WO1984001774A1

WO1984001774A1 - A process for the preparation of 3-hydroxy-isoxazolole

Info

Publication number: WO1984001774A1
Application number: PCT/DK1983/000097
Authority: WO
Inventors: Niels Jacobsen; Hans Kolind-Andersen
Original assignee: Cheminova As
Priority date: 1982-10-26
Filing date: 1983-10-25
Publication date: 1984-05-10
Also published as: DK319283A; DK150615C; DK150615B; EP0125253A1; DK319283D0; JPS59501907A

Abstract

3-Isoxazolole having the formula (I), wherein R1 designates lower alkyl or substituted lower alkyl, aryl or substituted aryl, and R2 designates hydrogen, lower alkyl or substituted lower alkyl, or R1 forms together with R2 and the carbon atoms, to which they are attached, a ring having 5 to 7 carbon atoms, and tautomers thereof, are prepared in that to an aqueous alkaline solution of hydroxylamine having a pH-value in the range 8 to 12 one adds either a) a beta-keto ester having the formula R1 .CO.CH(R2)COOR3, where R1 and R2 have the stated meaning, and R3 is an ester-forming group, which may be part of R2, or b) diketene, taking care of quick intermixing with the alkaline solution and of maintenance of the pH-value of the mixture within the stated range during the reaction, as well as of keeping the temperature of the mixture below about 30oC, and that after completion of the reaction of hydroxylamine with beta-keto ester or dikatene one mixes the reaction mixture quickly with an excess of aqueous acid to obtain a strongly acid mixture so that 3-isoxazolole isformed as a predominant reaction product, whereupon this product is isolated.

Description

A PROCESS FOR THE PREPARATION OF 3-HYDROXY-ISOXAZOLOLE

The invention relates to a special process for the preparation of heterocyclic compounds, viz. 3-isoxazololes, some of which are known. They are useful as fungicides for plant protection or as intermediates for the preparation of, for example, pesticides.

The compounds have the general formula I

wherein R₁ designates lower alkyl or substituted lower alkyl, aryl or substituted aryl, and R₂ designates hydrogen, lower alkyl or substituted lower alkyl, or R₁ forms together with R₂ and the carbon atoms, to which they are attached, a ring having 5 to 7 carbon atoms, or are tautomers. thereof.

In the above definitions, "lower alkyl" preferably means a straight or branched chain alkyl group having up to 6 carbon atoms, in particular alkyl groups having up to 4 carbon atoms, and examples of substituents in such alkyl groups are alkoxy (having up to 6, preferably up to 4 carbon atoms), OH, halogen atoms, preferably chlorine, bromine and iodine atoms, NH₂ and NO₂."Aryl" preferably consists of aryl groups having 4 to 10 carbon atoms, possibly also containing one or more hetero-atoms, in particular O, S and/or N, preferably phenyl or substituted phenyl, but also comprises other, possibly substituted, aryl groups such as, for example, naphthyl, thiopen and pyridine. The possible substituents in such aryl groups may be of the same type as the afore-mentioned substituents in the alkyl groups.

It is known to prepare various substituted 3-isoxazololes by adding a suitably substituted β-keto ester, for example, the methyl or ethyl ester, to an aqueous alkaline solution of hydroxylamine and subsequent quick mixing of the reaction mixture with an excess of an aqueous acid, for example concentrated hydrochloric acid, so as to form a strongly acid mixture, wherein the desired 3-isoxazolole derivative is formed, and from which it can then be isolated(cf. Ref. 1, Ref.3-5 and Ref. 7-8 in the list of literature at the end of the present specification). If instead of the said quick mixing with an excess of acid one makes use of a slow acidification of the reaction mixture to a pH-value of 3-5, normally no 3-isoxazolole, but instead a 5-isoxazolone is obtained. Thus, R. Jacquier et al. (Ref. 5) by reacting the ethyl ester of γ-cyclopropyl-, α-methyl- or α-ethyl-acetoacetic acid with hydroxylamine in basic solution and subsequent slow acidification to pH 4.5 obtained 3-cyclopropyl-5-isoxazolone, 3 , 4-dimethyl-5-isoxazolone and 3-methyl-4-ethyl-5-isoxazolone, respectively, (in yields of 50 to 55%) , whereas by quick acidification with a large excess of concentrated hydrochloric acid it was possibleto isolate 5-cyclopropyl-3-isoxazolole, 4,5-dimethyl-3-isoxazolole and 4-ethyl-5-methyl-3-isoxazolole, respectively, (in yields of 35 to 40%) . For the reaction of hydroxylamine in alkaline solution with the non-substituted ethyl ester of acetoacetic acid Jacquier et al. (Ref. 5) states that this always leads to 3-methyl-5-isoxazolone and to a fused product, for which various structures have been proposed. In accordance therewith it appears from Table I and III in Ref. 7, pages 2687 and 2688, that the presence of 5-methyl-3-isoxazolole has not been demonstrated.

While in the literature it is also stated that substitution in the α-position in the β-keto ester normally favours the formation of 3-isoxazololes (Ref. 7, page 2688), the yields of 3-isoxazololes are also low when using substituted β-keto esters, as will appear from the above-mentioned Table I in Ref. 7, page 2687.

Therefore, various other processes have been proposed for the preparation of 3-isoxazololes. Thus, it has been proposed to prepare 5-methyl-3-isoxazolole, for example, by reacting hydroxylamine in alkaline solution with ethyl-3-chlorobut-2-enoate, said latter substance being prepared by the action of phosphorous pentachloride on ethyl-3-oxobutyrate, and it has been proposed to prepare this and other isoxazololes by blocking the β- carbonyl group in the β-keto ester, especially by the formation of a dimethylacetal group or ethyleneacetal group (1,3-dioxolane), and then reacting the ester having the blocked carbonyl group with hydroxylamine to form the corresponding hydroxamic acid, which by subsequent acidification of the hydroxamic acid-containing reaction mixture is cyclisized to form 5-methyl-3-isoxazolole (Ref. 6) .

Other processes for the preparation of 3-isoxazololes have been described in the DE-AS Specifications Nos. 1,620,306 and 1,795,821, US-patent specification No. 3,607,880 and DE-OS Specification No. 2,251,910. In the two first-mentioned of these publications it is proposed to prepare 3-isoxazololes by reacting a propiolic acid ester with hydroxylamine in an excess of alkali metal hydroxide and a water-miscible solvent and/or water and subsequent cyclisizing of the formed hydroxamic acid. In the US Specification No. 3,607,880 a propiolic acid ester is also reacted with hydroxylamine, but in the presence of an alkaline-earth metal hydroxide instead of an alkali metal hydroxide. However, there are, as also stated in the DE-OS Specification No. 2,251,910, difficulties connected with the use of propiolic acid esters for the preparation of 3-isoxazololes in technical production, because the propiolic acid ester used as starting material technically is not easily available. In the latter specification it is proposed instead to use β-alkoxyacrylic acid esters for the reaction with hydroxylamine in the presence of alkali. Such β-alkoxyacrylic acid esters can be considered to be "protected" acetoacetic acid esters, just as the afore-mentioned dimethylacetales and ethyleneacetales The use of such protected acetoacetic acid esters makes the preparation more difficult and expensive in relation to the use of non-protected acetoacetic acid esters. Thus, a preparation of 3-isoxazololes by a direct action of hydroxylamine on β-keto esters with subsequent acidification, without any need of preceding protection of the β-carbonyl group, would in comparison with the above-mentioned known processes be a technically simple and economically advantageous process, if it could be guided in such a way that the yields can be increased.

The invention is based on the recognition that this actually is possible, and even with attainment of yields of 3-isoxazololes which are at least as high and often also essentially higher than when using the known processes, if special measures are taken in the carrying out of the process. It has even been possible to have 3-isoxazololes formed in cases, in which it has previouslynotbeenpcssible to prove the formation thereof. The process of the invention is characterized in that to an aqueous alkaline solution of hydroxylamine having a pH-value in the range 8 to 12 one adds either a) a β-keto ester having the formula R₁·CO·CH(R₂)COOR₃, where R₁ and R₂ have the above-stated meaning, and R₃ is an ester-forming group, which may be part of R₂ (as, for example, in 2-acetylbutyrolacton), preferably a lower alkyl group, such as a methyl or ethyl group, or b)diketene, taking care of quick intermixing with the alkaline solution and of maintenance of the pH-value of the mixture within the stated range during reaction, as well as of keeping the temperature of the mixture below about 30°C, and that after completion of the reaction of hydroxylamine with the β-keto ester or diketene one mixes the reaction mixture quickly with an excess of an aqueous acid to form a strongly acid mixture, so that the 3-isoxazolole is formed as a predominant reaction product, whereupon this product is isolated. For this process it is important that care is taken of quick intermixing of the added ester or diketene with the alkaline solution, so that local excesses which may give rise to undesirable side-reactions, are not formed to any essential degree, and it is a special important feature of the process that during the reaction between hydroxylamine and β-keto ester or diketene care is taken to control the pH-value and maintaining at the same value in the stated range during reaction. Preferably pH is maintained on 10 or near 10, for example, 9,5, which has been shown to secure the best yields. The reaction mechanism in reactions of this kind has been discussed by several authors, and it has been considered probable (Ref. 7) that in the reaction between hydroxylamine and the β-keto ester there is formed two intermediates, viz. an oxime and a hydroxamic acid, and that the first-mentioned by suitable moderate or slow acidification cyclisizes to form a 5-isoxazolone, whereas the last-mentioned by quick acidification with a large excess of acid cyclisizes to form a 3-isoxazolole. Jacquier et al. (Ref 5) states that by using the two methods of acidification, and samples of the same reaction mixture, they obtained 5-isoxazolones and 3-isoxazololes, respectively, in yields which, added together, amount to less than 100%. In the process of the present invention the corresponding added yields from two identically taken samples at least in some cases exceed 100%. Since we have succeeded with the process to essentially increase the yield of the 3-isoxazololes in relation to the yield stated by Jacquier et al. (Ref. 5) , this points to the fact that in this process, with the selected and carefully maintained pH, there is a strong predominance of an intermediate, which by the strong acidification form 3-isoxazololes, while Jacquier et al. also must have an intermediate, which solely can form 5-isoxazolone. In the following table examples are stated on compounds prepared by the process of the invention, and there is also stated the obtained yields as well as the yields stated in the literature referred to. The numbers stated within sharp brackets are Chemical Abstracts Registry Numbers. Farthest to the left in the table is stated the ester group in the starting material as used.

In addition, we should make the following remarks about the compounds stated in the table:

4,5-Dimethyl-3- isoxazolole [930-83-6]: In Ref.5 this compound has been prepared using strong acidification of the reaction mixture as in the process of the present invention. In Ref. 7 the reaction mixture has first been slowly acidified to moderately low pH, whereupon the precipitated 5- isoxazolone has been isolated. Thereafter, the reaction mixture has been made strongly acid, and 4,5-dimethyl-3-isoxazolole has been isolated. 4,5,6,7-Tetrahydro-1,2-benzisoxazol-3-ole [27772-90-3] : In Ref. 7 it is stated to be impossible to prepare this compound from ethyl-2-cyclohexanone-carboxylate, and in Ref. 6 it is stated that it has not been possible to prepare the compound in any way other than via the dioxolane-protected β-keto ester. On the other hand, it has previously been possible from ethyl-2-cycloheptanone-carboxylate to prepare the corresponding compound with seven rings in a yield of 41% (Ref.4). 5-Isopropyl-3-isoxazolole [10004-47-4]: According to Ref. 7 it has apparently not previously been possible to prepare this compound directly from ethyl-isobutyrylacetate, whereas it may be prepared via dioxolane-protected ethyl-isobutyrylacetate (Ref.6). 5-Propyl-3-isoxazolole [10004-46-3]: Apparently this compound has not previously been prepared from butyrylacetate and hydroxylamine.

4- (2-Hydroxyethyl)-5-methyl-3-isoxazolole: This compound is novel. Reactions previously carried out between 2-acetylbutyrolactone and hydroxylamine have resulted in 4-(2-hydroxyethyl)-3-methyl-2-isoxazolin -5-one (Ref. 9) .

5-Phenyl-3-isoxazolole [939-05-9] :In cases where this compound has previously been prepared from an ester of benzoylacetate and hydroxylamine,this has taken place via dioxolane-protected benzoylacetate (Ref. 6 and Ref.

10). Reactions previously carried out between esters of benzoylacetate and hydroxylamine have resulted in 3- phenyl-2-isoxazolin-5-one (Ref. 7 and Ref. 11) , and in Ref. 7 it is stated, that it has not been possible to demonstrate the formation of the 3-isoxazblole from ethyl-benzoylacetate. 5-t-Butyl-3-isoxazolole: This compound is novel. Reactions previously carried out between ethyl-4, 4-dimethyl-3-oxovalerate and hydroxylamine have resulted in 3- t-butyl-2-isoxazolin-5-one [Ref. 3].

By the process of the invention it has moreover been possible fromhydroxylamine and acetoacetic acid ester or diketeneto prepare 5-methyl-3-isoxazolole in yields as high as 70%, whereas it has not been possible to show the presence of this 3-isoxazolole when carrying out the reaction in known manner, as will appear from Table I and Table III in Ref. 7.

Further details of carrying out the process of the invention in practice will appear from the following:

The alkaline solution of hydroxylamine used in the process may be prepared by dissolving the desired amount of hydroxylamine in the form of a salt, such as the chloride or sulphate, in an aqueous solution of alkalihydroxide, preferably an aqueous solution of sodium hydroxide, the concentration of which solution may be from 1 N to 20 N, preferably from 2 N to 6 N. The temperature during this procedure is not very important and may vary within rather wide limits, for example, from -5°C to +50°C. The pH of the solution is adjusted to the desired value in the range from 8 to 12, preferably on or about 10. Before the subsequent addition of β-keto ester or diketenecare is taken that the temperature of the solution is not so high that it may to any essential degree have any harmful influence on the course of reaction. During the reaction the temperature should be kept below about 30ºC, and normally an essentiallylower temperature is preferred, preferably a temperature in the range from about -5°C to about +10°C.

To the resulting alkaline solution of hydroxylamine is gradually added the β-keto esteror diketene which like acetoacetic acid ester results in 5-methyl-3-isoxazolole. The addition may take place by dropwise addition, in such a way that a quick intermixing with the alkaline solution takes place, and to support this inter-mixing use is conveniently made of mechanical stirring. During the reaction the pH-value of the reaction mixture is controlled, and the desired value may be maintained by the addition of the required amount of the aqueous base as used, which preferably is aqueous solution of sodium hydroxide having conveniently a concentration of between 1 N and 20 N, and preferably from 2 N to 6 N. Furthermore care is taken, if desired by the use of conventional cooling arrangement, that the reaction mixture is kept on the relatively low temperature below about 30ºC and preferably between about -5°C and about +10°C.

The β-keto ester or diketene used for reaction with hydroxylamine is preferably added in an amount which is essentially equivalent with the hydroxylamine. Any essential excess or deficit should be avoided to secure avoidance of unfavourable reactions in the mixture.

By suitably slow addition of the β-keto ester or diketens it will be possible to obtain that the reaction with hydroxylamine may be completed at substantially the same time as the completion of the addition. However, it is possible to add the said reactants at a somewhat faster rate (while securing the above-mentioned quick intermixing with the alkaline solution), in which case one should after completion of addition allow the mixture to stand a while for after-reaction. In that case the mixture is allowed to stand, until its consumption of base has essentially come to an end, which marks the completion of the reaction, and preferably the addition is adjusted so that the after-reaction is completed within 6 hours, and more preferably within from 1/2 to 1 hour, after completion of addition.

Thereafter, the resulting reaction mixture shall quickly be made strongly acid, preferably to obtain a negative pH, by means of a quick mixing with a large excess of an aqueous acid. For this purpose use is preferably in practice made of a mineral acid, first and foremost hydrochloric acid or sulphuric acid. It is obvious that in principle use may be made of other acids,but inter alia for economic and environmental, reasons and because of the desire to avoid risks for side-reactions the said two acids are preferred. Hydrochloric acid may suitably be used in the form of concentrated hydrochloric acid, while sulphuric acid is preferably used in diluted form.

Under any circumstance it should by the said acidification be secured that the end product resulting therefrom consists at any rate to a predominant degree of the desired 3-isoxazolole, and not instead the 5-isoxazolone, which as previously mentioned is formed to a predominant degree by slow acidificatin to pH 3 to 5. Thus, in the process of the invention use is made of the acidification measure which is known per se, and which in the literature, referred to above, has been designated as "violent" acidification ("acidification brusque" or "acidification brutale", cf. , for example, Ref. 5, page 3003, 2nd column, the first paragraph, and Ref. 7, page 2686, 1st column, the last paragraph). Also by this acidification care is taken that the temperature of the mixture is kept sufficiently low to secure that there will not to any essential degree occur decomposition -reactions, which, by the way, may result in a brown- or black- colouring of the isolated reaction product. Preferably care is taken that the temperature does not essentially exceed room temperature. The quick mixing with aqueous acid may suitably be performed by pouring all of the acid at the same time into the reaction mixture, or and this is considered preferable, that all of the reaction mixture at the same time is poured into the acid. In order to secure prompt and complete mixing one may, if so desired, make use of special measures, especially mechanical stirring. After intermixing of the two liquids it will normally be advisable to allow the resulting mixture to stand for some time to secure completion of the reaction. At room temperature this standing may conveniently last up to about 24 hours. At somewhat higher temperature a shorter period of standing may be satisfactory, and possibly it may be totally dispensed with.

After completion of the reaction in connection with the acidification, the desired reaction product is isolated from the reaction mixture, and this may take place by using procedures well known per se. Preferably, the formed 3-isoxazolole is isolated from the final reaction mixture by the use of filtration of precipitated product or by the use of extraction of the product by means of a water-immiscible, organic solvent such as, for example, dichbromethane,and if desired after preceding neutrdization of at least some of the acid, for example, to a pH in the range 0 to 3. By evaporation of the organic solution a product is obtained which, in addition to the 3-isoxazolole, usually contains a minor amount of byproduct. If it is desirable for the practical use of the isoxazolole, the product may be further purified in known manner, for example, by recrystallization. Physical and spedroscopic data for isolated , already known products agree with data mentioned in the references.

Among other organic solvents, which may be used as extractants, may be mentioned chloroform, ethylacetate and ether.

The process of the invention is further illustrated in the following examples.

Example 1 5-Methyl-3-isoxazolole.

13,90 g (0,2 mole) of NH₂OH·HCl were dissolved in a 2 N solution of sodium hydroxide at room temperature to obtain a solution, the pH-value of which was 10.0. The solution was cooled to a temperature between 0°C and5ºC, and, while stirring, 23.22 g (0.2 mole) of the methyl ester of acetoacetic acid were added dropwise in 21 minutes, while the pH-value of the reaction mixture was maintained at 10.0. Then the mixture was allowed to stand, while stirring, for 1 1/2 hour,constantly at pH 10.0, whereupon it was cooled and poured into 150 ml of previously cooled concentrated hydrochloric acid. The acid reaction mixture was allowed to stand at room temperature for 18 to 20 hours, after which it was extracted for about 24 hours with dichloromethane By evaporation of the dichloromethane phase ,16.7 g were obtained of a product containing 5-methyl-3-isoxazolole, and the purity of which by means HPLC was determined to be 81.7%. This was tantamount to a yield of 5-methyl-3-isoxazolole amounting to 68.2%.

Example 2. 5-Methyl-3-isoxazolole

13.90 g (0.2 mole) of NH₂OH·HCl were in 7 minutes at 0°C dissolved in an aqueous 2 N solution of sodium hydroxide to obtain a solution, the pH-value of which was 10.0. Then, still at 0°C and while stirring, 16.81 g (0.2 mole) of diketeiewere added dropwise in 30 minutes, while the pH-value of the reaction mixture was maintained at 10.0. Thereafter, the mixture was allowed to stand, while stirring, for 30 minutes at a temperature between 0ºC and -2ºC and at pH 10.0, whereupon it was poured into 150 ml of previously cooled concentrated hydrochloric acid. The acid reaction mixture was allowed to stand at room temperature for 22 hours, after which it was extracted for about 24 hours with dichlorometham. By evaporation of the dichloromethane phase 16 g were obtained of a product containing 5-methyl-3-isoxazolole, the purity of which by means of HPLC was determined to 87.5%. This was tantamount to a yield of 5-methyl-3-isoxazolole amounting to 70.6%.

Example 3. 4 ,5-Dimethyl-3-isoxazolole

13.09 g (0.2 mole) of NH₂OH·HCl were dissolved in a 2 N solution of sodium hydroxide at room temperature to obtain a solution, the pH-value of which was 10.0. The solution was cooled to a temperature of between 0°C and 5°C, and, while stirring, 21.9 g (0.15 mole) of ethyl-¬2 methylacetoacetate [contaminated with 6.9 g (0.04 mole) of ethyl-2,2-dimethylacetoacetate] were added dropwise in about 30 minutes, while the pH-value of the reaction mixture was maintained at 10.0 by means of 2 N solution of sodium hydroxide. Then the mixture was allowed to stand, while stirring, for 2 hours at +2°C, and constantly at pH 10.0, whereupon it was pouredinto 150 ml of previously cooled concentrated hydrochloric acid. The acid reaction mixture was allowed to stand for some hours at room temperature, after which it was extracted for about 18 hours with diσhloromethane.By evaporation of the dichloromethanephase 21.4 g were obtained of a product containing 4,5-dimethyl-3-isoxazolole, the purity of which by means of NMR was determined to be 78%, and by means of gas-chromatography (GC) was determined to be 64%. This is tantamount to a yield of 4.5-dimethyl-3-isoxazolole amounting to97% (NMR) and 80% (GC) , respectively. Recrystallization from 240 ml H₂O resulted in 11.5 g crystals having a melting point 122 to 124ºC (Ref. 6: 123 to 124°C).

Example 4. 4,5,6, 7-Tetrahydro-1,2-benzisoxazole-3-ole.

In the same manner as in Example 3 6.9 g (0.1 mole) of NH₂OH·HCl and 15.6 g (purity 92.5%) (0.093 mole) of ethyl-2-cyclohexanonecarboxylate were reacted and further processed. By evaporation of the dichloromethane phase 12.7 g were obtained of a product containing 4,5, 6,7-tetrahydro-1,2-benzisoxazole-3-ole, the purity of which by means of NMR was determined to be 90%. This is tantamount to a yield of 4,5,6,7-tetrahydro-1,2-benzisoxazole-3-ole amounting to 89%. Recrystallization from methyl acetate resulted in crystals having a melting point of 90.6 to 92.8°C.

Analysis: C₇H₉NO₂ requires: C 60,42%; H 6,52%; N 10,07%; O 22,99%. found: C 59,74%; H 6,49%;N 10,21%;

O 23,00%.

UV (EtOH) λ_max= 218 nm. Example 5.

5-Isopropyl-3-isoxazolole. In the same manner as in Example 3 7.0.g (0.1 mole) of NH₂OH,HCl and 15.8 g (purity 99.8%) (0.1 mole) of ethyl-isobutyrylacetate were reacted and further treated. By allowing the acid reaction mixture to stand for about 18 hours at about 10°C there occured a precipitation of 5.9 g of a product containing 5-isopropyl-3- isoxazolole, the purity of which by means of NMR was determined to be 95% , and by means of GC was determined to be 99%. This is tantamount to a yield of 5-isopropyl- 3-isoxazolole amounting to 44% (NMR) and 46% (GC) , respectively. The melting point was determined to be 40,0 to 43,6°C (Ref. 6: 41 to 42°C). The filtrate from the said 5.9 g was extracted for about 18 hours with dichloromethana.By evaporation of dichloromethanephase 4.8 g were obtained of a product containing 5-isopropyl -3-isoxazolole, the purity of which by means of NMR was determined to be 70%, and by means of GC was determined to 55%. This is tantamount to a yield of 5-isopropyl-3-isoxazolole amounting to 27% (NMR) and 21% (GC) ,respectively, and consequently tantamount to a overall yield of 5-isopropyl-3-isoxazolole amounting to 71% (NMR) and 67% (GC) , respectively. The said 4.8 g were determined by means of NMR and GC to contain 30% (NMR) and 41% (GC) , respectively, of 3-isopropyl-5-isoxazolone. This is tantamount to a yield of 3-isoproρyl-5-isoxazolone amounting to 11% (NMR) and 16% (GC), respectively. Example 6.

5-Propyl-3-isoxazolole.

In the same manner as in Example 3 13.9 g (0.2 mole) of NH₂OH·HCl and 31.6 g (purity 97.4%) (0.19 mole) of ethyl-butyrylacetate were reacted and further processed. By evaporation of the dichloromethars phase 21.8 g were obtained of a product containing 5-propyl-3-isoxazolole, the purity of which by means of GC was determined to be 67%. This is tantamount to a yield of 5-propyl-3- isoxazolole amounting to 59%. The said 21.8 g were by means of GC determined to contain 17% 3-propyl-5-isoxazolone. This is tantamount to a yield of 3-propyl-5-isoxazolone amounting to 15%. By recrystallization of the evaporated reaction mixture from water 5-propyl-3-isoxazolole was obtained having a melting point of 42°C.

Example 7. 4- (2-Hydroxyethyl)-5-methyl-3-isoxazolole. In the same manner as in Example 3.3.5 g (0.05 mole) of NH₂OH·HCl and 6.4 g (0.045 mole) of 2-acetylbutyrolactone were reacted and treated.After allowing the acid reaction mixture to stand in refrigerator filtration of the mixture resulted in2.1g 4-(2-hydroxyethyl)-5-methyl-3-isoxazolole having a melting point of 161 to 169ºC. The filtrate from the said 2.1 g was adjusted to pH = 1 by means of NaOH and was extracted for about 18 hours with diσhloromethane.After standing and cooling of the dichloromethanephase further 1.4 g of 4- (2-hydroxyethyl)-5-methyl-3-isoxazolole precipitated, and the total of 3.5 g is tantamount to a yield of 48%. The dichloromethanephase contained 2-acetylbutyrolactone, i.e. the starting material, in an amount corresponding to 24% of the starting amount and contained 3-acetyl-l-propanol; yield 24%.

Recrystallization of 4- (2-hydroxyethyl)-5-methyl-3-isoxazolole from methanol resulted in crystals having a melting point of 163 to 170°C. Analysis: C₆H₉NO₃ requires: C 50,34%; H 6,34%; N 9,79%; O 33,53%. found: C 50,26%; H 6,41%; N 9,76%;

UV (EtOH) : λ_max = 225 nm.

IR (KBr): 3180, 2940, 2810, 1660, 1520, 1390, 1350, 1330, 1245 and 1050 cm^-1. NMR (CDCl₃ + deut. DMSO) : δ = 2,33 ppm, s, (CH₃) ; δ =

2,53 ppm, t, J = 7,0 cps, (CH₂) ; δ = 3,77 ppm, t, J = 7,0 cps, (CH₂) ; δ = 7 - 9 ppm, wide signal, (2 x OH) .

Example 8. 5-Phenyl-3-isoxazolole.

In the same manner as in Example 3 13.9 g (0.2 mole) of NH₂OH·HCl and 35.6 g (0.2 mole) of methyl-benzoylacetate were reacted and further treated. After allowing the acid reaction mixture to stand at room temperature filtration resulted in 27.0 g of a product containing 5-phenyl-3-isoxazolole, the purity of which by means of HPLC was determined to be 59,2%. This is tantamount to a yield of 5-phenyl-3-isoxazolole amounting to 49%.

Example 9. 5-t-Butyl-3-isoxazolole.

In the same manner as in Example 3 8.7 g (0.125 mole) of NH₂OH·HCl and 19.8 g (0.125 mole) of ethyl-4,4- dimethyl-3-oxovalerate were reacted and further treated. After allowing the acid reaction mixture to stand for about 1 hour filtration resulted in 3.4 g of a product containing 5-t-butyl-3-isoxazolole, the purity of which by means of NMR was determined to be 21%. The filtrate from the said 3.4 g was allowed to stand for about 18 hours in refrigerator, and 11.5 g of precipitated 5-t- butyl-3-isoxazolole were removed by filtration; melting point 98 to 100°C. The filtrate from said 11.5 g was extracted three times with dichloromethans, and by evaporation there was obtained a product containing 5-t-butyl3-isoxazolole, the purity of which by means of NMR was determined to be 37%. This is tantamount to an overall yield of 5-t-butyl-3-isoxazolole amounting to 73%. The overall yield of 3-t-butyl-5-isoxazolone in similar manner was determined to be 22%.

The following spectroscopic data for 5-t-butyl-3-isoxazolole were observed: UV (EtOH):λ_max = 207 nm. IR (KBr): 3400, 2960, 1615, 1530,1455, 1365, 1345 and 1270 cm^-1. NMR (deut. DMSO): δ = 1,25 ppm, s, (9 H) ; δ= 5,65 ppm s, (1 H); δ = 10,5 ppm, wide s, (1 H) . References

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6. R. Jacquier, C. Petrus, F. Petrus and J. Verducci, Bull. Soc.Chim. France, 1970, 1978-85.

7. R. Jacquier, C. Petrus, F. Petrus and J. Verducci Bull. Soc.Chim. France, 1970, 2685-90 8. R. Jacquier, F. Petrus, J. Verudcci and Y. Vidal Bull. Soc.Chim. France, 1971, 3664-65. 9. H. Wamhoff and F. Korte, Chem. Ber. 99, 2962-70,

(1966) . 10.T. Kikuchi, J. Tagushi, S. Kanazawa and E. Tatsuya (Nippon Chemical Industrial Co., Ltd.) Japan Kokai 76, 127.072. CA 87, 68335, (1977).

11.L.K. Gibbons (FMC Corp.), U.S. 3,781,438. CA 80, 82936, (1974).

Claims

PATENT CLAIMS

1. A process for the preparation of 3-isoxazololes of the general formula I

wherein R₁ designates lower alkyl or substituted lower alkyl, aryl or substituted aryl, and R₂ designates hydrogen, lower alkyl or substituted lower alkyl, or R₁ forms together with R₂and the carbon atoms, to which they are attached, a ring having 5 to 7 carbon atoms, and tautomers thereof, c h a r a c t e r i z e d in that to an aqueous alkaline solution of hydroxylamine having a pH-value in the range 8 to 12 one adds either a) a β -keto ester having the general formula R₁·CO·CH(R₂)COOR₃, where R₁ and R₂ have the above-stated meaning, and R₃ is an ester-forming group, which may be part of R₂,or b) diketene,taking care of quick intermixing with the alkaline solution and of maintenance of the pH-value of the mixture within the stated range during reaction, as well as of keeping the temperature of the mixture below about 30°C, and that after completion of the reaction of hydroxylamine with the β-keto ester or diketere one mixes the reaction mixture quickly with an excess of an aqueous acid in order to obtain a strongly acid mixture, so that the 3-isoxazolole is formed as a predominant reaction product, whereupon this product is isolated.

2. A process as claimed in claim 1 c h a r a c t e¬r i z e d in that compounds of the general formula I are prepared, wherein R₁ designates a straight or branched chain, and possibly substituted,alkyl group having up to 6, and preferably up to 4 carbon atoms, or a possibly substituted aryl group having 4 to 10 carbon atoms, and which may contain one or more hetero atoms, preferably selected among O, S and N, in particular a phenyl group, R₂ designates hydrogen or a straight or branched chain, and possibly substituted, alkyl group having up to 6, and preferably up to 4 carbon atoms, or R₁ and R₂ form together with the carbon atoms, to which they are attached, a ring having 5 to 7, and preferably 6 carbon atoms.

3. A process as claimed in claim 1 or 2, c h a r a ct e r i z e d in that substituents in the alkyl or aryl groups belong to the group consisting of OH, halogen, preferably chlorine, iodine and bromine, NH₂, NO₂ and alkoxy having up to 6, preferably up to 4 carbon atoms.

4. A process as claimed in any of the claims 1 to 3, c h a r a c t e r i z e d in that the pH of the reaction mixture is during the reaction between hydroxylamine and β-diketo ester or diketene maintained at a value on or near 10.

5. A process as claimed in any of the claims 1 to 4, c h a r a c t e r i z e d in that the temperature of the reaction mixture is during the reaction between the β-keto ester or diketene and hydroxylamine maintained at a value between about -5°C and about +10°C.

6. A process as claimed in any of the claims 1 to 5, c h a r a c t e r i z e d in that R₃ in the β-keto ester is a methyl or ethyl group.

7. A process as claimed in any of the claims 1 to 5, c h a r a c t e r i z e d in that the β -keto ester is 2-acetylbutyrolactone.

8. A process as claimed in any of the claims 1 to 7, c h a r a c t e r i z e d in that the reaction mixture is after completion of the addition of β -keto ester or diketene allowed to stand, until its consumption of base is substantially ceased.

9. A process as claimed in any of the claims 1 to 8, c h a r a c t e r i z e d in that after the quick intermixing with aqueous acid the reaction mixture is allowed to stand to secure completion of reaction, conveniently for a period of time which at room temperature is up to about 24 hours.

10. A process as claimed in any of the claims 1 to 9, c h a r a c t e r i z e d in that for the acidification use is made of hydrochlorid acid or diluted sulphuric acid, preferably concentrated hydrochloric acid.

11. A process as claimed in any of the claims 1 to 10, c h a r a c t e r i z e d in that the 3-isoxazolole is isolated from the final reaction mixture by means of extraction with a water-immiscible organic solvent for the isoxazolole, if desired after preceding neutralization of at least some of the acid.