JPH01224344A - Production of 2,6-dihydroxyacetophenone - Google Patents

Abstract

PURPOSE:To obtain the subject compound which is an intermediate raw material for medicines, such as antitussive and expectorant, in high yield at a low cost in a few steps, by acetylating the 2-position of a compound prepared by hydrogenating resorcin and subsequently dehydrogenating the resultant compound. CONSTITUTION:Resorcin is used as a raw material, hydrogenated in the presence of, e.g., Raney nickel catalyst, and converted into 1,3-cyclohexanedione. The 2-position of the resultant 1,3-cyclohexanedione is subsequently reacted with acetic anhydride, acetylated in the presence of, e.g., sodium acetate, and converted into 2-acetyl-1,3-cyclohexanedione, which is then directly dehydrogenated to afford the aimed compound. The dehydrogenating reaction is carried out by using a method for dehydrogenation in the presence of a catalyst while removing the formed hydrogen to the outside of the system or with a dehydrogenating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel method for producing 2,6-dihydroxyacetophenone.

[Conventional technology]

2.6-Dihydroxyacetophenone is useful as an intermediate raw material for pharmaceuticals such as antitussive expectorants. Various methods for producing 2,6-dihydroxyacetophenone are known, including a method via 4-methyl-7-hydroxycoumarin obtained by the reaction of resorcin and ethyl acetoacetate [Organic Synthesis Collective Volume (Org.

5yntheses Co11. Vol.), 3 volumes,
281 pages, 1955], via methyl β-resorcate [Journal of the Indian Chemical Society (J, Jnd, Chew,
Soc, ), vol. 28, p. 245, 1951], 2
- Method for aromatizing acetyl-2-chloro-1,3-cyclohexanedione [Tetrahedron (Tetrah)
edron), Volume 29, Page 3857, 1973].

[Problem to be solved by the invention]

All of these conventional methods have drawbacks such as long steps and insufficient yields. Furthermore, in the method of directly acetylating resorcinol in the presence of anhydrous aluminum chloride, the yield of 2,6-dihydroxyacetophenone is 1.
% or less.

The purpose of the present invention is to solve the above-mentioned conventional problems by producing 2,6-dihydroxyacetophenone, which is useful as an intermediate raw material for pharmaceuticals, and which can produce 2,6-dihydroxyacetophenone with a high yield in a small number of steps. The purpose of this invention is to propose a method for producing acetophenone.

[Means to solve the problem]

The present invention comprises a step of hydrogenating resorcinol to convert it into 1,3-cyclohexanedione [hereinafter referred to as compound (A)], and acetylating the 2-position of the obtained compound (A) to 2-cyclohexanedione.
-acetyl-1,3-cyclohexanedione (hereinafter referred to as compound (B))] and directly dehydrogenating the obtained compound CB).

The starting material of the present invention is resorcinol, and the route for producing the target product from it is as shown in the following formula.

Resorcinol Compound (A) Compound (B
) Compound (A) can be obtained by hydrogenating resorcinol. For example, a method of hydrogenating the monosodium salt of resorcinol in the presence of a Raney nickel catalyst [
Organic Synthesis Collective Volume (Org, 5yntheses Co11°Vol,
), Vol. 3, p. 278, 1955], compound (A) can be obtained in high yield.

Compound (B) can be obtained by acetylating the 2-position of compound (A). For example, a method of reacting compound (A) with acetic anhydride in the presence of sodium acetate (anhydrous) [Journal of the Chemical Society (J, Chem, Sac,), 1953, 803
Page], compound (B) can be produced.

The target compound, 2,6-dihydroxyacetophenone, can be obtained by directly dehydrogenating compound (B). The dehydrogenation reaction proceeds in the presence of a catalyst by dehydrogenating the generated hydrogen while removing it from the reaction system, or by dehydrogenating with a dehydrogenating agent, with a good yield of <2.6.
-Dihydroxyacetophenone can be produced.

In the case of a method using a catalyst, the catalyst is Ni or Rh.

Catalysts containing Group I metals such as Pd and Ir can be used. The Group (1) metals mentioned above can be used alone or in combination. In addition, the above-mentioned catalysts containing Group Ⅰ metals can be used alone, but usually,
It is used by supporting it on a carrier.

Examples of the carrier include activated carbon, γ-alumina, titania, silica-alumina, zeolite, magnesia, and the like. These carriers can be used alone or in combination.

When a carrier is used, the content of the Group Ⅰ metal in the catalyst is usually 0.01 to 15% by weight, preferably 0.
．． It is 5-10%.

Among the group (I) metal-support combinations, palladium-activated carbon and rhodium-alumina are particularly preferred since they provide a high yield of the target product, 2,6-dihydroxyacetophenone.

The amount of the catalyst used in the present invention is usually 0.01 to 1 part by weight, preferably 0.05 to 0 parts by weight, per 1 part by weight of compound (B).
．． It is a five-layered scene.

In addition to the method using the above catalyst, the dehydrogenation reaction can also be performed using sulfur,
It can also be carried out using a dehydrogenating agent that reacts with hydrogen, such as selenium. In this case, it is not necessary to use a catalyst, and the amount of the dehydrogenating agent used is generally 1 to 10 mol, preferably 1.1 to 3 mol, per 1 mol of compound (B).

In any of the above cases, the dehydrogenation reaction is usually carried out in the presence of a solvent. Examples of the solvent include tetraethylene glycol dimethyl ether, triethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol motumethyl ether, diphenyl ether, polyethylene glycol, and 1-octatool.

The dehydrogenation reaction is performed while removing generated hydrogen from the reaction system. Compound (B) is easily reduced with hydrogen, for example, in the presence of a 30% by weight palladium-activated carbon catalyst at normal temperature and pressure to form 2-acetylcyclohexanone and a small amount of 2-ethyl-1,3-cyclohexanedione. It is known that [Journal of the Chemical Society (J.

Chem, Soc, ), 1953, 803 pages]
, while removing the generated hydrogen from the reaction system together with 2-propertool vapor and/or nitrogen, or α
- It is preferable to dehydrogenate while capturing hydrogen generated with a hydrogen acceptor such as methylstyrene.

Among these, a method in which generated hydrogen is removed from the reaction system together with 2-propanol vapor and/or nitrogen is particularly preferred. The method of adding a hydrogen acceptor is applied when using a catalyst.

The temperature of the dehydrogenation reaction is usually 100 to 250°C, and the reaction time is usually 0.5 to 20 hours. When using a catalyst, the reaction may be performed at a relatively low temperature, and when using a dehydrogenating agent, the reaction may be performed at a relatively high temperature. In the dehydrogenation reaction, the compound (B) may be charged into the reactor in advance, or may be dissolved in 2-propanol or the like and appropriately fed to the reactor.

The 2,6-dihydroxyacetophenone thus produced can be purified by conventional means such as recrystallization and distillation.

〔Effect of the invention〕

According to the present invention, the steps are short and the yield of each step is high, so the target compound can be produced at low cost.

〔Example〕

The method of the present invention will be explained in more detail below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. In each example, percentages are weighted percentages unless otherwise noted.

Example 1 (1) 22.0 g (0.2 mol) of resorcin, 9.6 g (0.24 mol) of sodium hydroxide, 40 rnQ water and 4.0 g of Raney nickel were placed in a 200+oQ autoclave, and the mixture was heated to 80 kg/dG with hydrogen. 1 at 50℃
Stirred for 0 hours. After cooling, the pressure was removed and the catalyst was removed by filtration, and the catalyst was thoroughly washed with a 10% aqueous sodium hydroxide solution. The filtrate and washing liquid were combined, adjusted to pH 3 with 36% hydrochloric acid, and extracted with ether. The ether solution was dried over sodium sulfate (anhydrous), filtered, and the filtrate was concentrated. The residue was recrystallized from toluene and removed toluene in a vacuum dryer, resulting in a melting point of 103~
Crystals (1,3-cyclohexanedione) at 104°C 20
．． 4 g (yield 91.0%) was obtained.

(2) 11.2 g (0.1 mol) of 1,3-cyclohexanedione obtained in (1) above, 20.5 g (0.1 mol) of acetic anhydride (
0.2 mol) and sodium acetate (anhydrous) 1.64
g (0.02 mol) was heated under reflux at 125° C. for 7 hours. After cooling, add 2.03 g of 36% hydrochloric acid to the reaction mixture.
(0.02 mol) was added to neutralize the mixture, excess acetic anhydride and the acetic acid produced were distilled off using an evaporator, and the residue was distilled under reduced pressure.
13.3 g of Hg fraction was obtained. 10% PEG 20
According to gas chromatography analysis using an M-Chromosorb WAlil 0MCS column (manufactured by Gascro Industries Co., Ltd., trade name), the purity of 2-acetyl-1,3-cyclohexanedione was 95.0%, and the purity of 3-acetoxy-2-
It was found that it contained 3% cyclohexenone.

In order to remove by-products, ether and a saturated aqueous sodium carbonate solution were added to the distillate to separate the layers, the aqueous layer was neutralized with 10% hydrochloric acid, extracted with ether, dried, and distilled under reduced pressure after distilling off the ether. 2-acetyl-1 with 99.9% purity
, 12.34 g of 3-cyclohexanedione (yield: 80.
0 mol%) was obtained.

(3) Add 1.54 g of 2-acetyl-1,3-cyclohexanedione obtained in (2) above to a mixture of 0.10 g of 5% palladium-activated carbon and 10.0 g of tetraethylene glycol dimethyl ether at 185°C.
0.01 mol) of 2-propatool (Log) solution at 1
It dripped over time. After the dropwise addition was completed, the mixture was further heated to 185° C. for 5 hours while blowing nitrogen gas. After cooling, the reaction mixture was filtered to remove the catalyst, and the catalyst was thoroughly washed with diethyl ether. The filtrate and washing liquid were combined, the diethyl ether solution was extracted with water to remove tetraethylene glycol dimethyl ether, and the diethyl ether solution was dried over sodium sulfate (anhydrous). Sodium sulfate was filtered off, diethyl ether was distilled off, and the residue was recrystallized from toluene to give pale yellow crystals 1, 2 with a melting point of 157-158°C.
9g was obtained.

3%5ilicon 0V-17Chromosorb
According to gas chromatography analysis using a WAV 0MCS column (manufactured by Gas Kuro Kogyo Co., Ltd., trade name), the purity of 2,6-dihydroxyacetophenone was 99.7%, and the yield was 8.
It was 4.6 mol%.

Example 2 Example 1 (2) into a mixture consisting of 0.10 g of 5% palladium-activated carbon, 1.30 g (0.011 mol) of α-methylstyrene and 10.0 g of triethylene glycol dimethyl ether at 185°C. 1.54 g of 2-acetyl-1°3-cyclohexanedione (0,
A solution of 2-propanol (01 mol) was added dropwise over 1 hour. After the dropwise addition was completed, the mixture was further heated to 185° C. for 5 hours. After treatment in the same manner as in Example 1 (3), the purity was 99.5%.
1.25 g (yield: 81.8 mol%) of 2,6-dihydroxyacetophenone was obtained.

Comparative Example 5.5 g (0.05 mol) of Lusorcin and. - 7.0 g (0,0525 mol) of anhydrous aluminum chloride was added to a mixture consisting of 50 g of dichlorobenzene, and the mixture was stirred at 80° C. for 2 hours. To this, 4.71 g of acetyl chloride (0.06
mol) was added dropwise and heated at 80°C for 30 minutes and at 150°C for 30 minutes. After cooling, the reaction mixture was added with ether and 10
% hydrochloric acid was added for hydrolysis, and the mixture was separated. The ether solution was washed with water, dried, concentrated, and subjected to gas chromatography analysis. As a result, it was found that the conversion rate of resorcin was 66 mol% and the yield of 2,6-dihydroxyacetophenone was 0.3 mol%.

The main product was 2,4-dihydroxyacetophenone (yield 49 mol%).

Comparative Example 2 In Comparative Example 1, the amount of anhydrous aluminum chloride was 14.0
When the reaction was carried out in the same manner as in Comparative Example 1 except that the amount was changed to g (0,105 mol), the resorcin conversion rate was 70 mol%,
The yield of 2,6-dihydroxyacetophenone was 0.9 mol%, and the yield of 2,4-dihydroxyacetophenone, the main product, was 57 mol%.

Agent: Patent Attorney W. Hara

Claims (1)

[Claims] (1) A step of hydrogenating resorcin to convert it into 1,3-cyclohexanedione, acetylating the 2-position of the obtained 1,3-cyclohexanedione to 2-acetyl-1,
A method for producing 2,6-dihydroxyacetophenone, comprising a step of converting it into 3-cyclohexanedione, and a step of directly dehydrogenating the obtained 2-acetyl-1,3-cyclohexanedione.