DK149649B - Process for preparing a 5-methyl-3-isoxazolol - Google Patents

Description

149649

The invention relates to a particular process for the preparation of 5-methyl-3-isoxazolol (also referred to as 5-methyl-isoxazol-3-ol), which is known as an effective soil fungicide with growth-promoting properties.

The compound has the formula and its melting point is set at 86 ° C.

It is known to prepare various substituted 3-isoxazolols by the addition of a suitably substituted acetic acetic ester, e.g. the methyl or ethyl ester, to an aqueous alkaline solution of hydroxylamine and subsequently rapid mixing of the reaction mixture with an excess of aqueous acid, e.g. concentrated hydrochloric acid to form a highly acidic mixture in which the desired 3-isoxazolol is formed and from which it can then be isolated [cf. thus 1) R. Jacquier et al. in Bull. Soc. Chem. France 1970, pages 1978-1985 and 2685-20 2690, and the same journal 1967, pages 3003-3004, 2) A.R.

Katritzky et al. in Proc. Chem. Soc. (London), 1961, pages 387-388, and 2) A.J.Boulton et al. in Tetrahedron 20 (1964), pages 2835-2840]. If, instead of said rapid mixture with excess acid, a slow acidification of the reaction mixture is used to a pH of 3-5, no 3-isoxazolol is normally obtained, but instead a 5-isoxazolone. Thus, R. Jacquier et al. (Bull. Soc. Chem. France 1967, pp. 3003-3004, and 1970, pp. 2685-2690) by the effect of γ-cyclopropyl, α-methyl or α-ethyl acetate acetic acid ethyl ester on hydroxylamine in basic solution and subsequent slow acidification to pH 4.5, respectively 3-cyclopropyl-5-isoxazolone, 3,4-dimethyl-5-isoxazolone and 3-methyl-4-ethyl-5-isoxazolone (in yields of 50-55%), while at rapid acidification with large excess of concentrated hydrochloric acid could be isolated respectively 5-cyclopropyl-3-isoxazolol, 4,5-dimethyl-3-isoxazolol and 4-ethyl-5-methyl-3-isoxazolol (in yields of 35-40 %) in addition to the 5-isoxazolones mentioned.

149649 2

The reaction mechanism of reactions of this kind has been discussed by several authors and has been considered probable (R. Jacquier et al. In Bull. Soc.

Chem. France 1970, pages 2685-2690) that in the reaction between hydroxylamine and the β-keto ester two intermediates are formed, namely an oxime and a hydroxamic acid, and the first, by appropriate moderate acidification, cycles to a 5-isoxazolone, while the latter by rapid acidification with a large excess of acidic ring ends to a 3-isoxazolol.

It is also stated in the literature that substitution at the α-position of the β-keto ester usually favors the formation of 3-isoxazolols (Bull. Soc. Chem.

France 1970, page 2688), and it is further stated in the literature (Bull. Soc. Chem. France 1967, page 3004) that the effect of hydroxylamine in alkaline solution on the unsubstituted acetic acetic acid ethyl ester always leads to 3-methyl-5 -isoxazolone and to a condensed product for which different structures have been proposed. Accordingly, Table 20 I and Table III of Bull show this. Soc. Chem.France 1970, pages 2687 and 2688, that 5-methyl-3-isoxazolol has not been detected.

Thus, it has apparently not been possible to prepare 5-methyl-3-isoxazolol by the direct action of hydroxylamine on the acetic acetic ester and subsequent rapid acidification of the reaction mixture. The preparation was done either by using completely different reaction pathways (e.g. by reacting hydroxylamine in alkaline solution with ethyl 3-chlorobut-2-enoate, the latter being prepared by the action of phorphorpentar chloride on ethyl 3-oxobutyrate) or by blocking the β-carbonyl group in the acetic acetic acid ester, in particular by forming a dimethyl acetal group, after which the ester of the blocked carbonyl group is reacted with hydroxylamine to the corresponding hydroxamic acid which, by subsequent acidification of the hydroxamic acid-containing reaction mixture, is cyclized to 5-methyl isoxazolol (Bull. Soc.

Chem. France 1970, pages 1978-1985).

It is to be understood, however, that a preparation of 5- methyl-3-isoxazolol by a direct action of hydroxylamine on unsubstituted acetic acid esters with subsequent acidification in a similar manner as using substituted acetic acid esters, without the need for precursor blocking of the β-carbonyl group would be a technically simple and economically advantageous method in comparison with the known methods of preparing this compound.

The invention is based on the realization that such a preparation is indeed possible, even with high yields of 5-methyl-3-isoxazolol, when special precautions are taken into account in carrying out the process, and it has further been found that using these precautions, instead of 15 acetic acid esters, the diket can be used.

The process according to the invention is characterized by adding to the aqueous alkaline solution of hydroxy 1-amine having a pH in the range of 8-12, the diketene or an ester of acetacetic acid, providing for rapid mixing in the alkaline solution and maintaining the pH of the mixture within the range indicated during the reaction, and maintaining the temperature of the mixture below ca. 30 ° C, and after completion of the reaction of hydroxylamine with the diketene or acetacetic acid ester, the reaction mixture is rapidly mixed with an excess of aqueous acid to give a highly acidic mixture to form 5-methyl-3-isoxazolol as the predominant reaction product. , on which to isolate this procluJi.

It is important for this process to ensure rapid mixing of the added diket or ester in the alkaline solution so that no local excesses are formed which may cause undesired side reactions, and it is a particular important feature of the process is that during the reaction of hydroxylamine with the diketene or acetic acetic acid ester, the pH value is maintained and this value maintained in the specified range. Preferably, the pH is maintained at a value of about 10. It is surprising that, by adhering to these simple precautions, it has also been possible to obtain 5-methyl-3-isoxazolol in an otherwise known per se and also in yields as high as about 70%. In addition to 5-methyl-3-is-5 oxazolol, 3-methyl-5-isoxazolone, its dimer isation product and other by-products are also usually formed. If, instead of the said acidification by rapid mixing with strong acid, the aforementioned slow acidification to pH 3-5 is used, as in the known process almost 3-methyl-5-isoxazolone is obtained in high yield . It has been found that the yields obtained by these two acidification methods from the same reaction mixture (obtained after reaction of hydroxylamine and acetic acid ester or diketene), thiisam · 15 but will exceed 100% common intermediate for the two products, in contrast to the above, by R. Jacquier et al. found result by the known method.

Details of practicing the process of the invention will become apparent in practice as follows: The alkaline solution of hydroxylamine used can be prepared by dissolving the desired amount of hydroxylamine in the form of a salt, such as the chloride or sulfate, in a aqueous alkali hydroxide solution, preferably an aqueous sodium hydroxide solution which may be of a concentration of 1 N to 20 N, best 2 N to 6 N. The temperature below is not so significant and may vary within quite wide limits, e.g. from -5 ° C to + 50 ° C. The pH of the solution is adjusted to the desired value in the range of 30 to 12, and as previously mentioned, preferably about 10. Prior to the subsequent addition of acetic acid ester or the diket, care is taken that the temperature of the solution is not so high that it will substantially could damage the course of the reaction. During the reaction, as mentioned, the temperature should be kept below ca. 30 ° C, and it is generally preferred to have a substantially lower temperature, preferably a temperature in the range of about 30 ° C. -5 ° C ti! ca. + 10 ° C.

To the obtained alkaline solution of hydroxylamine is added the diketene or acetic acid ester gradually, e.g. by dripping, in such a way that a rapid mixing in the alkaline solution occurs, and auxiliary mechanical stirring is conveniently used. During the reaction, the pH of the reaction mixture is checked and the desired value can be maintained by adding the required amount of the aqueous base used, which is preferably aqueous sodium hydroxide solution, suitably at a concentration between 1 N and 10 N and preferably from 2 N. to 6 N. Furthermore, if possible, using conventional cooling arrangement, the reaction mixture is kept at the relatively low temperature, below approx. 30 ° C and, as mentioned, preferably between ca. -5 ° C and approx. + 10 ° C.

The diet or acetic acid ester used for reaction with the hydroxylamine is preferably added in a substantially equivalent amount with the hydroxylamine. Significant surplus should be entered to ensure avoidance of adverse reactions in the mixture. In principle any arbitrary ester of acetic acetic acid may be used, but it is in practice advantageous to use the methyl or ethyl ester.

By suitable slow addition of the ester or diketene, it will be possible to achieve that the reaction 25 with hydroxylamine can be completed practically at the same time as the addition is complete. However, the said reactants may well be added somewhat more rapidly (while ensuring the said rapid mixing in the alkaline solution), since only after the addition has been completed the mixture must be left for some time after reaction. In this case, the mixture is allowed to stand until its consumption of base has essentially ceased, which marks the end of the reaction, and preferably the addition is adjusted so that the post-reaction is completed within 6 hours, preferably 1/2 to 1 hour, after ended addition.

The reaction mixture obtained must then be rapidly acidified, preferably to obtain a negative pH, at a rapid mixture with a large excess of aqueous acid. For this purpose, hydrochloric or sulfuric acid is preferably used in practice. It is clear that in principle other acids can be used, but based on 5, among other things, economist and environmental considerations and the desire to avoid the risk of side reactions, these two acids are preferred. Hydrochloric acid may be suitably used in the form of concentrated hydrochloric acid, while sulfuric acid is best used in dilute form.

In any case, it must be ensured, by the said acidification, that the final product thus formed consists, at least to a large extent, of the desired 5-methyl-3-isoxazolol, and not instead of 3-methyl-5-isoxazolone, which as previously mentioned, it is predominantly formed by long acidification to pH 3-5. Thus, the method according to the invention uses the acidification measure known per se, which in the aforementioned literature is referred to as "acidification brusque" or "acidification brutale", cf., for example, Bull. Soc.

Chem. France 1967, page 3003, second column, first paragraph, and the same journal 1970, page 2686, first column, last paragraph). Also during this acidification, care is taken to ensure that the temperature of the mixture is kept sufficiently low that no decomposition reactions occur, which may otherwise give rise to brown or black stains of the isolated reaction product. It is best to ensure that the temperature does not significantly exceed room temperature. The rapid mixing with aqueous acid may conveniently be effected by pouring the acid into the reaction mixture at one time or, what is considered best, the reaction mixture being poured into the acid at one time.

In order to ensure immediate, complete mixing, special measures, especially mechanical stirring, may be used if desired. After the mixing of the two liquids 35, it will usually be advisable to leave the obtained mixture for some time to ensure completion of the reaction. This allowance may suitably be at room temperature for up to about 24 hours at room temperature. At U98A9 7 a somewhat higher temperature, you can settle for a shorter delay and possibly completely without delay.

After completion of the reaction in connection with the acidification, the desired reaction product is isolated from the reaction mixture and this can be done using well known working methods. Preferably, the resulting 5-methyl-3-isoxazolol is isolated from the final reaction mixture using extraction with a water-immiscible organic solvent 10 for the isoxazolol, such as e.g. dichloromethane, if desired after prior blunting of the acid, e.g. to pH 0 to 3. Evaporation of the organic solution gives a product which usually contains, in addition to 5-methyl-3-isoxazolol, a minor amount of by-product of the aforementioned nature. If desired for the practical use of the isoxazolol, the product may be further purified in known manner, e.g. by recrystallization. Physical and spectroscopic data on the isolated product are identical to other 5-methyl-3-isoxazolol 20 data. If desired, the isoxazolol can be transferred into a salt thereof.

Other organic solvents which can be used as extractants include chloroform, ethyl acetate and ether.

The process according to the invention is further elucidated in the following embodiments.

Example 1 13.90 g (0.2 mole) of NH 2 OH.HCl was dissolved in a 2 N sodium hydroxide solution at room temperature to give a solution whose pH was 10.0. The solution was cooled to a temperature between Q and 5 ° C and, with stirring, 23.22 g (0.2 mole) of acetic acetic acid methyl ester was added dropwise over 21 minutes while maintaining the pH of the reaction mixture at 10.0. The mixture was then allowed to stir for 1 1/2 hours, constantly cooled to pH 10.0 / iv and poured into 150 ml of pre-cooled concentrated hydrochloric acid. The acidic reaction mixture was left at room temperature for 18-20 hours, then extracted for approx. 24 hours with dichloromethane. Evaporation of the dichloromethane phase gave 16.7 g of a product containing 5-methyl-3-isoxazolol and the purity of which was determined by HPLC to 81.7%. This was equivalent to a yield of 5-methyl-3-isoxazolol of 68.2%.

Example 2 13.90 g (0.2 mol) of NH 2 OH.HCl was dissolved over 7 minutes at 0 ° C in an aqueous 2 N sodium hydroxide solution 10 to obtain a solution whose pH was 10.0.

Then, at 0 ° C, while still stirring, for 30 minutes, 16.81 g (0.2 mole) of dike was added dropwise while maintaining the pH of the reaction mixture at 10.0.

The mixture was then allowed to stir for 30 minutes 15 at a temperature between 0 and -2 ° C and at pH 10.0 and then poured into 150 ml of pre-cooled concentrated hydrochloric acid. The acidic reaction mixture was allowed to stand at room temperature for 22 hours, then extracted for ca. 24 hours with dichloromethane. By evaporation of the dichloromethane phase, 16 g of a product containing 5-methyl-3-isoxazolol were obtained and the purity of which was determined by HPLC to 87.5%. This was equivalent to a yield of 70.6% of 5-methyl-3-isoxazolol.

Claims (6)

Process for the preparation of 5-methyl-3-isoxazolol, characterized in that an aqueous alkaline solution of hydroxylamine having a pH in the range of 8-12 is added to the diketene or an ester of acetacetic acid, care is taken to ensure rapid mixing in the alkaline solution and maintaining the pH of the mixture within the specified range during the reaction, and to maintain the temperature of the mixture below approx. 30 ° C, and after completion of the reaction of hydroxylamine with the diketene or acetic acid ester, the reaction mixture is rapidly mixed with an excess of aqueous acid to give a strongly acidic mixture to form 5-methyl-3-isoxazolol as the predominant reaction product. to isolate this product. Process according to claim 1, characterized in that the pH of the reaction mixture is maintained at a value of about 10 during the reaction between the diketene or acetic acid ester and hydroxylamine. Process according to claim 1 or 2, characterized in that the temperature of the reaction mixture during the reaction between the diketene or acetic acetic ester and hydroxylamine is maintained at a value between approx. -5 ° C and approx. + 10 ° C. Process according to any one of claims 25 to 1-3, characterized in that the methyl or ethyl ester is used as the ester of acetic acid. Process according to any one of claims 1-4, characterized in that the reaction mixture, after completion of the addition of the diket or 30-acetic acid ester, is left until its consumption of base has essentially ceased. Process according to any one of claims 1-5, characterized in that, after the rapid mixing with aqueous acid, the reaction mixture is left to ensure reaction completion, suitably for a period which rises to about 24 hours at room temperature. .