Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D261/12—Oxygen atoms

Definitions

• 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.
• R 1 designates lower alkyl or substituted lower alkyl, aryl or substituted aryl
• R 2 designates hydrogen, lower alkyl or substituted lower alkyl, or R 1 forms together with R 2 and the carbon atoms, to which they are attached, a ring having 5 to 7 carbon atoms, or are tautomers. thereof.
• 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, NH 2 and NO 2 .”
• 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.
• 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.
• an alkaline-earth metal hydroxide instead of an alkali metal hydroxide.
• Such ⁇ -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.
• a preparation of 3-isoxazololes by a direct action of hydroxylamine on ⁇ -keto esters with subsequent acidification, without any need of preceding protection of the ⁇ -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 ⁇ -keto ester having the formula R 1 ⁇ CO ⁇ CH(R 2 )COOR 3 , where R 1 and R 2 have the above-stated meaning, and R 3 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)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 ⁇ -keto ester or diketene one mixes the reaction mixture quickly with an excess of an aqueous acid to form a strongly acid mixture
• 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.
• 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.
• a salt such as the chloride or sulphate
• an aqueous solution of alkalihydroxide preferably an aqueous solution of sodium hydroxide
• 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.
• 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.
• 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.
• the ⁇ -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.
• 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.
• the reaction mixture is kept on the relatively low temperature below about 30oC and preferably between about -5°C and about +10°C.
• the ⁇ -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.
• the reaction with hydroxylamine may be completed at substantially the same time as the completion of the addition.
• 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.
• 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.
• a mineral acid first and foremost hydrochloric acid or sulphuric acid.
• Hydrochloric acid may suitably be used in the form of concentrated hydrochloric acid, while sulphuric acid is preferably used in diluted form.
• 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.
• 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.
• the desired reaction product is isolated from the reaction mixture, and this may take place by using procedures well known per se.
• 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.
• 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.
• a water-immiscible, organic solvent such as, for example, dichbromethane
• 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.
• organic solvents which may be used as extractants, may be mentioned chloroform, ethylacetate and ether.
• 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
• 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%.
• 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.
• 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 7 4- (2-Hydroxyethyl)-5-methyl-3-isoxazolole.
• Example 3.3.5 g (0.05 mole) of NH 2 OH ⁇ 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 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%.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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Citations (7)

• 1983
  • 1983-07-11 DK DK319283A patent/DK150615C/da not_active IP Right Cessation
  • 1983-10-25 WO PCT/DK1983/000097 patent/WO1984001774A1/en not_active Application Discontinuation
  • 1983-10-25 EP EP19830903381 patent/EP0125253A1/en not_active Withdrawn
  • 1983-10-25 JP JP50346883A patent/JPS59501907A/ja active Pending

Patent Citations (8)

Non-Patent Citations (3)

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