Polyfluoroalkylisoxazolylamines, their preparation and use

Abstract: Novel compounds useful as intermediates for synthesiz­ ing, inter alia, pesticides and medicines, have the formula: in which: R is an alkyl group having a plurality of fluorines; R¹ is hydrogen, alkyl, halogen or optionally substituted phenyl; and R² is hydrogen or alkyl; and the invention includes salts there­ of.

Description: The present invention relates to novel 5-polyfluoroalkylisoxazolylamines which are useful as intermediates for synthesizing pesticides such as herbicides, fungicides and bactericides, and medicines. Various herbicides, fungicides, bactericides etc. having an isoxazolyl group have been provided. For example, U.S. Patent No. 4268679, and Japanese Patent Laid open Publication Nos. 56-131580, 57-31672, 57-53484 and 57-81467 disclose various isoxazolylamines as their intermediates for synthesis. However, no literature has disclosed specifically isoxazolylamines having an alkyl group in the 5-position substituted by a plurality of fluorine atoms. Copending European Application No. A-0375670 relates to the preparation of 3-polyfluoroalkylisoxazolylamines. The 5-polyfluoroalkylisoxazolylamines of the present invention are compounds of the formula (I): wherein R is alkyl having a plurality of fluorine atoms; R¹ is hydrogen, alkyl, halogen or optionally substituted phenyl; and R² is hydrogen or alkyl, and salts thereof. Examples of alkyl groups having a plurality of fluorine atoms for group R include groups having 1-9 fluorine atoms and 1-4 carbon atoms, for example, trifluoromethyl, pentafluoroethyl, heptafluoropropyl and 2-(trifluoromethyl)propyl. Examples of alkyl Groups for R¹ include C₁₋₅ alkyl, for example, methyl, ethyl, isopropyl and tert.-butyl. Examples of halogen for R¹ include chlorine, bromine, iodine, etc. Examples of substituents in the substituted phenyl groups which may be represented by R¹ includes halogen (ie fluorine, chlorine, etc.), C₁₋₄ alkyl (i.e. methyl, ethyl, isopropyl, etc.) and C₁₋₄ alkoxy (i.e. methoxy, isopropoxy, etc.). There may be two or more substituents and they may form, together with the carbon atom to which they are attached, a group such as methylenedioxy, ethylenedioxy, etc. . Examples of alkyl groups for R² include C₁₋₄ alkyl, for example, methyl, ethyl, isopropyl and tert.-butyl. Examples of salts of compounds (I) include inorganic salts such as the hydrochloride, sulfate and nitrate and organic salts such as the acetate p-toluenesulfonate and methanesulfonate. Typical examples of the compounds of the present invention are: (1) the compound of the formula (I) which R is trifluoromethyl and R¹ and R² are hydrogen; (2) the compound of the formula (I) which R is trifluoromethyl, R¹ is methyl and R² is hydrogen; (3) the compound of the formula (I) which R is trifluoromethyl, R¹ is phenyl and R² is hydrogen; (4) the compound of the formula (I) which R is trifluoromethyl, R¹ is 4-fluorophenyl and R² is hydrogen; (5) the compound of the formula (I) which R is trifluoromethyl, R¹ is 4-chlorophenyl and R² is hydrogen; (6) the compound of the formula (I) which R is trifluoromethyl, R¹ is 4-methylphenyl and R² is hydrogen; (7) the compound of the formula (I) which R is trifluoromethyl, R¹ is 4-methoxyphenyl and R² is hydrogen; (8) the compound of the formula (1) which R is trifluoromethyl, R¹ is 3,4-dinethoxyphenyl ani R² is hydrogen; (9) the compound of the formula (I) which R is trifluoromethyl, R¹ is 3,4-methylenedioxyphenyl and R² is hydrogen; (10) the compound of the formula (I) which R is pentafluoroethyl and R¹ and R² are hydrogen; (11) the compound of the formula (I) which R is pentafluoroethyl, R¹ is methyl and R² is hydrogen; (12) the compound of the formula (I) which R is pentafluoroethyl, R¹ is phenyl and R² is hydrogen; (13) the compound of the formula (I) which R is heptafluoropropyl and R¹ and R² are hydrogen; (14) the compound of the formula (I) which R is 2-(trifluoromethyl)propyl and R¹ and R² are hydrogen; The compounds of the present invention can be prepared by the following procedures. (a) They can be prepared by the reaction of β-ketonitriles of the formula (II): wherein R is alkyl having a plurality of fluorine atoms and R¹ is hydrogen, alkyl or optionally substituted phenyl, with hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxyurea, etc.. Preferably, this reaction is carried out in a solvent such as water, methanol, ethanol or ethylene glycol, neutralized with an alkali such as sodium bicarbonate, sodium carbonate or sodium hydroxide as necessary, at 60 - 120°C and then with the addition of 5 - 36 % hydrochloric acid (1 - 2 eq.) at 60 - 120°C. (b)They can be prepared by the reaction of enol ethers of the formula (III): wherein R and R¹ are as defined hereinbefore, with hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxyurea, etc. . Preferably, this reaction is carried out in a solvent such as water, methanol, ethanol or ethylene glycol, neutralized with an alkali such as sodium methylate or sodium ethylate as necessary, at 60 - 120°C and then with the addition of 5 - 36 % hydrochloric acid (1 - 2 eq.) at 60 - 120°C. (c)They can be prepared by the reaction of amidoximesof the formula (IV): wherein R¹ is as defined hereinbefore, with carboxylic acid esters of the formula (V): RCO₂R³ (V) wherein R is as defined hereinbefore and R³ is alkyl. Preferably, this reaction is carried out in the presence of lithium diisopropylamide in a solvent such as tetrahydrofuran or diethylether at -78 - 0°C and then with the addition of 5 - 36 % hydrochloric acid (6 - 20 eq.) at 30 - 60°C. (d)They can be prepared by hydrolysis of compounds of the formula (VI): wherein R and R¹ are as defined hereinbefore. Preferably, this reaction is carried out with the addition of 18 -36 % hydrochloric acid (1.2 - 10 eq.) in a solvent such as methanol, ethanol, n-propanol or ethylene glycol, preferably in 1 l of ethylene glycol to 1 mole of the compound (I), at 60 - 120°C. (e)They can be prepared by decomposition of compounds of the formula (VI) by the use of phthalic anhydride and hydrazine hydrate in the usual way. (f)They can be prepared by decomposition of compounds of the formula (VII): wherein R and R¹ are as defined hereinbefore, by the use of hydrazine hydrate in the usual way. (g)They can be prepared by hydrolysis of compounds of the formula (VIII): wherein R and R¹ are as defined hereinbefore and R⁴ is alkyl or phenyl. Preferably, this reaction is carried out with the addition of 18 - 36 % hydrochloric acid (1.2 - 10 eq.) in a solvent such as methanol, ethanol, n-propanol or ethylene glycol, preferably in 1 l of ethylene glycol to 1 mole of the compound (VIII), at 60 - 120°C. Preferably, the preparative processes described above may be suitably selected depending upon the particular substituted position of R and the nature of R¹ For example, the compounds (1), (3), (10), (12), (13) and (14) described above are preferably prepared by procedures (d) - (g), the compound (2) is prepared by the procedure (b). Advantageously, for example, compound (11) is prepared by procedure (a). The compounds of the present invention wherein R¹ is halogen can be prepared by halogenation of the compound of the formula (I) wherein R¹ is hydrogen in the usual way. Of compounds of the formula (II), used as the starting materials in the preparation of the compounds of formula (I), the compounds wherein R¹ is hydrogen or alkyl are novel compounds. They can, for example, be prepared by the condensation reaction of compounds of the formula (V) with compounds of the formula (IX): R¹ CH₂CN (IX) wherein R¹ is as defined hereinbefore, in the presence of lithium diisopropylamide in tetrahydrofuran. Preferably, the condensation reaction is carried out in a solvent such as tetrahydrofuran or diethyl ether at -78 - 0°C. The compounds wherein R¹ is phenyl or substituted phenyl, can be prepared by known methods, for example, the method described in W.R. Nes and A. Barger, J. Am. Chem. Soc., 72 , 5409 (1950). The compounds of the formula (III) can be prepared by methylation of compounds of the formula (II) with diazomethane in the usual way. The compounds of the formula (IV) can be prepared by known methods, for example, the method described in F. Eloy and R. Lenaers, Chem. Reviews, 62 , 155 (1962). The compounds of the formula (V) are known or can be prepared by known methods. The compounds of the formula (VI) are novel compounds and can be prepared from compounds of the formula (X): wherein R¹ is as defined hereinbefore, by known methods, for example, the method described in Japanese Patent Laid Open Publication No. 57-175175 via compounds of the formula (XI) and (XII): wherein R and R¹ are as defined hereinbefore. The compounds (XI) and (XII) are also novel. The compounds of the formula (X) can be prepared by known methods, for example, the reaction of compounds of the formula: prepared by the method described in U.S. Patent Nos. 3227725 and 3264318, with dimethylamine. The compounds of the formula (VIII) can also be prepared by the method described in U.S. Patent Nos. 3227725 and 3264318 and Japanese Patent Laid Open Publication No. 57-175175. The compounds of the formula (VII) can be prepared by reaction of compounds of the formula: wherein R and R¹ are as defined hereinbefore, which is prepared by reaction of compounds of the formula (VI) with phthalic anhydride in the usual way, with methanol by a known method. The compounds of formula (I) of the present invention thus obtained are useful as intermediates for synthesizing pesticides such as herbicides, fungicides and bactericides and medicines, in particular, herbicides and fungicides. The following preparations and examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof. Preparation 1 Trifluoroacetoacetonitrile A solution of n-butyllithium in n-hexane (280 ml, 0.44 mole) was added to dry diisopropylamine (64 ml, 0.46 mole) dissolved in dry tetrahydrofuran (400 ml), while keeping below 0°C. After being stirred at 0°C for 30 minutes, the solution was cooled below -72°C. A solution of methyl trifluoroacetate (25.61 g, 0.200 mole), acetonitrile (16.42 g, 0.40 mole) and dry tetrahydrofuran (200 ml) were added dropwise, while keeping below -72°C, and the solution, being kept at -75°C for additional 45 minutes, was warmed to room temperature over 1 hour. Ice-water (700 ml) was added to the solution and tetrahydrofuran and n-hexane were then evaporated under reduced pressure in a water bath at 40°C. The resulting residue was extracted with diethyl ether to remove neutral and basic components, adjusted to pH 1 with 36 % HCl and then extracted with methylene chloride to remove by-products such as acetoacetonitrile. The solution was extracted with diethyl ether. After the extract was dried with anhydrous sodium sulfate, p-toluenesulfonic acid (40 mg, 0.0002 mole) was added to the extract. The extract was distilled at atmospheric pressure and then distilled under reduced pressure to give 26.82 g (crude yield 97.8 %) of a crude product. This product was further distilled under reduced pressure to give 16.78 g (61.2 %) of the title compound, b.p. 37°C/2.4 mmHg - 43°C/2.5 mmHg. The resulting compound was dissolved in d⁶-acetone to measured NMR, the ratio of the keto form/the enol form was found to be 17/83. Preparation 2 Pentafluoropropionylacetonitrile Acetonitrile (4.1 g, 0.10 mole), ethyl pentafluoropropionate (9.61 g, 0.05 mole) and a solution of n-butyllithium in n-hexane (70 ml, 0.11 mole) were reacted as the procedure illustrated in the preceding Preparation 1 to give 7.28 g (77.8 %) of the title compound. The resulting compound was dissolved in CDCl₃ to measure NMR, the ratio of the keto form/the enol form was found to be 26/74, m.p. 47 - 54°C (deliquescence), b.p. 69 - 71°C/18 mmHg. Anal. Calcd. for C₅H₂NOF₅ 1/7H₂O: C, 31.66; H, 1.22; N, 7.39. Found: C, 31.65, H, 1.59; N, 7.23. Preparation 3 2-(Trifluoroaceto)propionitrile a) Propionitrile (19.8 g, 0.36 mole), methyl trifluoroacetate (23.05 g, 0.18 mole) and a solution of n-butyllithium in n-hexane (252 ml, 0.396 mole) were reacted as the procedure illustrated in the preceding Preparation 1 to give 27.72 g (100 %) of the title compound. The resulting compound was dissolved in CDCl₃ to measure NMR, the ratio of the keto form/the enol form was found to be 49/51, b.p. 52 - 57°C/2.7 mmHg. b) The title compound was obtained according to the same procedure as in a) except that methyl trifluoroacetate was replaced with t-butyl trifluoroacetate. Yield: 14.70 g (54.1 %). Preparation 4 2-(Pentafluoropropionyl)propionitrile Propionitrile (13.2 g, 0.24 mole), ethyl pentafluoropropionate (23.05 g, 0.12 mole) and a solution of n-butyllithium in n-hexane (168 ml, 0.264 mole) were reacted as the procedure illustrated in the preceding Preparation 1 to give 22.72 g (crude yield 94.1 %) of the crude title compound. The yield calculated as the pure product was 84.1 %. The resulting compound was dissolved in CDCl₃ to measure NMR, the ratio of the keto form/the enol form was found to be 71/29, b.p. 63 - 65°C/28 mmHg. Anal. Calcd. for C₆H₄NOF₅: C, 35.83; H, 2.01; N, 6.97. Found: C, 35.10; H, 2.52; N, 7.21. Example 1 5-Trifluoromethyl-4-methyl-3-aminoisoxazole A 8 % solution of sodium bicarbonate (288 ml, 0.27 mole, 1.5 eq.) was added to 96 % hydroxylamine hydrochloride (19.54 g, 0.27 mole, 1.5 eq.) dissolved in water (180 ml), with stirring below 10°C, to form free hydroxylamine and then crude 2-(trifluoroaceto)propionitrile (27.72 g, 0.18 mole) obtained from Preparation 3 a) was added to this mixture (pH of the reaction mixture became 6.2). After heating under reflux for 8 hours, 36 % hydrochloric acid (15.3 ml, 0.178 mole, 1.0 eq.) was added and the mixture was heated under reflux to react for an additional hour (to cyclize the oxime compound). After completion of the reaction, 48 % solution of sodium hydroxide was added dropwise to be adjust above pH 10 while cooling and the solution was extracted witn methylene chloride. After the extract was dried with anhydrous sodium sulfate, methylene chloride was evaporated and the resulting residue was purified by column chromatography on silica gel (Lobar column) to give 9.49 g (31.7 %) of the title compound as colorless crystals, m.p. 34.5 - 36.0°C, b.p. 67 - 70°C/0.78 mmHg. Anal. Calcd. for C₅H₅N₂OF₃: C, 36.15; H, 3.04; N, 16.87. Found: C, 36.20; H, 3.10; N, 16.84. The structure of this product was also comfirmed by IR, NMR and UV. 3-Trifluoromethyl-4-methyl-5-aminoisoxazole was also obtained. Yield: 0.79 g (2.6 %), b.p. 85 - 87°C/12 mmHg. Example 2 5-Trifluoromethyl-3-aminoisoxazole In water (15 ml) was dissolved 96 % hydroxylamine hydrochloride (1.63 g, 0.0225 mole, 1.5 eq.). A 8 % solution of sodium bicarbonate (24 ml, 0.0225 mole, 1.5 eq.) was added to the solution with stirring below 10°C to form free hydroxylamine. Crude trifluoroacetoacetonitrile (2.16 g, 0.015 mole) was then added to this mixture and the mixture was heated under reflux for 2.5 hours. After the addition of 36 % hydrochloric acid (5.7 ml), the mixture was heated under reflux to react for an additional hour. After completion of the reaction, a 48 % solution of sodium hydroxide was added dropwise to be adjust above pH 10 while cooling and the solution was extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, methylene chloride was evaporated and the resulting residue was purified by column chromatography on silica gel (Lobar column) to give the mixture (0.60 g, 26.0 %) of the title compound and 3-trifluoromethyl-5-aminoisoxazole (the ratio of both by NMR measurement was 4.9 : 95.6). Example 3 5-Pentafluoroethyl-3-aminoisoxazole The title compound was obtained according to the same procedure as described in Example 1 except that crude pentafluoropropionylacetonitrile (2.20 g, 0.010 mole) and water (10 ml) were used. Yield: 0.0104 g (0.5 %). 3-Pentafluoroethyl-5-aminoisoxazole was also obtained. Yield: 0.025 g (1.2 %). Example 4 5-Pentafluoroethyl-4-methyl-3-aminoisoxazole The title compound was obtained as colorless crystals according to the same procedure as described in Example 1 except that 2-(pentafluropropionyl)propionitrile (25.11 g, 0.12 mole), water (120 ml) and 36 % hydrochloric acid (10.2 ml) were used. Yield: 9.04 g (34.9 %), m.p. 32 - 34°C, b.p. 86 - 87°C/2.7 mmHg. Anal. Calcd. for C₆H₅N₂OF₅: C, 33.34; H, 2.34; N, 12.96. Found: C, 33.09; H, 2.54; N, 13.06. 3-Pentafluoroethyl-4-methyl-5-aminoisoxazole was also obtained. Yiled: 0.96 g (3.7 %). Example 5 5-Trifluoromethyl-3-aminoisoxazole Dry methanol (220 ml) and 96 % hydroxylamine hydrochloride (11.52 g, 0.159 mole) were added to trifluoroacetoacetonitrile (16.78 g, 0.122 mole) and the mixture was heated under reflux with stirring for 68 hours. Methanol was then evaporated under reduced pressure and after the addition of water (240 ml) a 48 % solution of sodium hydroxide was added to the resulting residue to be adjust above pH 11. The solution was extracted with methylene chloride and after the extract being dried with anhydrous soidum sulfate, the solvent was evaporated under reduced pressure to give the title compound (10.30 g, 55.2 %) as little colored crystals, m.p. 57 - 58°C, b.p. 66 - 67°C/0.8 mmHg. Example 6 5-trifluoromethyl-3-aminoisoxazole Trifluoroacetoacetonitrile (1.37 g, 0.010 mole), hydroxylamine hydrochloride (1.04 g, 0.015 mole) and a 8 % solution of sodium bicarbonate (15.75 g, 0.015 mole) were heated under reflux for 2.5 hours. After the addition of 36 % hydrochloric acid (1.01 g, 0.010 mole), the mixture was heated under reflux for an additional hour to give a product (1.2 g, 78 %). According to the measurement of NMR, it was found that this compound contained 94 % of 3-trifluoromethyl-5-aminoisoxazole and 6 % of 5-trifluoromethyl-3-aminoisoxazole. Preparation 5 α-Trifluoroacetyl-p-fluorophenylacetnitrile Dry ethanol (15 ml) was added to sodium metal (1.22 g, 0.0530 mole) and the mixture was heated under reflux to dissolve sodium metal perfectly. A mixture of ethyl trifluoroacetate (7.53 g, 0.0530 mole) and p-fluorophenylacetonitrile (6.76 g, 0.0500 mole) was added dropwise over 30 minutes. The mixture, after being heated under reflux for 10 hours, was extracted with methylene chloride to remove neutral and basic components. To the mixture was then added 36 % hydrochloric acid to adjust below pH 2 and the mixture was extracted with diethyl ether again. After being dried, the solvent was distilled off under reduced pressure to give the crude title compound (10.47 g, 84.0 %). The product showed a single spot on thin-layer chromatography. The product was recrystallized from benzenecyclohexane to recover the monohydrate of the title compound (8.97 g, 77.0 %) as pale yellow prisms. The structure of this compound was confirmed by IR and NMR. Preparation 6 α-(Trifluoroacetyl)phenylacetonitrile The title compound was obtained according to the same procedure as described in Preparation 5 except that ethyl trifluoroacetate (50.00 g, 0.352 mole) was used. Yield: 70.45 g (92.3 %), m.p. 85 - 87°C. This compound was dissolved in CDCl₃ to measure NMR, the ratio of the enol form was found to be 100 %. This product was recrystallized from benzene-cyclohexane to give the monohydrate of the title compound as colorless needles, m.p. 87 - 88°C [see Nes et al., J Am. Chem. Soc., 72 , 5409 (1950).]. Preparation 7 α-(Pentafluoropropionyl)phenylacetonitrile The title compound was obtained according to the same procedure as described in Preparation 5 except that ethyl pentafluoropropionate (24.44 g, 0.127 g) was used. Yield: 19.41 g (61.5 %), m.p. 94 - 95°C. This compound was dissolved in CDCl₃ to measure NMR, the ratio of the keto form/the enol form was found to be 38/62. Anal. Calcd. for C₁₁H₆NOF₅: C, 50.20; H, 2.30; N, 5.32. Found: C, 50.48; H, 2.50; N, 5.36. Preparations 8 to 14 The following compounds were prepared according to the same procedure as described in Preparation 5. The results are shown in Table 1. In the table, the second column shows kinds and positions of one or more substituents on benzene ring of the formula (A): and the third column shows the amount of the compound of the formula (B): Example 7 5-trifluoromethyl-4-phenyl-3-aminoisoxazole A mixture of the title compound (4.8%) and 3-trifluoromethyl-4-phenyl-5-aminoisoxazole (82.9%) was obtained according to the same procedure as described in Example 5 except that α-(trifluoroacetyl)phenylacetonitrile (2.13 g, 0.010 mole) was used. Examples 8 to 14 The following compounds were prepared according to the same procedure as described in Example 7. The results are shown in Table 2. In the table, the second column shows kinds and positions of one or more substituents on benzene rings of compounds of the formula (B) and (C): The third column shows the yield of the compound purified by column chromatography on silica gel and the fourth column shows the ratio by weight of the compound of the formula (B) and (C) measured by HPLC. Ex. No. Substituent Yield (%) Content ratio (B)/(C) by weight 8 unsubstituted 86.3 94.5/5.5 9 4 - F 85.3 93.8/6.2 10 4 - Cl 65.1 87.2/12.8 11 4 - CH₃ 80.7 95.6/4.4 12 4 -OCH₃ 84.9 94.9/5.1 13 3-OCH₃ 85.0 96.1/3.9 4-OCH₃ 14 3,4-OCH₂O 84.6 95.1/4.9 The physical properties of the resulting compounds are shown in Table 3. In the table, the first column identifies the compounds by the number of the preparative example and the formula (B) or (C), and the fifth column shows the values of λ max and ε measured in 95 % ethanol. Example 15 5-Pentafluoroethyl-4-phenyl-3-aminoisoxazole 3-Pentafluoroethyl-4-phenyl-5-aminoisoxazole was obtained as colorless needles according to the same procedure as described in Example 5 except that α-(pentafluoropropionyl)phenylacetonitrile (13.61 g, 0.050 mole) was used. Yield: 0.97 g (7.0 %), m.p. 79 - 80°C. Anal. Calcd. for C₁₁H₇N₂OF₅: C, 47.49; H, 2.54; N, 10.07. Found: C, 47.49; H, 2.80; N, 10.20. Title compound (0.47 g, 3.4 %) was also obtained. Yield: 0.47 g (3.4 %). Example 16 5-trifluoromethyl-4-phenyl-3-aminoisoxazole A crude product was obtained according to the same procedure as described in Example 1 except that α-(trifluoroacetyl)phenylacetonitrile (23.12 g, 0.10 mole) was used. Crude yield: 3.69 g (16.2 %). According to the measurement of NMR, it was found that this compound contained 83.2 % of 5-trifluoromethyl-4-phenyl-3-aminoisoxazole and 11.8 % of 3-trifluoromethyl-4-phenyl-5-aminoisoxazole. The crude product was purified by column chromatography on silica gel as described in Example 1 to give the title compound (3.06 g, 13.4 %) as colorless crystals, m.p. 91.5 - 92.0°C. Example 17 5-Trifluoromethyl-4-phenyl-3-aminoisoxazole Water (170 ml) was added to 96 % hydroxylamine hydrochloride (2.17 g, 0.0300 mole, 1.5 eq.). The solution was neutralized with a 8 % solution of sodium bicarbonate (31.5 g, 0.0300 mole, 1.5 eq.), while keeping below 10°C. To this was added -(trifluroacetyl)phenylacetonitrile (4.62 g, 0.0200 mole) and the mixture was heat under reflux for 8 hours. After 36 % hydrochloric acid (1.7 ml, 0.0200 mole) being added, the mixture was heated under reflux for an additional hour. A 8 % solution of sodium bicarbonate was then added to neutralize and the solution was extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, it was concentrated and purified by column chromatography on silica gel to give 0.7 g of the product. According to the measurement of HPLC, it was found that this product contained 83.3 % of the title compound and 16.7 % of 3-trifluoromethyl-4-phenyl-5-aminoisoxazole. Preparation 15 3-Methoxy-3-(trifluoromethyl)acrylonitrile Diethylether (300 ml) was added to trifluoroacetoacetonitrile (13.7 g, 0.100 mole) and to this was added an ethereal solution of diazomethane, which was prepared from N-nitrosomethylurea (25.77 g, 0.250 mole), a 50 % solution of potassium hydroxide (112.22 g, 1.00 mole) and diethylether (180 ml), with ice cooling. The solution was allowed to stand over night while cooling with ice. Next day, until the pH being 3 - 4 (by an universal test paper) acetic acid in limited amounts was added to the reaction mixture to decompose an excess of diazomethane and the solution was concentrated to about 200 ml at atmospheric pressure by using a distillation apparatus equipped with a fractionating column. The concentrate was washed with a 8 % solution of sodium bicarbonate and water and dried with anhydrous sodium sulfate. Diethyl ether was distilled off by using a distillation apparatus equipped with a fractionating column at atmospheric pressure and the residue was distilled under reduced pressure to give the title compound (5.31 g, 35.1 %) as a colorless liquid, b.p. 58.0°C/68 mmHg - 64.0°C/70.0 mmHg. The structure of the product was confirmed by IR and NMR. Preparation 16 3-Methoxy-3-(pentafluoroethyl)acrylonitrile The title compound was obtained as a colorless liquid according to the same procedure as described in Preparation 15 except that pentafluoropropionylacetonitrile (18.7 g, 0.100 mole) was used. Yield: 13.63 g (67.8 %), b.p. 65 - 69°C/69 mmHg. The structure of the product was confirmed by NMR. Preparation 17 3-Methoxy-3-(trifluoromethyl)methacrylonitrile The title compound was obtained as a colorless liquid according to the same procedure as described in Preparation 15 except that 2-(trifluoroaceto)propionitrile (15.11 g, 0.100 mole) was used. Yield: 11.4 g (69.6 %), b.p. 68 - 76.5°C/28 mmHg. It was found that the title compound was the mixture of the E- and the Z-form by the measurement of NMR. The ratio of both was 20/80 but no assignment was made. Preparation 18 3-Methoxy-3-(pentafluoroethyl)methacrylonitrile The title compound was obtained as a colorless liquid (2.31 g) from the forerun and a pale brown liquid (6.66 g) from the main distillate of the vacuum distillation according to the same procedure as described in Preparation 15 except that 2-(pentafluoropropionyl)propionitrile was used. Each fraction was a mixture of the E- and the Z-form, 37/63 and 3/97, respectively (no assignment). The boiling point of the forerun is 85 - 89°C/48 mmHg and that of the main distillate is 80 - 86°C/28 mmHg. Preparation 19 3-Methoxy-2-phenyl-3-(trifluoromethyl)acrylonitrile The crude title compound was obtained according to the same procedure as described in Preparation 15 except that (trifluoroaceto)phenylacetonitrile (2.13 g, 0.010 mole) was used. This product was employed for a further reaction without additional purification. Preparation 20 3-Methoxy-3-pentafluoroethyl-2-phenylacrylonitrile The crude title compound was obtained according to the same procedure as described in Preparation 15 except that (pentafluoropropionyl)phenylacetonitrile(0.79 g, 0.003 mole) was used and the reaction was carried out with ice cooling for 30 minutes. This product was employed for a further reaction without additional purification. Example 18 5-Trifluoromethyl-3-aminoisoxazole Sodium metal (0.48 g, 0.0210 mole, 1.5 eq.) was added to dry methanol (28 ml) and 97 % hydroxylamine hydrochloride (1.50 g, 0.0210 mole, 1.5 eq.), obtained from Nakarai Chemicals, was then added to the resulting solution with ice cooling. After being stirred at room temperature for 15 minutes, 3-methoxy-3-(trifluromethyl)acrylonitrile (2.12 g, 0.0140 mole) was added and heated under reflux for 16 hours. To the solution was then added 36 % hydrochloric acid (3.54 g, 0.0350 mole, 2.5 eq.) and it was heated under reflux for 1 hour. Methanol was distilled off at atmospheric pressure over 1 hour by using a distillation apparatus equipped with a fractionating column. Water (28 ml) was added to the residue and it was extracted with methylene chloride after pH being adjusted above 11 with 48 % sodium hydroxide. The extract was dried with anhydrous sodium sulfate and it was distilled at atmospheric pressure and then under reduced pressure at room temperature by using a distillation apparatus equipped with a fractionating column to give the crude title compound (0.8968 g). This product was purified by column chromatography on silica gel to give the title compound (0.2201 g, 10.3 %) and 3-trifluoromethyl-5-aminoisoxazole (0.4738 g, 22.3 %). Example 19 3-Amino-5-pentafluoroethylisoxazole The title compound (0.9571 g, 33.8 %) and 3-pentafluoroethyl-5-aminoisoxazole (0.2181 g, 7.7 %) were obtained according to the same proceudre as described in Example 18 except that 3-methoxy-3-(pentafluoroethyl)acrylonitrile (2.82 g, 0.0140 mole) was used. Example 20 5-Trifluoromethyl-4-methyl-3-aminoisoxazole The title compound (1.4988 g, 64.5 %) and 3-trifluoromethyl-4-methyl-5-aminoisoxazole (0.0249 g, 1.1 %) were obtained according to the same procedure described in Example 18 except that 3-methoxy-3-(trifluoromethyl)methacrylonitrile (2.31 g, 0.0140 mole) and 36 % hydrochloric acid (1.42 g, 0.0140 mole, 1 eq.) were used and reflux was carried out for 68 hours. Example 21 5-Pentafluoroethyl-4-methyl-3-aminoisoxazole The title compound (0.3497 g, 11.6 %) and 3-pentafluoroethyl-4-methyl-5-aminoisoxazole (0.0923 g, 3.1 %) were obtained according to the same procedure as described in Examle 18 except that 3-methoxy-3-(pentafluroethyl)methacrylonitrile (3.01 g, 0.0410 mole) was used. Example 22 5-Pentafluoroethyl-4-phenyl-3-aminoisoxazole The title compound (0.0675 g) and 3-pentafluoroethyl-4-phenyl-5-aminoisoxazole (0.1125 g) were obtained according to the same procedure as described in Example 18 except that 3-methoxy-2-phenyl-3-pentafluoroethylacrylonitrile (8.31 g, 0.030 mole) was used, reflux was carried out for 38 hours and hydrochloric acid was not used. Example 23 5-Trifluoromethyl-4-phenyl-3-aminoisoxazole Under a nitrogen atmosphere, dry tetrahydrofuran (90 ml) was added to diisopropylamine (14.5 ml, 0.105 mole, 5.23 mole) and then to the solution was added a 15 % solution of butyllithium in n-hexane (64 ml, 0.100 mole, 5.0 eq.) with cooling below 0°C. After keeping the mixture at 0°C for 30 minutes, it was cooled at -75°C. The mixture of t-butyl trifluoroacetate (10.21 g, 0.0600 mole, 3 eq.), phenylacetamide oxime (3.00 g, 0.0200 mole) and dry tetrahydrofuran (45 ml) was added dropwise, keeping the mixture below -72°C. After the mixture was stirred at -75°C for 1 hour, it was allowed to warm to room temperature over 1 hour. To the mixture was added 10 % hydrochloric acid (90 ml, 0.246 mole) and refluxed for 2.5 hours. The reaction mixture was distilled under reduced pressure to remove tetrahydrofuran and n-hexane. The resulting residue was adjusted above pH 13 with a 48 % solution of sodium hydroxide and extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography on alumina and silica gel to give the title compound (0.60 g, 13.1 %). This product was recrystallized from cyclohexane to give colorless needles, m.p. 92.0 - 93.0°C. The structure of this compound was confirmed by IR, NMR and UV. Example 24 5-Pentafluoroethyl-4-phenyl-3-aminoisoxazole The title compound was obtained according to the same procedure as described in Example 23 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used. Yield: 0.07 g (2.5 %). Preparation 21 3-(2,2-Dihydroxy-2-trifluoromethyl)ethyl-5-diethylamino-1,2,4-oxadiazole Dry diisopropylamine (33.75 g, 0.334 mole) was dissolved in dry tetrahydrofuran (290 ml) and the solution was then cooled to -60°C. A 15 % solution of n-butyllithium in n-hexane (200 ml, 0.318 mole) was added to this solution and it was stirred at 0°C for 30 minutes. A solution of 5-dimethylamino-3-methyl-1,2,4-oxadiazole (18.55 g, 0.145 mole), previously prepared, t-butyl trifluoroacetate (37.00 g, 0.218 mole) and tetrahydrofuran (145 ml) was added dropwise to this reaction solution, being cooled to -75°C (the temperature was kept below -75°C during the addition). After being stirred at -75°C for 1 hour, the cooling bath was removed. When the temperature rose to 0°C, the solution was cooled again to -25°C and cold 2N hydrochloric acid (346 ml, 0.652 mole) was added to neutralize the solution (the temperature rose to 3°C). Tetrahydrofuran and n-hexane were evaporated under reduced pressure in a water bath at 30°C and the resulting residue was extracted with diethyl ether. The extract was evaporated under reduced pressure in a water at 30°C to give 43.55 g of crystals. This product was recrystallized from benzene to give the title compound as colorless prisms. Yield: 27.75 g, m.p. 84.0 - 85.0°C. NMR (CDCl₃,δ): 3.04 (s, 2H, -CH₂-), 3.14 (s, 6H, -N(CH₃)₂), 5.25 (b.s., 2H, -C(OH)₂-). IR (CHCl₃, cm⁻¹): 3570(OH), 3270 br. * (OH), 1650(C=N) (*br.=broad). Anal. Calcd. for C₇H₁₀N₃O₃F₃: C, 34.86; H, 4.18; N, 17.42. Found: C, 34.89; H, 4.16; N, 17.54. The mother liquor was purified by column chromatography on silica gel and recrystallization from benzene to give 6.11 g of crystals. This product contains the title compound and 3-dimethylcarbamoylamino-5-trifluoromethylisoxazole in the ratio 7 : 3. Both yields calculated as the pure product were 92.6 % and 5.7 %, respectively. Preparation 22 5-Dimethylamino-3-(2-hydroxy-2-pentafluroethyl)-vinyl-1,2,4-oxadiazole The title compound was obtained as colorless flakes according to the same procedure as described in Preparation 21 except that 5-dimethylamino-3-methyl-1,2,4-oxadiazole (1.27 g, 0.010 mole) and t-butyl pentafluropropionate (3.3 g, 0.015 mole) were used. Yield calculated as the pure product: 71.1 %, m.p. 103.0 - 104.0°C (recrystallization solvent: cyclohexane). NMR (CDCl₃,δ): 3.17 (s, 6H, -N(CH₃)₂) , 5.95 (s, 1H, -CH=). IR (CHCl₃, cm⁻¹): 2950 br (OH), 1660, 1670, 1680 (C=N). Anal. Calcd. for C₈H₈N₃O₂F₅: C, 35.18; H, 2.95; N, 15.38. Found: C, 35.14; H, 3.10; N, 15.49. 3-Dimethylcarbamoylamino-5-pentafluoroethylisoxazole (0.68 g, 24.9 %) was also obtained. Preparation 23 5-Dimethylamino-3-(2-hydroxy-2-heptafluoropropyl)-vinyl-1,2,4-oxadiazole The title compound was obtained as colorless plates according to the same procedure as described in Preparation 21 except that 5-dimethylamino-3-methyl-1,2,4-oxadiazole (2.90 g, 0.028 mole) and t-butyl heptafluorobutyrate (11.34 g, 0.042 mole) were used and purification methods were changed (recrystallization from cyclohexane, column chromatography on silica gel and then recrystallization from dichloroethane-n-hexane). Yield calculated as the pure product: 42.1 %, m.p. 81.5 - 82.5°C. NMR (CDCl₃,δ): 3.19 (s, 6H, -N(CH₃)₂), 5.97 (s, 1H, -CH=). IR (CHCl₃, cm⁻¹): 2950 br. (OH), 1650, 1670 (C=N). Anal. Calcd. for C₉H₈N₃O₂F₇: C, 33.45; H, 2.50; N, 13.00. Found: C, 33.23; H, 2.61; N, 13.30. 3-Dimethylcarbamoylamino-5-heptafluorobutylisoxazole (4.225 g, 57.3 %) was also obtained. Preparation 24 5-Dimethylamino-3-(3-trifluoromethyl)butyrylmethyl-1,2,4-oxadiazole The title compound was obtained as pale yellow crystals according to the same procedure as described in Preparation 21 except that 5-dimethylamino-3-methyl-1,2,4-oxadiazole (6.07 g, 0.0477 mole) and methyl 3-trifluoromethylbutyrate (12.17 g, 0.0716 mole) were used and purification methods were changed (silica gel column chromatography and then sublimation). Yield: 0.472 g (3.7 %), m.p. 46.0 - 47.5°C. NMR (CDCl₃, ): 1.11 (d, 3H, 3.12 (s, 6H, -N(CH₃)₂), 3.63 (s, 2H, -COCH₂-) , 2.5 - 3.0 (m, 3H, IR (CCL₄, cm⁻¹): 1640 (C=N), 1730 (C=O). Anal. Calcd. for C₁₀H₁₄N₃O₂F₃: C, 45.28; H, 5.32; N, 15.84. Found: C, 45.16; H, 5.30; N, 15.77. 3-Dimethylcarbmoylamino-5-(2-trifluoromethyl)isopropylisoxazole (1.11 g, 8.8 %) was also obtained. Preparation 25 3-Dimethylcarbomoylamino-5-trifluoromethylisoxazole After 3-(2,2-dihydroxy-2-trifluoromethyl)ethyl-5-dimethylamino-1,2,4-oxadiazole (19.42 g, 0.08052 mole) was heated with stirring at 90°C for 1.5 hours, the product was dried under reduced pressure to give the crude title compound (18.24 g, crude yield 101.5 %) as colorless prisms, m.p. 126.0 - 126.5°C. Preparations 26 to 28 According to the same procedure as described in Preparation 25, the following compounds were prepared. The results are shown in Table 4. Preparation 29 3-Dimethylcarbamoylamino-5-trifluoromethylisoxazole Dry tetrahydrofuran (84.6 ml) was added to diisopropylamine (dried with potassium hydroxide, 9.85 g, 0.0973 mole) under a nitrogen atmosphere. The solution was cooled to -60°C and thereto was added a 15 % solution of n-butyllithium in n-hexane (58.5 ml, 0.0901 mole). After being stirred at 0°C for 30 minutes, it was cooled to -75°C. A mixture of t-butyl trifluoroacetate (10.80 g, 0.0635 mole), 5-dimethylamino-3-methyl-1,2,4-oxadiazole (5.72 g, 0.0423 mole) and dry tetrahydrofuran (423 ml) was added dropwise to it at -73 - -75°C over 1.5 hours. After being stirred at -75°C for 1 hour, it was allowed to warm to room temperature over 1 hour. It was further heated to 50°C and stirred for 30 minutes. 1N hydrochloric acid (190 ml) was then added thereto with ice cooling and tetrahydrofuran and n-hexane were distilled off under reudced pressure in a water bath at 40°C. After being extracted with methylene chloride, the extract was concentrated and purified column chromatrography on silica gel to give the crude title compound (8.91 g, crude yield 94.4 %). Repeated recrystallizations from benzene gave colorless fine needles, m.p. 126.0 - 126.5°C. The structure of this compound was confirmed by IR, NMR and elemental analysis. Anal. Calcd. for C₇H₈N₃C₂F₃: C, 37.68; H, 3.61; N, 18.83. Found: C, 37.49; H, 3.62; N, 18.76. Preparation 30 3-Dimethylcarbamoylamino-5-trifluoromethylisoxazole The same reaction as described in Preparation 21 was carried out except that 5-dimethylamino-3-methyl-1,2,4-oxadiazole (18.51 g, 0.145 mole) was used. The reaction mixture was allowed to warm to room temperature and tetrahydrofuran and n-hexane were evaporated under reduced pressure. Cold 2N hydrochloric acid (346 ml, 0.652 mole) was added to the residue to neutralize and the mixture was then extracted with diethyl ether. Diethyl ether was evaporated under reduced pressure and the resulting residue was heated for 70 minutes, while low boiling point materials were distilled off by heating to 90°C, to give 32.56 g of crystals. This product was recrystallized from benzene to give the title compound (24.35 g) The mother liquor was purified by column chromatography on silica gel to give the title compound (5.10 g) as crystals. Yield: 91 %. This compound was sublimed at 106 - 110°C/0.3 mmHg. Preparation 31 3-Dimethylcarbamoyl-4-phenyl-5-trifluoromethylisoxazole The same reaction as described in Preparation 21 was carried out except that 3-benzyl-5-dimethylamino-1,2,4-oxadiazole (5.08 g, 0.025 mole) was used. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 1 hour. After cooling, 1N hydrochloric acid (125 ml) was added to the reaction mixture and tetrahydrofuran and n-hexane were then evaporated under reduced pressure. Water (100 ml) was added to the residue and the mixture was extracted with methylene chloride. The extract was washed successively with a 5 % solution of sodium hydroxide and a saturated aqueous sodium chloride and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the purification of the residue by column chromatography on silica gel was repeated to give the title compound as colorless neeldes. Yield: 3.75 g (48.7 %), m.p. 138 - 139°C (dec.). Preparations 32 to 38 The reactions in Preparations 32 to 34 were carried out according to the same procedure as described in Preparation 30 and the reactions in Preparations 35 to 38 were carried out according to the same procedure as described in Preparation 31 to give the following compounds. The results are shown in Table 5. Preparation 39 3-Phthalimino-5-trifluoromethylisoxazole A mixture of 3-dimethylcarbamoylamino-5-trifluoromethylisoxazole (2.26 g, 0.010 mole) and phthalic anhydride (3.26 g, 0.022 mole, 2.2 eq.) was heated with stirring at 130°C for 40 minutes (the reaction mixture was liquefied in the course of the reaction and then solidified again) and then cooled to room temperature. The reaction mixture was dissolved in methylene chloride (30 ml), shaked with a 8 % solution of sodium bicarbonate (30 ml) and then washed with water (30 ml). The aqueous sodium bicarbonate and the water layer were extracted with methylene chloride (30 ml) and the extract was combined with the initial solution of methylene chloride. Methylene chloride was evaporated under reduced pressure to give crude crystals (2.80 g). These crude crystals were recrystallized from benzene to give the title compound (2.30 g) as colorless needles. The mother liquor was purified by column chromatography on silica gel to give the title compound (0.37 g) as crystals. Yield: 94.6 %, m.p. 161.0 - 162.5°C Anal. Calcd. for C₁₂H₅N₂O₃F₃: C, 51.08; H, 1.79; N, 9.93. Found: C, 50.87; H, 1.99; N, 10.10. 1,3-Di(5-trifluoromethyl-3-isoxazole)urea (45 mg, 2.7 %) was also obtained as colorless flakes. m.p. 245°C<(dec.). Preparations 40 to 42 According to the same procedure as described in Preparation 39, the following compounds were prepared. The results are shown in Table 6. In the table, the starting compound represents the compound of the formula: the product represents the compound of the formula: and the by-product represents the compound of the formula: Preparation 43 5-Trifluoromethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole Methanol (10 ml) was added to 3-phthalimino-5-trifluoromethylisoxazole (2.82 g, 0.010 mole) and the mixture was heated under reflux for 1 hour. Methanol was then evaporated under reduced pressure and the residue was recrystallized from a mixture of benzene and cyclohexane to give the title compound as colorless needles. This compound decomposed in a silica gel column. Yield: 3.07 g (97.8 %), m.p. 116 - 117°C. Anal. Calcd. for C₁₃H₉N₂O₄F₃: C, 49.69; H, 2.89; N, 8.92. Found: C, 49.73; H, 3.02; N, 9.00. Preparation 44 5-Pentafluoroethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole The title compound was obtained as colorless prisms according to the same procedure as described in Preparation 43 except that 3-phthalimino-5-pentafluoroethylisoxazole was used. Yield: 59.4 %, m.p. 97 -100°C. Anal. Calcd. for C₁₄H₉N₂O₄F₅: C, 46.17; H, 2.49; N, 7.69. Found: C, 46.11; H, 2.62; N, 7.68. Example 25 5-Trifluoromethyl-3-aminoisoxazole In methanol (15 ml) was dissolved 5-trifluoromethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole (1.57 g, 0.0050 mole) and 90 % hydrazine hydrate (0.42 g, 0.0075 mole) was added to the solution. It was allowed to stand to room temperature for 46 hours. Water (30 ml) was added to it and the mixture was stirred at room temperature for 15 minutes. Crystals were filtered off. The filtered off crystals were washed repeatedly with methylene chloride (45 ml) and the filtrate was extracted with these washings. The filtrate was further extracted with methylene chloride (45 ml x 2) and the solvent was distilled off from the combined extract at atmospheric pressure by using a distillation apparatus equipped with a fractionating column packed with glass raschig rings (15 mm in diameter, 200 mm in length). The residue was purified by column chromatography on silica gel to give the title compound. Yield: 0.714 g (93.9 %). Example 26 5-Pentafluoroethyl-3-aminoisoxazole The title compound was obtained in a 95.7 % yield according to the same procedure as described in Example 25 except that 5-pentafluoromethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole was used and reflux was carried out for 45 minutes. Example 27 5-Trifluoromethyl-3-aminoisoxazole Methanol (20 ml) and 90 % hydrazine hydrate (1.67 g, 0.030 mole) were added to 3-phthalimino-5-trifluoromethylisoxazole (5.63 g, 0.020 mole). After stirring at room temperature for 10 minutes, the mixture was heated under reflux and reacted for 45 minutes. After cooling, water (40 ml) was added and the mixture was stirred at room temperature for 15 minutes. The precipitated crystals were filtered off. The crystals were washed with methylene chloride (60 ml) and the filtrate was washed with the washings. It was further extracted with methylene chloride (60 ml x 2). The combined extract was distilled off at atmospheric pressure by using a distillation apparatus equipped with a fractionating column packed with glass raschig ring (15 mm in diameter, 200 mm in length). The residue was then distilled under reduced pressure at room temperature to give the title compound as colorless plates (if the solvents were distilled under reduced pressure, the yield lowered for the volatility of the desired product). Yield: 2.84 g (93.4 %), m.p. 44 - 45°C, b.p. 79°C/10 mmHg. Examples 28 to 36 The reactions in Examples 28 to 36 were carried out according to the same procedure as described in Example 27. The results are shown in Table 7. In the table, the starting material represents the compound of the formula: and the product represents the compound of the formula: Example 37 5-Trifluoromethyl-3-aminoisoxazole Phthalic anhydride (6.52 g, 0.044 mole) was added to 5-trifluoromehtyl-3-dimethylcarbonylaminoisoxazole (4.46 g, 0.020 mole) and the mixture was heated at 130°C for 40 minutes. After cooling, methanol (20 ml) and hydrazine hydrate (1.89 g, 0.034 mole) were added. The mixture was stirred at room temperature for 10 minutes and then heated under reflux for 45 minutes. After cooling, water (40 ml) was added and the mixture was stirred at room temperature for 15 minutes. The title compound (2.77 g, 91.1 %) was obtained according to the same work up as described in Example 27. 1,3-Di(5-trifluoromethyl-3-isoxazolyl)urea (2.8 %) was also obtained. Examples 38 to 40 The reactions in Examples 38 to 40 were carried out according to the same procedure as described in Example 37 except that the molar ratio of hydrazine hydrate to a starting material was changed. The results are shown in Table 8. In the table, the starting material represents the compound of the formula: the product represents the compound of the formula: and the by-product 1,2 and 3, respectively, represent the compound of the formula: Example 41 5-Trifluoromethyl-3-aminoisoxazole A mixture of 5-trifluormethyl-3-dimethylcarbamoylaminoisoxazole (1.15 g, 0.005 mole) and 36 % hydrochloric acid (10 eq.) were reacted at 100°c for 10 hours. The reaction mixture was worked up in the usual way to give the crude title compound. Crude yield: 0.20 g (26 %). Examples 42 to 55 The reactions in Examples 42 to 55 were carried out according to the same procedure as described in Example 41. The results are shown in Table 9. In the table, the starting material represents the compound of the formula: and the product represents the compound of the formula: Preparation 45 3-(2,2-Dihydroxy-2-trifluoromethyl)ethyl-5-phenyl-1,2,4-oxadiazole Diisopropylamine (molecular sieves 3A dried, 1.86 g, 18.4 mmole) was dissolved in tetrahydrofuran (molecular sieves 4A dried, 16 ml) and the solution was cooled to -60°C. To this solution was added a solution of n-butyllithium in n-hexane (11.1 ml, 17.6 mmole) and it was stirred at 0°C for 30 minutes. The reaction mixture was cooled to -75°C and a solution of 3-methyl-5-phenyl-1,2,4-isoxazole (1.28 g, 8.0 mmole), prepared previously, t-butyl trifluoroacetate (2.04 g, 12.0 mmole) and dry tetrahydrofuran (8 ml) was added dropwise to it below -75°C over 45 minutes. After stirring at -75°C for 1 hour, the cooling bath was removed. When the temperature of the reaction mixture reached to 0°C over 1 hour, it was cooled again to -25°C and cold 2N hydrochloric acid (19 ml, 35.8 mmole) was added to neutralize it. The reaction mixture was then worked up to obtain crude crystals (2.5363 g), according to the same procedure as described in Example 65. A part (0.6184 g) of this product was purified by column chromatography on silica gel to give pale brown crystals (0.4973 g), m.p. 71 - 76°C. The composition etc. of this product are shown in Table 10. These pale brown crystals (0.2289 g) were further recrystallized from acetone/n-hexane to give the title compound as colorless needles. Yield: 0.1328 g, m.p. 71.0 - 81.0°C. NMR (d₆-DMSO,δ): 3.20 (s, 2H, -CH₂-), 7.17 (s, 2H, -C(OH)₂-), 7.4 - 7.8 (m, 3H, -C₆H₅), 8.0 - 8.2 (m, 2H, -C₆H₅). IR (CHCl₃, cm⁻¹): 3560, 3350 br. (OH), 1565 (C=N). Anal. Calcd. for C₁₁H₉N₂O₃F₃: C, 48.18; H, 3.31; N, 10.22. Found: C, 48.05; H, 3.48; N, 10.49. After the title compound was dissolved in CDCl₃ and 5 hours passed, it became to the mixture of product 1 (28.8 w/w %), 2 (9.6 w/w %) and 3 (61.6 w/w %) shown in Table 10, but it was stable in d₆-DMSO. Preparation 46 3-(2,2-Dihydroxy-2-trifluoromethyl)ethyl-5-t-butyl-1,2,4-oxadiazole Crude crystals (2.8084 g) were obtained according to the same procedure as described in Preparation 45 except that 3-methyl-5-t-butyl-1,2,4-oxadiazole (1.40 g, 10.0 mmole), t-butyl trifluoroacetate (2.55 g, 15.0 mmole), diisopropylamine (2.33 g, 23.0 mmole), a solution of n-butyllithium in n-hexane (13.8 ml, 22.0 mmole) and tetrahydrofuran (20 ml) were used. A part (1.4209 g) of this product was purified by column chromatography on silica gel to give tan crystals (1.1106 g). The composition etc. of this product are shown in Table 10. These tan crystals (0.8852 g) were further recrystallized from benzene/n-hexane to give the title compound as colorless plates. Yield: 0.2895 g, m.p. 59.0 - 67.0°C. NMR (d₆-DMSO,δ): 1.37 (s, 9H, 3.08 (s, 2H, -CH₂-), 7.08 (s, 2H, -C(OH)₂-). IR (CHCl₃, cm⁻¹): 3560, 3330 br. (OH), 1570 (C=N). Anal. Calcd. for C₉H₁₃N₂O₃F₃: C, 42.52; H, 5.15; N, 11.02. Found: C, 42,43; H, 5.09; N, 11.16. After the title compound was dissolved in CDCl₃ and 5 hours passed, it became to the mixture of product 1 (31.6 w/w %), 2 (7.6 w/w %) and 3 (60.8 w/w %) shown in Table 10, but it was stable in d₆-DMSO. Preparation 47 3-(2,2-Dihydroxy-2-trifluoromethyl)ethyl-5-trichloromethyl-1,2,4-oxadiazole The crude title compound was obtained according to the same procedure as described in Preparation 45 except that 3-methyl-5-trichloromethyl-1,2,4-oxadiazole (2.01 g, 10.0 mmole) was used. The composition etc. of this compound are shown in Table 10. In table 10, product 1, 2 and 3, respectively, represent and converted yield represents the value calculated from NMR determination. Preparation 48 5-Trifluoromethyl-3-benzoylaminoisoxazole (a) Dimethylsulfoxide (molecular sieve 4A dried, 0.46 ml) was added to the pale brown crystals (0.2291 g, 0.864 mmole) obtained from Preparation 45, with stirring and the mixture was heated at 90°C for 1.5 hours. After cooling to room temperature, water (10 ml) was added thereto and it was extracted with methylene chloride. The extract was dried with anhydrous sodium sulfate and the solvent was evaporated from the extract to give the crude title compound (0.39 g). This product was purified by column chromatogrpahy on silica gel to give the title compound (0.1765 g, 79.5 %). The compound was further recrystallized from benzene to give the title compound (0.1354 g) as colorless columns, m.p. 151.5 - 153.5°C. The structure of this compound was confirmed by IR and NMR. (b) The title compound was obtained according to the same procedure as described in (a) except that the compound (0.1371 g, 0.500 mmole) obtain from Preparation 45 and dimethylsulfoxide (0.27 ml) were used. Yield: 0.1013 g (79.1 %). The structure of this product was confirmed by IR. Preparation 49 5-Trifluoromethyl-3-pivaloylaminoisoxazole (a) The title compound was obtained according to the same procedure as described in Preparation 48(a) except that the tan crystals (1.1402 g, 4.69 mmole) obtained from Preparation 46 was used. Yield: 0.9542 g (86.0 %). The structure of this product was confirmed by IR. (b) The title compound was obtained according to the same procedure as described in Preparation 48(a) except that the compound (0.0582 g, 0.229 mmole) obtained from Preparation 46 and dimethyl sulfoxide (0.12 ml) were used. Yield: 0.0430 g (79.5 %). The structure of this product was confirmed by IR. Preparation 50 5-Trifiuoromethyl-3-trichloroacetylaminoisoxazole The title compound was obtained according to the same procedure as described in Preparation 48(a) except that the crude compound (1.1848 g) obtained from Preparation 47 and dimethylsulfoxide (2.4 ml) were used. Yield: 0.0461 g. This compound was recrystallized from n-hexane to give the title compound as colorless neeldes, m.p. 113.5 - 114.5°C. The structure of this product was confirmed by IR and NMR. Example 56 5-Trifluoromethyl-3-aminoisoxazole (a) The reaction was carried out according to the same procedure as described in Example 41 except that 5-trifluoromethyl-3-benzoylaminoisoxazole (0.8738 g, 3.41 mmole), 36 % hydrochloric acid (0.87 g, 8.53 mmole) and ethylene glycol (3.4 ml) were used. The product was then purified by column chromatography on silica gel to give the title compound. Yield: 0.3686 g (75.7 %). The structure of this product was confirmed by NMR. (b) The reaction was carried out according to the same procedure as described in Example 41 except that 5-trifluoromethyl-3-pivaloylaminoisoxazole (0.7553 g, 3.20 mmole), 36 % hydrochloric acid (0.81 g, 8.00 mmole) and ehtylene glycol (3.2 ml) were used. The product was then purified by column chromatography on silica gel to give the title compound. Yield: 0.3686 g (75.7 %). The structure of this product was confirmed by NMR. (c) The reaction was carried out according to the same procedure as described in Example 41 except that 5-trifluoromethyl-3-acetylaminoisoxazole (2.21 g, 11.4 mmole), 36 % hydrochloric acid (2.89 g, 28.5 mmole) and ehtylene glycol (11.4 ml) were used. The product was then purified by column chromatography on silica gel and further distilled under reduced pressure to give the title compound. Yield: 1.22 g (70.4 %), b.p. 84 - 85°C/13.0 mmHg. Example 57 5-Trifluoromethyl-3-methylaminoisoxazole In dry methylene chloride (20 ml) was dissolved 5-trifluoromethyl-3-aminoisoxazole (3.04 g, 20.0 mmole) and trifluoroacetic anhydride (4.83 g, 23.0 mmole) was added dropwise to the solution while keeping the mixture at room temperature. After stirring at room temperature for 1 hour, precipitated crystals were filtered off to give colorless prisms (1.83 g), m.p. 126 - 127°C. This compound is 5-trifluoromethyl-3-trifluoroacetylaminoisoxazole. The filtrate was evaporated under reduced pressure to give additional crystals (3.43 g). The combined crystals were dissolved in acetone (100 ml). Anhydrous sodium carbonate (6.35 g, 60 mmole) and dimethyl sulfate (5.05 g, 40 mmole) were added to the solution and the mixture was stirred at room temperature for 20 hours. The precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in benzene. After being washed with a 8 % solution of sodium bicarbonate the solvent was evaporated under reduced pressure to give a mixture (2.88 g) of 5-trifluoromethyl-3-N-methyl-N-trifluoroacetylaminoisoxazole and 5-trifluoromethyl-3-methylaminoisoxazole as residue. To this were added methanol (20 ml) and a 5 % solution of sodium hydroxide (19.2 g). After standing at room temperature for 15 minutes, the solvent was evaporated under reduced pressure. Methylene chloride was added to the residue and the precipitated crystals were filtered off to give the title compound (2.05 g, 61.7 %). The product was recrystallised from n-hexane to give colorless prisms, m.p. 39.0 - 41.0°C. Example 58 5-Pentafluoroethyl-3-methylaminoisoxazole The reaction and work up were carried out to obtain a colorless liquid according to the same procedure as described in Example 57 except that 5-pentafluoroethyl-3-aminoisoxazole was used. b.p. 88°C/12 mmHg.

Claims: A compound of the formula: in which: R is alkyl having a plurality of fluorines; R¹ is hydrogen, alkyl, halogen or optionally substituted phenyl; and R² is hydrogen or alkyl. A compound selected from 5-trifluoromethyl-3-aminoisoxazole, 5-pentafluoroethyl-3-aminoisoxazole, 5-heptafluoropropyl-3-aminoisoxazole, 5-(2-(trifluoromethyl)propyl)-3-aminoisoxazole, 5-trifluoromethyl-4-methyl-3-aminoisoxazole, 5-pentafluoroethyl-4-methyl-3-aminoisoxazole, 5-trifluoromethyl-4-phenyl-3-aminoisoxazole, 5-pentafluoroethyl-4-phenyl-3-aminoisoxazole, 5-trifluoromethyl-4-(4-fluorophenyl)-3-aminoisoxazole, 5-trifluoromethyl-4-(4-chlorophenyl)-3-aminoisoxazole, 5-trifluoromethyl-4-(4-methylphenyl)-3-aminoisoxazole, 5-trifluoromethyl-4-(4-methoxyphenyl)-3-aminoisoxazole, 5-trifluoromethyl-4-(3,4-dimethoxyphenyl)-3-aminoisoxazole, and 5-trifluoromethyl-4-(3,4-methylenedioxyphenyl)-3-aminoisoxazole. A salt of a compound as claimed in claim 1 or claim 2. A process for preparing a compound as claimed in claim 1 comprising either: (a) reacting a compound of formula in which R¹ is hydrogen, alkyl or optionally substituted phenyl, with hydroxylamine or a salt thereof or hydroxyurea; or (b) reacting a compound of formula wherein R¹ is as defined above, with hydroxylamine or a salt thereof or hydroxyurea; or (c) reacting a compound of formula wherein R¹ is as defined above, with a compound of the formula RCO₂R³ (V), wherein R³ is alkyl; or (d) hydrolysing a compound of formula wherein R¹ is as defined above; or (e) decomposing a compound (VI) as aforesaid using phthalic anhydride and hydrazine hydrate; or (f) decomposing a compound of formula wherein R¹ is as defined above, using hydrazine hydrate; or (g) hydrolysing a compound of formula wherein R¹ is as defined above and R⁴ is alkyl or phenyl; or (h) halogenating a compound as defined in claim 1 wherein R¹ is hydrogen. An intermediate of any of the following formulae: wherein R and R¹ are as defined in claim 1. The use of a compound as claimed in any one of Claims 1 to 3 in the production of a herbicide, fungicide or bactericide.

Inventors: ISHIZUKI ICHIRO, KAI HIROYUKI, SUMIMOTO SHINZABURO, TAKASE AKIRA, UEDA SHIRO, ISHIZUKI, ICHIRO, KAI, HIROYUKI, SUMIMOTO, SHINZABURO, TAKASE, AKIRA, UEDA, SHIRO
Applicants: SHIONOGI & CO, SHIONOGI & CO., LTD.
Application year: 1986
Main classification: C07D261
IPC codes: C07D271, C07D261, A01N43