A PROCESS FOR THE PREPARATION OF 3-HYDROXY-ISOXAZOLOLE

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 30<o>C, 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-isoxa- zololes, some of which are known. They are useful as 5 fungicides for plant protection or as intermediates for the preparation of, for example, pesticides. The compounds have the general formula I wherein R, designates lower alkyl or substituted lower alkyl, aryl or substituted aryl, and R_ designates hydro¬ gen, lower alkyl or substituted lower alkyl, or R. forms , c together with R~ 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" prefer¬ ably means a straight or branched chain alkyl group Q 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, prefer¬ ably up to 4 carbon atoms), OH, halogen atoms, preferably chlorine, bromine and iodine atoms, NH 2 and N0 2 ."Aryl" e preferably consists of aryl groups having 4 to 10 carbon atoms, possibly also containing one or more hetero-atoms, in particular 0, S and/or N, preferably phenyl or sub¬ stituted phenyl, but also comprises other, possibly sub¬ stituted, aryl groups such as, for example, naphthyl, 0 thiopen and pyridine. The possible substituents in such aryl groups may be of the same type as the afore-mention¬ ed substituents in the alkyl groups. It is known to prepare various substituted 3- isoxazololes by adding a suitably substituted β-keto 5 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 react- ing the ethyl ester of ry-σyclopropyl-, cC-methyl- or σC- ethyl-acetoacetic acid with, hydroxylamine in basic solu¬ tion and subsequent slow acidification to pH 4.5 obtained 3-cyclopropyl-5-isoxazolone, 3,4-dimethyl-5-iso azolone 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-dime- thyl-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 aceto- acetic 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 appr-.ars 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 oc-position in the jS-keto ester normaL- ly 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 pro- posed for the preparation of 3-isoxazololes. Thus, it has been proposed to prepare 5-methyl-3-isoxazolole, for ex¬ ample, by reacting hydroxylamine in alkaline solution with ethyl-3-chlorobut-2-enoate, said latter substance I being prepared by the action of phosphorous pentachlori- de on ethyl-3-oxobutyrate, and it has been proposed to prepare this and other isoxazololes by blocking the /3- 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 subse¬ quent acidification of the hydroxamic acid-containing reaction mixture is cyclisized to form 5-methyl-3-isoxa- zolole (Ref. 6) . Other processes for the preparation of 3-isoxaz;o-. loles havebeen 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. 2,251,91o. In the two first-mentioned of these publications it is proposed to prepare 3-isoxazololes by reacting a propio- lic acid ester with hydroxylamine in an excess of alkali metal hydroxide and a water-miscible solvent and/or wa- ter and subsequent cyclisizing of the formed hydroxamic acid. In the US Specification No. 3,6o7,880 a propiolic acid ester is also reacted with hydroxylamine, but in the presence of an alkaline-earth metal hydroxide in¬ stead 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 techni¬ cal production, because the propioliσ acid ester used as starting material technically is not easily available. In the latter specification it is proposed instead to use β-alkoxyaσrylic acid esters for the reaction with hydroxylamine in the presence of alkali. Such β-alkoxy- acrylic acid esters can be considered to be "protected" acetoacetic acid esters, just as the afore-mentioned di- methylacetales" and ethyleneacetales The use of such protected acetoacetic £cid 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 di¬ rect action of hydroxylamine on<3-keto esters with sub¬ sequent acidification, without any need of preceding p33>- tection of the (J-carbonyl group, would in comparison with the above-mentioned known processes be a technical¬ ly 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 |3-keto ester having the formula R, * CO * CH(R 2 )COOR 3 , where R- and R- have the above-stated meaning, and R- is an ester-forming group, which may be part of R 2 (as, for example, in 2-acetylbutyrolacton) , preferably a lower alkyl group, such as a methyl or ethyl group, or b)d__re- tene, taking care of quick intermixing with the alkaline solution and of maintenance of the pH-value of the mix¬ ture 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 hy- droxylamine with the /3-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-iso- xazolole 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 dikete¬ ne with the alkaline solution, so that local excesses which may give rise to undesirable side-reactions, are . - 5 . - _ - 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. Preferab¬ ly pH is maintained on 10 or near 10, for example, 9,5, which has been shown to secure the best yields. • 3he 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 /S-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, where- as 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 reac¬ tion mixture, they obtained 5-isoxazolones and 3-isoxa- zololes, respectively, in yields which, added together, amount to less than 100%. In the process of the present invention the corresponding added yields from two iden¬ tically 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. Table Yields In the preparation of 3-isoxazαloles. Table (continued) Yields In the preparation of 3-isoxazololes . In addition, we should make the following r.emaris 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 acidifica- tion 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, where¬ upon the precipitated 5- isoxaz'olone 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-l,2-benzisoxazol-3-ole J27772-90-3} : In Ref. 7 it is stated to be impossible to prepare this compound from ethyl-2-cyclohexanone-carbox- ylate, 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 /3-keto ester. On the other hand, it has previously been possible from ethyl-2-cyclo- heptanone-carboxylate to prepare the corresponding com¬ pound with seven rings in a yield of 41%(Ref.4). 5-Isopropyl-3-isoxazolole J10004-47- J: According to Ref. 7 it has apparently not previously been possible to prepare this compound directly from ethyl-isobutyryl- aσetate, whereas it may be prepared via dioxolane-pro¬ tected ethyl-isobutyrylacetate (Ref.6). 5-Propyl-3-isoxazolole ΪL0004-46-3J: Apparently this compound has not previously been prepared from bu- tyrylacetate and hydroxylamine. 4-(2-Hydroxyeth l)-5-methyl-3-isoxazolole: This compound is novel. Reactions previously carried out bet- ween 2-acetylbutyrolactone and hydroxylamine have resul¬ ted in 4-(2-hydroxyethyl)-3-methyl-2-isoxazolin -5-one (Ref. 9) . 5-Phenyl-3-isoxazolole |39-05-9} :In cases where this compound has previously been prepared from an ester of benzoylacetate and hydroxylamine, his h s 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-dime¬ thyl-3-oxovalerate and hydroxylamine have resulted in 3- t-butyl-2-isoxazolin-5-one JjRef. 3]. By the process of the invention it has moreover been possible frαn hydroxylamine 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^tempe- rature 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 de¬ sired value in the range from 8 to 12, preferably on or about 10. Before the subsequent addition of #-keto ester or diketenecare is taken that the temperature of the so¬ lution 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 30 C, and normally an essentially ower temperature is preferred, preferably a temperature in the range from about -5°C to about +10°C. To the resulting alkaline solution of hydroxyl¬ amine is gradually added the /3-keto esteror diketene Ofy.Pl which like acetoacetic acid ester results in 5-methyl-3- isoxazolole. The addition may take place by dropwise ad¬ dition, 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 30 C and pre- ferably between about -5°C and about +10°C. The (3-keto ester or diketeneused for reaction with hydroxylamine is preferably added in an amount which is essentially equivalent with the hydroxylamine. Any es- sential excess or deficit should be avoided to secure avoidance of unfavourable reactions in the mixture. By suitably slow addition of the 3-keto ester or diketensit 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 fast¬ er rate (while securing the above-mentioned quick inter¬ mixing 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 mix- ture is allowed to stand, until its consumption of base has essentially come to an end, which marks the complet¬ ion of the reaction, and preferably the addition is ad¬ justed 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 excess of an aqueous acid. For this purpose use is pre¬ ferably in practice made of a mineral acid, first and foremost hydrochloric acid or sulphuric acid. It is obvi¬ ous that in principle use may be made of other acids,but inter alia for economic and environmental, reasons and be¬ cause of the desire to avoid risks for side-reactions the said two acids are preferred. Hydrochloric acid may suit¬ ably 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 aci¬ dification 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-isoxazo- lone, which as previously mentioned is formed to a predo-_ minant degree by slow acidificatin to pH 3 to 5. Thus, in the process of the invention use is made of the acidi¬ fication measure which is known per se, and which in the literature, referred to above, has been designated as "violent" acidification ("acidification brusque" or "aci¬ dification 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 acidifica¬ tion 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- co¬ louring 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 con¬ sidered 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 advi.sable 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 reac¬ tion 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, dich_cromethaιe,and if desired after preceding neutrd-ization of at least some of the acid, for example, to a pH in the range 0 to 3. By evaporation of the organ¬ ic solution a product is obtained which,in addition to the 3-isoxazolole, usually contains a minor amount of by¬ product. 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, ethylaceta- te and ether. The process of the invention is further illustra¬ ted in the following examples. Example 1 5-Methyl-3-isoxazolole. 13,90 g-.-:... (0,2 mole) of NH 2 0H * HC1 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 and 5 C, 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 tem- perature for 18 to 20 hours, after which it was extract^ ed for..about 24 hours, with dichloromethane By evapora-. tion of the dich- rcmetharephase ,16.7 g were obtained of a product containing5-mehyl-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 amount¬ ing to 68.2%. Example 2. 5- ethyl-3-isoxazolole 13.90 g (0.2 mole) of NH^OH'HCl were in 7 minut- es 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 diketeie ere 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 0 C and -2 C and at pH 10.0, whereupon it was poured into 150 ml of previously cooled concentrated hy¬ drochloric 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 dichlorometha . By evaporation of the dichloromethanephase 16 g were obtain¬ ed 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 NH 2 0H * HC1 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. T.he solution was cooled to a temperature of between 0°C and 5°C, and, while stirring, 21.9 g (o.l5 mole) of ethyl-2- OMPI methylacetoacetate gontaminated with 6.9 g (0.04 mole) of ethyl-2,2-dimethylacetoacetat^ 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 con¬ stantly at pH 10.0, whereupon it was pourediήto 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 diσhloromethanephase 21.4 g were obtained of a product containing 4,5-dimethyl-3-isoxazolole, the puri¬ ty 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) , re¬ spectively. Recrystallization from 240 ml H-O resulted in 11.5 g crystals having a melting point 122 to 124 C (Ref. 6: 123 tol24°C). Example 4. 4,5,6,7-Tetrahydro-l,2-benzisoxazole-3-ole. In the same manner as in Example 3 6.9 g (0.1 mole) of NH 2 0H * HC1 and 15.6 g (purity 92,5%) (0.093 role) 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-l,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-l,2-benzis- oxazole-3-ole amounting to 89%. Recrystallization from methyl acetate resulted in crystals having a melting point of 90.6 to 92.8°C. Analysis: C 7 H g N0 2 requires: C 60,42%; H 6,52%; N 10,07%; 0 22,99%. found: C 59,74%; H 6,49%;N 10,21%; 0 23,00%. UV (EtOH) λ maχ = 218 nm. jURtA,-/ OfrlPl Example 5. 5-Isopropyl-3-isoxazolole-: .- In the same manner as in Example 3 7.0.g (0.1 mole) of NH 2 0H,HC1 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 preci¬ pitation of 5.9 g of a product containing 5-isopropyl-3- isoxazolole, the purity of which by means of NMR was de- termined 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) , re¬ spectively. 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.B evaporation of dichloromethaiβphase 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 tant¬ amount 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-iso- propyl-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 NH 2 0H * HC1 and 31.6 g (purity 97.4%) (0.19 mole) of ethyl-butyrylacetate were reacted and further proσess- ed. By evaporation of the dichlorometharsphase 21.8 g were obtained of a product containing 5-propyl-3-isoxazo- lole, the purity of which by means of GC was determined to be 67%. This is tantamount to a yield of 5-propyl-3- _0iV.PI s > VViBΛ isoxazolole amounting to 59%. The said 21.8 g were by means of GC determined to contain 17% 3-propyl-5-isoxazo- lone. This is tantamount to a yield of 3-propyl-5-isoxa- zolone 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-Hydrox eth l)-5-methyl-3-isoxazolole. In the same manner as in Example 3.3.5 g (0.05 mole) of NH 2 0H * HC1 and 6.4 g (0.045 mole)of 2-acetylbuty- rolactone were reacted and treated.After allowing the acid reaction mixture to stand in refrigerator filtrati¬ on of the mixture resulted in2.1g 4-(2-hydroxyethyl)-5- methyl-3-isoxazolole having a melting point of 161 to 169 C. 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-hydroxy- ethyl)-5-methyl-3-isoxazolole precipitated, and the total of 3.5 g is tantamount to a yield of 48%. The di¬ chloromethanephase 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: CgHgNC^ 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) : ma a x_ = 225 nm. IR (KBr): 3180, 2940, 2810, 1660, 1520, 1390, 1350, 1330, 1245 and 1050 cm -1 . NMR (CDC1 3 + deut. DMSO) : δ = 2,33 ppm, s, (CH 3 ) ; 6 ~ 2,53 ppm, t, J = 7,0 cps, (CH 2 ) ; δ = 3,77 ppm, t, J = 7,0 cps, (CH 2 ) ; S = 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 NH 2 0H * HC1 and 35.6 g (0.2 mole) of methyl-benzo- ylacetate were reacted and further treated. After allow¬ ing the acid reaction mixture to stand at room tempera¬ ture filtration resulted in 27.0 g of a product contain¬ ing 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 NH 2 0H'HC1 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 ex- tracted three times with dichloromethans, and by evapora¬ tion there was obtained a product containing 5-t-butyl- 3-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 raaχ - 207 nut. IR (KBr): 3400, 2960, 1615, 1530,1455, 1365, 1345 and 1270 cm "1 . NMR (deut. DMSO): 6 = 1,25 ppm, s, (9 H) ; 6= 5,65 ppm s, (1 H); ό = 10,5 ppm, wide s, (1 H) . References 1. R. ϋhlenhuth, Annalen der Chemie, 296, 33-62, (1897). 2. A.J. Boulton and A.R. Katritzky, Tetrahedron, 12, 41-50, (1961). 3. A.R. Katritzky and S. øksne, Proc.Chem.Soc. 1961, 387-88. 4. A.J. Boulton, A.R. Katritzky, A.M. Hamid and S. øksne. Tetrahedron, 20, 2835-40, (1964). 5. R. Jacquier, C. Petrus, F. Petrus and J. Verducci, Bull. Soc.Chim. France, 1967, 3003-4 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, Che . Ber. 9£, 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). ll.L.K. Gibbons (FMC Corp.), U.S. 3,781,438. CA 8p_, 82936, (1974). _o.y_p.

Claims: PATENT CLAIMS 1. A process for the preparation of 3-isoxazololes of the general formula I wherein R, designates lower alkyl or substituted lower alkyl, aryl or substituted aryl, and R 2 designates hydro¬ 0 gen, lower alkyl or substituted lower alkyl, or R, forms together with R 2 and 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 -ke- to ester having the general formula R * CO * CH(R 2 )CGOR-, where R, and R have the above-stated meaning, and R 3 is an ester-forming group, which may be part of 2 ,or b) diketene,taking care of quick intermixing with the alka- Q -line 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 hy¬ droxylamine with the β-keto ester or diketereone mixes 5 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 l c h a r a c t e- Q r i z e d in that compounds of the general formula I are prepared, wherein R. 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 5 which may contain one or more hetero atoms, preferably selected among O, S and N, in particular a phenyl group, R 2 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 R, and R 2 form OMPl . together with the carbon atoms, to which they are attach¬ ed, 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 c¬ t 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, NH 2 , NO-, 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 3-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 /*-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 R 3 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 f. -keto ester is 2-acetylbutyro1actone. 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 -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 inter¬ mixing 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 neutraliza¬ tion of at least some of the acid.

Inventors: JACOBSEN NIELS, KOLIND-ANDERSEN HANS, JACOBSEN, NIELS, KOLIND-ANDERSEN, HANS
Applicants: CHEMINOVA AS, A/S CHEMINOVA
Application year: 1983
Main classification: C07D261
IPC codes: C07D261