JP2787602B2 - Isoxazoline derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel isoxazoline derivative.

The isoxazoline derivative of the present invention has a general formula useful as an anti-inflammatory agent, an analgesic and an antipyretic. (Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkoxy group.) As a production intermediate of a (3,4-diarylisoxazol-5-yl) acetic acid derivative represented by Useful.

(Prior Art) JP-A-56-59764 discloses (3,4-diarylisoxazol-5-yl) acetic acid derivatives as compounds having anti-inflammatory, analgesic and antipyretic effects. The production method includes (1) the same publication and (2) JP-A-60-75471.
There is known a method described in Japanese Patent Application Laid-Open Publication No. HEI 9-86139.

(Wherein, R ¹ and R ² are the same as described above) 3,4-Diaryl-5-methylisoxazole is placed in tetrahydrofuran under cooling with dry ice-acetone and n
-Treatment with butyllithium, then pouring the resulting reaction mixture into crushed dry ice, followed by acid treatment.

(Wherein X represents a halogen atom, and R ¹ and R ² are the same as described above.) 3,4-Diaryl-5-methylisoxazole is reacted with a halogenating agent and then with a cyanating agent to give 3,4- A method of obtaining diaryl-5-cyanomethylisoxazole and subjecting it to solvolysis.

We have (3,4-diarylisoxazole-5).
-Yl) Acetic acid derivatives have been studied for industrial production, but it has been found that the methods shown in (1) and (2) have various problems. That is, in the method (1), n-butyllithium, which is a synthetic reagent, has high ignitability, and there is a problem in terms of fire and safety when used in a large amount. Furthermore, using dry ice having high hygroscopicity in a reaction in which anhydrous conditions are indispensable, and performing the reaction under a low-temperature reaction condition of -70 ° C have problems in work efficiency including operability.
The method (2) is more complicated than the step (1), and uses a cyanide compound, which is not preferable in terms of safety as an industrial production method.

(Problems to be Solved by the Invention) An object of the present invention is to provide an intermediate for producing the compound (A) by a method which is excellent in terms of safety and operability by a simple process, without using dangerous reagents, and To provide a novel isoxazoline derivative which is useful as a compound.

(Means for Solving the Problems) The present invention has a general formula (Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkoxy group, R ³ represents a cyano group or an alkoxycarbonyl group. However, when R ³ is a cyano group, R ¹ and R ² Is a lower alkoxy group at the same time.)

In the above formula, preferred lower alkoxy groups represented by R ¹ and R ² are linear or branched alkoxy groups having 1 to 6 carbon atoms, and specifically, methoxy, ethoxy, propoxy, iso -Propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

In the above formula, examples of the alkoxycarbonyl group represented by R ³ include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
Examples thereof include linear or branched alkoxycarbonyl groups having 2 to 7 carbon atoms, such as pentyloxycarbonyl and hexyloxycarbonyl groups.

The isoxazoline derivative of the present invention has a general formula useful as an anti-inflammatory agent, an analgesic and an antipyretic. (Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or a lower alkoxy group.) As a production intermediate of a (3,4-diarylisoxazol-5-yl) acetic acid derivative represented by Useful.

The compound (I) of the present invention has the general formula (Wherein R ¹ , R ² and R ³ are the same as described above)
Produced by cyclizing a β-unsaturated ketoxime derivative.

Compound (II) used in the present production method can be produced according to the following reaction scheme.

(In the formula, R ¹ , R ² and R ³ are the same as above. Z represents a lower alkyl group.) In the above, examples of the lower alkyl group represented by Z include methyl, ethyl, propyl, isopropyl,
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms such as butyl, sec-butyl, tert-butyl, pentyl and hexyl groups.

Each step in the above reaction scheme is performed in more detail as follows.

<Step A> By reacting a deoxybenzoin derivative represented by the general formula (III) with an alkoxyacrylonitrile or alkoxyacrylic acid derivative represented by the general formula (IV) in a suitable solvent in the presence of a base, The compound represented by V) is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and for example, methanol, ethanol, tert-butanol, tetrahydrofuran,
Dioxane, benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, acetonitrile,
Various organic solvents such as pyridine and dimethylformamide can be used alone or in combination. As the base, for example, sodium hydroxide, sodium methoxide, potassium
Inorganic bases such as tert-butoxide and butyllithium, and organic bases such as triethylamine and dimethylaminopyridine can be used. The reaction ratio is preferably such that the compound of the general formula (IV) is used in an amount of 1 to 3 times the molar amount of the compound of the general formula (III), and the base is used in an amount of 0.1 to 3 times the molar amount of the compound of the general formula (III). The reaction is carried out at a temperature of 200 ° C. or lower, preferably at 0 ° C. to the boiling point of the solvent, and the reaction is usually completed in about 0.5 to 20 hours.

<Step B> The compound represented by the general formula (V) obtained in the step A is reacted with hydroxylamine or a salt thereof in a suitable solvent to obtain a compound represented by the general formula (II). The salt of hydroxylamine used in the reaction is not particularly limited, and examples thereof include hydrochloride and sulfate. The solvent is not particularly limited as long as it does not participate in the reaction, and for example, methanol, ethanol, tert
-Various organic solvents such as butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane, acetonitrile, pyridine, and dimethylformamide can be used alone or in combination. Regarding the reaction ratio, it is preferable to use hydroxylamine or a salt thereof in an amount of 1 to 10 times the molar amount of the compound of the general formula (V). The reaction temperature is 0 to 200 ° C,
The reaction is preferably carried out at a temperature from 40 ° C. to the boiling point of the solvent, and the reaction is usually completed in about 1 to 30 hours.

The compound of the present invention can be obtained by cyclizing compound (II) obtained by the above reaction scheme in an appropriate solvent or in the absence of a solvent in the presence of a catalyst. The catalyst is not particularly limited, and examples thereof include acids and bases.

The acid is not particularly limited, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, formic acid, acetic acid,
Organic acids such as trifluoroacetic acid, oxalic acid and p-toluenesulfonic acid, and phosphoric acids such as phosphoric acid and polyphosphoric acid can be used alone or in combination.

The base is not particularly limited. For example, pyridine, 4
-Organic bases such as dimethylaminopyridine, triethylamine, sodium hydroxide, sodium carbonate, sodium hydride, sodium amide, sodium methoxide,
Inorganic bases such as potassium tert-butoxide and n-butyllithium can be used. The amounts of the acid and the base are represented by the general formula (I
It is preferred to use 0.1 to 10 times the molar amount of the compound of I).
The reaction is carried out at a temperature of from 0 to 200 ° C, preferably from 0 ° C to about the boiling point of the solvent, and the reaction is usually completed in about 1 to 30 hours.

The compound of the present invention thus obtained can be isolated and purified by generally known separation and purification means, specifically, distillation, recrystallization, silica gel column chromatography, and the like.

In the present invention, the isoxazoline derivative represented by the general formula (I) includes an isomer based on cis-trans isomerism of a monocyclic compound, and the present invention includes any isomer.

The compound of the present invention is represented by the general formula (A), which has an anti-inflammatory and analgesic action (3,4-diarylisoxazole-5-).
In order to derive the yl) acetic acid derivative, the isoxazoline derivative represented by the general formula (I) synthesized by the above-mentioned production method is isolated or oxidized in an appropriate solvent without isolation to give 3,4-diaryl isoxanes. It is achieved by sol-5-acetic acid ester or 3,4-diarylisoxazole-5-acetonitrile derivative, followed by solvolysis or hydrolysis in the presence of an acid or a base. Examples of the oxidizing agent include, but are not particularly limited to, chlorine, bromine, iodine, halogenating agents such as N-chlorosuccinimide, N-bromosuccinimide, inorganic oxidizing agents such as manganese dioxide and potassium permanganate, and 2,3. Organic oxidizing agents such as -dichloro-5,6-dicyano-1,4-benzoquinone and metachloroperbenzoic acid. There is no particular limitation on the solvent as long as it does not participate in the reaction, for example, dichloromethane, chloroform, carbon tetrachloride, acetone, hexane,
Benzene, toluene, methanol, ethanol, ether, tetrahydrofuran and the like can be used. In the above oxidation reaction, the oxidizing agent is preferably used in an amount of 1 to 10 times the molar amount of the isoxazoline derivative represented by the general formula (I). The reaction is carried out at a temperature of 0 to 200 ° C, preferably at 0 ° C to about the boiling point of the solvent. The solvolysis or hydrolysis is carried out by a solvolysis method described in JP-A-60-75471, or a hydrolysis method commonly used in the art. As the acid, an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid is generally used, and as the base, an inorganic base such as sodium hydroxide, potassium hydroxide or sodium carbonate is generally used.

(Examples) Next, the present invention will be specifically described with reference to examples and reference examples.

Reference Example 1 Methyl 4,5-bis (4-methoxyphenyl) -5
Synthesis of oxo-3-pentenoate In 430 ml of tert-butanol, deoxyanisoin 128 was added.
g, potassium tert-butoxide 67.3 g, and methyl 3-methoxyacrylate 116 g were added, and the mixture was stirred at 70 ° C. for 3 hours. After completion of the reaction, n-hexane was added to the reaction mixture,
It was left at room temperature. Remove the precipitate and add 1000 ml of ethyl acetate.
After adding and dissolving 300 ml of 3N-sulfuric acid, the organic layer was separated and collected.
The organic layer was washed with 3N-sulfuric acid and saturated saline and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain 153 g (yield 90%) of the title compound as an oil.

This compound was a mixture of isomers (about 6: 4) based on a double bond from an NMR spectrum. The mixture was crystallized from hexane-ethyl acetate as needed to isolate one isomer as white crystals.

Melting point 101-103 ° C Infrared absorption spectrum (KBr) ν _max (cm ^-1 ) 1732, 1640, 1600 NMR spectrum (CDCl ₃ ) δ (ppm) 3.31 (2H, d), 3.72 (3H, s), 3.80 ( 3H, s), 3.85 (3H, s), 6.37 (1H, t), 6.90 (4H, d), 7.23 (2H, d), 7.89 (2H, d) I got something.

Infrared absorption spectrum (KBr) ν _max (cm ^-1 ) 1732, 1662, 1596 NMR spectrum (CDCl ₃ ) δ (ppm) 3.15 (2H, d), 3.65 (3H, s), 3.77 (3H, s), 3.83 (3H, s), 6.30 (1H, t), 6.6 to 7.1 (4H, m), 7.30 (2H, d), 7.92 (2H, d) Reference Example 2 4,5-bis (4-methoxyphenyl) ) -5-oxo-
Synthesis of 3-pentenenitrile 3-methoxyacrylonitrile was used in place of methyl 3-methoxyacrylate, and the reaction was carried out in the same manner as in Reference Example 1 to obtain an oily substance as the title compound.

Infrared absorption spectrum (NaCl) ν _max (cm ^-1 ) 2250, 1660, 1606 NMR spectrum (CDCl ₃ ) δ (ppm) 3.17 (2H, d), 3.78 (3H, s), 3.85 (3H, s), 6.03 (3H, t), 6.7 to 7.0 (4H, m), 7.27 (2H, d), 7.90 (2H, d) Reference Example 3 Synthesis of methyl 4,5-diphenyl-5-oxo-3-pentenoate Deoxyaniso By using deoxybenzoin in place of in and reacting in the same manner as in Reference Example 1, an oily substance as the title compound was obtained.

NMR spectrum (CDCl ₃ ) δ (ppm) 3.18, 3.30 (2H, d), 3.65, 3.70 (3H, s), 6.46, 6.56 (1H, t), 7.1 to 8.2 (10H, m) Mass spectrum M ⁺ ( m / z) 280 Reference Example 4 Synthesis of methyl 5-hydroxyimino-4,5-bis (4-methoxyphenyl) -3-pentenoate Methyl 4,5-bis (4-methoxyphenyl) obtained in Reference Example 1. 24.5 g of an isomer mixture of) -5-oxo-3-pentenoate and 51.5 g of hydroxylamine hydrochloride were heated under reflux in 650 ml of methanol and 72 ml of water for 23 hours. At this time, 0.9 equivalent of sodium bicarbonate was added to the reaction solution in portions according to the progress of the reaction. After completion of the reaction, methanol was distilled off under reduced pressure. Water and ethyl acetate were added to the residue to dissolve it, and the organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent, ethyl acetate-
n-hexane) to give 23 g (yield 90%) of the title compound as an oil.

Infrared absorption spectrum (NaCl) ν _max (cm ^-1 ) 1732, 1608 NMR spectrum (CDCl ₃ ) δ (ppm) 3.1 to 3.2 (2H, m), 3.65 (3H, s), 3.76 (3H, s), 3.77 (3H, s), 6.48 (1H, t), 6.81 (4H, d), 7.35 (2H, d), 7.58 (4H, d), 8.72 (1H, bs) Reference Example 5 5-Hydroxyimino-4 Of 5,5-bis (4-methoxyphenyl) -3-pentenenitrile Methyl 4,5-bis (4-methoxyphenyl) -5
Instead of oxo-3-pentenoate, 4,5-bis (4-
The same reaction as in Reference Example 4 was carried out using methoxyphenyl) -5-oxo-3-pentenenitrile to obtain an oily substance as the title compound.

Infrared absorption spectrum (NaCl) ν _max (cm ^-1 ) 2252, 1596 NMR spectrum (CDCl ₃ ) δ (ppm) 3.12, 3.15 (2H, dd), 3.77 (3H, s), 3.78 (3H, s), 6.18 (1H, t), 6.84 (4H, d), 7.32 (2H, d), 7.55 (2H, d), 8.46 (1H, bs) Reference Example 6 Methyl 5-hydroxyimino-4,5-diphenyl-
Synthesis of 3-pentenoate Methyl 4,5-bis (4-methoxyphenyl) -5
Reference Example 4 was repeated using 4,5-diphenyl-5-oxo-3-pentenoate instead of oxo-3-pentenoate.
By reacting in the same manner as described above, an oily substance as the title compound was obtained.

NMR spectrum (CDCl ₃ ) δ (ppm) 3.1-3.3 (2H, m), 3.64 (3H, s), 6.63 (1H, t), 7.1-7.8 (10H, m), 9.18 (1H, bs) Mass spectrum M ⁺ (m / z) 295 Example 1 Synthesis of 5-methoxycarbonylmethyl-3,4-bis (4-methoxyphenyl) -isoxazoline Methyl 5-hydroxyimino-4,5 obtained in Reference Example 4.
-Bis (4-methoxyphenyl) -3-pentenoate
1.23 g was heated and stirred at 60 ° C. in 20 ml of methanol in the presence of 1.5 g of concentrated hydrochloric acid. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate-n-hexane) to obtain 1 g (yield 81%) of the title compound as an oil.

Infrared absorption spectrum (NaCl) ν _max (cm ^-1 ) 1736, 1610 NMR spectrum (CDCl ₃ ) δ (ppm) 2.0 to 2.8 (2H, m), 3.62, 3.70 (3H, s), 3.76 (6H, s ), 4.5-5.2 (2H, m), 6.7-7.1 (4H, m), 7.6 (2H, d) Mass spectrum M ⁺ (m / z) 355 Example 2 5-methoxycarbonylmethyl-3,4-diphenyl −
Synthesis of isoxazoline Methyl 5-hydroxyimino-4,5-diphenyl-3-pentenoate obtained in Reference Example 6 was used instead of methyl 5-hydroxyimino-4,5-bis (4-methoxyphenyl) -3-pentenoate. The title compound was obtained as a white powder in the same manner as in Example 1 (yield: 85%).

Melting point 55-57 ° C Infrared absorption spectrum (KBr) ν _max (cm ^-1 ) 1734 NMR spectrum (CDCl ₃ ) δ (ppm) 2.1-3.0 (2H, m), 3.59, 3.69 (3H, s), 4.6- 5.3 (2H, m), 6.9 to 7.4 (8H, m), 7.4 to 7.8 (2H, m) Example 3 Synthesis of 5-cyanomethyl-3,4-bis (4-methoxyphenyl) -isoxazoline Reference Example 5 5-hydroxyimino-4,5-bis (4-methoxyphenyl) -3-pentenenitrile 322m obtained in
g of tetrahydrofuran solution in 10 ml of sodium hydrogencarbonate 336 mg and water 2.4 ml were added dropwise, and then potassium iodide 56
A solution of 4 mg, 267 mg of iodine and 2.1 mg of water was added, and the mixture was stirred at room temperature for 90 minutes. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated saline solution and a saturated aqueous solution of sodium thiosulfate, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate-n-hexane) to give 298 mg of the title compound as an oil.
(93% yield).

Infrared absorption spectrum (NaCl) ν _max (cm ⁻¹ ) 2252, 1606 NMR spectrum (CDCl ₃ ) δ (ppm) 2.1 to 2.8 (2H, m), 3.78 (6H, s), 4.5 to 5.1 (2H, m ), 6.7-7.0 (4H, m), 7.0-7.3 (2H, m), 7.4-7.7 (2H, m) Mass spectrum M ⁺ (m / z) 322 Reference Example 7 [3,4-bis (4- Synthesis of methoxyphenyl) isoxazol-5-yl] acetic acid 5-methoxycarbonylmethyl-3,4 obtained in Example 1
-Bis (4-methoxyphenyl) -isoxazoline 0.76
g in 9 ml of carbon tetrachloride, then 0.38 g of N-bromosuccinimide, 0.2 g of 2,2'-azobis-isobutyronitrile.
After adding 04 g, the mixture was heated under reflux for 2 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate-n-hexane) to give 3,4-bis (4-methoxyphenyl) -isoxazole as a white solid 0.65 g of -5-acetic acid methyl ester
(83% yield).

Melting point 67-68 ° C Infrared absorption spectrum (KBr) ν _max (cm ^-1 ) 1730 NMR spectrum (CDCl ₃ ) δ (ppm) 3.73 (3H, s), 3.77 (2H, s), 3.79 (3H, s) , 3.82 (3H, s), 6.83 (2H, d), 6.90 (2H, d), 7.15 (2H, d), 7.40 (2H, d) The compound obtained above was added to a 2% aqueous sodium hydroxide solution. The mixture was stirred at 40 ° C. overnight. After completion of the reaction, the reaction solution was washed twice with ether, and then added with 10% hydrochloric acid under ice-cooling, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound as a white solid (melting point: 147 to 148 ° C).

(Effect of the Invention) By oxidizing and hydrolyzing the isoxazoline derivative of the present invention, a (3,4-diaryl-isoxazol-5-yl) acetic acid derivative can be obtained in high yield. The compound (3,4-diaryl-isoxazole-
The synthesis method of the 5-yl) acetic acid derivative is, as compared with the conventional method,
The use of dry ice, which has high hygroscopicity, results in shortening of the manufacturing process, and the use of highly ignitable butyl lithium eliminates the danger of fire.

Claims (1)

(57) [Claims] (1) General formula (Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkoxy group, R ³ represents a cyano group or an alkoxycarbonyl group. However, when R ³ is a cyano group, R ¹ and R ² Is a lower alkoxy group at the same time.).