JPH0480021B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel diphenylthioether compounds. The compound of the present invention is an extremely useful compound as a synthetic intermediate for a new pyrazolotriazine derivative useful as an anti-gout agent.

Structure and Effects of the Invention The diphenylthioether compound of the present invention has the following general formula: [In the formula, R ¹ represents a lower alkyl group or a lower alkoxy group] This is a compound represented by the following formula.

In this specification, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl,
Straight chain or branched alkyl groups such as butyl, t-butyl, pentyl, hexyl and the like are included. Examples of the lower alkoxy group include linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.

Furthermore, phenyl groups that may have lower alkyl groups as substituents include, for example, phenyl,
2-methylphenyl, 3-methylphenyl, 4-
Methylphenyl, 4-ethylphenyl, 3-(1
-propyl)phenyl, 4-(1-butyl)phenyl, 4-(t-butyl)phenyl, 4-(1-pentyl)phenyl, 4-(1-hexyl)phenyl, and the like.

The compounds of the present invention can be produced by various methods,
For example, it is produced by the method shown in Reaction Formula-1 below.

[In the formula, R ¹ is the same as above, and R ² represents a lower alkyl group or a phenyl group that may have a lower alkyl group as a substituent. ] The above reaction is carried out by adding thiophenol in an inert solvent at 100 to 200°C, preferably at 130°C, at least about an equimolar amount, preferably about 1 to 3 times the molar amount, to the benzaldehyde derivative represented by general formula (2). The reaction is carried out at ~160°C for about 1 to 100 hours, preferably about 2 to 70 hours.

As the inert solvent used in the present invention, any solvent can be used as long as it does not adversely affect the reaction. For example, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, N,N- -dimethylacetamide,
Examples include hexamethylphosphoric acid triamide (HMPA). Among them, N,N-dimethylformamide (DMF) and hexamethylphosphoric acid triamide (HMPA) are preferred. The above solvents may be used alone or in combination of two or more.

As the above reaction progresses, sulfonic acid derivatives are produced, so the solvent contains alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metals such as sodium carbonate, potassium carbonate, and calcium carbonate. Alternatively, it is preferable to include an inorganic base such as an alkaline earth metal carbonate, or an organic base such as pyridine or triethylamine. Among these bases, it is particularly preferable to use pyridine or calcium carbonate because the diphenylthioether compound represented by general formula (1) can be obtained in high yield. The above bases may be used alone or in combination of two or more.

Further, the above reaction is preferably carried out under a stream of an inert gas such as nitrogen gas or argon gas. The diphenylthioether compound produced by the above method can be purified by a conventional purification method, for example, by the following method.

That is, the diphenylthioether compound is dissolved in an aqueous solution containing an alkali metal salt of bisulfite such as sodium bisulfite or potassium bisulfite in an amount equivalent to at least an equimolar amount to the diphenylthioether compound, and the aqueous solution is dissolved in benzene, toluene, After washing with an organic solvent such as diethyl ether, the pH is made slightly alkaline with a base such as potassium carbonate, and highly purified diphenylthioether is obtained by extraction with an organic solvent such as ethyl acetate, diethyl ether, toluene, or benzene.

The diphenylthioether compound of the present invention is useful as a synthetic intermediate for pyrazolotriazine derivatives represented by formulas (8) and (9) below, which are useful as anti-gout agents.

In order to produce the pyrazolotriazine derivative from the compound of the present invention, for example, the method shown in Reaction Formula 2 below is employed.

That is, the compound (1) of the present invention is reduced to form the compound
Leads to (3). This reduction reaction is performed by using a hydrogenation reducing agent such as lithium aluminum hydride, aluminum hydride, diisopropyl aluminum hydride, diisobutyl aluminum hydride, lithium borohydride, sodium borohydride, diborane, etc. to the compound (1). It is carried out in the usual manner. The reaction is usually carried out in a solvent, and examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene and toluene, and methanol. and lower alcohols such as ethanol. The hydrogenation reducing agent is preferably used in an amount of at least 0.5 times, preferably 0.6 to 1.2 times, the amount of compound (1). The reaction is usually carried out under ice cooling.
It is carried out at 100℃, preferably about 0 to 50℃, and 30℃
It will finish in about 10 minutes to 10 hours.

The obtained compound (3) is treated with a halogenating agent to halogenate it, leading to compound (4). The halogenation reaction is carried out, for example, by reacting a thionyl halide such as thionyl chloride or thionyl bromide as a halogenating agent in a halogenated hydrocarbon solvent such as methylene chloride or chloroform. The amount of the halogenating agent to be used is preferably at least equimolar to compound (3). The above reaction is preferably carried out at about 0 to 50°C,
It usually takes about 30 minutes to 5 hours to complete.

Then, compound (5) is obtained by reacting the obtained compound (4) with a cyanide compound such as sodium cyanide or potassium cyanide in an aprotic polar solvent such as N,N-dimethylformamide or dimethyl sulfoxide. . The amount of cyanide to be used is approximately 1 to 1.3 times the molar amount of compound (4). The above reaction is preferably carried out at room temperature to around 100°C and is usually completed in about 1 to 20 hours.

Compound (6) is obtained by reacting the above compound (5) with at least an equimolar amount of formic acid ester (for example, methyl formate, ethyl formate, etc.) in an aromatic hydrocarbon solvent such as benzene or toluene. be able to. This reaction is usually carried out under ice cooling.
It is preferable to carry out the heating for about 5 to 20 minutes, and then for about 4 to 12 hours at room temperature. In order to allow the above reaction to proceed sufficiently, it is preferable that a sodium alkoxide such as sodium methoxide be present in at least an equimolar amount relative to the formic acid ester. The generated compound (6) can be isolated by adding water to the reaction solution after the reaction, separating the aqueous layer, and adjusting the pH to 3 to 4 with a mineral acid such as hydrochloric acid. .

The obtained compound (6) was added with semicarbazide under ice cooling.
Compound (7) is obtained by dropping at least an equimolar amount of the mineral acid salt and then reacting at room temperature for about 4 to 15 hours to effect ring closure. This reaction is carried out using, for example, a lower alcohol such as methanol or ethanol, or a mixed solvent of lower alcohol and water.
The mixing ratio of lower alcohol and water is (1:1) ~
(10:1) can be used.

Compound (7) obtained by the above method can be converted into pyrazolotriazine derivatives of formulas (8) and (9) useful as anti-gout agents by the following method.

That is, compound (8) is obtained by reacting compound (7) with an alkyl orthoformate such as methyl orthoformate or ethyl orthoformate to cause ring closure. The above reaction can be carried out using a solvent that does not adversely affect the reaction, but since the alkyl orthoformate functions as a solvent, it is not necessarily necessary to use a separate solvent. The reaction uses about 15 times the molar amount of alkyl orthoformate relative to compound (7), and usually 80
The process is completed in about 2 to 15 hours at ~120°C.

Compound (9) can be obtained by treating and oxidizing the obtained compound (8) with an oxidizing agent in a conventional manner. That is, compound (8) is added with a metaperiodate salt such as sodium metaperiodate or potassium metaperiodate, or hydrogen peroxide in acetic acid in a mixed solvent of lower alcohol and water (40:1). Compound (9) is obtained by adding about twice the molar amount of (8) and reacting at room temperature for about 40 hours.

Next, the compound of the present invention and the method for producing the same will be explained in more detail with reference to Examples and Reference Examples.

Example 1 Preparation of 3-methoxy-4-phenylthiobenzaldehyde: 430 g (2.0 M) of 3-methoxy-4-methylsulfonyloxybenzaldehyde and pyridine
Heat a 200ml solution of DMF1.8 and 200ml HMPA to 130°C under a nitrogen gas stream, and add 277ml of thiophenol. Reflux for another 2.5 hours (140-150
°C). After cooling, a solution of 500 g of NaHSO ₃ in 1 water is added and stirred for 2 hours. Pour the reaction solution into a separatory funnel, add 5 parts of water, wash with 3 parts of toluene, and extract the toluene layer with 3 parts of water. The aqueous layers were combined, washed with 1.5 toluene, made weakly alkaline with 500 g of K ₂ CO ₃ and extracted twice with ethyl acetate (5+2). The organic layer is washed with 10% HCl (2), then water and saturated brine, and dried over magnesium sulfate. The solvent is distilled off to obtain the desired product as pale yellow crystals. Yield 258g (53%), melting point 57-58°C (ether: recrystallized from n-hexane) ^1H -NMR ( _CDCl3 , ppm): 9.86 (1H, s), 7.44
~7.57 (5H, m), 7.35 (1H, d, J=1.7),
7.24 (1H, dd, J = 1.7, 7.9), 6.80 (1H, d,
J = 7.9), 3.99 (3H, s) Example 2 Production of 3-methyl-4-phenylthiobenzaldehyde: 6.5 g (30.3 m
A suspension of 4.1 g of calcium carbonate (mol) and 4.1 g of calcium carbonate in 30 ml of DMF is heated to 110°C under a nitrogen gas stream, 4.2 ml of thiophenol is added thereto, and the mixture is stirred at 140°C for 22 hours. After cooling, the reaction solution is filtered and the filtrate is concentrated. An aqueous solution of 10 g of sodium bisulfite is added to the residue and stirred for 1 hour. Transfer the reaction solution to a separating funnel, wash with ether, and add potassium carbonate to the aqueous layer.
Make it slightly alkaline with 10g of aqueous solution and add ethyl acetate.
Extract with 300ml. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography (ether:hexane=1:2) to obtain the desired 3-methyl-4-phenylthiobenzaldehyde as a colorless oil.
Yield 4.1g (59%) ^1H -NMR ( _CDCl3 , ppm): 9.90 (1H, s), 7.66
(1H, s), 7.40-7.52 (6H, m), 6.96 (1H,
d, J=7.9), 2.46 (3H, s) Reference Example 3 Production of methyl-4-methylsulfonyloxybenzaldehyde: 4.5 g (33.1 mmol) of 4-hydroxy-3-methylbenzaldehyde and triethylamine
Add 5.1 ml of dichloromethane to 30 ml of dichloromethane solution under ice-cooling and stirring.
Add 2.8 ml of methanesulfonyl chloride dropwise and stir at the same temperature for 1 hour. Transfer the reaction solution to a separatory funnel, add water, and extract with 100 ml of dichloromethane.
After washing the organic layer with 10% HCl aqueous solution and saturated saline,
Dry with sodium sulfate. The solvent is distilled off and used as the desired product. 3-Methyl-4-methylsulfonyloxybenzaldehyde is obtained as an orange oil. Yield 6.5g (92%) ^1H -NMR ( _CDCl3 , ppm): 9.98 (1H, s), 7.81
(1H, s), 7.77 (1H, d, J=8.4), 7.48 (1H,
d, J=8.4), 3.27 (3H, s), 2.44 (3H, s)

Claims (1)

[Claims] 1. General formula A diphenylthioether compound represented by [In the formula, R ¹ represents a lower alkyl group or a lower alkoxy group].