IL95752A - Preparation of isoxazole-5-carboxamide derivatives - Google Patents

Description

Preparation o 1soxazole-5-carboxara1de derivatives BASF Aktlengesellscbaft C. 81708 O.Z. 0050/41146 The preparation of isoxazole-5-carboxamide derivatives The present invention relates to a process for preparing isoxazole-5-carboxamide derivatives of the formula I C00R2 Rlv. ^ \\ R* C-N II \ e 0 R5 where R1 is an aliphatic radical of 1 to 20, a cycloaliphatic radical of 3 to 10, an aromatic radical of 6 to 10, a heteroaromatic or heterocyclic radical of 3 to 10 or an araliphatic radical of 4 to 12 carbon atoms, it being possible for these radicals to carry substituents which are inert under the reaction conditions, R2 is alkyl, R* and R5 are identical or different and are each hydrogen, Cx-Cg-alkyl, Ci-Cg-cyanoalkyl, C2-C6-alkenyl or C2-C6-alkynyl , and/or C3-C8-cycloalkyl which is unsubstituted or substituted by from 1 to 3 C1-C4- alkyl groups, or are linked to form a 5- to 8- membered cycloaliphatic ring which can contain another nitrogen or an oxygen, with the proviso that R2 is not ethyl if R1 is methyl and R4 and Rs are a combination of hydrogen and isopropyl.

Isoxazole-5-carboxamide derivatives of the formula I are important as intermediates for the preparation of herbicides, for example those described in EP-A-337 263.

It is an object of the present invention to find a process which is as straightforward and economic as possible for converting the isoxazole-4,5-dicarboxylic diesters of the formula II, which are easily obtained by 1,3-dipolar cycloaddition of acetylenedicarboxylic - 2 - O.Z. 0050/41146 diesters with appropriately substituted nitrile oxides which are generated in situ (cf., for example, Chem. Pharm. Bull. 28 (1980) 3296-3303; Tetrahedron 30 (1974) 1365-1371), as selectively as possible into the isox-azole-5-carboxamide derivatives I.

We have found that this object is achieved by a process for preparing isoxazole-5-carboxamide derivatives of the formula I where R1 is an aliphatic radical of 1 to 20, a cycloaliphatic radical of 3 to 10, an aromatic radical of 6 to 10, a heteroaromatic or heterocyclic radical of 3 to 10 or an araliphatic radical of 4 to 12 carbon atoms, it being possible for these radicals to carry substituents which are inert under the reaction conditions , R2 is alkyl, R4 and R5 are identical or different and are each hydrogen, Ci-Ce-alkyl, d-Co-cyanoalkyl , C2-C6-alkenyl or C2-C6-alkynyl , and/or C3-C8-cycloalkyl which is unsubstituted or substituted by from 1 to 3 Ci-C^- alkyl groups, or are linked to form a 5- to 8- membered cycloaliphatic ring which can contain another nitrogen or an oxygen, with the proviso that R2 is not ethyl if R1 is methyl and R* and R5 are a combination of hydrogen and isopropyl, which comprises reacting isoxazole-4,5-dicarboxylic diesters of the formula II II - 3 - O.Z. 0050/41146 where R3 is alkyl which is identical to or different from R2, with an amine of the formula III / HN \ III R5 at from 0 to 100 eC.

The reaction, according to the invention, of the isoxazole-4,5-dicarboxylic diesters II with the amines III surprisingly results virtually exclusively in the isoxazole-5-carboxamide derivatives I . The corresponding isoxazole-4-carboxamide derivatives IV and the isoxazole-4,5-dicarboxamides V which were expected to be formed to a considerable extent in the reaction according to the invention, are formed to only a negligible extent, if at all, under the reaction conditions employed.

In the process according to the invention, the isoxazole-4 , 5-dicarboxylic diester II used as starting compound is reacted with the amine III at from 0 to 100°C, particularly preferably at from 20 to 80eC. In this connection, it is expedient to react amines which are not sterically hindered at from 20 to 60 °C, whereas higher temperatures are generally used for amines III - 4 - O.Z. 0050/41146 which have one or two sterically demanding substituents R4 and R5, in particular from 60 to 80 °C.

The reaction according to the invention can advantageously be carried out in a solvent which is inert under the reaction conditions. Solvents which are preferably used are ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, methyl tert-butyl ether, tetra-hydrofuran or dioxane, halohydrocarbons such as methylene chloride or chloroform, aromatic hydrocarbons such as benzene, toluene or xylenes, and sulfoxides such as dimethyl sulfoxide or sulfolane. However, particularly preferred solvents are alcohols such as methanol, etha-nol, propanol, isopropanol, butanol, tert-butanol etc. It is, of course, also possible to use mixtures of solvents.

In a particularly preferred embodiment of the process according to the invention the amine used for the amidation is employed in excess relative to the isox-azole-4,5-dicarboxylic diester II, in which case the excess amine itself acts as solvent.

According to the different procedures, the amine III can be employed in stoichiometric amount as well as in virtually any desired molar excess relative to the reactant II. However, it is advantageous to use the amine III in from 1 to 5 times the molar amount of the diester II. It may also, however, be advantageous to add the amine III to the isoxazole-4,5-dicarboxylic diester II in such a way that the amount of the former is stoichio-metrically less than that of the latter virtually throughout the course of the reaction.

The process according to the invention is generally carried out under atmospheric pressure. However, it may be particularly advantageous, depending on the nature of the amine or solvent, to carry out the reaction under elevated pressure, in particular under autogenous pressure in an autoclave. This gives particularly advantageous results when low-boiling amines III, such as methyl-amine, ethylamine or isopropylamine, or low-boiling - 5 - O.Z. 0050/41146 solvents, such as diethyl ether or methanol, are used. It is, of course, also possible to carry out the process according to the invention under a pressure elevated by exogenous means, expediently in the range from 1 to 50 bar, but this procedure does not generally improve the result of the process further.

The process according to the invention can be carried out in a conventional manner batchwise in stirred vessels or autoclaves or else continuously in cascades of stirred vessels or tube reactors. Overall, no special techniques are used in the process according to the invention so that further details on this are unnecessary.

Depending on the conditions used in the process, such as pressure and temperature, and depending on the starting compounds, the reaction is generally complete after from 1 to 10 hours. Since the desired isoxazole-5-carboxamide derivatives are formed with high selectivity in the process according to the invention, in many cases it suffices to remove the solvent and/or excess amine III by distillation to obtain a product I which is sufficiently pure for further processing. However, it is also possible to work up the reaction mixture in a conventional manner by extracting the excess amine with dilute aqueous acids and isolating the product I from the organic phase. This procedure is particularly preferred when the amines which are to be removed are relatively involatile .

The process according to the invention can be used to react the isoxazole-4,5-dicarboxylic diesters II selectively with virtually all primary and secondary amines of the formulae Ilia (R* = H) and Illb (R4 j= H) respectively R5-NH2 NH Ilia 11 lb - 6 - O.Z. 0050/41146 to give the corresponding isoxazole-5-carboxamide derivatives I .

However, it is preferable to employ amines III in which R4 and R5 are identical or different and are each hydrogen, Cj-Ce-alkyl , C1-Cg-cyanoalkyl, C2-C6-alkenyl or C2-C6-alkynyl , and/or C3-C8-cycloalkyl which is unsub-stituted or substituted by from 1 to 3 C1-C4-alkyl groups . It is additionally preferable to use amines III in which R4 and R5 are linked together to form a 5- to 8-membered cycloaliphatic ring which can contain another nitrogen or an oxygen.

The isoxazole-4 , 5-dicarboxylic diesters II are particularly preferably reacted with simple primary amines such as methylamine, ethylamine, propylamine, isopropylamine, isobutylamine, tert-butylamine, neo-pentylamine and 2-amino-2-methylbutane, unsaturated amines such as 3-amino-3-methyl-l-butyne or 3-amino-3-methyl-l-butene, cyano-substituted amines such as 2-amino-2-cyanopropane, cyclic primary amines such as cyclopropylamine, cyclopentylamine, cyclohexylamine, 1-amino-l-methylcyclopropane, l-amino-2-methylcyclopropane, 1-amino-1-methylcyclopentane, 1-amino-l-methylcyclo-hexane, 1-amino-l-methylcyclopropane or 1-amino-l-methyl-4-methylcyclohexane, simple secondary amines such as dimethylamine, diethylamine, dipropylamine, dibutylamine or diisopropylamine, and cyclic secondary amines such as pyrrolidine, piperidine, imidazolidine, piperazine, morpholine, 3-methylmorpholine or 3,5-dimethylmorpholine.

The process according to the invention can be used to convert isoxazole-4, 5-dicarboxylic diesters of the formula II into the corresponding isoxazole-5-carbox-ylic acid derivatives. Thus, it is possible to use diesters II where R1 is an aliphatic radical of 1 to 20, a cycloaliphatic radical of 3 to 10, an aromatic radical of 6 to 10, a heteroaromatic or heterocyclic radical of 3 to 10 or an araliphatic radical of 4 to 12 carbon atoms . The limitation on the number of carbon atoms in R1 - 7 - O.Z. 0050/41146 derives solely from the suitability and utility of the relevant compounds and not from any lack of applicability of the process according to the invention to larger R1 radicals .

It is possible and advantageous in the process according to the invention to react isoxazole-4 , 5-dicar-boxylic diesters in which R1 is C^-Cu,-, in particular (^-C6-, alkyl, C2-C10-/ in particular C2-C6-, alkenyl, C3-C8-, in particular C3-C7-, cycloalkyl, a 5- to 7-membered, aromatic or aliphatic heterocyclic radical which contains 1 or 2 oxygen, nitrogen and/or sulfur, in particular oxygen and/or sulfur, atoms, or is phenyl or benzyl.

The R1 radicals can also be substituted. The nature and the number of the substituents can be chosen as desired, with the obvious proviso that they are chemically possible, as long as the substituents are inert to the amine III under the reaction conditions.

Thus, R1 as alkyl can be substituted, depending on its size, by 1, 2, 3, 4 or 5, preferably up to 3, identical or different substituents such as C3-C7-cyclo-alkyl, Cj-Cj-alkoxy, cyano, or phenyl which can be substituted by up to 3, preferably by one or 2, halogen, Ci-Ci-alkyl, C^-C^-alkoxy, cyano or nitro groups, the phenyl substitution pattern generally not being critical.

R1 alkyl groups can be straight-chain or branched. It is possible and particularly advantageous according to the invention to react isoxazole-4, 5-dicarboxylic diesters in which R1 is alkyl which is substituted by alkoxy and/or phenyl, the latter preferably carrying halogen and/or C^-C^-alkyl substituents. It is also possible and advantageous to prepare by the process according to the invention isoxazole carboxamides I where R1 contains an acetal moiety.

R1 as cycloalkyl can carry, depending on its size, 1, 2, 3, 4 or 5, preferably up to 3, identical or different Cx-Ci-alkyl and/or C1-Cj-alkox substituents.

It is also possible and advantageous to prepare - 8 - O.Z. 0050/41146 by the process according to the invention isoxazole-5-carboxamide derivatives I where R1 is a 5- to 7-membered heterocyclic radical which can be substituted by from 1 to 3 identical or different C^-C^-alkyl and/or (^-C^alkoxy groups. The heterocyclic R1 can be aromatic or cyclo-aliphatic . Heteroaromatic R1 radicals 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, for example, isox-azolecarboxamides I where R1 is substituted or unsubstituted furyl, pyrrolyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxa-zolyl, thiazolyl, isoxazolyl or isothiazolyl .

It is likewise possible and advantageous to prepare by the process according to the invention isox-azole derivatives I where R1 is a 5- to 7-membered cyclo-aliphatic radical which contains one or two nitrogen and/or, preferably, oxygen atoms. Examples of such heterocyclic radicals R1 are substituted or unsubstituted tetrahydrofuryl, tetrahydropyranyl, 1, 3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, oxepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl, 1,5-dioxepanyl, pyrrolidinyl, imidazolidinyl, piperidinyl and piperazinyl.

It is also possible and advantageous to convert by the process according to the invention isoxazole-4,5-dicarboxylic diesters II into the corresponding isox-azole-5-carboxamide derivatives in which R1 is substituted or unsubstituted C6-C10-aryl or C7-C12-aralkyl , in particular phenyl or benzyl. The aryl radicals, in particular phenyl, can carry 1, 2 or 3 identical or different Ci-Ce-alkoxy, halogen, nitro or cyano substituents .

The aliphatic, araliphatic or cycloaliphatic R1 radicals in the isoxazole-5-carboxamides I which can be prepared according to the invention can also contain one or more double bonds, and in the case of the cycloaliphatic radicals R1 these double bonds can be either - 9 - O.Z. 0050/41146 endocyclic or exocyclic.

The nature of R2 and R3 in the isoxazoledicarboxy-lic dxesters used as starting compounds is not in general critical for the process according to the invention, although the R2 and R3 radicals, in particular alkyl radicals, which are expediently preferred are those which provide no steric hindrance to the reaction. R2 and R3 are each particularly preferably C1-C4-alkyl. R2 and R3 can be identical or different but the preferred starting compounds are isoxazole-4,5-dicarboxylic dxesters in which these radicals are identical, because they are more readily available.

The process according to the invention makes it possible for the first time to prepare straightforwardly, highly selectively and economically isoxazole-5-carbox-amide derivatives I starting from the isoxazole-4 , 5-dicarboxylic dxesters II.

EXAMPLES EXAMPLE 1 50 g (0.25 mol) of dimethyl 3-methylisoxazole-4,5-dicarboxylate were heated with 91.7 g (1.25 mol) of diethylamine and 40 ml of methanol under autogenous pressure under nitrogen in an autoclave at 60 °C for 8 h. The solvent and the excess amine were removed from the crude product by distillation, and the latter was taken up in methyl tert-butyl ether (MTBE ) , and the solution was washed with 1 N hydrochloric acid and then with sodium carbonate solution, dried over sodium sulfate and distilled to remove MTBE and leave N , N-diethyl-3-methyl-4-methoxy carbonylisoxazole-5-carboxamide as a solid.

Yield: 76 %.

EXAMPLE 2 50 g (0.25 mol) of dimethyl 3-methylisoxazole- 4,5-dicarboxylate were heated with 55 g (0.75 mol) of tert-butylamine and 100 ml of methanol under autogenous pressure under nitrogen in a stirred autoclave at 60°C for 4 h. The solvent and excess amine were removed by distillation, after which the product N-tert-butyl-3-methyl-4-methoxycarbonylisoxazole-5-carboxamide - 10 - O.Z. 0050/41146 crystallized out. Yield: 94 %.

The further reactions in Examples 3 to 13 were carried out in a similar manner to Example 1. The reac-tants and results of these reactions and the data on the i-NMR spectra of the resulting compounds are listed in the table.

The following abbreviations are used in the table: Me: methyl; Et: ethyl; i-Prop: isopropyl; t-But: tert-butyl; H: hydrogen; RT: reaction temperature; CDC13: deuterochloroform; s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet.

TABLE Example R1 R2, R3 R*, R5 Equivalents of R*R5-NH Me Me, Me Et, Et 5 60°C 1. 2. 3.

Me Me, Me H, t-But 3 60 1.

. Et Me, Me H, t-But 3 70°C 1. 2. 9.

-Prop Me, Me H, t-But 1. 3. 9.

Me, Me H, t-But 3 70 1. 3. 4. 3. 5.

TABLE (continuation) Example R1 R2, R3 RA, R5 Eeqquuiivvaalleenntts RT Yield Of R*R5-NH . 4. 4. 8. 10 X Me, Me H, t-But 10 50°C 95 1. 3. 5.

TABLE (continuation) Example R1 R2, R3 R , R5 Equivalents RT Yield of R*R5-NH 3. 3. 4. 12 6. 8 13 3. 5 TABLE (continuation) Example R1 R2, R3 R*, R5 In addition, the compounds listed under serial numbers 14 to 19 can be o according to the invention. 14 Me Me , Me _ H 15 Me Me, Me H 16 Me Me, Me R R 5-NH = HN 0 18 Me Me, Me - -A 19 Me Me, Me H -|-C≡N

Claims (2)

- 15 - O.Z. 0050/41146 We claim:

1. A process for preparing isoxazole-5-carboxamide derivatives of the formula I where R1 is an aliphatic radical of 1 to 20, a cycloaliphatic radical of 3 to 10, an aromatic radical of 6 to 10, a heteroaromatic or heterocyclic radical of 3 to 10 or an araliphatic radical of 4 to 12 carbon atoms, it being possible for these radicals to carry substituents which are inert under the reaction conditions , R2 is alkyl, R* and R5 are identical or different and are each hydrogen, Ci-Cg-alkyl, Ci-Ce-cyanoalkyl, C2-C6-alkenyl or C2-C6-alkynyl , and/or C3-C8-cycloalkyl which is unsubstituted or substituted by from 1 to 3 C1-C4- alkyl groups, or are linked to form a 5- to 8- membered cycloaliphatic ring which can contain another nitrogen or an oxygen, with the proviso that R2 is not ethyl if R1 is methyl and R4 and R3 are a combination of hydrogen and isopropyl, which comprises reacting isoxazole-4,5-dicarboxylic diesters of the formula II where is alkyl which is identical to or different from R2 with an amine of the formula III - 16 - O.Z. 0050/41146 HN III R5 at from 0 to 100 °C.

2. A process as claimed in claim 1, wherein the reaction is carried out with from 1 to 5 moles of amine per mole of isoxazole-4,5-dicarboxylic diester. For fhe Applicant DR. RElNHOiD COHN AND PARTNERS