 3) The division of the ketal: (a) hydrolysis and (b) amination b) HO-NH2 [H +] IV la: X = 0 Ib: X = N-OH The ketal is generally divided into an acidic medium. A pH from 0 to 2 and preferably from 0.5 to 1.5 has been found to be advantageous. The aforementioned pH range can be established using any customary acid. Acetic acid, hydrochloric acid or sulfuric acid, for example, have been found appropriate. The division of the ketal can be carried out with or without the addition of a solvent. It has been found advantageous to use organic solvents which are stable in the aforementioned pH range (for example ethyl acetate). It is also advantageous to use a solvent which is monophasically miscible with water / acid. Particularly suitable herein are alcohols, such as, for example, methanol. The division of the ketal can advantageously be carried out, for example, in water / methanol / glacial acetic acid (a suitable mixing ratio is, for example: 1/1 / 0.2) or mixtures of ethyl acetate / water. The aminolysis afforded by the compounds Ib is carried out under the aforementioned conditions for the ketal division, but in the presence of hydroxylamine or its acid addition salts. All customary acids are suitable for preparing the acid addition salts. Hydrochloric acid or sulfuric acid have been found to be particularly advantageous. The hydroxylamine or its acid addition salts are generally employed in a reaction from 1 to 2 and preferably from 1 to 1.3 molar equivalents, based on the cetal ether bioxima IV. The reaction temperature is generally 0-150 ° C. Low reaction temperatures from 20 to 40 ° C have been found to be particularly advantageous for the preparation of the 'and in particular Ib'. A high reaction temperature (> 40 ° C), The proportion of the isomers la1 1 and Ib "generally increases. Preparing the reaction mixture is preferably carried out as described in the two preceding steps, by extraction. The compounds of the formula Ib can be purified, for example, by means of their sodium salts. By adding a base, the oximes can be converted into the corresponding salt. The oxime bioxime ether Ib can subsequently be reliberated by subsequent acidification of the salt which can be, if appropriate, separated or purified.

The suitable process of the invention is particularly suitable for preparing ketals of the formula III, ketals of bisoxime ether of the formula IV and bisoxime ether ketones of the formula I wherein the substituents each have the following meanings R1, R3 are each unsubstituted, partially or fully halogenated C? -C6 alkyl or C3-C6 cycloalkyl; R2, R4 are each C? -C4 alkyl or alkenyl of C2-C4- unsubstituted, C2-C4 alkynyl or substituted phenyl-methyl; X is oxygen or N-OH; j R5, R6 are each Ci-Cß-alkyl, benzyl or C1-C3-haloalkyl or R5, R6 together with the carbon and the two oxygen atoms of the ketal function form a ring A, RX where the substituents and in table n have the following meanings R7, R8, R11, R12 are each hydrogen, halogen, C? -C4-alkyl, C? ~ C3-haloalkyl, C? -C-alkoxymethyl, C2-C4-alkenyl, C2-C4-alkynyl or phenyl, where the latter can be substituted by nitro or halogen; R9, R10 each has one of the meanings for R7, R8, R11 or R12 and R9 and R10 together form an exo-methylene group or a carbonyl group and n is 0, 1 or 2. Intermediates suitable for the preparation of the IV components (wherein R4 is not hydrogen) are components of the formula IV in which R4 is hydrogen (see formula IVa). In the definitions of the compounds I, II and IV given above, the collective terms representing the individual enumerations of each of the members of the group were used for the radicals R1 to R12. The alkyl, alkenyl or alkynyl radicals can be linear or branched chains.

The term "partially or fully halogenated" is intended to express that in the groups thus characterized some or all of the hydrogen atoms may be replaced by identical or different atoms of halogen. The term "halogen" in each case represents fluorine, chlorine, bromine or iodine. Examples of other meanings are: -C 4 -C 4 alkyl: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C 1 -C 4 alkyl: C 1 -C 4 alkyl as mentioned above, and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3 dimethyl butyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-3-methylpropyl; - haloalkyl of C? ~ C3: a C 1 -C 3 alkyl radical as mentioned above, which is partially or totally substituted by fluoro, chloro, bromo and / or iodo, ie, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3, 3, 3-trifluoropropyl, 3,3, 3-trichloropropyl, 2, 2, 3, 3, 3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromoethyl; - C 4 -C 4 alkoxy in the alkoxy portion of the C 4 -C 4 alkoxymethyl: methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy; C2-C4 alkenyl: ethenyl, prop-1-ene-l-yl, prop-2-ene-l-yl, 1-methylethyl, but-1-ene-l-yl, but-2-ene-l- il, but-3-ene-l-yl, 1-methyl-prop-l-ene-l-yl, 2-methyl-prop-l-ene-l-yl, l-methyl-prop-2-ene- 1-yl and 2-methyl-prop-2-ene-1-yl; - C2-C4 alkynyl: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl; - C3-C6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Considering their suitability as intermediaries for preparing the known crop protection agents of WO-A 97/15552, a particular preference is given to the compounds of formulas I, III and IV having the following substituents, the preference exists in each case separately or in combination: R1, R3 are each methyl, ethyl, trifluoromethyl or trichloromethyl and in particular methyl or ethyl; R2, R4 are each methyl, ethyl, benzyl or propargyl and in particular methyl; X is oxygen or N-OH; R5, R6 are each methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or benzyl and in particular R5, R6 together with the carbon and the two oxygen atoms of the ketal function form a ring TO wherein the substituents and the index n have the following meanings R7, R8, R11, R12 are each hydrogen, bromine or methyl and preferably hydrogen or methyl; R9, R10 each has one of the meanings given for R7, R8, R11 or R12 and n is O or 1 and in particular 1. Taking into account the suitability as intermediates for preparing the protection agents of the known culture of WO-A 97 / 15552, still more preference is given to the compounds of formulas IV, ', and Ib'. Particular preference is given to the compounds listed in the following preparation examples.

Preparation Examples Preparation of diones II (precursors) 3-oxime pentane-2,3,4-trione Variant a): in a mixing vessel, 21 1 of 20% strong sulfuric acid and 6 kg (60 moles) of acetylacetone were initially charged. The mixture was cooled to about 17 ° C and, at 15-20 ° C, 4.2 kg (60.84 moles) of 40.5% strong aqueous sodium nitrite solution were metered into it. The mixture was subsequently stirred at about 17 ° C for another 20 minutes and then extracted with 25 1 of ethyl acetate. The organic phase was concentrated under reduced pressure, resulting 7.42 kg (96% yield) of the title compound. Variant b): 1225 g of 20% strong sulfuric acid were metered into a solution of 500 g (5 moles) of acetylacetone, 1 1 of water and 1305 g of 25% strong aqueous sodium nitrite solution, the pH being adjusted from 3-5 and the internal temperature from 25-17 ° C. The valuable product was isolated as in variant a). This gave 570 g of the title compound (89% yield). Variant c): 490 g (2.5 moles) of 50% strong sulfuric acid and 852 g (5 moles) of 40.5% strong aqueous sodium nitrite solution in a mixture of 500 g (5 moles) were dosed in parallel. of acetylacetone and 2 1 of water, with the pH adjusted to 3.7-4.2 and the temperature of 15-18 ° C. Prepared as in variant a) gave 588 g of the title compound (91% yield). 3- (O-methyloxime) of pentane-2,3,4-trione. They were suspended in a vessel of 20 1, 4.5 kg (32.6 moles) of potassium carbonate in 3.2 1 of methyl tert-butyl ether and one liter of DMF. The mixture was cooled by stirring from 0 to -10 ° C. A solution of 4128 g (32 mol) 3-oxime of pentane-2,3,4-trione, 2 1 of DMF and 4032 g (32 mol) of dimethyl sulfate were then dosed therein at an internal temperature of <; 25 ° C for a period of 2 hours. The mixture was stirred at room temperature for another 3.5 hours. Another 20 1 of water were then added, the upper organic phase was removed, the aqueous phase was washed with 2 1 of methyl tert-butyl ether, the organic phases were washed with 1 1 of 5% strong hydrochloric acid and the solvent It was distilled. This gave 4214 g of the title compound with a purity of 96.6% (percent GC area), corresponding to a yield of 89%.

Preparation of the ketals III (step 1) Example 1 3 (E) - (O-methyloxime) of 4,4-dimethoxypentane-2,3-dione (Tablel, III.1) 4.3 g (0.03 mole) of 3 were dissolved - (0-methyloxime) of pentane-2,3,4-trione and 6.2 g (0.06 mole) of trimethyl orthoformate in 15 ml of methanol and mixed with the tip of a spatula of p-toluenesulfonic acid. The mixture was subsequently stirred at 50 ° C for 5 h, after which the solvent was distilled. This gave 5.5 g of an oil (98% yield) (physical data see Table 1).

Example 2 1 (E) - (O-methyloxime) 1- (2-methyl- [1,3] dioxolane-2-yl) propane-1,2-dione (Table 1, III.2) 2400 g were heated ( 39 moles) of ethylene glycol, 430 g (3.62 moles) of trimethyl orthoformate, 550 g (3.9 moles) of 3- (O-methyloxime) pentane-2,3,4-trione and 9 g of p-toluene sulphonic acid ( 46 mmoles) with stirring at 85 ° C for a period of 15 min. After 30 min. at 85 ° C, the mixture was cooled to room temperature. During the reaction, the volatile components were distilled through a main column. To prepare, the mixture was washed with a saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether, and the combined organic phases were washed twice with water and finally dried over magnesium sulfate. Removal by distillation of the solvent gave 580 g of a red-brown oil (physical data see Table 1).

Example 3 1 (E) - (O-Methyloxime) of 1- (2-methyl- [1, 3] dioxane-2-yl) -propane-1,2-dione (Table 1, III.3) Starting from 103 g ( 0.72 moles) of pentane-2,3,4-trione 3- (O-methyloxime), 275 g (3.62 moles) of 1,3-propanediol, 80 g (0.76 moles) of trimethyl orthoformate and 1.6 g of p-acid. toluene sulfonic acid (9 mmoles) and using the procedure of Example 2, 137 g (94% yield) of a reddish oil were obtained, which according to HPLC, had a purity of 70% (physical data see Table 1) .

Example 4 1 (E) - (O-methyloxime) of 1- (2,5,5-trimethyl- [1, 3] -dioxane-2-yl) propane-l, 2-dione (Table 1, III.4) a ) using trimethyl orthoformate as a dehydrating agent. Over a period of 30 min, 430 g (3 moles) 3- (O-methyl oxime) of pentane-2,3,4-trione, 1600 g (15 moles) of neopentyl were heated glycol, 330 g (3.15 mol) of trimethyl orthoformate and 7 g of p-toluenesulfonic acid with stirring at 60 ° C. After 90 minutes, the reaction was terminated (verified by TLC or HPLC). To prepare, the mixture was cooled to 20 ° C and stirred with a saturated sodium bicarbonate solution for 15 min. Water was added to the reaction mixture, which was then extracted with cyclohexane. The organic phase was washed once with water, dried through magnesium sulfate and concentrated. This gave 663 g of the title compound with a purity of 90%, which corresponds to a product of 87% percent of the product (physical data see Table 1). b) by removal of (separating agent: cyclohexane) 100 g (0.69 mole) of pentane-2,3,4-trione 3- (O-methyloxime), 216 g (2.08 mole) of neopentyl glycol and 0.25 g of p-toluenesulfonic acid in 400 ml of cyclohexane until boiling until no water was separated in the water separator (approximately 13 hours). The reaction mixture was cooled to room temperature and mixed with water and methylene chloride. The organic phase was dried over sodium sulfate. The solvent was distilled, giving 158.7 g of an oil of a purity of 90% according to the HPLC quantifications, which corresponds to 90% of the product. c) by water removal (separating agent: toluene) 20 g (0.14 mole) 3- (O-methyl oxime) pentane-2,3,4-trione, 43.4 g (0.42 mole) of neopentyl glycol and 0.1 g were heated of concentrated sulfuric acid in 80 ml of toluene until boiling them in a water separator at a pressure of 800 mbar for 2 hours. The mixture was extracted with water and toluene and then prepared as in Example 4b). This gave 30 g of an oil of a purity of 84% (79% yield). Table 1: Analytical data of the selected ketals III Preparation of the bisoxime ether ketals IV (stage 2 Example 5 bis (O-methyloxime), -dimetoxypentane-2,3 (E, E) -dione (Table 2, IV.1) 23 ml (0.3 mole) of pyridine and 2.5 g (0.03 mole) of methoxyamine hydrochloride were initially charged at room temperature. 5.5 g were then added dropwise (0.03 mol) of the ketal (Example 1) dissolved in 5 ml of methanol. The reaction mixture was stirred at room temperature for approximately 18 hours. To prepare, the reaction mixture was concentrated, placed in methyl tert-butyl ether and washed successively with distilled water. Diluted HCl and a solution of sodium bicarbonate. The mixture was dried over magnesium sulfate and the solvent was then distilled. This gave 4 g (61% yield) of the title compound (physical data of E, E-isomers see Table 2).

Example 6 bis (O-methyloxime) of 1- (2-methyl- [1, 3] dioxolan-2-yl) propane-1,2-dione (Table 2, IV.2) By the method of Example 5, 508 g (2.72 moles) of ketal (Example 2), 430 g (5.43 moles) of pyridine and 1570 g (2.72 moles) of a 14% strong solution of methoxyamine hydrochloride in methanol gave 492 g of the title compound (physical data of E, E-isomers see Table 2).

Example 7 bis (O-methyloxime) 1- (2-methyl- [1,3] dioxane-2-yl) propane-1,2-dione (Table 2, IV.3) a) in the presence of pyridine / methanol Through the method of Example 5, 50 g (0.25 moles) of ketal (Example 3), 40 g (0.5 moles) of pyridine and 140 g (0.25 moles) of a strong solution of 14% methoxyamine hydrochloride in methanol gave 46 g of the title compound (physical data of E, E-isomers see Table 2). b) in the presence of pyridine / water 45.5 g (0.2 mol) of propane diol was stirred (89% pure), 125.7 g of water, 40.9 g (0.517 mol) of pyridine and 134.7 g (0.484 mol) of a methoxyamine hydrochloride solution (30% in water) at 25 ° C for 22 hours. Then 100 ml of methylene chloride and 300 ml of 2% strong hydrochloric acid were added and the organic phase was separated. The inorganic phase was extracted twice with methylene chloride. The organic phases were combined, washed with water and subsequently dried over sodium sulfate. The solvent was distilled. As residue, 45.1 g of the title compound had an EE-isomer content of 86.2% were obtained with 84.5% product. c) in the presence of sodium acetate / methanol 239 g (0.4 mole) of 14% of a strong methanolic methoxyamine solution, 50 g (0.6 mole) of sodium acetate (anhydrous), dissolved in 250 ml of methanol, were charged initially. , 75 g of magnesium sulfate and 92 g of ketal (Example 3), dissolved in 100 ml of methanol, at room temperature. The pH meter showed a value of 6. The mixture was stirred for 10 minutes, during which the pH decreased from 5.2, and a pH of 4.2 was installed by the dropwise addition of sodium acetate. The mixture was stirred at room temperature for another 20 hours and the transformation was monitored with HPLC. 7% of the start material left behind. After a further 4 hours of stirring, the reaction mixture was neutralized using an aqueous sodium hydroxide solution diluted with water. The mixture was extracted with methyl tert-butyl ether. The combined organic phases were washed with a diluted ammonium chloride solution, dried over magnesium sulfate and concentrated. This gave 92 g (89% yield) of the title compound. d) Initially prepared in the presence of sodium acetate / glacial acetic acid / water, 22.3 g (0.1 mole) of propane diol ketal (90% pure), 61 g of water, 8.2 g of sodium acetate (0.1 mole) and 55.7 g. g (0.2 mol) of methoxyamine hydrochloride solution (30% of a strong solution in water). A pH of 3.5 was installed by the addition of glacial acetic acid. The mixture was subsequently stirred at 25 ° C for 4 hours, and 8.2 g (0.1 moles) of sodium acetate were then added. The mixture was stirred at 25 ° C for another 7 hours, 50 ml of methylene chloride were added and the organic phase was separated. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were washed twice with water and dried. The solvent was distilled, and 25 g of the title compound (87.8% yield) having an EE-isomer content of 80.8%, subtracted Example 8 1- (2, 5, 5-trimethylo [1,3] dioxane-2-yl) propane-1,2-dione bis (0-methyl-oxime) (Table 2, IV.) A) starting from Example 4 At temperature environment, 350 g (4.4 moles) of pyridine and 1.3 kg (2.2 moles) of a methanol solution of 14% strong methoxyamine hydrochloride were initially charged. 458 g (2.0 moles) of ketal (Example 4) dissolved in 300 ml of methanol were added dropwise, and the reaction mixture was stirred for 18 hours. Prepared by the method of Example 5 gave 484 g (93% product) of the title compound (physical data of E, E-isomers see Table 2). b) starting from pentane-2, 3, 4-trione 3- (0-methyloxime) 214.5 g (1.5 moles) pentane-2, 3, 4-trione 3- (O-methyloxime), 2.75 g (0.0144 moles) ) of p-toluenesulfonic acid, 191 g (1.80 moles) of trimethyl orthoformate and 779.5 g (7.5 moles) of neopentyl glycol were heated at 85 ° C for a period of about 15 minutes. The mixture was stirred at 85 ° C for 30 minutes and subsequently cooled to 25 ° C. The reaction mixture was mixed with 215.8 g (2.84 mol) of pyridine and 1904 g (3.12 mol) of a solution of methoxyamine hydrochloride (13.7% strong methanol) and stirred at 25 ° C for 24 hours. 2803 g of water were added, the pH was set to 7 by the addition of 207 ml of a 50% strong aqueous sodium hydroxide solution and the mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were washed twice with 5% strength hydrochloric acid and subsequently with water. The mixture was dried over sodium sulfate and the solvent was distilled. As a residue, 334 g of the title compound having an EE-isomer content of 78.4% were obtained from the product, through two steps of 67.6%. c) start of Example 10 In a stirred vessel and at 25 ° C, 51.5 g of oxime ketal (Example 10) and 221.5 ml of DMF were initially prepared and mixed with 40.0 g (0.2 mole) of a strong sodium methoxide solution at room temperature. 27% The mixture was stirred at 25 ° C for 30 minutes and the methanol that had formed was then distilled. 27.7 g (0.22 mol) of dimethyl sulfate was then added at 20-25 ° C (ice-cool) and the mixture was stirred at 25 ° C for 1 h. The reaction mixture was then concentrated using a rotary evaporator. The residue (84.8 g) was taken in 551.1 g of toluene, 33.6 g of water and 8.4 g of dimethylamino solution (40% strength) and mixed at room temperature for 1.5 h. The phases were separated and the aqueous phase was extracted with toluene. The organic phases were washed with water, and the solvent was then distilled under reduced pressure. This gave 52.0 g of the title compound, corresponding to 92% of the product (according to the HPLC quantitation: 90.1% EE).

Example 9 1- (2-methyl- [1,3] dioxolane-2-yl) propane-1,2-dione 1- (O-methyloxime) 2-oxime (Table 2, IV.5) 24 g (0.03 moles) ) of a 50% strong aqueous sodium hydroxide solution and 200 ml of water were initially charged at 25 ° C and mixed little by little with a total of 25 g (0.0152 mole) of hydroxylammonium sulfate. 50 g (0.0267 moles) of ketal (Example 2) were then added dropwise, and the reaction mixture was stirred at 50 ° C (pH = 7-8) for 9 hours. A pH of 5-6 was then established using an aqueous sodium hydroxide solution, and the mixture was stirred at 50 ° C for 48 hours. Another 25 g of hydroxylammonium sulfate and 24 g of 50% strength aqueous sodium hydroxide solution were metered in, and the mixture was stirred at 50 ° C for another 20 hours. 300 ml of the methyl tert-butyl ether were then added. The solid which is insoluble in the two phases of the mixture was filtered, washed with a little hexane and dried. This gave 9 g of the title compound (physical data of the E, E-isomers see Table 2). The organic phase of the two-phase mixture obtained as the stock solution was dried over sodium sulfate and subsequently concentrated in a rotary evaporator. This gave another 17.5 g of the title compound.

Example 10 1- (2,5,5-Trimethyl- [1,3] dioxane-2-yl) propane-1,2-dione 1- (O-methyloxime) 2-oxime (Table 2, IV.6) In In a manner similar to that described above, 51 g of ketal (Example 4) gave 57.7 g of the title compound (purity: about 90%) (physical data of E, E-isomers see Table 2). Table 2: Analytical data of selected bioxima ether ketals IV Preparation of oximes of bioxime ether (stage 3a) Example 11 Petane-2,3,4-trione 3,4-bis (O-methyloxime) 4.2 g of Example 5 and 4.2 g of silica gel 60 were added in 10 ml of acetonitrile. 10 ml of water and 3 drops of trifluoroacetic acid. After 30 minutes the solid that formed was separated, the filtrate was extracted with cyclohexane and the solvent was distilled. This gave 1.7 g of the title compound. 1 H NMR (CDC13, d [ppm]): 3.9 (2s, 6H), 2.3 (s, 3H), 2.0 (s, 3H).

Preparation of oximes bioxime ether Ib (step 3b) Example 12 Petane-2,3,4-trione 3,4-bis (O-methyloxime) 2-oxime a) Oximation with hydroxylammonium chloride aa) start of Example 8 Added 387 g (1.5 moles) of Example 8, dissolved in 500 ml of methanol, to 125 g of hydroxylammonium chloride in 500 ml of water. 500 ml of glacial acetic acid were added, and the mixture was stirred at room temperature for 3 hours (monitored by HPLC). To prepare, the reaction mixture was neutralized by cooling with a 20% strength aqueous sodium hydroxide solution. The mixture was extracted with methyl tert-butyl ether, and the solvent was removed using a rotary evaporator. The oil remained in a dilute aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether. The organic phase was discarded, and the aqueous phase was acidified with HCl and extracted with methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and the solvent was distilled in a rotary evaporator.

The oil that remained fixed crystallized: 250 g (89% yield); Isomer ratio: EZE / EZZ: 96: 4. XH NMR (CDC13; d [ppm]): 1.92 (s, 3H); 2.12 (s, 3H); 3.92 (s, 3H); 3.99 (s, 3H), 9.92 (s, 1H); ab) start of Example 7 45 g (0.2 moles) of Example 7 (80% pure) were dissolved in 100 ml of methanol. 16 g (0.24 mole) of hydroxylammonium chloride were dissolved in 100 ml of water, and 100 ml of glacial acetic acid were added. A turbid solution was formed which was stirred at room temperature for 16 hours until the transformation was complete (monitored by HPLC). To prepare it, the mixture was neutralized with a 50% strength aqueous sodium hydroxide solution and extracted with methyl tert-butyl ether, and the organic phase was washed with 2N NaOH. The NaOH phase was mixed with a mixture of ice and ethyl acetate, and the pH was adjusted to 2 using hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed with a solution of saturated sodium bicarbonate and water. The organic phase was dried over magnesium sulfate and concentrated to give 29 g of oil; Isomer ratio: EZE / EZZ: 96: 4. ac) starting from Example 6 Through process method 12 aa), 216 g (1 moles) of ketal (Example 6), and 139 g (2 moles) of hydroxylammonium chloride in a solvent mixture of 500 ml of THF, 500 ml of water and 500 ml of glacial acetic acid yielded 125 g of the title compound of less colorful crystals, corresponding to 67% of the product, b) Oximation with hydroxylammonium sulfate ba) starting from Example 8 25 ° C, 740 ml of water, 74 ml of concentrated hydrochloric acid, 148 ml of glacial acetic acid and 73.3 g (0.447 Moles) of hydroxylammonium sulfate with a solution of 297 g (0.739 Moles) of Example 8 (crude; 64.2 % EE-isomer) in 740 ml of methanol. The mixture was stirred at 25 ° C for 24 hours. Upon addition of dilute NaOH, a pH of 6 was set and the reaction solution was extracted twice with methyl tert-butyl ether. The combined organic phases were washed with a saturated NaHCO 3 solution and dried. The solvent was distilled in a rotary evaporator. 190.9 g of the title compound having an EZE: EZZ isomer ratio of 89.4: 10.6 was isolated. According to the HPLC quantitation, the EZE isomer product was 87.9%. In further experiments, it was shown that the presence of the cosolvent glacial acetic acid can be dispensed with.

Claims (9)

1. CLAIMS 1. A - process for preparing trione bis (oxime ether) derivatives of formula I wherein the substituents have the following meanings R1, R3 are each C1-C2 alkyl, partially or fully halogenated or C3-C6 cycloalkyl unsubstituted; R2, R4 are each unsubstituted C1-C4 alkyl or alkenyl of C2-C4, C2-C4 alkenyl or methyl substituted with phenyl and X is oxygen or N-OH, comprising i) reacting a dione of the formula II, wherein the substituents R1, R2 and R3 are each as defined above, with an alcohol or diol in the presence of an acid to give a ketal of the formula III, wherein the substituents R5 and R6 are each C? -C6 alkyl, benzyl or haloalkyl of C? -C3 or R5 and R6 together with the carbon and the two oxygen atoms of the ketal function form a ring A wherein the substituents and the index n have the following meanings: R7, R8, R11, R12 are each hydrogen, halogen, C1-C4 alkyl, C1-C3 haloalkyl, C1-C4 alkoxymethyl, C2-C4 alkenyl, C2-C4 alkynyl or phenyl, where the latter can be substituted by nitrogen or halogen; R9, R1 each has one of the meanings given for R7, R8, R11 or R12 and R9 and R10 together form an exo-methylene group or carbonyl group and n is 0, 1 or 2, ii) convert the resulting ketal III a) with an alkoxyamine of the formula R40-NH2, wherein R4 is as defined above, or one of its acid addition salts, or b) with a hydroxylamine or its acid addition salts and subsequent alkylation with an alkylating agent R-L1, wherein R 4 is as defined above and L 1 is a nucleophilically replaceable leaving group, in cetal ether bioxima IV, where the substituents R1 to R6 are each as defined above, and iii) hydrolysing the cetal ether bioxime IV obtained in this way in the presence of acid, a) producing the ketone bioxime ether, b) amine with hydroxylamine or its acid addition salts to produce the oxime bioxima ether Ib,
2. 2. The process according to claim 1, characterized in that the dione of the formula II is reacted with a diol in step 1).
3. 3. The process according to claim 2, characterized in that the diol used is a glycol of ethylene, 1,3-propanediol or 2,2-dimethylo-1,3-propanediol.
4. 4. The process according to claim 1 or 2, characterized in that in step 2a) the ketal III is reacted with an acid addition salt of the alkoxyamine R40-NH2 at 20-65 ° C and the acid that is released during the reaction it is at least partially bound by the addition of bases.
5. 5. The process according to any of claims 1, 2 and 4, characterized in that in the step 3a) / 3b) the hydrolysis / aminolysis starts with a pH from 0.5 to 1.5 and is carried out at 20-40 ° C.
6. 6. A ketal of the formula III, wherein the substituents have the following meanings R1, R3 are each C6-C6 alkyl or partially halogenated or unsubstituted C3-C6 cycloalkyl; R2 is unsubstituted C2-C4 alkyl or C2-C4 alkenyl, C2-C4 alkynyl or methyl substituted with phenyl; R5, R6 are each C? -C6 alkyl, benzyl or C1-C3 haloalkyl or R5, R6 together with the carbon and the two oxygen atoms of the ketal function form a ring A, wherein R7, R8, R11, R12 are each hydrogen, halogen, C1-C4 alkyl, C1-C3 haloalkyl, C1-C4 alkoxymethyl, C2-C4 alkenyl, C2-C4 alkynyl or phenyl, wherein the The latter can be replaced by nitrogen or halogen; R9, R10 each has one of the meanings given for R7, R8, R11 or R12 and R9 and R00 together form an exo-methylene group or a carbonyl group and n is 0, 1 or 2.
7. 7. To cetal ether bioxime of the formula IV, wherein R 4 is hydrogen, C 1 -C 4 alkyl or unsubstituted C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or substituted methyl phenyl and the other substituents are each as defined in claim 6.
8. 8. A cetal ether bioxima of formula IV, wherein the substituents R1 to R6 are each as defined in claim 7.
9. 9. 3, 4-bis (O-methyloxime) of pentane-2, 3, 4, trione.