JP3228533B2 - Azoxy group-containing compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel azoxy group-containing compound, and more particularly to an antifungal substance KA-.
Azoxy group-containing compound which is an analog of 7367, an antifungal agent containing the same as an active ingredient, and a KA and a KA
-7367.

[0002]

BACKGROUND OF THE INVENTION The present inventors previously reported that Streptomyces spKC isolated from soil in Maniwa-gun, Okayama Prefecture.
-7367 (FERM BP-1277) was found to produce a substance showing strong antibacterial activity against fungi, and furthermore, two antifungal substances KA-73 were obtained from the culture broth.
67A (maniwamycin A) and KA-7367B (maniwamycin B) were isolated and identified (JP-A-1-624).
No. 8). The antifungal substances KA-7367A and KA-7367B are represented by the following formula.

Embedded image X = -CO-: KA-7368A X = -CHOH-: KA-7367B

Further, the present inventors have confirmed that a 2-imino derivative obtained by iminating the carbonyl group at position 2 of KA-7367A as a raw material exhibits excellent antifungal activity and stability, Patent application (PCT / J
P89 / 01082). However, although these compounds show excellent antibacterial activity and stability, in order to apply them to the treatment of dermatomycosis, for example, tinea pedis, a compound having better anti-trichophyton activity is needed. is there. In order to obtain a better antifungal agent, it is necessary to synthesize various derivatives.
Synthesis using 7367 as a raw material has the disadvantage that the productivity of the raw material and the type of derivative are limited.

[0004]

Means for Solving the Problems The present inventors have attempted to solve the above problems by using KA-7367 by an organic synthesis method.
As a result of intensive research for the production of A, KA-7
By completing the organic synthesis method of 367A and further synthesizing its analogs, they found that they were useful as antifungal agents, and completed the present invention. The present invention has the general formula

Embedded image (Wherein R ₁ is a hydrogen atom or a lower alkyl group; R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom or a group
-A-CH ₂ shows a -B-X, where A is an oxygen atom or a single bond, B is a triple bond of carbon atoms, X is azoxy group-containing compound represented by means a halogen atom).

The lower alkyl group for the substituent R _{1 in} the compounds of the formula I includes straight-chain or branched C ₁ -C 6
Are preferred. As the halogen atom for R ₂ , R ₃ and X, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are preferable. The compounds of formula I have both anti- and syn-isomers for the oxime hydroxyl group.

The compound (I) of the present invention has the general formula

Embedded image Wherein R ₁ , R ₂ and R ₃ have the above-mentioned meaning, and n is 2 or 3
Is reacted with an acid to give a compound of the general formula

Embedded image (Wherein each symbol has the meaning described above), and then the compound can be produced by reacting the compound with hydroxylamine. The compound of formula III is
General formula

Embedded image (The symbols in the formula have the same meanings as described above), and the compound can be produced by introducing a carbon-carbon double bond by dehydration.

The compound of formula IV has the general formula

Embedded image (Wherein the symbols have the above-mentioned meanings)

Embedded image (Wherein the symbols have the same meanings as described above).

The reaction is represented by the following reaction formula.

Embedded image

The reaction of compound (V) with compound (VI) gives compound (IV). This reaction is preferably performed after activating the carbon atom of the methyl group bonded to the azoxy group of compound (V) using a strong base. Examples of the base include lithium diisopropylamide, lithium hexamethyldisilazide, sodium hydride and the like. For example, when lithium diisopropylamide is used as the base, the compound (V) and preferably a newly prepared base are reacted at −20 ° C. to + 50 ° C. for several minutes to several hours in a solvent to give methyl (V) of the compound (V). The carbon atom of the group is activated, and 1 to 5 mol of compound (VI) is added to this reaction solution based on compound (V), and the reaction is carried out preferably at the same temperature for several minutes to several hours. Examples of the solvent include hydrocarbons such as methylene chloride, benzene, toluene, xylene, and cyclohexane; ethers such as ether, dioxane, and tetrahydrofuran.

When the compound (IV) thus obtained is dehydrated, a carbon-carbon double bond is introduced to obtain a compound (III). As a dehydration method, for example, the compound (a)
Examples of the method include sulfonylation of the hydroxyl group in V) followed by desulfonation, and (b) replacement of the hydroxyl group of the compound (IV) with a halogen atom followed by dehydrohalogenation. As the sulfonylation in the method a, methanesulfonylation, p-toluenesulfonylation and the like are preferable. For example, to perform methanesulfonylation, a reactive derivative of methanesulfonic acid, for example, methanesulfonic acid chloride and compound (IV) are added at -20 ° C in a solvent, preferably in the presence of a base.
The reaction is preferably carried out at a temperature of + 100 ° C for 1-50 hours.

As the base, for example, pyridine, triethylamine, sodium hydride and the like are preferable. As the solvent, the above-mentioned ones can be used, but the above-mentioned base can be used in excess to be used as the solvent. It is industrially advantageous that the obtained sulfonyl compound is treated by a conventional method and then subjected to the subsequent desulfonate reaction without purification. The desulfonate reaction is preferably performed by reacting a sulfonyl compound with a base in a solvent at -20 ° C to + 100 ° C for 1 to 50 hours. Examples of the base include 1,8-diazabicyclo [5.4.0] -7-undecene, triethylamine, pyridine and the like. As the solvent, those described above can be used.

As the halogen atom in the method (b),
Chlorine, bromine, iodine and the like are used, and chlorine is particularly preferred. Examples of the halogenating agent include thionyl halide, phosphorus oxyhalide and the like. The reaction is performed with the compound (I
V) and the halogenating agent are preferably carried out in a solvent at -20 ° C to + 50 ° C for several minutes to several hours, preferably in the presence of a base. It is industrially advantageous that the obtained halogen compound is treated by a conventional method and then subjected to the next dehydrohalogenation reaction without purification. The dehydrohalogenation reaction is preferably carried out by reacting the obtained halogen compound with a base in a solvent at -20 ° C to + 100 ° C for 1 to 50 hours. As the base and the solvent, those described above can be used.

The compound (III) thus obtained is reacted with an acid to give the desired compound (II). Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid and p-toluenesulfonic acid; Lewis acids such as ferric chloride-silica gel; and cation exchange resins such as Amberlyst 15. The reaction is preferably carried out by reacting compound (III) and an acid in a solvent at -20 ° C to + 100 ° C for several minutes to several hours. As the solvent, in addition to those described above, acetone, tetrahydrofuran, acetonitrile and the like can also be used.

The compound (II) thus obtained is reacted with hydroxylamine or a salt thereof to give the desired compound (I)
Is obtained. The reaction is usually carried out in a suitable solvent and, if appropriate, in the presence of a base, at about −10 ° C. to the reflux temperature of the solvent,
Preferably, it can be performed at a temperature of about 5 ° C to about 100 ° C. Examples of the solvent that can be used here include alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as chloroform and methylene chloride; hydrocarbons such as benzene, toluene, xylene and cyclohexane; ethers, dioxane and tetrahydrofuran. Ether and the like.

The bases that can be used if necessary include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; triethylamine, pyridine, 4-N, N-dimethylaminopyridine and the like. Organic base and the like. These bases can generally be used in the range of 0.1 to 100 equivalents, particularly 1 to 10 equivalents, per 1 mol of compound (II). Compound (II), which is a starting material for this reaction, can be used in this reaction without purification after completion of the previous step. In the case of producing a compound in which R ₂ or R ₃ in the formula is a group -A-CH ₂ -BX, halogenation can be carried out in any of the above steps, but a dehydration step [IV → III ] Is preferably applied at the stage after completion of the above.

The target compound can be purified by a usual method, but it can be purified by column chromatography, recrystallization,
A lyophilization method is preferred. The starting compound (IV) is obtained, for example, by converting alanine into ethyl carbamate using ethyl chloroformate, performing methylation using methyllithium to form a ketone, protecting the ketone with a ketal, and then using the method of Moss et al. J. Org. Chem. 31 (1966) 1082] to react nitrosation and potassium t-butyrate

Embedded image Wherein n has the meaning described above, and a diazotate represented by the general formula

Embedded image The compound can be produced by reacting a compound represented by CH ₃ —Y (wherein Y represents a halogen atom).

The compound (I) of the present invention has excellent antifungal activity, for example, Candida, Cryptococcus,
Fungi infecting warm-blooded animals including humans, such as Aspergillus and Trichophyton;
It exhibits excellent antibacterial activity against fungi infecting agricultural and horticultural crops such as Saccharomyces and Septoria and fruit trees.

Minimum inhibitory concentration (μg / ml) of the compound (I) of the present invention prepared in the following Examples against a typical fungus
Table 1 shows the measurement results. The minimum inhibitory concentration was determined by agar plate dilution using Sabouraud dextrose medium.

[0019]

[Table 1]

As described above, the compound of the present invention has excellent antibacterial activity against fungi infecting warm-blooded animals including humans, and fungi infecting agricultural and horticultural crops and fruit trees. It is useful as an antifungal agent for medicine, veterinary medicine and agricultural and horticultural use.

When the compound of the present invention is used as an antifungal agent, it can be formulated into a form suitable for each use and used. For example, when the compound of the present invention is used as a medicine or veterinary medicine (animal drug), an excipient, a binder, a disintegrant, a coating agent, an emulsifier, a suspending agent, a solvent may be added to the compound of the present invention or a salt thereof. Auxiliaries such as stabilizers, absorption aids, and ointment bases are appropriately added, and the mixture can be formulated into a dosage form for oral administration, injection administration, rectal administration, external use, and the like by a conventional method.

Pharmaceutical preparations for oral administration include granules, tablets,
Formulations for injection administration, such as sugar-coated tablets, capsules, pills, solutions, emulsions, suspensions, etc., include those for intravenous injection, intramuscular injection, subcutaneous injection, drip injection, etc., and those for rectal administration. Suppositories, soft capsules and the like. As an external preparation,
Ointments, lotions, liniments, creams and the like are preferred. In addition, it may be in the form of eye drops, ear drops and the like.

When used as an antifungal agent for agricultural and horticultural use,
According to a conventional method, the preparation can be made into a liquid, emulsion, granule, powder, dust, paste or the like. The dose of the compound of the present invention when administered to warm-blooded animals including humans may vary over a wide range depending on the type of animal to be administered, the severity of the symptoms, body weight, sex, judgment of the treating physician, etc. It is usually about 0.1 to about 500 mg / kg body weight per day, and can be administered once or several times a day. When used for agricultural and horticultural purposes, the compounds of the present invention can be applied to fungal habitats for soil treatment, foliage treatment, etc., and the application amount is usually about 0005 to
It is about 5 kg / ha.

[0024]

EXAMPLES Reference Example Production of 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane [compound (V)] (a) 45 g of L-alanine and 127 g of sodium carbonate were dissolved in 400 ml of water. 64 ml of ethyl chloroformate under ice-cooling
After dropwise addition, the mixture was stirred at room temperature for 30 minutes. 3 in the reaction solution
5% hydrochloric acid was added to make it acidic, and it was adsorbed on a column of Diaion HP-20 (6.5 × 60 cm).
Eluted with methanol. The eluate was concentrated under reduced pressure to obtain 69 g (96% yield) of N-ethoxycarbonylalanine as an oil.

¹ H-NMR value: δ CDCl ₃ , ppm 1.26 (3H, t, J = 7 Hz) 1.46 (3H, d, J = 7 Hz) 4.15 (2H, q, J = 7 Hz) 4.40 (1H, m) 5.28 (1H, br.d, J = 7 Hz) 7.35 (1H, br.s) IR value: νmax, cm ⁻¹ 1719, 1697

(B) 3 g of N-ethoxycarbonylalanine obtained in the above (a) was dissolved in 60 ml of tetrahydrofuran under a nitrogen atmosphere, and stirred at -78 ° C. for 1.
48 ml of a 19N methyllithium ether solution were added over 30 minutes. After stirring at the same temperature for 40 minutes,
Stirred for hours. The reaction solution was poured into cold 10% aqueous phosphoric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: chloroform-n-hexane (5: 1) to obtain 1.8 g of 3-ethoxycarbonylamino-2-oxobutane (yield: 60%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.24 (3H, t, J = 7 Hz) 1.38 (3H, d, J = 7 Hz) 2.20 (3H, s) 4.12 ( 2H, q, J = 7 Hz) 4.37 (1H, br.t, J = 7 Hz) 4.44 (1H, br.s) IR value: νmax, CHCl ₃ , cm ⁻¹ 1706, 1500

(C) 6.34 of the ketone obtained in the above (b)
g and 500 mg of pyridine salt of p-toluenesulfonic acid were dissolved in 280 ml of benzene, 22 ml of 1,3-propanediol was added, and the mixture was heated under reflux for 4 hours. After allowing the reaction solution to cool, a saturated aqueous solution of sodium hydrogen carbonate was added thereto to separate the organic layer, and the aqueous layer was extracted with benzene. The organic layers are combined and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography [solvent: ether-n-hexane (1: 3) to give 3-ethoxycarbonylamino-2,2-propylenedioxybutane 8]. .25 g (95% yield) were obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.17 (3H, d, J = 7 Hz) 1.24 (3H, t, J = 7 Hz) 1.37 to 1.50 (1 H, m) 1.42 (3H, s) 1.80 to 2.02 (1H, m) 3.76 to 4.06 (5H, m) 4.11 (2H, q, J = 7 Hz) 4.90 (1H, m) br.s) IR value: νmax, CHCl ₃ , cm ^-1 1701, 1507

(D) 4.49 g of the compound obtained in the above (c)
Was dissolved in 30 ml of anhydrous ether under a nitrogen atmosphere, 8.7 g of sodium hydrogen carbonate was added, the solution was cooled to -25 ° C, and a solution of 3.3 ml of 3.3 ml of dinitrogen tetroxide in anhydrous ether was added.
ml was added dropwise and stirred at the same temperature for 3.5 hours. The reaction solution was extracted into a saturated aqueous sodium hydrogen carbonate solution with cold ether.
After the ether layer was dried and concentrated under reduced pressure at 30 ° C. or lower, water was removed azeotropically. Potassium t-butoxide4.
64 g were suspended in 20 ml of dimethylformamide and cooled to -30 ° C under a nitrogen atmosphere. In addition to the previously prepared N
6 ml of a dimethylformamide solution of a -nitroso compound was added dropwise, and the mixture was stirred at -30 ° C for 2.5 hours.

6.44 ml of methyl iodide was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography [solvent: ethyl acetate-n-hexane (1: 3)]. The obtained residue was dissolved in pyridine (3 ml), acetic anhydride (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over saturated sodium hydrogen carbonate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate-n-hexane (1: 3)] to give 1.49 g of the desired product (yield 3).
8%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.13 (3H, d, J = 7 Hz) 1.45 (3H, s) 1.59 to 1.92 (2H, m) 3.85 ( 4H, m) 4.10 (3H, s) 4.49 (1H, q, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 1503, 1424, 1370, 1330

Example 1 2-hydroxyimino-3- [2- (4- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] butane [Compound (I): R ₁ = methyl group, R ₂ = 4- (3-iodopropargyl) oxy group, R ₃
= Hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 249 obtained in Reference Example
mg was dissolved in 3 ml of tetrahydrofuran under a nitrogen atmosphere. Under ice cooling, 1.15 ml of cyclohexane of 1.7 mmol of lithium diisopropylamide was added to the solution, and the mixture was stirred for 30 minutes. To this solution was added a solution of 4-propargyloxyacetophenone (358 mg) in tetrahydrofuran (4 ml), and the mixture was further stirred under ice-cooling for 30 minutes.

Under ice-cooling, 5 ml of a 10% aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred for 5 minutes and extracted with 50 ml of ether. The extract was washed with saturated saline, dried, and concentrated under reduced pressure. The obtained oil (650 mg) was purified by silica gel column chromatography (eluent: 50% ether-hexane solution) to give 3- [2-hydroxy-2- (4-propargyloxyphenyl) propyl-.
242 mg (yield: 51%) of a diastereomer mixture of ONN-azoxy] -2,2-propylenedioxybutane (IV) (1: 1) was obtained as a colorless oil.

Diastereomer (a) ¹ H-NMR value: δ CDCl ₃ , ppm 7.42 (2H, d, J = 9 Hz) 6.95 (2H, d, J = 9 Hz) 5.24 (1H, br, s) 4.67 (2H, d, J = 2 Hz) 4.51 (1H, d, J = 12 Hz) 4.39 (1H, d, J = 12 Hz) 4.35 (1H, q, J = 7 Hz) 3.70-3.97 (4H, m) 2.51 (1H, t, J = 2 Hz) 1.71-187 (1H, m) 1.54 (3H, s) 1.46-159 ( 1H, m) 1.26 (3H, s) 1.07 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3430 (br), 3290, 1505, 1225 (br)

Diastereomer (b) ¹ H-NMR value: δCDCl ₃ , ppm 7.40 (2H, d, J = 9 Hz) 6.93 (2H, d, J = 9 Hz) 5.24 (1H, br, s) 4.67 (2H, d, J = 2 Hz) 4.57 (1H, d, J = 12 Hz) 4.43 (1H, q, J = 7 Hz) 4.40 (1H, d, J = 12 Hz) 3.77-3.98 (4H, m) 2.50 (1H, t, J = 2 Hz) 1.66-1.84 (1H, m) 1.55-1.66 (1H, m) 1.54 (3H, s) 1.36 (3H, s) 0.74 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3420 (br), 3290, 1505, 1225 ( br)

(2) 155 mg of the hydroxy compound (IV) obtained in the above (1) was dissolved in 0.4 ml of pyridine, 0.05 ml of thionyl chloride was added under ice cooling, and the mixture was stirred for 15 minutes. Then, 0.6 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was further stirred under ice-cooling for 15 hours.
50 ml of ether and 5 ml of 1N hydrochloric acid were added to the reaction solution, and the ether layer was separated, washed successively with 5 ml of saturated saline, 5 ml of saturated aqueous sodium hydrogen carbonate solution and 5 ml of saturated saline, dried, and dried under reduced pressure. Concentrated. 170 mg of the obtained oil was purified by silica gel column chromatography (solvent: benzene) to give 3- [2- (4-propargyloxyphenyl) -1-propenyl-ONN-azoxy) -2,2-propylenedioxybutane. 150 mg (III%) of (III ') was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (2H, d, J = 9 Hz) 7.19 (2H, q, J = 1 Hz) 6.91 (2H, d, J = 9 Hz) 4.66 (1H, q, J = 7 Hz) 4.65 (2H, d, J = 2 Hz) 3.86-3.93 (4H, m) 2.47 (1H, t, J = 2 Hz) 38 (3H, d, J = 1 Hz) 1.67 to 1.81 (1H, m) 1.52 to 1.64 (1H, m) 1.43 (3H, s) 1.15 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3290, 1505, 1225 (br)

(3) 63 mg of the propargy compound (III ') obtained in the above (2) was dissolved in 1.5 ml of methanol, and 0.07 ml of a 10 M aqueous sodium hydroxide solution and iodine
After the reaction compound became homogeneous, the mixture was stirred at room temperature for 15 minutes. 50 ml of ether and 1
5 ml of M sodium thiosulfate aqueous solution was added, and the ether layer was separated, washed with 5 ml of saturated saline, dried, and concentrated under reduced pressure. The obtained oil (183 mg) was subjected to silica gel preparative thin-layer chromatography [solvent: ethyl acetate-].
Purified with benzene (1: 5)] to give 3- [2- (4-
85 mg (99% yield) of (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III) as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.39 (2H, d, J = 9 Hz) 7.12 (1H, q, J = 1 Hz) 6.96 (2H, d, J = 9 Hz) 4.85 (2H, s) 4.73 (1H, q, J = 7 Hz) 3.93 to 3.99 (4H, m) 2.45 (3H, d, J = 1 Hz) 1.50 (3H, s) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 1505, 1225 (br)

(4) 61 mg of the propylenedioxy compound (III) obtained in the above (3) is dissolved in 0.5 ml of acetone,
115 mg of iron chloride-silica gel (11% by weight) was added, and the mixture was stirred at room temperature for 2 hours. After adding 10 ml of carbon tetrachloride to the reaction mixture, the mixture was filtered with suction using celite, and the filtrate was concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography [solvent: ether-hexane (1:
1)] to give 3- [2- (4- (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN
-Azoxy] -2-oxobutane (II) was obtained as a colorless oil (43 mg, yield 79%).

¹ H-NMR value: δ CDCl ₃ , ppm 7.41 (2H, d, J = 9 Hz) 7.19 (1H, q, J = 1 Hz) 6.98 (2H, d, J = 9 Hz) 4.86 (2H, s) 4.62 (1H, q, J = 7 Hz) 2.50 (3H, d, J = 1 Hz) 2.23 (3H, s) 1.51 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 1715, 1505, 1220 [α] _D ²³ -21 ° ( C 2.9, chloroform)

(5) The oxo compound (I) obtained in the above (4)
I) 33.2 mg dissolved in 0.3 ml methanol, 11.1 mg hydroxylamine hydrochloride and 0.02 ml pyridine
Was added and stirred at room temperature for 10 minutes. 25 ml of ether and 5 ml of water were added to the reaction mixture, and the ether layer was separated, washed with saturated saline, dried and concentrated under reduced pressure. 37 mg of the obtained oil was purified by silica gel preparative thin-layer chromatography [solvent: ethyl acetate-benzene (1: 1)].
3)] to give 11.7 mg (yield 51%) and 9.2 mg (yield 27%) of the anti- and syn-isomers related to the oxime hydroxyl group of the desired product (I) as colorless oils, respectively.
%)Obtained.

(A) Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.40 (2H, d, J = 9 Hz) 7.12 (1H, s) 6.97 (2H, d, J = 9 Hz) 4.85 (2H, s) 4.82 (1H, q, J = 7 Hz) 2.48 (3H, s) 1.97 (3H, s) 1.42 (3H, d, J = 7 Hz) ) IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3270 (br), 1605, 1505, 12
20 (br) [α] _D ²³ + 17 ° ( C 2.5, chloroform)

(B) Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.41 (2H, d, J = 9 Hz) 7.16 (1H, q, J = 1 Hz) 6.97 (2H) , D, J = 9 Hz) 5.40 (1H, q, J = 7 Hz) 4.86 (2H, s) 2.51 (3H, d, J = 1 Hz) 1.81 (3H, s) 1.45 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3560, 3240 (br), 1605, 1505, 12
25 (br) [α] _D ²³ + 84 ° ( C 1.0, chloroform)

Example 2 2-hydroxyimino-3- [2- (2- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] butane [Compound (I): R ₁ = methyl group, R ₂ = 2- (3-iodopropargyl) oxy group, R ₃
= Hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) and 2 obtained in Reference Example
Example 1 using propargyloxyacetophenone
After the reaction treatment in the same manner as in (a), 3- [2-hydroxy-
2- (2-propargyloxyphenyl) -propyl-
ONN-azoxy] -2,2-propylene dioxybutane (IV) diastereomer mixture (1: 1) was obtained.

Diastereomer (a) (colorless oil) ¹ H-NMR value: δCDCl ₃ , ppm 7.70 (1H, dd, J = 8, 2 Hz) 7.23 (1H, td, J = 8) , 2 Hz) 6.99 (1H, t, J = 8 Hz) 6.94 (1H, d, J = 8 Hz) 5.39 (1H, s) 5.15 (1H, d, J = 12 Hz) 4.75 (2H, d, J = 2 Hz) 4.45 (1H, d, J = 12 Hz) 4.41 (1H, q, J = 7 Hz) 3.77-3.88 (2H, m) 3.48-3 .57 (1H, m) 3.32 to 3.42 (1H, m) 2.54 (1H, t, J = 2 Hz) 1.59 to 1.70 (2H, m) 1.61 (3H, s) 1.23 (3H, s) 0.96 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3430 (br), 3290, 1485, 1225 (br)

Diastereomer (b) colorless prisms (mp 127.0-130.5 ° C.) ¹ H-NMR value: δ CDCl ₃ , ppm 7.66 (1H, dd, J = 8, 2 Hz) 7 .24 (1H, td, J = 8, 2 Hz) 6.98 (1H, t, J = 8 Hz) 6.94 (1H, d, J = 8 Hz) 5.28 (1H, s) 5.23 (1H) , D, J = 11 Hz) 4.73 (2H, d, J = 2 Hz) 4.35 (1H, d, J = 11 Hz) 4.36 (1H, q, J = 7 Hz) 3.74-3.91 (4H, m) 1.63 (3H, s) 1.33 (3H, s) 0.44 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3440 (br), 3270 , 1485, 1385, 12
40, 1090

(2) The hydroxy compound (IV ') obtained in the above (1) was reacted and treated in the same manner as in Example 1 (2) to give 3- [2- (2-propargyloxyphenyl). −
1-propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III ') was obtained as a colorless oil. ¹ H-NMR value: δ CDCl ₃ , ppm

7.32 (1H, ddd, J = 8, 7, 2 Hz) 7.21 (1H, dd, J = 7, 2 Hz) 7.04 (1H, d, J = 8 Hz) 6.99 (1H) , T, J = 7 Hz) 6.94 (1H, q, J = 1 Hz) 4.74 (1H, q, J = 7 Hz) 4.73 (2H, d, J = 2 Hz) 3.93 to 3.99 (4H, m) 2.25 (1H, t, J = 2 Hz) 2.43 (3H, d, J = 1 Hz) 1.60 to 187 (2H, m) 1.50 (3H, s) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3290, 1485, 1450

(3) Using the propargyl compound (III ') obtained in the above (2), a reaction treatment was carried out in the same manner as in Example 1 (3) to give 3- [2- (2- (3-iodopropargyl). ) Oxyphenyl) -1-propenyl-ONN-azoxy]-
2,2-propylenedioxybutane (III) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1 H, t, J = 7 Hz) 7.21 (1 H, d, J = 7 Hz) 7.03 (1 H, d, J = 7 Hz) 6.99 (1H, t, J = 7 Hz) 6.94 (1H, s) 4.86 (2H, s) 4.74 (1H, q, J = 7 Hz) 3.93 to 3.99 (4H, m) 2.42 (3H, s) 1.60 to 1.88 (2H, m) 1.50 (3H, s) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 1485, 1450

(4) Using the propylene dioxy compound (III) obtained in the above (3), a reaction was carried out in the same manner as in Example 1 (4).
Treatment provided 3- [2- (2- (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-oxobutane as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.35 (1H, ddd, J = 8, 7, 2 Hz) 7.21 (1H, dd, J = 7, 2 Hz) 7.04 (1H, d, J = 8 Hz) 7.01 (1H, t, J = 7 Hz) 7.01 (1H, q, J = 1 Hz) 4.87 (2H, s) 4.61 (1H, q, J = 7 Hz) 2.45 (3H, d, J = 1 Hz) 2.23 (3H, s) 1.50 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1485, 1450 [α ] _D ²³ -37 ° (C 3.5, chloroform)

(5) The oxo compound (II) obtained in the above (4) was reacted and treated in the same manner as in Example 1 (5).
The anti- and syn-isomers for the oxime hydroxyl group of the desired product (I) were obtained as colorless oils, respectively.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1 H, ddd, J = 8, 7, 2 Hz) 7.20 (1 H, dd, J = 7, 2 Hz) 7. 03 (1H, d, J = 8 Hz) 7.00 (1H, t, J = 7 Hz) 6.94 (1H, q, J = 1 Hz) 4.86 (2H, s) 4.83 (1H, q, J = 7 Hz) 2.43 (3H, d, J = 1 Hz) 1.98 (3H, s) 1.41 (3H, d, J = 7 Hz)

IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3260 (br), 1485, 1445 [α] _D ²³ + 8.0 ° ( C 0.56, chloroform) Syn-isomer ¹ H-NMR value : Δ CDCl ₃ , ppm 7.34 (1H, ddd, J = 8, 7, 2 Hz) 7.21 (1H, dd, J = 7, 2 Hz) 7.04 (1H, d, J = 8 Hz) 01 (1H, t, J = 7 Hz) 6.97 (1H, q, J = 1 Hz) 5.42 (1H, q, J = 7 Hz) 4.87 (2H, s) 2.46 (3H, d, J = 1 Hz) 1.83 (3H, s) 1.48 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3560, 3240 (br), 1485, 1450 [α] _D ²³ + 36 ° ( C 0.25, chloroform)

Example 3 2-hydroxyimino-3- [2- (3- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] butane [Compound (I): R ₁ = methyl group, R ₂ = 3- (3-iodopropargyl) oxy group, R ₃
= Hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) and 3 obtained in Reference Example
Example 1 using propargyloxyacetophenone
The reaction and treatment are carried out in the same manner as in (1) to give 3- [2-hydroxy-
2- (3-propargyloxyphenyl) -propyl-
ONN-azoxy] -2,2-propylene dioxybutane (IV), a mixture of diastereomers (1: 1) was obtained as an oil.

Diastereomer (a) ¹ H-NMR value: δ CDCl ₃ , ppm 7.26 (1 H, t, J = 8 Hz) 7.16 (1 H, br, s) 7.08 (1 H, d, J = 8 Hz) 6.87 (1H, dd, J = 8, 3 Hz) 5.28 (1H, br, s) 4.69 (2H, d, J = 2 Hz) 4.54 (1H, d, J = 13 Hz) 4.41 (1H, d, J = 13 Hz) 4.36 (1H, q, J = 7 Hz) 3.69-3.97 (4H, m) 2.52 (1H, t, J = 2 Hz) 1.71 to 1.86 (1H, m) 1.55 (3H, s) 1.48 to 159 (1H, m) 1.26 (3H, s) 1.06 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3430 (br), 3290, 1600, 1500, 12
30 (br)

Diastereomer (b) ¹ H-NMR value: δ CDCl ₃ , ppm 7.25 (1 H, t, J = 8 Hz) 7.14 (1 H, t, J = 2 Hz) 7.06 (1 H, br, d, J = 8 Hz) 6.87 (1 H, dd, J = 8, 2 Hz) 5.29 (1 H, br, s) 4.69 (2 H, d, J = 2 Hz) 4.59 (1 H, d, J = 12 Hz) 4.42 (1H, d, J = 12 Hz) 4.42 (1H, q, J = 7 Hz) 3.77-3.96 (4H, m) 2.52 (1H, t, J = 2 Hz) 1.68 to 1.82 (1H, m) 1.58 to 1.66 (1H, m) 1.55 (3H, s) 1.36 (3H, s) 0.74 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3420 (br), 3290, 1600, 1500, 12
25 (br)

(2) The hydroxy compound (IV ') obtained in the above (1) was reacted and treated in the same manner as in Example 1 (2) to give 3- [2- (3-propargyloxyphenyl). −
1-propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III ') was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.31 (1 H, t, J = 8 Hz) 7.12 (1 H, q, J = 1 Hz) 7.06 (1 H, Br. D, J = 8 Hz) 7.03 (1H, t, J = 2 Hz) 6.98 (1H, dd, J = 8, 2 Hz) 4.72 (1H, d, J = 2 Hz) 4.72 (1H, q, J = 7Hz) 3.93-4.00 (4H, m) 2.52 (1H, t, J = 2 Hz) 2.45 (3H, d, J = 1 Hz) 1.74-1.89 (1H, m) 1.60 to 1.71 (1H, m) 1.51 (3H, s) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3290, 1570, 1480, 1220 (Br)

(3) Using the propargyl compound (III ') obtained in the above (2), the reaction and treatment were carried out in the same manner as in Example 1 (3) to give 3- [2- (3- (3-iodo iodide). Propargyl) oxyphenyl) -1-propenyl-ONN-azoxy]
-2,2-propylenedioxybutane (III) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.31 (1 H, t, J = 8 Hz) 7.12 (1 H, q, J = 1 Hz) 7.07 (1 H, br.d, J = 2. 8 Hz) 7.01 (1 H, t, J = 2 Hz) 6.96 (1 H, dd, J = 8, 2 Hz) 4.85 (2 H, s) 4.73 (1 H, q, J = 7 Hz) 93-3.99 (4H, m) 2.45 (3H, d, J = 1 Hz) 1.74-1.89 (1H, m) 1.61-1.71 (1H, m) 1.51 ( 3H, s) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1575, 1480, 1215 (br)

(4) Using the propylene dioxy compound (III) obtained in the above (3), a reaction was carried out in the same manner as in Example 1 (3).
Treatment provided 3- [2- (3- (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-oxobutane as an oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1 H, t, J = 8 Hz) 7.18 (1 H, q, J = 1 Hz) 7.08 (1 H, br.d, J = 8 Hz) 7.02 (1 H, t, J = 2 Hz) 6.99 (1 H, dd, J = 8, 2 Hz) 4.85 (2 H, s) 4.62 (1 H, q, J = 7 Hz) 50 (3H, d, J = 1 Hz) 2.24 (3H, s) 1.52 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1595, 1440 (br), 1285 [α] _D ²³ -30 ° ( C 1.7, chloroform)

(5) The oxo compound (I) obtained in the above (4)
Using I), the reaction and treatment were carried out in the same manner as in Example 1 (5) to obtain the anti- and syn-isomers for the oxime hydroxyl group of the target product (I) as colorless oils.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.32 (1H, t, J = 8 Hz) 7.12 (1H, br.s) 7.06 (1H, d, J = 8 Hz) 7.01 (1H, br.s) 6.97 (1H, d, J = 8 Hz) 4.85 (2H, s) 4.83 (1H, q, J = 7 Hz) 2.47 (3H, s) 1.98 (3H, s) 1.42 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3270 (br), 1695, 1465, 12
85 [α] _D ²³ + 7.1 ° ( C 0.68, chloroform)

Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1H, t, J = 8 Hz) 7.16 (1H, q, J = 1 Hz) 7.08 (1H, br. d, J = 8 Hz) 7.02 (1H, t, J = 2 Hz) 6.98 (1H, dd, J = 8, 2 Hz) 5.41 (1H, q, J = 7 Hz) 4.86 (2H, s) 2.51 (3H, d, J = 1 Hz) 1.83 (3H, s) 1.46 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3560, 3240 (br ), 1600, 1460, 12
85 [α] _D ²³ + 67 ° ( C 0.19, chloroform)

Example 4 2-hydroxyimino-3- [2- (4- (3-iodopropargyl) oxyphenyl) -vinyl-ONN-azoxy] butane [Compound (I): R ₁ = hydrogen atom, R ₂ = 4
Production of-(3-iodopropargyl) oxy group, R ₃ = hydrogen atom]: (1) 3- (methyl-ON) obtained in Reference Example
Using 743 mg of (N-azoxy) -2,2-propylenedioxybutane (V) and 1.08 g of 4-propargyloxybenzaldehyde (VI), the reaction and treatment were carried out in the same manner as in Example 1 (a) to give 3- [ 2-hydroxy-2- (4-
Propargyloxyphenyl) -ethyl-ONN-azoxy] -2,2-propylene dioxybutane (IV ') 1.00 g (73%) of a diastereomer mixture (4: 5) was obtained as a colorless oil.

Diastereomer (a) ¹ H-NMR value: δCDCl ₃ , ppm 7.35 (2H, d, J = 9 Hz) 6.99 (2H, d, J = 9 Hz) 5.32 (1H, 3.br (d, J = 8 Hz) 4.70 (2H, d, J = 2 Hz) 4.54 (1H, dd, J = 13, 2 Hz) 4.36 (1H, dd, J = 13, 8 Hz) 32 (1H, br.s) 3.91 to 4.06 (2H, m) 3.86 (1H, q, J = 7 Hz) 3.74 to 3.86 (2H, m) 2.52 (1H, t, J = 2 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3410 (br), 3240, 1495, 1220 (br)
, 1155

Diastereomer (b) ¹ H-NMR value: δCDCl ₃ , ppm 7.36 (2H, d, J = 9 Hz) 6.98 (2H, d, J = 9 Hz) 5.32 (1H, br.d, J = 9 Hz) 4.69 (2H, d, J = 2 Hz) 4.51 (1H, dd, J = 13, 9 Hz) 4.48 (1H, br.s) 4.27 (1H, dd, J = 13, 2 Hz) 3.92-4.06 (2H, m) 3.96 (1H, q, J = 6 Hz) 3.77-3.87 (2H, m) 2.51 (1H, t, J = 2 Hz) 1.89 to 2.07 (1 H, m) 1.50 (3 H, s) 1.33 to 1.45 (1 H, s) 1.20 (3 H, d, J = 6 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3390 (br), 3300, 1495, 1220 (br)
, 1155

(2) Using 449 mg of the hydroxy compound (IV ') obtained in the above (1), the reaction was carried out in the same manner as in Example 1 (2).
Treatment gives 3- [2- (4-propargyloxyphenyl) -vinyl-ONN-azoxy] -2,2-propylenedioxybutane (III ') as a colorless oil.
mg (56% yield).

¹ H-NMR value: δ CDCl ₃ , ppm 7.76 (1 H, d, J = 14 Hz) 7.57 (1 H, d, J = 14 Hz) 7.45 (2 H, d, J = 9 Hz) 6.99 (2H, d, J = 9 Hz) 4.73 (2H, d, J = 2 Hz) 4.71 (1H, q, J = 7 Hz) 3.92-4.02 (4H, m) 55 (1H, t, J = 2 Hz) 1.77 to 1.92 (1H, m) 1.61 to 1.69 (1H, m) 1.51 (3H, m) 1.22 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3290, 1605, 1510, 1450, 1230
(Br)

(3) Using 229 mg of the propargyl compound (III ') obtained in the above (2), the reaction and treatment were carried out in the same manner as in Example 1 (3) to give 3- [2- (4- (3- (3- 277 mg (88% yield) of iodopropargyl) oxyphenyl) -vinyl-ONN-azoxy] -2,2-propylenedioxybutane (III) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.76 (1 H, d, J = 14 Hz) 7.57 (1 H, d, J = 14 Hz) 7.45 (2 H, d, J = 9 Hz) 6.97 (2H, d, J = 9 Hz) 4.86 (2H, s) 4.71 (1H, q, J = 6 Hz) 3.90-4.01 (4H, m) 1.77-1. 92 (1H, m) 1.57-1.68 (1H, m) 1.51 (3H, s) 1.22 (3H, d, J = 6 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1605 , 1505, 1450, 1225 (br)

(4) Using 249 mg of the propylenedioxy compound (III) obtained in the above (3), the reaction and treatment were carried out in the same manner as in Example 1 (4) to give 3- [2- (4- (3 225 mg of a crude oil of-(iodopropargyl) oxyphenyl) -vinyl-ONN-azoxy] -2-oxobutane (II) were obtained. The crude oil was recrystallized from methanol to obtain pale yellow needles having a melting point of 86 ° C. (decomposition).

¹ H-NMR value: δ CDCl ₃ , ppm 7.79 (1 H, d, J = 14 Hz) 7.58 (1 H, d, J = 14 Hz) 7.47 (2 H, d, J = 9 Hz) 6.99 (2H, d, J = 9 Hz) 4.87 (2H, s) 4.68 (1H, q, J = 7 Hz) 2.21 (3H, s) 1.51 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1600, 1510, 1375, 1300,
1250, 1170

(5) The oxo compound (I) obtained in the above (4)
Using 225 mg of the crude oily product of I), the reaction and treatment were carried out in the same manner as in Example 1 (5) to give 136 mg and 52 mg of the anti- and syn-isomers for the oxime hydroxyl group of the target product (I) as colorless oils, respectively. Obtained.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.77 (1H, d, J = 14 Hz) 7.52 (1H, d, J = 14 Hz) 7.46 (2H, d, J = 9 Hz) 6.98 (2H, d, J = 9 Hz) 4.87 (1H, q, J = 7 Hz) 4.86 (2H, s) 1.98 (3H, s) 1.42 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3260 (br), 1605, 1505, 14
55, 1220 (br), 1170 [α] _D ²³ + 21 ° ( C 1.2, chloroform)

Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.79 (1H, d, J = 14 Hz) 7.53 (1H, d, J = 14 Hz) 7.47 (2H, d, J = 9 Hz) 6.98 (2H, d, J = 9 Hz) 5.43 (1H, q, J = 7 Hz) 4.87 (2H, s) 1.79 (3H, s) 1.46 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3260 (br), 1605, 1505, 14
55, 1220 (br), 1170 [α] _D ²³ + 44 ° ( C 0.63, chloroform)

Example 5 3- [2- (2-chlorophenyl) -vinyl-ONN-
Production of azoxy] -2-hydroxyiminobutane [compound (I): R ₁ = hydrogen atom, R ₂ = 2-chloro, R ₃ = hydrogen atom]: (1) 3- (methyl- ONN-azoxy) -2,2-propylenedioxybutane (V) 297
The reaction and treatment were carried out in the same manner as in Example 1 (1), using 0.3 mg of O-chlorobenzaldehyde (VI) and 3- [2
-(2-chlorophenyl) -2-hydroxyethyl-O
NN-azoxy] -2,2-propylenedioxybutane (IV) was obtained in an amount of 463 mg (yield 84%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.06 (3H, d, J = 6.3 Hz) 1.28 (3H, d, J = 6.5 Hz) 1.46 (3H, s) 1.48 (1H, s) 1.92 to 2.05 (4H) 3.76 to 4.90 (16H) 5.62 to 5.68 (2H) 7.24 to 7.77 (8H)

(2) Using 285 mg of the hydroxy compound (IV) obtained in the above (1), the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- [2- (2-chlorophenyl) -vinyl −
ONN-azoxy) -2,2-propylenedioxybutane (III) was obtained in an amount of 222 mg (yield: 82.3%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.23 (3H, d, J = 6.3 Hz) 1.51 (3H, s) 1.62 to 1.87 (2H) 3.94 to 4.01 (4H) 4.71 (1H, q, J = 6 Hz) 7.25 to 7.56 (4H) 7.94 (2H, q, J = 13 Hz) IR value: νmax, CHCl ₃ , cm ^{− 1} 1460 UV (EtOH, λmax) [nm] 276 [α] _D ²³ + 34.4 ° (C 1.0, CHCl ₃ )

(3) Using 32 mg of the propylenedioxy compound (III) obtained in the above (2), the reaction and treatment were carried out in the same manner as in Example 1 (4) to obtain a crude oil. This crude oily product was reacted and treated in the same manner as in Example 1 (5) without purification to obtain 18.3 mg (yield) of the target product (I) as a mixture of anti- and syn-isomers (3: 1). Rate of 66.2%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.43 (3H, d, J = 6.8 Hz) 1.47 (3H, d, J = 7.3 Hz) 1.82 (3H, s) 1.99 (3H, s) 4.88 (1H, q, J = 6.8 Hz) 7.29 to 7.63 (10H, s) 8.18 to 8.23 (2H, s) IR value: νmax , CHCl ₃ , cm ⁻¹ 1458

Example 6 3- [2- (2-chlorophenyl) -1-propenyl-
Production of ONN-azoxy] -2-hydroxyiminobutan [Compound (I): R ₁ = methyl group, R ₂ = 2-chloro, R ₃ = hydrogen atom]: (1) 3- (obtained in Reference Example Methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 320
The reaction and treatment were carried out in the same manner as in Example 1 (1), using 3-mg of O-chloroacetophenone and 045 ml of O-chloroacetophenone to give 3- [2- (2-chlorophenyl) -2-hydroxypropyl-ONN-azoxy] -2,2-. 194 mg (yield 33%) of propylene dioxybutane (IV) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 0.46 (3H, d, J = 6.3 Hz) 1.01 (3H, d, J = 6.3 Hz) 1.17 (3H, s) 1.36 (3H, s) 1.71 (3H, s) 1.72 (3H, s) 1.45 to 180 (4H) 3.65 to 385 (8H) 4.25 (1H, q, J = 6.3 Hz) 4.34 (1H, q, J = 6.3 Hz) 4.42 (1H, d, J = 12.2 Hz) 4.53 (1H, d, J = 12.7 Hz) 5.31 ( 1H, d, J = 12.7 Hz) 5.43 (1H, d, J = 12.2 Hz) 5.52 (1H, s) 5.66 (1H, s) 7.19 to 7.22 (6H) 7.84 to 7.90 (2H)

(2) Using 184 mg of the hydroxy compound (IV) obtained in the above (1), the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- [2- (2-chlorophenyl) -1. -Propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III) was obtained in an amount of 34.9 mg (yield: 20%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.22 (3H, d, J = 6.3 Hz) 1.50 (3H, s) 2.45 (3H, d, J = 1.9 Hz) 3.93 to 3.99 (4H) 4.71 (1H, q, J = 6.3 Hz) 6.88 (1H, d, J = 1.9 Hz) 7.24 to 7.42 (4H) IR value : Νmax, CHCl ₃ , cm ⁻¹ 1470 UV (EtOH, λmax) [nm] 233 [α] _D ²³ + 26.4 ° (C 1.0, CHCl ₃ )

(3) Using 27.4 mg of the propylenedioxy compound (III) obtained in the above (2), the reaction and treatment were carried out in the same manner as in Example 1 (4) to obtain a crude oil (II). Was. This crude oily product was reacted and treated in the same manner as in Example 1 (5) without purification to obtain 18.5 mg of the desired product (I) as a mixture of anti- and syn-isomers (4: 1) ( Yield 77.8
%)Obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.42 (3H, d, J = 6.3 Hz) 1.44 (3H, d, J = 6.7 Hz) 1.83 (3H, s) 1.98 (3H, s) 2.45 (3H, d, J = 1.9 Hz) 2.48 (3H, d, J = 1.9 Hz) 4.83 (1H, q, J = 6.3 Hz) 5.43 (1H, q, J = 6.7 Hz) 6.88 (1H, d, J = 1.9 Hz) 6.90 (1H, d, J = 1.9 Hz) 7.25 to 7.43 ( 8H) IR value: νmax, CHCl ₃ , cm ⁻¹ 1463

Example 7 3- [2- (2,4-difluorophenyl) -1-propenyl-ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = methyl group, R ₂ = 2 -Fluoro, R ₃ = 4-fluoro]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 309 obtained in Reference Example
mg and 2,4-difluoroacetophenone, and reacted and treated in the same manner as in Example 1 (1) to give 3- [2
419 mg (yield: 74.2%) of-(2,4-difluorophenyl) -2-hydroxypropyl-ONN-azoxy] -2,2-propylenedioxybutane (IV) was obtained.

(2) Using 419 mg of the hydroxy compound (IV) obtained in the above (1), the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- [2- (2,4-difluorophenyl). )-
6-5.4 mg of 1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III) (yield: 16.
5%).

(3) Using 65 mg of the propylenedioxy compound (III) obtained in the above (2), the reaction and treatment were carried out in the same manner as in Example 1 (4) to give the desired product (I) as anti- and syn- 38.8 mg (68.8 yield) as a mixture of isomers (2: 1).
%)Obtained. ¹ H-NMR value: δ CDCl ₃ , ppm 1.42 (3H, d, J = 6.8 Hz) 1.45 (3H, d, J = 6.8 Hz) 1.83 (3H, s) 1.98 (3H, s) 2.44 (3H, d, J = 1.9 Hz) 2.47 (3H, d, J = 1.9 Hz) 4.83 (1H, q, J = 6.8 Hz) 5.41 (1H, q, J = 6.8 Hz) 6.87 (1H, d, J = 1.9 Hz) 6.84 to 7.30 (6H, s) IR value: νmax, CHCl ₃ , cm ⁻¹ 1464

Continued on the front page (72) Inventor Yukihiro Okuno 2-17-43, Noguchi-cho, Higashimurayama-shi, Tokyo (72) Inventor Hisatsuka 461 Imafuku, Kawagoe-shi, Saitama 2-205 Denen Heights Kawagoe 2-205 (72) Inventor Shozo Shirachi 4-43-2 Zanbori, Musashimurayama-shi, Tokyo (56) References International Publication 90/4585 (WO, A1) Patent Application Publication No. 2036514, Canadian Patent Application (CA, 2036514, A) (58) Fields surveyed ( Int.Cl. ⁷ , DB name) CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (Wherein R ₁ is a hydrogen atom or a lower alkyl group; R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom or a group
-A-CH ₂ -BX, wherein A is an oxygen atom or a single bond,
B represents a triple bond between carbon atoms, and X represents a halogen atom). 2. The compound according to claim 1, which is an anti-isomer with respect to the oxime hydroxyl group of the compound of the general formula I. 3. The compound according to claim 1, which is a syn-isomer with respect to the oxime hydroxyl group of the compound of general formula I. 4. A compound of the general formula Wherein R ₁ , R ₂ and R ₃ have the above-mentioned meaning, and n is 2 or 3
Is reacted with an acid to form a compound represented by the general formula: 2. A process for preparing a compound according to claim 1, wherein a compound represented by the formula (wherein each symbol has the above-mentioned meaning) is obtained, and then the compound is reacted with hydroxylamine. 5. A compound of the general formula Wherein n has the meaning described above, and a compound represented by the general formula: (Wherein each symbol has the same meaning as described above), the compound represented by the general formula 5. The method according to claim 4, wherein a compound represented by the formula (wherein each symbol has the above-mentioned meaning) is obtained, and then the compound (III) obtained by dehydrating the compound is used. 6. An antifungal agent comprising the compound according to claim 1 as an active ingredient.