CA2026761C - Preparation of isoxazole-4,5-dicarboxylic diesters - Google Patents

Abstract

A process for preparing novel isoxazole-4,5-dicarboxylic diesters of the formula I
(see formula I) where R1 is an aliphatic radical of 1 to 20, cycloaliphatic radical of 3 to 10, aromatic radical of 6 to 10, heteroaromatic or heterocyclic radical of 3 to 10 or araliphatic radical of 4 to 12 carbon atoms, each radical being unsubstituted or substituted by substituents which are inert under the reaction conditions, and where R2 and R3 are each alkyl, comprises reacting an aldoxime of the formula II
(see formula II) with an acetylenedicarboxylic diester of the formula III
R2OOC-C~C-COOR3 (III) in solution, in the presence of an aqueous solution of a hypohalite in the pH range from 5 to 10.

Description

o.z. 0050/~11~5 The preparation of isoxazole-4 5-dicarbox~~lic diesters The present invention relates to a process for preparing isoxazole-4,5-dicarbaxylic diesters of the formula I

R1 NI 0 I ORS (I) where R1 is an aliphatic radical of 1 to 20, cycloaliphatic radical of 3 to 10, aromatic radical of 6 to 10, heteroaromatic ar heterocyclic radical of 3 to 10 or aratiphatic radical of 4 to 12 carbon atoms, each radical being unsubstituted or substituted by substituents which are inert under the ruction conditions, and where RZ and R3 are each alkyl, and to novel isoxazate-4,5-dicarbaxytic diest~rs~.
Isoxazole derivatives, including isoxazale-4,5 dicarboxytic diesters, can be Qrepared by 1,3-dipotar cycloaddiaion of nitrite oxides IV auto dauble ar, in particular, triple bonds as shown in the general equation (1).
R-CAN--s0 + X-CdC-Y -> R N°~0 I Y ( 1 ) IV
Because the nitrite axides IV required for the reaction are very reactive and only few of those known are stable after isolation, it is usually necessary to generate those required for the reaction according to equ~~tion (1). 3.n situ in the reaction mixture.
Tho generation of nitrite oxides generally starts fro~a correspondingly substituted nltrome~thyl compounds ~~~~r~s~ ~.

- 2 - o.~. ao5~o4145 which react with activating agents such as phenyl iso-cyanate, acetic anhydride or acetyl chloride in the presence of catalytic or stoichiometric amounts of bases, such as sodium acetate, sodium alcoholates or tart.
amines to give adducts which are unstable under the reaction conditions and spontaneously decompose to the corresponding nitrite oxides (cf. Chem. Pharm. Bull. z6 (1978) 3254-3256 and 28 (1980) 3296-3303; Tetrahedron ~0 (1974) 1365-1371 and 42 ((1986) 3825-3840; Bull. Chew.
Soc. Jpn. 59 (1986) 2827-2831). Furthermore, the nitrite oxide IV can be obtained from the relevant nitramethyl compounds by acid-catalyzed elimination of water (Bull.
Chem. Soc. Jpn. 57 (1984) 2531-2534).
These processes for preparing isoxazole deriv atives have the disadvantage that many nitromethyl derivatives are toxicologically unacceptable and the preparation thereof is elaborate in some cases and often uneconomic. Furthermore, the reaction of the nitromethyl derivatives to give the corresponding nitrite oxides and subsequently to give the relevant isoxazole derivatives results in a considerable quantity of various by-products which are very costly to remove. Accordingly, these processes are generally not suitable for transfer to the industrial scale.
This is why processes have been developed for generating the nitrite oxides by oxidizing the corres-ponding aldoximes using inorganic hypochlorites. These processes (cf. DF-A 27 54 832; Synthesis (1982) 508-509) have the advantage that the niarile oxides can be pre pared from the aldoximes which are easily obtainable from the corresponding aldehydes. The disadvantage of these processes is that their applicability is limited. Thus, to date it has been possible in this way to prepare only isoxazole derivatives with alkyl or aryl substituents, but not isoxazole-4,5-dicarboxylic diesters, One possible reason for this is that the acetylenedicarboxylic di-esters required as dipolarophile for preparing these ~L~~~~~~~~

3 - O.Z. 0050/41145 compounds are themselves so reactive that they react very vigorously with the relevant aldoximes even in the absence of the hypochlorite oxidizing agent (see Compara°
tive Experiment .~). Especially in the pxesence of cata-lytic amounts of bases (hypohalites are bases) this reaction takes place in an uncontrolled and almost explosive fashion (see Comparative Experiment ~).
Since isoxazole-4,5-dicarboxylic diesters are intermediates for preparing crop protection agents, it was an object of the present invention to develop a process which allows them to be prepared at low cost from easily obtainable starting compounds, eg. aldoximes.
Another object was to find novel isoxazole-4,5-dicar-boxylic diesters which are suitable as intermediates for preparing crop protection agents.
We have found that this object is achieved by a process for preparing isoxazole-4,5-dicarboxylic diesters of the formula _T

N) ~OR3 (r) (Y~0 where Rl is an aliphatic radical of 1 to 20, cycloaliphatic radical of 3 to 10, aromatic radical of 6 to 10, heteroaromatic or heterocyclic radical of 3 to 10 or araliphatic radical of 4 to 12 carbon atoms, each radical being unsubstituted or substituted by substituents which are inert under the reaction conditions, and where ' RZ and R3 are each alkyl, which comprises reacting an aldox3.me of the formula II

Ri H
(II) N
OOH
with an acetylenedicarbox~:rlic diester of the formula III
R200C-C-C-COOR3 (III) in solution of an organic solvant, in the presence of an aqueous solution of a hypohalite in the pH range from 5 to 10.
Furthermore, novel isoxazole-4,5-dicarboxylic diesters of the formula I' li RZi R ~ ~ ~U (I~) N~R3~
where R1~ is C3-Cg-alkyl, ethenyl, isopropenyl, or monocyclic C3-Cg-cycloalkyl or C5-Cg-cycloalkenyl which is unsubstituted or substituted by 1, 2 or 3 Cl-C4-alkyl groups, or C1-C6-alkyl or which is substitued by 1,2 or 3 C3-C~-cycloalkyl, Cl-C4-alkoxy, halogen and/or cyano groups, or C2-C6-alkyl which is substituted by 1, 2 or 3 unsubstituted phenyl groups or 1, 2 or 3 phenyl groups substituted by halogen and/or C1-C4-alkyl, or tetrahydrofuryl, tetrahydro-pyranyl, dioxolanyl, dioxanyl or dioxepanyl, each of which is unsubstituted or substituted by 1, 2 or 3 C1-C3-alkyl and/or halogen groups, and where R2~ and R3' are identical or different and are each C1-C4-alkyl.
The process according to the invention makes it possible for the first time to prepare isoxazole-4,5-dicarboxylic diesters I from the aldoximes II and acetyl-enedicarboxylic diesters III in accordance with ~~~~"~~~.

- 5 - O.Z. 0050/41145 equation (2):

+ R ZOOC-CSC-COOR 2 h~°halite R 1 ~ ( COOK 2 N~OH N~0 C00R3 II III I
In this reaction, the aldoxime II is oxidized in the reaction medium by the hypohalite to the correspond-s ing nitrile oxide which is a very reactive 1,3-dipole and is continuously removed, as it is produced, by the dipolarophile acetylenedicarboxylic Blaster, which is likewise present in the reaction medium, in a 1,3-Bipolar cycloaddition to form the isoxazole compound I.
The hypohalites generally used in the process according to the invention are hypobromites and hypo-chlorites, preferably the latter. It is possible to use for this purpose aqueous solutions of hypochlorous or hypobromous acid, but preferably alkali metal or alkaline earth metal hygochlorites or hypobromites are employed, for example sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, magnesium hypochlorite, strontium hypochlorite, barium hypochlorite or the corresponding hypobromites. Sod~.um, potassium and calcium hypochlorite are particularly preferred, specifically ~.n the form of their commercial aqueous solutions. It is, of course, also possible to use mixtures of various hypohalite solutions in the process according to the invention.
Since the'hypohalites are generally added as aqueous solutions to the reaction mixture, whereas the acetylenedicarboxylic diesters xzL are usually insoluble or only slightly soluble in the a~aeous phase, this addition usually results in two phases. In order to avoid reaction between the acetylenedicarboxylic Blaster III
and the aldoxime II, the compounds are exp~diently dissolved in an organic solvent. It is possible to use for this purpose both; solvents which arc immiscible with - 6 - O.Z. 0050/41145 the aqueous phase and those which dissolve in both phases, the organic and the aqueous, and thus produce a homogeneous reaction medium.
Examples of solvents suitable for the process according to the invention axe alcohols such as methanol, ethanol, propanol or isopropanol, ketones such as acetone or methyl ethyl ketone, ethers such as diethyl ether, methyl tent-butyl ether, tetrahydrofuran or dioxane, hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, white oils or naphtha, aliphatic halo-hydrocarbons such as methylene chloride, chloroform, tetrachloromethane, dichloroethane, trichloroethane, tetrachloroethane or perchloroethane, aromatic compounds such as benzene, toluene, xylenes or chlorobenzenes, esters such as ethyl acetate, and dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane etc. It is, of course, also possible to use mixtures of solvents.
The concentration of the solutions of the.aldox ime and of the acetylenedicarboxylic diester in the particular solvents is not in general critical for the success of the process according to the invention, ie. it is possible to employ both dilute and relatively concen-trated solutions of these compounds. It is self-evident that the concentration of the solutions of the aldoxime and the acetylenedicaxboxylic diester also depends on the solubility of these compounds in the particular solvent used> However, it is expedient to use from 0.1 to 2 molar solutions of the aldoximes and of the acetylenedi-carboxylic diester~.
When solvents which are insoluble in water are used it may be advantageous for the progress and result of the reaction to add phase-transfer catalysts such as quaternary ammonium or phosphonium salts, eg. triethyl-benzylammonium chloride, tri,methylbenxylammonium bromide, triphenylbenzylammonium chlorid~, rnethyltributylammonium iodide, tetrabutylammonium bisulfate or benzyltributyl-phosphonium bromide, to tha reaction medium in amounts - 7 - O.Z. 0050/41145 of, in general, from 0.1 to 10 g/1 of reaction mixture.
It is expedient to stir the reaction mixture particularly vigorously when the system contains two or more phases.
The temperature at which the reaction is carried out can vary within wide limits. As a rule, the reaction takes place at -15°C or even lower, and the upper temper ature limit is determined in principle only by the boiling point of the solvent used, because the reaction is expediently carried out under atmospheric pressure. zt is expediently carried out at from 0 to 40°C. The reac-tion can also be carried out under elevated pressure, especially under autogenous pressure, but atmospheric pressure is preferred.
In order for the process according to the inven tion to succeed, and in particular to avoid the side reactions which have bean described above plus some others, it is particularly important to carry out the reaction in the pH range.fram 5 to 10 and particularly advantageously from 6 to 8, ie. when using a two-phase system that the pH of the aqueous phase is within this range, while when using a homogeneous reaction mixture that this is the pH of the aqueous/organic mixture.
It is expedient to adjust the desired pH of the aqueous phase or of the aqueous/arganic solution using buffer substances or solutions before addition of the hypohalite. Then, dubing the addition of hypohalite, the pH is advantageously checked continuously and kept in the desired pH range, preferably constant, by adding further buffers or acids o~ alkalis if necessary.
The buffer systems which can be used are in principle all those able to exert their buffering action in the stated pH range. However, conventional buffers such as sodium bicarbonate, sodium acetate or the sodium dihydrogen phosphate/disodium hydrogen phosphate buffer system are preferably used. The buffers can be added to the reaction mixture as solids,..but buff~r solutions are expediently used. The strength of the buffer solutions ~~'~~'~~~.
._ 8 - O.Z. 0050/41145 can in principle be chosen arbitrarily, but in general from 0.1 to 1 molar buffer solutions are used in order not to have to handle excessive quantities of liquid.
The procedure for the reactions is usually such that all the components of the reaction system, except for the hypohalite, are introduced into the aqueous/
organic reaction mixture, and then the hypohal3.te solu tion is added to this mixture while stirring vigorously and continuously monitoring the pH. The optimal rate of hypohalite addition depends in general on the reactivity of the reactants and is expediently determined in a preliminary test.
It may prove advantageous when reacting sensi tive, ie. particularly reactive, compounds II and/or III
to introduce only one of these into the buffered reaction mixture and then to add the other reactant at the same time as the hypohalite. Another possibility in this case is to introduce one of the reactants II or III completely and the other reactant only in .a small amount, for example one tenth of the amount required, and to add the remainder of this reactant at the same time as the hypohalite to the reaction mixture. The addition of the hypohalite solution is advantageously controlled so that the concentration of hypohalite and nitrila oxide in the reaction mixture is never high.
To prepare the isoxazole-4,5-dicarboxylic di-esters I it is expedient to react equimolar amounts of the aldoxime II and of the acetyhnedicarboxylic di-ester III with the hypohalite. The hypohalite can be added in the stoichiometric amount to the reaction mixture, but as a xule a slight excess, up to a 'two-fold excess, will be metered into the reaction mixture. It may be advantageous, for technical reasons, to limit the conversion by using less than the stoichiometri,c amount of hypohalite, for example from 50 to 90 mol-% of hypo-halite per mole of II. It is likewise possible to use amounts of the reactants II or III which are above or - O.Z. 0050/4115 below stoichiometric.
The process according to the invention otherwise displays no technical peculiarities so that further details are not necessary. The process can be carried out by conventional techniques, such as use of tube reactors or stirred vessel cascades, and continuously. Since the isoxazole derivatives I generally are preferentially soluble in organic solvents, the working up of the reaction mixture and the isolation of the isoxazole-4,5-dicarboxylic diesters can usually be carried out in a conventional manner, by extraction, distillation or crystallization. Excess hypohalite, which may impede working up, can be destroyed by adding reducing agents such as iron(II) sulfate, thiosulfates or sulfites.
The aldoximes II required in the process accord-ing to the invention are either known or can be easily prepared by generally known processes (see, for example, Houben-Weyl, Methoden der organischen Chemie, Vol. 10/4, pages 55 to 66, Thieme, Stuttgart 1968) by reacting the corresponding aldehydes with hydroxylamine. The aldox imes II can, of course, be used both in the form of their E or Z isomer and as mixtures of these stereoisomers. The acetylenedicarboxylic diesters are available commercially or by known methods ( see, for example, Organic; Syntheses, Coll: Vol. 4, page 329).
The process according to the invention fox preparing isoxazole-4,5-dicarboxylic diesters I can be applied virtually universally. Thus, it is possible to obtain compounds I from the correspanding aldoximes II
where R1 is an aliphatic radical of 1 to 20, a cycloali-phatic radical of 3 to 10, an aromatic radical of 6 to 10, a heteraaromatic or heteracyclic radical of 3 to 10 or an araliphatic radical of 4 to 12 carbon atoms.
The upper limit on the number of carbons in Rg is deter-mined so~.ely by the utilizability of the relevant com-pounds and daes not derive from a lack of applicability of the process according to th~ invention when Ri is - 10 - O.Z. 0050/411A5 larger.
The R1 radicals can also be substituted. The nature and the number of the substituents can in princi-.
ple be chosen as desired, naturally on the condition that they are chemically possible, and on the condition that the substituents are inert to the oxidizing agent, ie.
the basic hypohalite solution, and to the nitrite oxide which is formed in situ under the reaction conditions.
Thus, the process according to the invention can be used to prepare isoxazole derivatives I where the aliphatic, araliphatic or cycloaliphatic radicals R1 contain double bonds or in which the carbon chains are interrupted by hetero atoms, especially oxygen atoms.
The nature of RZ and R3, which are introduced into the compound I from the acetylenedicarboxylic diester, is not in general critical for the progress of the reaction and can accordingly be chosen as desired. However, RZ and R3 are expediently each alkyl, in particular C1-C4-,alkyl.
R2 and R3 can be identical,or different. If they are different, the cycloaddition of the nitrite oxide IV
with the acetylenedicarboxylic diester III generally results in a mixture of the regioisomers Ia and Ib it1 COORZ R1 COORS
N) I COOK 3 NI ( COOR 2 Ia I~
in a ratio which i~ essentially determined by the steric requirements of R1, RZ and R3. This effect is not critical and may even be desired depending on how the intermediate compounds are to be further processed. however, in general, acetylenedicarboxylic diesters III where R2 and R3 are identical axe preferably reacted to give compounds I.
It is possible. and advantageous to prepare by the process according t~ the invention isoxaxoha-4,S-di-~~~~~'"~~.
- 11 - O.Z. 0050/41145 carboxylic diesters I where R1 is C1-Clo-, especially C1-Cs-, alkyl, Cz-Clo°. especially Cz-Cs-, alkenyl, C3-CB-, especially C3-C,-, cycloalkyl or cycloalkenyl, a 5- to 7-membered aromatic or cycloaliphatic heterocyclic radical which contains one or two oxygen, nitrogen and/or sulfur atoms, especially oxygen and/or nitrogen, or phenyl or benzyl.
R1 can be unsubstituted or carry substituents which are inert under the reaction conditions.
Thus, alkyl or alkenyl can carry, depending on the size of Rl, 1, 2, 3, 4 or 5, preferably up to 3, identical or different substituents such as C3-C,-cyclo-alkyl, C1-C3-alkoxy, halogen, cyano or phenyl, it being possible for the phenyl in turn to be substituted by up to 3, preferably one or two, of the substituents halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy, cyano or vitro, and the substitution pattern of these phenyl substituents not being critical in general.
R1 as alkyl can be straight-chain or branched. It is possible and particularly advantageous to prepare according tc~ the invention compounds I where R' is alkyl which is substituted by C1-C4-alkoxy, halogen and/or phenyl, the latter being substituted by, preferably, halogen atoms and/or Ci-C4-alkyl groups.
It is self-evident to those skilled in the art that the number of substituents depends on the number of carbon atoms in the aliphatic radical R1. The substitution pattern of the aliphatic radical R1 is not in general critical for the ruction according to the invention.
It is also possible and advantageous to prepare by the process according to the invention isoxazole.
derivatives I where one carbon atom is substituted by up to 3 of the said substituents, in particular C1-C$-alkoxy or halogen substituents. Thus, it is possible and advant-ageous to prepare compounds I where the aliphatic radi-cal, especially the alkyl radical, Rl contains the group ~~,~Hl :~.
- 12 - o.z. 0050141145 ~c(oR4) a,-cM(oRw) a ox °c(oR~) 3 where RG is C1-C4-alkyl, ie. acetal, ketal or orthoester moieties.
The cycloalkyl groups R1 can be substituted, depending on their size, by 1, 2, 3, 4 or 5, preferably by up to 3, identical or different C1-C4-alkyl, C1-C3 alkoxy or halogen substituents.
It is also possible and advawtageous to produce by the process according to the invention isoxazole-4,5 dicarboxylic diesters where Rz is a 5- to 7-membered heterocyclic radical which can b~ substituted by Z to 3 identical or different C1-C4-alkyl, C1-C4-alkoxy, and/or C1-C4-alkoxycarbonyl, particularly preferably, Cl-C4-alkyl groups: Heterocyclic R1 can be aromatic or cycloaliphatic in nature. Heteroaromatic radicals R1 can contain 1 or 2 oxygen, nitrogen and/or sulfur atoms. It is possible and advantageous to prepare by the process according to the invention the isoxazole derivatives I where R1 is substi-tuted or unsubstituted thienyl, pyridyl, pyrazinyl, pyrianidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazo-lyl, thiazolyl, isoxazolyl and isothiazolyl.
It is likewise possible and advantageous to prepare isoxazole derivatives I according to the inven-tion where R1 is a 5- to 6-membered cycloaliphatic radi-cal which contains 1 or 2 nitrogen and/or, preferably, oxygen atoms. Examples of such heterocycloaliphatic radicals Rl are substituted or unsubstituted tetrahydro-furyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, oxepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl, 1,5-d~.oxepanyl, pyrrolidinyl, imidazolidinyl, piperidinyl or piperazinyl.
It is also possible and advantageous to prepare by th~ process according to the invention .isoxazole derivatives I where R1 is substituted or unsubstituted C6-Clo-aryl or C,-C12-aralkyl, in particular phenyl or benzyl. The aryl radicals, especially phenyl, can carry 1, 2 or 3 identical or different C1-C6-alkyl, C1-C6-halo-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, halogen, nitro or cyano groups.
It is also possible and advantageous to prepare by the process according to the invention in particular the novel isoxazole-4,5-dicarboxylic diesters of the formula I' Rl OR2~
NI O~OR 3' where Rl~ is C3-CB-alkyl, CZ-Clo-alkenyl, or monocyclic C3-Ce-cycl.oalkyl or CS-Ce-cycloalkenyl which is unsubstituted or substitut-ed by 1, 2 or 3 C1-C4-alkyl groups, or C1-C6-alkyl or CZ-C6-alkenyl which is substituted by 1, 2 or 3 C3-C,-cycloalkyl, C1-C4-alkoxy, halogen and/or cyano groups, or Cz-C6-alkyl or -alkenyl which is substituted by 1, 2 or 3 unsubstituted phenyl groups or 1, 2 or 3 phenyl groups substituted by halogen and/or C1-C4-alkyl, or tetrahydro-furyl, tetrahydropyranyl, dioxolanyl, dioxanyl or dioxe-panyl, each of which is unsubstituted or substituted by 1, 2 or 3 Cl-C3-alkyl and/or halogen groups, and where R2~
and R3' are identical or different and are each C1-C4-alkyl.
These novel isoxazole-4,5-dicarboxylic diesters are used as intermediates for preparing the novel isoxazole-5-carboxamides with herbicidal activity which are described in European laid-open Patent Application EP-A-0337263.
The alkyl groups R1~ in the novel isoxazole-4,5-dicarboxylic diesters can be straight-chain or branched.
Particularly preferable with a view to the activity of -- 1~ - O.Z. 0050/1145 the herbicides prepared therefrom are C3- and C4-alkyl, in particular isopropyl, sec-butyl arid isobutyl.
The CZ-C8-alkenyl groups R~' in the novel com pounds I' can likewise be straight-chain or branched and contain one or twa double bonds. Particularly preferable with a view to the activity of the crop protection agents prepared therefrom are ethenyl and isopropenyl.
Preferred cycloalkyl groups Rz' are cyclopropyl and methyl-, ethyl- and dimethylcyclopropyl.
Particularly preferred substituted alkyl groups R'' are C1-C3-alkoxymethyl, di-C1-C3-alkoxymethyl, a-C1-C3-alkoxyethyl, a-C1-C3-alkoxypropyl and a-C1-C3-alkoxybutyl, and ethyl, propyl, isopropyl, isobutyl, sec-butyl and n-butyl each of which is substituted by 1 to 3 fluorine, chlorine or bromine atoms.
Preferred isoxazole-4,5-dicarboxylic diesters I' with heterocyclic radicals R~' are those where R1' is tetrahydrofuryl, tetrahydropyranyl, 1,3-dioxanyl and dioxolanyl.
EXAMPLES
COMPARATIVE EXPERIMENT At 1.8 g (0.01 mol) of diethyl acetylenedicarboxyl-ate and 0.59 g {0.01 mol) of acetaldoxime were mixed at room temperature, the solution immediately becoming yellow. The temperature of the mixture rose to 60°C
within 8 min, after which it was cooled by immersing the vessel in a dry ice/acetone bath (-60°C). A sample was taken from the resulting tarry product after 1~ hours and was analyzed. The c~as chromatogram showed a large number of compounds, acetaldoxime being no longer detectable.
COIdPARATIVE EXPERIMENT Bs 5 g of dimethyl acetylenedicarboxylate and 5 g of acetaldoxime were mixed, and one drop of 10 ~ by weight sodium hydroxide solution was added. The mixture turned yellow and heated up within 20 sec to 150 to 200°C (d) so that it started to boil out of the reaction vessel.
After the reaction subsided, the flask contained a black - 15 - O.Z. 0050/41145 tarry mass which was not investigated further.

A mixture of 59 g (1.0 mol) of acetaldoxim~, 17.8 g (0.1 mol) of disodium hydrogen phosphate dihy drate, 15.6 g (0.1 mol) of sodium dihydrogen phosphate dehydrate, 400 m1 of methylene chloride and 400 ml of water was cooled to 0°C. The pH of the aqueous phase was adjusted to 7, and then 14.2 g (0.1 mol) of dimethyl acetylenedicarboxylate were added to the mixture. To this vigorously stirred mixture were added dropwise, at from 0 to 10°C, simultaneously but separately 128 g (0.9 mol) of dimethyl acetylenedicarboxylate dissolved in methylene chloride (420 ml of solution) and 420 ml of a 13.4 ~ ?~v weight aqueous solution of sodium hypochlorite (0.9 mol) over the course of 2 hours, during which the pH was continuously checked and maintained constant by adding hydrochloric acid or sodium hydroxide solution. Subse-quently a further 93 ml of sodium hypochlorite solution (0.2 mol) were added dropwise. The mixture was then stirred for 2 hours, after which the aqueous phase was separated off and extracted twice with methylene chlor-ide, and the organic phases were combined, washed with water, dried over sodium sulfate and distilled to remove solvent.
Dimethyl 3-methylisoxaole-4,5-dicarboxylate was obtained in a yield of 98 ~ of theory.
The product was further purified by vacuum distillation, after which the yield was 89.5 ~ of theory.
Melting point 34-35°C

100 ml of methylene chloride, 400 ml of water, 17.8 g (0.1 mot) of disodium hydrogen phosphate dehydrate and 15.6 g (O.l mo1) of sodium dihydrogen phosphate dehydrate were mixed and the pH of the aqueous phase was adjusted to 6.5. At 15°C, 142 g (1.0 m1) of dimethyl acetylenedicarboxylate were added, fallowed by 5.9 g (0.1 mol) of aoetaldoxim~. Then, simultaneously but - 16 - O.z. 0050/41145 separately, a solution of 53.2 g of acetaldoxime (0.95 mol) in 550 ml of methylene chloride and 550 ml of a 13.4 ~ by weight aqueous solution of sodium hypochlo-rite (1.15 mol) were added dropwise over the course of 3 hours while the reaction mixture was vigorously stirred and its pH was continuously checked. After the addition was complete, the mixture was stirred for 2 hours and then worked up as described in Example 1.
Yield: 91.5 ~ of theory.

To 4 . 2 g ( 0 . 03 mol ) of lpethylpyrazole-4-aldoxa.me in 40 ml of methylene chloride were successively added, at 0°C, 6.4 g (0.045 mol) of dimethyl acetylenedicar-boxylate and 0.1 g of triethylbenzylammonium chloride.
Then 50 ml of an approximately 12 ~ by weight sodium hypochlorite solution were added dropwise over the course of one hour, after which the reaction mixture was stirred overnight and then worked up as described in Example 1.
The crude product was purified .by chromatography on silica gel (eluent: 3/1 (v/v) cyclohexane/ethyl acetate).
Yield of dimethyl 3-(1-ethyl-4-pyrazolyl)isoxa zole-4, 5-dicarbaxylate: 30 ~ of theory ( see table for P1MR
data) EXAMPhES 4 TO 29 Examples 4 to 29 were carried out in a similar manner to Example 2. The results of these reactions are listed in the table which contains, apart frori the isoxazole derivatives I prepared, data on the reaction temperature, yield, melting point (m. p.) for crystalline compounds or boiling point (b. p.) if the products were distilled, and the principal data of the 250 MHz 1H-1~1MR
spectra of these compounds in deuterochloroform (CDC13).
The following abbreviations are used in the table:
Me: methyl;
Et: ethyl;
iPr: isopropyl ~0~~'~~~.
- 17 -- O.Z. 0050/41145 c-Pr: cyclopropyl;

t-Hu: tert-butyl;

s: singlet;

d: doublet;

to triglet;

q: quartet;

ms multiplet;

~i~~~r~~:~.
.- m -. o.z. oQ~o~~m5 ..

M..~
g ~, .

cV _ ~
~
N
i .. NM u1 .
v -v' o ~ x M M

_ ~,"~~ M N .-n r,~ N
s C9 U d . ~ s a p .. v N~ V1 Md V . a ~ ~ J . .,Qy E Z ~ a .
S ~-~

~ 1 .,r MM.-~ E

~ E MM

tIl ~ ~ f0 ~ w'-'ue....
N

NtplL1 X ~ ~, ~p C

i ~ N ICf .U M ~ W
O O~ 01 W

G! , o .
N~ N ~Mf~. i .
~'1 e ~
~

~ ~ ,- .-a ..
...
..

N

fIl N

L L

a v c~ '~ ' U

. O O ~

\ \
.a ~ W f7 w M M M U U

I ~ i ~ ~ I

d M M M ,-a E

8g ~ 3$
.

-C , .r Q1 .r Q M ~ .-a CO O1 tb CO r.Q1 d1 U

O
~

v c ~

~ ~ ~ Q o w m n ro r ~ " N a-a 161 N
6.

i-~ ~ tC1 O G7 V N
d t0 E

M , Oi M

CC

~ ~ ~ ~ ~ ~ ~ ~

~
- a 47 N ~ ~ asa.,, ~ ~ t , s ~ w ~
~ .

d m.

x ~. N c1 ~ a<1 GO
tD
n f.. w ~fi~~~"~~ ~.
- 19 - O.Z, 0050/41145 s .. . M
..

r o n ~ ~
~ n .r ~ ~ c c r~-c l -eo v .. _ .. a ..

N x~ ~ VI r..l e~' v E E

~ ~ _ ier ~

. c~ cs O o~M Ic .

NZ U1 VI ~ Cr'1~9'M.? Zd ~tT1 _ td'1~....y..~. .. ..t,~ .., M ~ tT M~ Ch ~GO ~t .~~

.-, = m v e~ 2 ~ z Vi =
V9 r a U -9"~ M M~ M -~M NM ~D~

O ,p~ ~" .... ..~ ."." ..

Y A
' ~ E ~ ~i ~
' g - M zm as xui g x -N ~ MM lD 661M Id~M.~ .~.o.-..
~ " "~ .
.

QC a ~ .vr .~. s s a~ o~
~~ 'C9 .. vi 'v cn N N N x ~.-.
~ ~n x vi'o vy x x I wM d..r.H~.ta1i ! I .-r I
.-~M ~w.e ..., t C~ ~Ohape u1 O~ON1Cpo tL"f .4'~9 v ; ' ~~
s ~

s ~-a'~1.~ie'r1M- . ~ s-.~tC1.- a r L L

E

M N

d , O O

"~ U

V

O O ! I 1 !

.~ O

a o N

E

. -D

N~ ~ d&, 8S ~ 'be 3e ~ ~ ~ ~

n ~ ~ ~

p ~

C p 161 i.i p. <"" tf1 -4 c0 P ~ O O C id1 I I

~ "~ ,.,,.., P, I o v 1 O

U 1 ~
a ~

c0 E

~, ~

-- 20 ~. O.Z. 0050/42.45 s c~ N ~.
1 ~f9 o ~ O

p~pp ...M~6'1~~- ~ .

M ~ . ~'f~1~

NN"J ~ ....gN gn ~
N

m ~ Z
c..

, of ~
~

, ~~ ~ M ,~ ~~
~
~

~ "~V
' Op . O
r'Z M1 ~ VI 6 Cn a Vi -..~'e .

. e ~ ~
.

.p~ r r . .~tp N

~ r Z Z ~C~'t~~I~
~

o ~.r~ ~ , ~ , ~ ..~

~v ve y,..
, +JZ~ g tllZ'$,' 1 ~ ~~ ~ ~VM ~'y p~ .~ c'~7 cs~

Hmne Nv a E

'P

v ..., ~ o c " .e.

.r L

V
N ~

~ ~ ~ ~

N Qa 1 1 p D; fir. ~ O p i p .~.

rn ~

N ~ ~ ~. ~

- al - o.z. 0o5o~~m~s I ~ I C7.... .~. , ..
.....
cn ~ ~ ~ ~ ~' _ r.
N 1'~ ° '..-a h..-~O
. a .,ps Z
Mh M ~
M~~
U9~ V1 w~..~~~.. .~ NB000 a , a.n ~.~-eP'o O ~ '°
.-~ C5 ~°°~~
OeC ~ ~~r1~flP~ 02 4 mt V d't'~ ,t a.m .. ~.~.a..~ ~?Q0.-~
p . ~ ~G
.~~.~. :C r~ ~ ov ...,°°~ ~
g = ~ = t~'1l0'~n M h~
f'r1N MCn ~~'h C~le.e0p VI~ y .w .~
tP1 E Z°~. ~C9e-~a~ t/1 ~~~
w IlIM
f79N OOtD h dfi 01 .v~ C9~ILlh v Z s a a v vU1 i. d ~ ~h9~ ~
MI°. tT'Ih f,'1°~~R'~ F1~.
s a s a ~ ~ , ~ g:; 82 bk 3~ ~
.r M 9~ M IC1 ~
r A~ CCD ~ tt'r ...
~ V

C ~~..i .~..
n ~o ~r L
+, ~
t7 d u1 ~t7 ~P1 tC1 W 0 B O O dO
~ ~
fr 1.~.
g~
N
\ / \
1~
.P ~

~ ~ ~ ~ ~ ~
~ ~ N N N N N

~~~t~r~~~.~.

- 22 Q.Z.0050/1145 -z N

.f,i ..

_ ~D 2 .-.
M

~.~ .. ..

~ ~~

t0 ~wp ~ N N

~ILI o M

M Z ~: ~..r E o h' ~

Mtl1 M ~ N
I

NM Vih ~ .161rrMB'1 'r' V1~~aVI M
o a M Of~ a ~ M N
V1 Vf I a aw O . ..
v ' ..

M 00 ?M 01 .r-~.~..0~awa~...~
.

~" a ~ a .~ ~ Z N =
v a t/i x . ~

V M~ ..~ M~ w N~ 09.~w T

p .. x . ,.." "
. .. ~ "

. ~

$ =1P'9M ~T

QOM tlf.-iM aN MM 6C1iC1tf7111 ~

0~ . ~ .r-v N
.rr . n ~ '~9 Vi "~f~N ,-a .a.~
VI T t/1~
=

x .......... ,~,--.-.M u, 1 m I I
I --I MO~ ~N N Orow.-eOfn1M NM
. .

a v .VI s a a v wVl a .

.r .-.Ma Mi'4Nr Mf~ NM .-.~'.-.~' o L L

rp \ ~

O
.

.D 1 I 1 1 ~ .

,..,'\.t~7 it1 s 1 M.-b w a ao 00 o o a a ~ as ae ae. a~ a~ ae ae ,~ ~ ~ t~ n 0~ /'m ~

r ~ ,n N M ao co ~

L.V

C
+~
w L

~ g ~ O o n O
a In .. ,. a-. .. .~ ...

v ~ ~ ~ o o a o v ~
~., ~ ~ a~ a~ as ar ~ .w .

n ~ ~ ~ g a~ s~ ur O L

.. r ~ ~ ~

~ . ~ p ~ \
,.

.,.

~ N N p ~ x N a P M trf V '1

Claims (7)

1. A process for preparing an isoxazole-4,5-dicarboxylic diester of the formula I
where R1 is an aliphatic radical of 1 to 20, cycloaliphatic radical of 3 to 10, aromatic radical of 6 to 10, heteroaromatic or heterocyclic radical of 3 to 10 or araliphatic radical of 4 to 12 carbon atoms, each radical being unsubstituted or substituted by substituents which are inert under the reaction conditions, and R2 and R3 are each alkyl, which comprises reacting an aldoxime of the formula II
with an acetylenedicarboxylic diester of the formula III
R2OOC-C=C-COOR3 (III) in solution with an organic solvent, in the presence of an aqueous solution of a hypohalite in the pH range from to 10.

2. A process as claimed in claim 1, wherein use is made of an aldoxime of the formula II where R1 is C1-C10-alkyl or C2-C10-alkenyl, each of which is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different C3-C7-cycloalkyl, C1-C3-alkoxy, halogen, cyano or phenyl groups, it being possible for the latter to be unsubstituted or substituted by 1, 2 or 3 halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, cyano or nitro groups, or is C3-C8-cycloalkyl or C5-C8-cycloalkenyl, each of which is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different C1-C4-alkyl, C1-C3-alkoxy or halogen groups, or is a 5- to 7-membered heterocyclic radical which contains 1 or 2 oxygen, nitrogen and/or sulfur atoms and is unsubstituted or substituted by 1 to 3 identical or different C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkoxycarbonyl groups, or is phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, halogen, nitro and/or cyano groups.

3. A process as claimed in claim 1, wherein use is made of an aldoxime of the formula II where R1 is C1-C6-alkyl or C2-C6-alkenyl, each of which is unsubstituted or substituted by 1, 2 or 3 identical or different C1-C4-alkoxy, halogen or phenyl groups, it being possible for the latter to be substituted by 1 to 3 halogen and/or C1-C4-alkyl groups, or is C3-C7-cycloalkyl or C5-C7-cycloalkenyl, each of which is unsubstituted or substituted by 1, 2 or 3 identical or different C1-C4-alkyl groups, or is tetrahydrofuryl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl or 1,4-dioxanyl, each of which is unsubstituted or substituted by 1, 2 or 3 C1-C4-alkyl groups.

4. A process as claimed in claim 1, 2 or 3, wherein sodium hypochlorite, potassium hypochlorite and/or calcium hypochlorite is used as said hypohalite.

5. A process as claimed in any one of claims 1 to 4, wherein the reaction is carried out in the pH range from 6 to 8.

6. A process as claimed in any one of claims 1 to 5, wherein the reaction is carried out at from 0 to 40°C.

7. An isoxazole-4,5-dicarboxylic diester of the formula I' where R1' is C3-C8-alkyl, ethenyl or isopropenyl, monocyclic C3-C8-cycloalkyl or C5-C8-cycloalkenyl which is unsubstituted or substituted by 1, 2 or 3 C1-C4-alkyl groups, or C1-C6-alkyl which is substituted by 1, 2 or 3 C3-C7-cycloalkyl, C1-C4-alkoxy, halogen and/or cyano groups, or C2-C6-alkyl which is substituted by 1, 2 or 3 unsubstituted phenyl groups or 1, 2 or 3 phenyl groups substituted by halogen and/or C1-C4-alkyl, or tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl or dioxepanyl, each of which is unsubstituted or substituted by 1, 2 or 3 C1-C3-alkyl and/or halogen groups, and where R2' and R3' are identical or different and are each C1-C4-alkyl.