PROCESS FOR THE PREPARATION OF METHOXYMINOPHENYLGLYOXYLIC ACID DERIVATIVES

Abstract: The present invention relates to a process for the preparation of o-chloro-methylphenylmethoximinoglyoxylic acid esters of formula (I), wherein R is C3-C8 alkyl, in which process o-chloromethylphenylglyoxylic acid amide of formula (III) is, in any order or concurrently, a) oximated with O-methylhydroxylamine and b) esterified under acid conditions with an R-OH alcohol, wherein R is C3-C8 alkyl. A process for the preparation of compound (III) is also described, as well as the use of the compounds of formula (I) in the preparation of fungicides.

Description: PROCESS FOR THE PREPARATION OF METHOXYMINOPHENYLGLYOXYLIC ACID DERIVATIVES The present invention relates to a process for the preparation of o-chloromethylphenyl- methoximinoglyoxylic acid esters of formula 1 wherein R is C 3 -C 8 alkyl, in which process o-ch!oromethylphenylglyoxylιc acid amide of formula III is, in any order or concurrently, a) oximated with O-methylhydroxylamine and b) esterified under acid conditions with a R-OH alcohol, wherein R is C 3 -C 8 alkyl. Both reaction steps are conveniently earned out in the temperature range from 20° to 70°C, preferably from 40° to 70°C. The O-methylhydroxylamine is used as such, but preferably as salt. Preferred salts are suitably those with mineral acids, such as hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid and the like, but also with organic acids, such as sulfonic acids (methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid and the like), acetic acid, trichloroacetic acid, lactic acid, maleic acid, oxalic acid, and others. The compounds of formula I are valuable intermediates for obtaining E-configurated fungicides of the methoximinophenylglyoxyhc acid ester seπes of formula IV, of which the methyl esters, in particular, are of high economic importance (EP-254426, EP-460575, EP- 463488, EP-472300, EP-299694, EP-253213, WO-95/18789, WO-95/21153, and others). In one of its aspects, the invention relates to the compounds of formula IV. The compounds according to this invention correspond to the general formula IV wherein R is C 5 -C 8 alkyl, and R 2 = hydrogen, Cι-C 4 alkyl, C C 4 haloalkyl, C 3 -C 6 cycloalkyl; R 3 = Cι-C 6 alkyl, aryl-Ci-C 4 alkyl, heteroaryl-C C 4 alkyl, C 2 -C 6 alkenyl, aryl-C 2 -C 6 alkenyl, heteroaryl-C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heteroaryl, aryl, or aryl which is substituted by one to three halogen, CrC 4 alkyl, Cι-C 4 haloalkyl. Particularly preferred compounds of formula IV are those, wherein R 2 = hydrogen or d-C 4 alkyl, and R 3 = aryl, or aryl which is substituted by Cι-C 4 haloalkyl. A particularly preferred compound of formula IV is that wherein R 2 = methyl and R 3 = 3-trifluoromethylphenyl. A particularly preferred compound of formula IV is that , wherein R = pentyl and A = -N=C(CH 3 )(3-trifluoromethylphenyl) Aryl is phenyl or naphthyl, preferably phenyl. Entirely suφrisingly, it has now been found that the synthesis of the rnethoxirninoglyoxylic acid ester part of formula I and each further reaction in the chloromethyl side chain of this intermediate to a fungicide derived therefrom proceeds in particularly high puπty and high yields if the methyl ester is not obtained direct from the o-chloromethylphenylglyoxyiic acid amide III by methanolysis but if a long-chain ester is prepared first and the transesterifi¬ cation to the methyl ester is earned out at a later stage of the process The o-chloromethylphenylmethoximmoglyoxylic acid esters of formula I can have the E- configuration, or a Z-configuration, at the imino double bond desirable for the biological activity A very special advantage of the present synthesis of compounds of formula I is that by this process, which proceeds via a long-chain ester, the E-configuration is formed almost exclusively (E/Z ratio higher than 90 ■ 10) Accordingly, suitable alkanols for obtaining intermediates of formula I according to this invention are n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol as well as n-pentanol, n-hexanol, n-heptanol, n-octanol and the corresponding isomers thereof. The Cs-C 6 alkanols in all isomeπc forms are preferred, in partiuclar n-pentanol The esterification of compound III or of the corresponding oxime can be earned out in conventional manner under acid reaction conditions, e g by adding sulfuric acid or by introducing HCl gas into the reaction medium The C 3 -C 8 alkanol serving the estenfication can be used in excess and can also serve as only solvent or diluent It can also be reacted in admixture with one or more than one inert diluent Suitable diluents are, for example, hydrocarbons or halogenated hydrocarbons, typically hexane, heptane, octane, chloroform, dichloroethane; aromatic hydrocarbons or aromatic halogenated hydrocarbons, typically toluene, xylene, chlorobenzene, dichlorobenzene; or ethers such as dioxane, tetrahydrofuran, diisopropyl ether; ketones such as acetone, methyl isobutyl ketone, cyclopentanone; or mixtures thereof. The esterification can be earned out either direct with exclusion of water or under aqueous conditions via pπor hydrolysis The hydrolysis of the amide III is preferably carried out in the presence of stoichiometric amounts of water in the form of the corresponding aqueous concentrated hydrohalic acid, preferably in hydrochloric acid, at a concentration of 25% or more The alkanolysis can be catalysed by small amounts of sulfuπc acid or phosphoπc acid Said alkanolysis is carried out in the temperature range from -10° to +120°C, preferably from 0° to 50°C and, particularly preferably, from 20° to 50°C in the presence of the C 3 -Cβalkanol Accordingly, hydrolysis and esteπfication proceed in one single reaction step of the alkanolysis The reaction of the keto group in the compound of formula III with O-methylhydroxylamine or its salt can be carried out before or after this alkanolysis step of compound III, but is preferably earned out concurrently It is an essential feature of this invention that the conversion of III to I can be carried out in one single process step The invention also relates to a process for obtaining o-chloromethylphenylglyoxylic acid amide of formula III by partial hydrolysis of o-chloromethylbenzoyl cyanide of formula II, which process compnses acid saponification with 0 8 to 1 5 mol of water per mol of starting product. Suitable acids are mineral acids such as hydrohalic acid, sulfuπc acid, sulfurous acid, phosphoπc acid, phosphorous acid, nitπc acid and the like as well as mixtures of these acids, and also organic acids, typically sulfonic acids, acetic acid, propionic acid, trifluoro¬ acetic acid, and others It is conveniently possible to work in concentrated acetic acid into which hydrochloπc gas is introduced and/or to which concentrated aqueous hydrochloπc acid is added The temperature is in the range from 10°C to 50°C, preferably from 15°C to 30°C The reaction can also be earned out in the presence of a solvent It is preferred to use toluene, xylene, chlorobenzene, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, hexane and others The invention also relates to a combined process for the preparation of o-chloromethyl- phenylmethoximinoglyoxylic acid esters of formula I by a) partial acid saponification of o-chloromethylbenzoyl cyanide of formula II to o-chloromethylphenylglyoxylic acid amide of formula III, and b) reaction of the o-chloromethyiphenylglyoxylic acid amide so obtained in any order or concurrently with O-methylhydroxylamine and with a R-OH alcohol, wherein R is C 3 -C 8 alkyl, according to the scheme ROH III The invention also relates to the novel o-chloromethylphenylglyoxylic acid amide product of formula III as well as to the novel o-chloromethylphenylmethoximinoglyoxyhc acid esters of formula I, wherein R is C 5 -C 8 alkyl, preferably Cs-Cβalkyl The process of this invention has the surpπsing advantage of affording the novel amide III in crystalline form in high yield and puπty The use of pure amide III for prepanng the com¬ pounds of formula I constitutes another advantage of the present process The invention also relates to the use of the compounds of formula I as intermediates containing a reactive o-chloromethyl group for prepaπng pesticides Such pesticides can be fungicides, insecticides, acaπcides, nematicides or herbicides such as are disclosed in EP- A-254426, EP-A-460575, EP-A-463488, EP-A-472300, EP-A-299694, EP-A-253213, WO- 95/18799, WO-95/21153 as well as in other publications Working Examples W-1 Preparation of o-chloromethylphenylglyoxylic acid amide III A) 20 g of hydrochloric gas (0.55 mol) are introduced to a suspension of 179.6 g of o- chloromethylbenzoyl cyanide (1 mol) in 400 g of acetic acid over 1 hour. To this mixture are then added 31 .8 g of 32% aqueous hydrochloric acid (1.2 mol of water). The suspension is stirred for a further 28 hours at room temperature. The product, which is partly crystallised, is isolated by filtration, washed with 2x50 ml of n-pentanol and 2x50 ml of hexane and then dried. Yield: 89.2 g (45.1 %). The mother liquor is recycled in the next batch as diluent. B) 33.1 g of acetic acid are added to a suspension of 179.6 g of o-chloromethylbenzoyl cyanide (1 mol) in 482.9 g of mother liquor of the preceeding batch and then 5 g of hydro¬ chloric gas (0.14 mol) are introduced. 24.3 g of aqueous 32% hydrochloric acid (0.92 mol of water) are added to the reaction mixture at room temperature. The reaction mixture is stirred for 21 hours at room temperature and then filtered. The crystals are washed with pentanol and hexane and then dried. Yield: 172.8 g (87.4%). The mother liquor (486.1 g) is used as diluent in the next batch. W-2 : Preparation of o-chloromethylphenyl-O-methoximinoglyoxylic acid pentyl ester Over one hour, 50 g (1.37 mol) of hydrochloric acid gas are introduced to a cooled suspension (0° to -10°C) of 41.8 g of O-methylhydroxylamine hydrochloride (0.5 mol) in 250 g of n-pentanol. The mixture is then heated to about 50°-55°C and a first portion of o- chloromethylphenylglyoxylic acid amide (49.4 g; 0.25 mol) is added. The mixture is stirred for 2 hours at 50°-55°C and then a second portion of o-chloromethylphenylglyoxylic acid amide (49.4 g; 0.25 mol) is added. The mixture is stirred for 24 hours at 50-60°C and then cooled to 20°C amd diluted with 175 ml of water. 159.7 g of a 30% aqueous sodium hydroxide solution are added such that the temperature is kept at 20°-30°C. The organic phase is isolated, dried and concentrated. Yield: 133.1 g (79%). The E/Z isomer ratio based on the O-methyloxime side chain is 92.6 : 7.4. Replacing n-pentanol in the above process with methanol would result in a very unfavourable E/Z isomer ratio of 83 : 17. W-3 : Preparation of 2-[α-{[(α-methyl-3-trifluoromethylbenzyl)imino]oxy}-o-tolyl]glyoxylic acid pentyl ester-O-methyloxime 87 g of a 30% sodium methylate solution in methanol are added dropwise to a solution of 98.2 g of 3-trifluoromethylacetophenonoxime (0.48 mol) in 200 ml of dimethyl acetamide over 20 minutes. 196 ml of solvent are then distilled off under a slight vacuum at 55°-70°C. After the addition of 1 g of potassium iodide, 150 g of o-chloromethylphenyl-O-methoximino- glyoxylic acid pentyl ester having a purity of 95.9% (0.48 mol) are added over 1 hour at 55°- 65°C. After 2 hours, the reaction mixture is added over 30 minutes to a mixture of 400 ml of water and 250 ml of toluene at room temperature, the pH being adjusted to 5 with concentrated hydrochloric acid. The aqueous phase is extracted twice with 150 ml of toluene. The combined organic phases are washed with 150 ml of water. The solvent is distilled off under vacuum at 60°C. 227 g of crude oil are obtained having a 83% content.

Claims: What is claimed is 1 A process for the preparation of an o-chloromethylphenylmethoximinoglyoxylic acid ester of formula I wherein R is C;rC 8 alkyl, in which process o-chloromethylphenylglyoxylic acid amide of formula III is, in any order or concurrently, a) oximated with O-methylhydroxylamine and b) estenfied under acid conditions with a C 3 -C 8 alkanol, in the presence or absence of a diluent 2 A process according to claim 1 , which compnses carrying out oximation and esterification concurrently 3 A process according to claim 2, which compnses carrying out the reaction in the temperature range from 20°C to 70°C 4 A process according to claim 3, which comprises carrying out the reaction in the temperature range from 40°C to 70°C 5 A process according to claim 1 , which comprises using the C 3 -C 8 alkanol reactant as diluent 6 A process according to claim 5, which comprises using n-pentanol 7 A process for the preparation of o-chloromethylphenylglyoxylic acid amide of formula by partial hydrolysis of o-chloromethylbenzoyl cyanide of formula 8 A process according to claim 7, which comprises carrying out the acid hydrolysis with 0 8 to 1 5 mol of water in the temperature range from 10°C to 50°C 9 A process according to claim 7, which compnses carrying out the reaction in concen¬ trated acetic acid with the addition of hydrochloric gas and/or concentrated aqueous hydrochloπc acid 10 A process for the preparation of an o-chloromethylphenylmethoximinoglyoxylic acid ester of formula I wherein R is C 3 -C 8 alkyl, which process comprises a) partial acid saponification of o-chloromethylbenzoyl cyanide of formula II to o-chloromethylphenylglyoxylic acid amide of formula 111 and b) conversion of the o-chloromethylphenylglyoxylic acid amide so obtained, in any order or concurrently, with O-methylhydroxylamine and with a C 3 -C 8 alkanol. 11 A process according to claim 10, which comprises using a C 5 -C 6 alkanol 12. A process according to claim 11 , which comprises using n-pentanol 13 The compound of formula III 14 A compound of formula wherein R is C 5 -C 8 alkyl 15 A compound of formula I according to claim 14, wherein R is Cs-C-βalkyi 16 A compound of formula I according to claim 15, wherein R is n-pentyl 17 A compound of formula IV wherein R is C 5 -C 8 alkyl, and A is -N=CR 2 R 3 , and R 2 = hydrogen, d-dalkyl, d-dhaloalkyl; R 3 = d-dalkyl, aryl-Cι-C 4 alkyl, aryl, or aryl which is substituted by one to three halogen, Ci- dalkyl, d-dhaloalkyl. 18. A compound of formula IV according to claim 17, wherein R is C 5 -C 6 alkyl, and R 2 = d-dalkyl; R 3 = Ci-dhaloalkyl-substituted aryl. 19. A compound of formula IV according to claim 8, wherein R is n-pentyl, and R 2 = methyl, and R 3 = 3-trifluoromethylphenyl.

Inventors: ASSERCQ JEAN-MARIE, BREITSCHUH RICHARD, PFAFF WERNER, ASSERCQ, JEAN-MARIE, BREITSCHUH, RICHARD, PFAFF, WERNER
Applicants: ASSERCQ JEAN MARIE, BREITSCHUH RICHARD, CIBA GEIGY AG, PFAFF WERNER, ASSERCQ, JEAN-MARIE, BREITSCHUH, RICHARD, NOVARTIS AG, PFAFF, WERNER
Application year: 1996
Main classification: C07C249
IPC codes: C07C231, C07C235, C07C249, C07C251