JP2920211B1 - Method for producing 1,3-benzodioxan-4-one compound - Google Patents

Abstract

Abstract: PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing a 1,3-benzodioxan-4-one compound. SOLUTION: The following general formula (1): (Wherein, R ^{1 represents} hydrogen or a substituent, n represents an integer of 1 to 4, Ar ¹ and Ar ^{2 each} represent an aryl group, and Ar ¹ and Ar ² may be bonded to each other.) The method for producing a 1,3-benzodioxan-4-one compound described above, wherein the salicylic acid compound and the arylthioketone compound are subjected to a desulfurization condensation reaction in the presence of a desulfurizing agent and a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 1,3-benzodioxan-4-one compound and a 1,3-benzodioxan-4-one compound obtained by the method.

[0002]

2. Description of the Related Art Org. Chem. , 1982, 4
7, 11 show compounds represented by the following formulas.

Embedded image This compound has the formula

Embedded image Is synthesized by reacting a diazoalkane represented by In the case of the prior art, it is difficult to synthesize a diazoalkane used as a reaction material, and
Since the reaction conditions are severe and the yield of the target product is not good, it is unsatisfactory as an industrial method.

[0003]

SUMMARY OF THE INVENTION The present invention provides an industrially advantageous method for producing a 1,3-benzodioxan-4-one compound, and a novel 1,3 compound obtained by the method. An object of the present invention is to provide a benzodioxan-4-one compound.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have completed the present invention. That is, according to the present invention, the following general formula (1)

Embedded image ( Wherein , R ¹ is hydrogen, or a chain or cyclic alkyl group,
Alkoxy group, dialkylamino group, acyl group, alcohol
Selected from xycarbonyl, halogen and nitro
And n represents an integer of 1 to 4, Ar ¹ and Ar ^{2 each} represent an aryl group, and Ar ¹ and Ar ² may be bonded to each other. Dioxane-
In the method for producing a 4-one compound, the following general formula (2)

Embedded image (Wherein R ¹ has the same meaning as described above) and a salicylic acid compound represented by the following general formula (3)

Embedded image (Wherein, Ar ¹ and Ar ² have the same meanings as described above), wherein the arylthioketone compound is subjected to a desulfurization condensation reaction in the presence of a desulfurizing agent and a base. You. Further, according to the present invention, the following general formula (1)

Embedded image ( Wherein , R ¹ is hydrogen, or a chain or cyclic alkyl group,
Alkoxy group, dialkylamino group, acyl group, alcohol
Selected from xycarbonyl, halogen and nitro
Indicates a substituent, n is an integer of 1 to 4, Ar ¹ and Ar ² represents an aryl group, 1,3-dioxane and Ar ¹ and Ar ² are represented by bound) - A 4-one compound is provided.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (1) showing a 1,3-benzodioxan-4-one compound which is a production target compound of the present invention, R ¹ represents hydrogen or a substituent. The substitution may be any as long as it is inert to the reaction of the present invention. Such a substituent includes a chain or cyclic alkyl group, alkoxy group, dialkylamino group, acyl group, alkoxycarbonyl group, halogen atom, nitro group and the like. The alkyl group bonded to these substituents usually has 1 to 6 carbon atoms. Ar ¹ and Ar ² in the general formula (1) represent aryl groups, and these aryl groups include phenyl, tolyl,
Xylyl, naphthyl, biphenyl and the like can be mentioned. These aryl groups may also have a substituent such as a halogen atom, an alkoxy group, a nitro group, a dialkylamino group, an acyl group, and an alkoxycarbonyl group. Ar ¹ and Ar ² may be bonded to each other via one atom or atomic group. In this case, a bonded body of Ar ¹ and Ar ² is represented by the following general formula (4). Condensed polycyclic groups.

Embedded image In the above formula, R ² and R ³ represent hydrogen or a substituent. In this case, the substituent may be any as long as it is inert to the reaction of the present invention. Such substituents include a chain or cyclic alkyl group, alkoxy group, dialkylamino group, acyl group, alkoxycarbonyl group, halogen atom, nitro group and the like. The alkyl group contained in these substituents usually has 1 to 6 carbon atoms. M and n are 1
And an integer of 1 to 4, usually an integer of 1 or 2. In the aforementioned-(X) t-, t represents 0 or 1. When t is 0,-(X) t- represents a mere joint (-), and when t is 1, it represents a divalent group -X-. In the divalent group X,
—O—, —S—, —N (R) — (R: alkyl group), lower alkylene group, lower alkenylene and the like are included. Specific examples of the condensed polycyclic group represented by the general formula (4) are shown below.

[0006]

Embedded image

According to the present invention, the 1,3-benzodioxan-4-one compound comprises a salicylic acid compound represented by the general formula (2) and an arylthioketone compound represented by the general formula (3) And a desulfurization condensation reaction of The desulfurization condensation reaction can proceed smoothly in the presence of a desulfurizing agent and a base. The desulfurizing agent is
Any substance that has the ability to form sulfides may be used.
Metals and metal compounds are included. As the metal, Ag,
Cu, Fe, Zn, Pb and the like can be mentioned. Examples of the metal compound include salts and oxides of metals such as Ag, Cu, Fe, Zn, and Pb, which easily form sulfides. The use ratio of the desulfurizing agent is at least 1 equivalent, preferably 2 to 2.5 equivalents, per equivalent of the arylthioketone compound. The base generates a carboxylate anion from salicylic acid and acts as an acceptor for the cation H ⁺ generated as the reaction proceeds. As the base, any base can be used as long as it exhibits the above-mentioned action without hindering the above-mentioned desulfurization condensation reaction. Examples of such a compound include an alkali metal salt, an alkaline earth metal salt, and a third salt which are present in a liquid or solid state in the reaction system.
Secondary amines and the like. As the alkali metal salt or the alkaline earth metal salt, an alkali metal salt or an alkaline earth metal salt of an organic carboxylic acid is preferably used. The ratio of the base used is at least 2 per equivalent of the salicylic acid compound.
It is a ratio of equivalents, preferably 3 to 4 equivalents. The desulfurization condensation reaction is preferably carried out in the presence of a reaction solvent. In this case, the reaction solvent includes hexane, benzene, a hydrocarbon solvent such as toluene, chloroform, a chlorine solvent such as dichloromethane, THF, Examples thereof include ethers such as isopropyl ether, esters such as ethyl acetate, and nitrogen-containing organic solvent systems such as pyridine, acetonitrile, and DMF. These organic solvents are used alone or in the form of a mixture.

In order to carry out the method of the present invention preferably, the arylthioketone compound 1 represented by the general formula (3)
The equivalent amount and about 1.2 equivalents of the salicylic acid compound represented by the general formula (2) are added to the reaction solvent and mixed to form a uniform solution. Next, a desulfurizing agent and a base are added to the solution, and stirring is continued at room temperature or under heating for several hours as necessary. The end of the reaction can be determined by using as a guide that the sulfide of the black metal usually precipitates and the reaction solution becomes transparent. Since the target substance is usually dissolved in a solution, an insoluble substance is separated by filtration and then poured into a large amount of water or a solvent is distilled off to obtain a crude product. The obtained crude product may be purified by recrystallization with an appropriate solvent such as isopropyl ether or ethyl acetate, or may be separated and purified by vacuum distillation, column chromatography or the like, if necessary.

Next, the compounds obtained by the present invention are shown below. (1) Compound (1)

Embedded image (2) Compound (2)

Embedded image (3) Compound (3)

Embedded image

[0010]

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples. In addition, 1, manufactured by the following example,
The 3-benzodioxan-4-one compound was identified based on the results of elemental analysis, nuclear magnetic resonance spectrum of hydrogen and carbon, and the result of infrared absorption spectrum measurement as main criteria. That is, in the nuclear magnetic resonance spectrum of the product, the structure of the compound and the number of hydrogen were confirmed from the chemical shift and the integrated value of each signal.
Absorption attributable to the OH stretching vibration derived from the salicylic acid compound as the raw material is not observed at m- ¹ or more, 1740c
A strong absorption attributed to C ＝ O stretching vibration was observed near m ⁻¹ , confirming the skeleton structure.

Further, the produced compounds (1) to (3)
Corresponds to the compounds (1) to (3) shown above, and their physical property values indicate the melting point (mp) and the solvent used for recrystallization in parentheses. Are shown in the order of nuclear magnetic resonance spectrum (H-NMR, C-NMR), infrared absorption spectrum (IR) and elemental analysis.

Example 1 Preparation of Compound (1) A solution of salicylic acid (166 mg), 4,4'-bis (dimethylamino) thiobenzophenone (284 mg) and triethylamine (360 mg) in acetonitrile (5 ml) was stirred while stirring. , Silver nitrate (420mg)
Was added little by little. After stirring at room temperature for 3 hours, the reaction solution from which insoluble silver sulfide was removed by filtration was developed on a silica gel column chromatography (developing solvent: ethyl acetate and hexane 1: 1).
1 mixture), and the target product was separated and recrystallized from isopropyl ether to obtain the compound (1).

Yield 280 mg (72%); mp 194 ° C.
(Methanol); H-NMR (ppm) 2.92 (12
H), 6.61 to 7.83 (12H); C-NMR (p
pm) 40.10, 108.58, 111.57, 11
5.29, 117.41, 122.41, 27.30,
128.10, 129.70, 136.16, 150.
74, 157.17, 162.35; IR (cm ^-1 ) 1
736, 1610, 1280, 1238, 1188. C ₂₄ H ₂₄ N ₂ Elementary analysis as O ₃ (%) measurements: C, 74.21; H, 6.23 ; N, 7.21. Calculated = C, 74.22; H, 6.23; N, 7, 19.

Example 2 Preparation of compound (2) In the same manner as in Example 1 except that 4,4'-dimethoxythiobenzophenone (258 mg) was used instead of 4,4'-bis (dimethylamino) thiobenzophenone. hand,
Compound (2) was obtained. Yield 246 mg (68%); mp 112 ° C (methanol); H-NMR (ppm) 3.77 (6H), 6.8
3-7.87 (12H); C-NMR (ppm)
21, 107.40, 113.78, 115.08, 1
17.44, 122.88, 128.32, 129.8
3,131.94,136.50,156.72,16
0.21, 161, 63; IR (cm ^-1 ) 1743,1
610, 1305, 1253, 1176. C ₂₂ H ₁₈ Elementary analysis as O ₅ (%) measurements: C, 72.92; H, 5.01 . Calculated value = C, 72.86; H, 5.00.

Example 3 Preparation of compound (3) The compound (3) was prepared in the same manner as in Example 1 except that xanthene-9-thione (212 mg) was used instead of 4,4'bis (dimethylamino) thiobenzophenone. 3) was obtained. Yield 256 mg (81%); mp 182 ° C (ethyl acetate-hexane); H-NMR (ppm) 6.86-8.1.
2 (12H); C-NMR (ppm) 98.85, 11
3.32, 117.21, 117.31, 120.1
8, 123.16, 123.60, 125.86, 12
9.60, 131.31, 137.14, 150.9
4,155.75,160.28; IR (cm ^-1 ) 17
41, 1460, 1300, 1236, 754. C ₂₀ H ₁₂ Elementary analysis as O ₄ (%) measurements: C, 75.94; H, 3.82 . Calculated: C, 76.02; H, 3.74.

[0016]

The desulfurization-condensation reaction in the present invention proceeds very easily under mild conditions, and the 1,3-benzodioxane-
A 4-one compound can be obtained with good yield. The salicylic acid compound as a raw material used in the present invention is a pharmacologically active substance, and 1,3-benzodioxane-4 obtained therefrom.
The -one compound is a similar pharmacological agent. The 1,3-benzodioxan-4-one compound obtained from the present invention is also a compound having a structure in which a hydroxyl group and a carboxyl group of a salicylic acid compound are simultaneously protected, and is easily hydrolyzed in the presence of an acid to form an original salicylic acid compound. Return to Therefore, the 1,3-benzodioxan-4-one compound of the present invention is
When this is taken into the human body, it returns to the salicylic acid compound by the action of gastric juice, and exhibits a pharmacological effect.

──────────────────────────────────────────────────続 き Continuation of front page (56) References Org. Chem. (1982), 47 (11), p. 2114-2117 (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 319/08 C07D 493/10 C07D 495/10 CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] [Claim 1] The following general formula (1) ( Wherein , R ¹ is hydrogen, or a chain or cyclic alkyl group,
Alkoxy group, dialkylamino group, acyl group, alcohol
Selected from xycarbonyl, halogen and nitro
And n represents an integer of 1 to 4, Ar ¹ and Ar ^{2 each} represent an aryl group, and Ar ¹ and Ar ² may be bonded to each other. Dioxane-
In a method for producing a 4-one compound, a compound represented by the following general formula (2): (Wherein R ¹ has the same meaning as described above) and a salicylic acid compound represented by the following general formula (3): (Wherein, Ar ¹ and Ar ² have the same meanings as described above), which is subjected to a desulfurization condensation reaction in the presence of a desulfurizing agent and a base. 2. The following general formula (1): ( Wherein , R ¹ is hydrogen, or a chain or cyclic alkyl group,
Alkoxy group, dialkylamino group, acyl group, alcohol
Selected from xycarbonyl, halogen and nitro
Indicates a substituent, n is an integer of 1 to 4, Ar ¹ and Ar ² represents an aryl group, 1,3-dioxane and Ar ¹ and Ar ² are represented by bound) - 4-one compounds. 3. The compound according to claim ² , wherein the conjugate of Ar ¹ and Ar ² is a condensed polycyclic group represented by the following general formula (4). Embedded image ( Wherein R ² and R ³ are hydrogen, or a chain or cyclic alkyl)
Group, alkoxy group, dialkylamino group, acyl group,
From alkoxycarbonyl group, halogen atom and nitro group
And m and p each represents an integer of 1 to 4; X represents -O-, -S-, -N (R)-(R: alkyl
Group), lower alkylene group, lower alkenylene group
And t represents 0 or 1.)