MXPA97007538A - Procedure for obtaining alpha-bisoximasisomeras pu - Google Patents

Abstract

Process for obtaining substantially pure isomeric alpha-bisoximes of the formula Ia, in which the groups R 1 O- and R 2 are in the cis position with each other in the N = C bond and in which the radicals have the following meanings: R 1, R4 means hydrogen or an organic C radical, R2 means hydrogen, cyano, nitro, hydroxy, amino, halogen or an organic radical that can be linked directly or via an oxygen atom, sulfur or nitrogen to the skeleton; , cyano, nitro, hydroxy, amino, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino or cycloalkyl, from a mixture of the isomers of the alpha-bisoximes Ia and

Description

Procedure for obtaining pure isomeric a-bisoximes Description The present invention relates to a process for the preparation of substantially pure isomeric isomers of the formula R10-N-CR2-CR3-N-OR4 wherein R10- and R2 groups are in the cis position with each other in the N = C bond and in which the radicals have the following meanings: R ^ R4 means hydrogen or an organic C radical; R 2 signifies hydrogen, cyano, nitro, hydroxy, amino, halogen or an organic radical which may be linked, directly or via an oxygen, sulfur or nitrogen atom to the backbone; R3 is hydrogen, cyano, nitro, hydroxy, amino, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino or cycloalkyl.

The a-bisoximes are known from the literature as intermediates and active substances for combating noxious fungi or animals (WO-A 95 / 18,789, WO-A 95 / 21,153, WO-A 95 / 21,154, WO-A 95 / 21,156; German patent application No. P 44 32 336.0, German patent application No. P 44 41 674.1).

Generally, the active substances have very varied actions, depending on the configuration of the double bond of the R group: 0-N = CR2-, but the action of those compounds in which the R10- and R2 groups are in position is usually higher cis to each other in the link N = C. In view of the above, it is proposed in the literature mentioned above to separate the isomers in a conventional manner (eg by chromatography). The separation of the desired isomer from a mixture of isomers has the disadvantage that a considerable part of costly intermediate and final products is not used because it is present in the "false" configuration.

From the literature there are known methods for the isomerization of a-bisoxímas, which have the disadvantages, which are limited to certain oximes with radicals (stable) and / or which are not selective and / or have poor yields [DE-A 29 08 688; J. General Chem. USSR 58/1. 181 (1988); Tetrahedron AXI21, 5181 (1985); J. Org. Chem. USSR 2Ü. 135 (1984); J. Org. Chem. USSR 2211, 97 (1991); J. Phys. Chem. 91/26. 6490 (1987); Recl. Trav. Chim. Pays-Bas H1Z2., 79 (1992)].

In addition, the transformation of bis-oximes under acid catalysis into a certain isomer [Synth. Rea t. Inorg. Met.-Org. Chem. 18 (10). 975 (1988); Synth Re-akt. Inorg. Met.-Org. Chem. 11 (7). 621 (1981); Spectrosc. Lett. 23 (6). 713 (1990); Z. Anorg. Allg. Chem. 4 ££, 197 (1983)]. However, these processes have the disadvantage that they can only be used for those processes whose substituents are stable against acids.

Furthermore, the isomerization of compounds A by giving A 'in ethers with HCl is described in the above patent application WO-A 95 / 21,153, obtaining a yield of 75%.

The subject of the present invention is a process of general application for the preparation of substantially pure isomeric isomers of the formula R10-N-CR2-CR3-N-OR4 wherein the RiO- and R2 groups are in cis position with each other in the N = C bond, which procedure is applicable, especially, to those compounds in which the substituents R1, R2 , R3 and R4 are not stable against acids or do not contain stable groups against acids.

Therefore, a procedure was found for obtaining substantially pure isomeric isomers of the formula R'O-N-CR ^ R ^ N-OR4 where the groups? -O- and R2 are in cis-cission with each other in the bond N = C, whose process is characterized in that a mixture of the isomers of the a-bisoximes la and Ib is treated.

R0-N-CR2-CR3-N-OR4 R10-N "CR2-CR-N-OR4" trans "Ib in an organic solvent with a Lewis acid.

According to the process of the invention, the substantially pure isomeric a-bisoximes of the formula can also be obtained by treatment of an a-bisoxime ib, in which the groups R 10 - and R 2 are in the trans position in the N = C bond, in an organic solvent with a Lewis acid.

Basically, the process of the invention can be carried out in all organic solvents or diluents which do not liberate any protonic acid with Lewis acids. So it is preferred to use aprotic organic solvents.

Suitable solvents are, for example, aliphatic hydrocarbons, such as pentane, hexane, heptane, cyclohexane and petrolther, aromatic hydrocarbons, such as benzene, toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as chloride methylene, chloroform, 1,2-dichloroethane and chlorobenzene, the ethers, such as diethyl ether, diisopropyl ether, tere.-butylmethyl ether, dioxane, anisole and tetrahydrofuran, as well as dimemethyl sulfoxide, with preference being given to aliphatic hydrocarbons, such as pentane, hexane, heptane, cyclohexane and petrol ether and the aromatic hydrocarbons, such as benzene, toluene, o-, m- and p-xylene. Meclasses of the aforementioned solvents can also be used.

The reaction temperature depends on the type of a-bisoxim substitutes. Generally, isomerization will be carried out at temperatures of at least -40 ° C. At temperatures above 150 ° C, thermal decomposition of the bisoxy ace may already take place. This thermal decomposition depends, substantially, on the type and stability of the substituents, so that in the case of stable bisoxy, the reaction can also be carried out at higher temperatures.

So this transformation will be carried out, generally, at temperatures of -30 ° C to 140 ° C, preferably -10 ° C to 120 ° C.

As a rule, all Lewy acids which are sufficiently stable in the chosen solvent can be used in the reaction of the invention, and no protonic acids are released.

Thus, as Lewis acids, halides of a semimetal or a metal of the third or fourth main group or of a transient metal are generally appropriate. Boron halides, aluminum, tin, zinc, iron or titanium are preferred. As halides, fluorides, chlorides or bromides are particularly suitable. Examples of Lewis acids suitable for use in the process of the invention are: AICI3, AlBr3, FeCl3, BBr3, BCI3, BF3. SnCl4, ZnCl2, ZnBr2 or TÍCI4.

Generally, it is sufficient to use the Lewis acids in ca-talitic quantities, and the conversion rate can be increased with increasing amounts of the Lewis acid. As a rule, amounts of 0.1 to 500% by mole of Lewis acid are used (with respect to the amount of the bisoxime Ib or the mixture of the bisoximes la and Ib). Higher quantities do not affect the reaction but are not necessary from the economic point of view nor desirable from the point of view of an application of the procedure on an industrial scale (technical aspects of safety and environmental contamination). It is therefore recommended to use the Lewis acid in an amount of 0.5 mol% up to 300 mol%, preferably 1 mol% up to 150 mol%, especially 10 mol% up to 80 mol%.

According to the above-described process measures it is especially possible to prepare substantially pure isomeric isomers of the formula I, R10-N-CR2-CR3-N-OR4 where the Rio- and R2 groups and the R3 and -OR4 groups are in the cis position with each other at the N = C bonds, treating a mixture of the isomers of the -bisoxima the 'and Ib' R10-N-CR2-CR3-N-OR4 R10-N-CR2-CR3-M-OR4"cis" "cis" "trans" "cis" the 'Ib' in an organic solvent with a Lewis acid.

According to the process of the invention, the substantially pure isomeric a-bisoximes can also be obtained when an a-bisoxime Ib 'is treated in an organic solvent with a Lewis acid.

The reaction mixtures are further processed in a conventional manner, for example by mixing them with water, separating the phases and purifying the crude products, optionally by chromatography. The final products are obtained, in part, in the form of viscous oils which are released at reduced pressure and slightly elevated temperature of the volatile or purified components. Provided that the final products are obtained as solids, purification can be carried out by recrystallization or digestion.

The process of the invention is widely applicable. It allows, in particular, to provide substantially pure isomeric isomers, either carrying unstable groups under acidic reaction conditions or capable of forming complexes with Lewis acids, for example, substitute compounds. - Stored by halogen atoms or ether or ester groups (see table 1).

Unexpectedly, they are obtained according to the procedure described above of four possible isomers of the a-bisoximes, predominantly the or isomer. The process of the invention has reaction conditions under which an isomerization of the N = C bond substituted by R ^ - preferably takes place, while an isomerization of the N = C double bond substituted by R40- can be substantially avoided. { see tables 2 and 3 ([ie]: Ix) > .

Furthermore, it has been found that the reaction according to the invention can be applied, especially also to those a-bisoximes, in which R1 and / or R4 mean hydrogen.

The process of the invention is especially suitable for the preparation of substantially pure isomers, which in the literature mentioned above are described as intermediates and active substances for combating harmful animals or fungi. So the terms "radical of organic C" and "organic radical" have, especially, the general and special meanings indicated in this literature.

Examples: General procedure for the reaction of isomer mixtures of a-bisoximes a) X moles of the isomeric mixture of the a-bisoximes [J; ratio of isomers (Ia ': Ib'): i °.] in X ml of the organic solvent fLSGMI are mixed with 3 mol% of Lewis acid [LS] and stirred for £ hours at a temperature [_E ° C] . After further processing, the isomer ratio [j¿] (3 ia'.Ib ') obtained under these conditions is examined by iSS gas chromatography, HPLC or by spectroscopy of iH-N (H? JB). The results of these tests are summarized in table 1. b) In other tests, the moles of the isomer mixture of a-bisoximes I 'are mixed [R1 = CH3, R2 = C6H5, R3 = CH3, R4 = H; ratio of isomers (Ia'.lb '): i £] in X mi of the organic solvent [L £ SM] with jj% in mol Lewis acid ISIS] and stir for £ hours at a temperature [_E ° C]. After processing, it is examined by gas chromatography (SSL). HPLC or iH-MR spectroscopy (NMR) isomer ratio [i *]: lx. { íil] = the ': Ib'} obtained under these conditions (Ix: quantity of another isomer is still unknown stereochemistry). The results of these tests are summarized in table 2. c) In other tests according to Z. Anorg. Chem. 496. 197 (1983) X moles of the isomer mixture of the a-bisoximes I '[R1 = CH3, R2 = C6H5, R3 = CH3, R4 = H; ratio of isomers (Ia ': Ib'): ¿] in X ml of the organic solvent rLSGMl are saturated with HCl gas and stirred for one hour at a temperature [_E ° C]. After further processing, the ratio of fj-β1: Ix isomers obtained under these conditions is determined according to gas chromatography (S £), HPLC or iH-MR spectroscopy (Ix: amount of another isomer of stereochemistry still unknown; [?] &Ia ': Ib'). The results of these comparative tests are summarized in table 3.

DO NOT Table 1: J Lp t-1 O Pg = CH2C = CH ? to THF = tetrahydrofuran OR Table 3: Example 01 (Table 1): Obtaining (E, E) -1-phenyl-l-methoxyimonopropan-2-on-2-oxime 40 g (0.208 mol) of (E, E / Z, E) -l-phenyl-l-methoxyiminopropan-2-on-2-oxime (ratio of E isomers, E: Z, E = 1: 1.4) in 200 ml of toluene are mixed with 2.77 g of AICI3. After 25 h at 30-40 ° C, the reaction mixture is mixed with ethyl acetate. The mixture is washed with 2N hydrochloric acid and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane, 32.5 g are obtained (81% of theory) of the title compound as colorless crystals (mp: 160-162 ° C). 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.10 (S, 3H); 3.91 (s, 3H); 7.17 (m, 2H); 7.40 (m, 3H); 8.66 (s wide, OH) Example 02 (Table 1): Obtaining (E, E) -1- (4-fluorophenyl) -l-methoxyiminopropan-2-on-2-oxime 115.9 g (0.552 mol) of (E, E / Z, E) -1- (4-fluorophenyl) -1-methoxyiminopropan-2-on-2-oxime (ratio of E, E: Z isomers, E = 1: 1.9) in 600 ml of toluene are mixed with 36.7 g of AlCl. After 9 h at 60 ° C and 20 h at room temperature (ca. 25 ° C), the reaction mixture is poured into a mixture of ethyl acetate and ice water. The mixture is mixed with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is washed and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane, 86.4 g (75% of theory) of the title compound are obtained as colorless crystals (mp .: 156-157 ° C). 1H-MR [CDCI3 / TMS; d (ppm)]: 2.10 (s, 3H); 3.91 (s, 3H); 7.03-7.25 (m, 4H); 8.67 (s, OH) Example 03 (Table 1): Obtaining (E, E) -1- (4-chlorophenyl) -l-methoxyiminopropan-2-on-2-oxime 4 g (0.018 mol) of (E, E / Z, E) -1- (4-chlorophenyl) -l-methoxyimino-propan-2-on-2-oxime (ratio of E isomers, E: Z, E = 1: 1.1) in 15 ml of toluene are mixed with 0.2 g of AICI3. After 72 h at room temperature (ca. 25 ° C), the reaction mixture is mixed with ice water. The mixture is extracted with tere. -butyl-methyl ether. The organic phase is washed with 10% hydrochloric acid and water and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane, 3.4 g (85% of theory) of the title compound are obtained as colorless crystals (mp .: 174-176 ° C). 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.13 (S, 3H); 3.92 (s, 3H); 7.12 (d, 2H); 7.36 (d, 2H); 8.42 (broad s, OH) Example 07 (Table 1): Obtaining (Z, E) -1- (3-methylisoxa-zol-5-yl) -l-methoxyiminopropan-2-on-2-oxime 76.4 g (0.388 mol) of (E, E / Z, E) -1- (3-methylisoxazol-5-yl) ~ l-methoxyiminopropan-2-on-2-oxime (ratio of Z isomers, E: E, E = 4: 1) in 400 ml of toluene are mixed with 5.2 g of AICI3. After 8 h at 30-40 ° C and a further 12 h at room temperature (ca. 25 ° C), the reaction mixture is added to a mixture of 100 ml of ethyl acetate and 200 ml of 2N hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is washed and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane 65 g (85% of theory) of the title compound are obtained as yellowish crystals in a purity of 90%. 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.18 (s, 3H); 2.35 (s, 3H); 4.07 (s, 3H); 6.57 (s, 1H); 9.67 (broad s, OH) Example 08 (Table 1): Obtaining (E, E) -l- (4-cyanophene-nyl) -l-methoxyiminopropan-2-on-2-oxime 71.4-g (0> 329 moles) of (E, E / Z, E) -1- (4-cyanophenyl) -1-methoxy-iminopropan-2-on-2-oxime (ratio of E isomers, E: Z, E = 1, 5: 1) in 400 ml of toluene are mixed with 4.4 g of AICI3. After 5 h at 35-40 ° C for a further 72 h at room temperature (ca. 25 ° C), the reaction mixture is added to a mixture of ethyl acetate and 2N hydrochloric acid. After extraction with ethyl acetate, the organic phase is washed and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane / methanol 60.6 g (85% of theory) of the title compound are obtained as yellowish crystals (m.p .: 165-170 ° C). 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.13 (s, 3H); 3.92 (s, 3H); 7.27 (d, 2H); 7.66 (d, 2H); 8.75 (s wide, OH) Example 09 (Table 1): Obtaining (E, E) -l- (3-cyanophene-nyl) -l-methoxyiminopropan-2-on-2-oxime 80.2 g (0.37 mol) of (E, E / Z, E) -1- (3-cyanophenyl) -l-methoxyimonopropan-2-on-2-oxime (ratio of E, E isomers: Z, E = 2: 1) in 400 ml of toluene is mixed with 4.9 g of AICI3. After 8 h at 30-40 ° C and another 16 h at room temperature (ca. 25 ° C), the reaction mixture is added to a mixture of ethyl acetate and 2N hydrochloric acid. After extraction with ethyl acetate, the organic phase is washed and dried. The solvent is then distilled under reduced pressure. After crystallization from n-pentane / methanol, 67.1 g (84% of theory) of the title compound are obtained as yellowish crystals (m.p.: 163-166 ° C). 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.13 (s, 3H); 3.93 (s, 3H); 7.40-7.66 (, 4H); 8.54 (broad s, OH) Example 25: Obtaining (E, E / Z, E) -1-phenyl-l-methoxyiminopro-pan-2-on-2-oxime 100 g (0.614 mole) of l-phenyl-1,2-propanedione-2-E-oxime in 200 ml of methanol and 144 g of pyridine are mixed with a solution of 77 g (0.922 mole) of O-methylhydroxylamine hydrochloride and 200 ml of methanol. After 24 h at room temperature (about 25 ° C), the solvent is distilled off under reduced pressure. The residue thus obtained is taken up in tert-butyl methyl ether and mixed with 2N hydrochloric acid. The aqueous phase is extracted neutrally with tert-butyl methyl ether. From the organic phases, after the washing, drying and elimination of the solvent, the mixture of the E, E: Z, E isomers is obtained in a ratio of 1: 1.4 (determined by GC) in a purity 90-95%. 1 H-NMR [CDCl 3 / TMS; d (ppm)]: 2.05 / 2.10 (2s, 1H, 1H *); 3.91 / 3.97 (2s, 1H, 1H *); 7.18 / 7.38 / 7.61 (3m, 5H, 5H *); 9.14 (broad s, OH, OH *) By proceeding accordingly, the compounds listed in Table 4 can be obtained, for example: Table 4: 00 Pg = CH2C = CH

Claims (1)

Claims

1. Process for obtaining substantially pure isomeric isomers of the formula R10-N = CR2-CR3-N-OR4 is the one in which the groups R ^ - and R2 are in the cis position with each other in the N = C bond and where the radicals have the following meanings: R] -, R4 means hydrogen or an organic C radical; R 2 signifies hydrogen, cyano, nitro, hydroxy, amino, halogen or an organic radical which may be linked directly or via an oxygen, sulfur or nitrogen atom to the backbone; R3 is hydrogen, cyano, nitro, hydroxy, amino, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino or cycloalkyl. whose method is characterized in that a mixture of the isomers of a-bisoximes la and Ib is treated R ^ N-CR ^ CR ^ N-OR R10-N "CRz-CR3-N-OR4" cis "" trans "Ib in an organic solvent with a Lewis acid. Process for obtaining substantially pure isomeric a-bisoxime, of the formula according to claim 1, characterized in that an a-bisoxime Ib is treated according to claim 1, in which the groups RxO- and R2 are in cis position with each other in the bond N = C, in an organic solvent, with a Lewis acid. Process for obtaining substantially pure isomeric a-bisoxime of the formula R1O-N-CR2-CR3 »N-0R4 wherein the groups s -O- and R2 and the groups R3 and -OR4 are each in cis position with each other in the bond N = C, according to claim 1, characterized because it is a mixture of the isomers of the a-bisoximes la 'and Ib' R10-N-CR2-CR3-N-OR4 R10-N-CR2-CR3-N-OR4"cis" "cis" "traps" "cis" the 'Ib' in an organic solvent with a Lewis acid. Process for obtaining substantially pure isomeric a-bisoxime of the formula according to claim 3, characterized in that an a-bisoxime Ib 'is treated according to claim 3, wherein the groups Rx0 and R2 are in trans position with each other in the link N = C and the groups R3 and -OR4 are in cis position with each other at the bond N = C, in an organic solvent with a Lewis acid. Process according to claims 1, 2, 3 or 4, characterized in that an aprotic organic solvent is used, Process according to claims 1, 2, 3 or 4, characterized in that the reaction is carried out at temperatures of -40 ° C up to 150 ° C. Process according to claims 1, 2, 3 or 4, characterized in that a halide of a semimetal or a metal of the third or fourth main group or a transient metal is used as the Lewis acid. Process according to claim 7, characterized in that a boron, alu i-nium, tin, zinc or titanium halide is used as the Lewis acid. Process according to claim 7, characterized in that a fluoride, chloride or bromide is used as the halide. Process according to claim 7, characterized in that a fluoride, chloride or bromide, a wall of a semimetal or a metal of the third or fourth main group or a transient metal is used as Lewis acid. Process according to claims 1, 2, 3 or 4, characterized in that as Lewis acid is used AICI3, AlBr3, FeCl3, BBr3, BCI3, BF3, SnCl, ZnCl2, ZnBr2 or TiCl. Process according to claims 1, 2, 3 or 4, characterized in that toluene, methylene chloride or tetrahydrofuran are used as the organic solvent.