JP2701114B2 - Method for producing 3'-amino-2'-hydroxyacetophenone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the formula (I) useful as an intermediate for pharmaceuticals

[0002]

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The present invention relates to a method for producing 3'-amino-2'-hydroxyacetophenone hydrochloride represented by the formula:

[0004]

2. Description of the Related Art A compound represented by the formula (I) is useful as a therapeutic agent for various allergic diseases caused by leukotriene.

[0005]

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8- [4- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl)
It is an important intermediate for producing 4-oxo-4H-1-benzopyran. JP-A-61-50977 discloses a compound of the formula (B)

[0007]

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A method for producing a pharmaceutical product represented by the formula (A) using a compound represented by the following formula as a key intermediate is described.
Japanese Patent Application Laid-Open No. 3-95144 describes a method for producing a drug represented by the formula (A) using a compound represented by the formula (I) as a key intermediate. Until now, various methods have been proposed as methods for producing the intermediate represented by the formula (I). For example, JP-A-3-95144 proposes a method represented by the following reaction step formula [A]. Further, Japanese Patent Application Laid-Open No. 3-77852 discloses a method in which the step of catalytic reduction in the above reaction scheme [A] is performed in a two-phase system of water / organic solvent. Furthermore, the present inventors have proposed a separate synthesis method as shown in the following reaction scheme [B] in Japanese Patent Application No. 4-108449 (filed on April 2, 1992).

[0009]

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[0010]

[0011]

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[0012]

[0013]

Problems of the Prior Art The method represented by the reaction formula [A] is a method for producing the compound represented by the formula (I),
(1) Selective nitration is possible, (2) Separation by column chromatography is not required, and (3) Raw materials are cheaper than those of other routes. The manufacturing method is almost completed.

However, 4-chlorophenol (ie, in formula 1, when Xa represents a chloro group)
When the compound of the formula (I) is produced according to the reaction process formula [A] using the compound of formula (I) as a starting material, the yield of the last step of catalytic reduction is inferior to the case of using p-bromophenol as a starting material. There was found.

[0015]

Means for Solving the Problems The present inventors have found that 5'-chloro-3'-nitro-2 'in the reaction scheme [A].
The reaction conditions for the catalytic reduction of -hydroxyacetophenone [compound represented by formula (II)] were repeated. As a result, when reduction is started under normal conditions (neutral or acidic conditions), the reduction reaction of the nitro group tends to proceed more easily between the reduction reaction of the nitro group and the elimination reaction of the chloro group. It was found that the ions react with the hydrogen gas to generate hydrochloric acid, the pH of the reaction solution was inclined to the acidic side, and the elimination reaction of the chloro group became more difficult to proceed under acidic conditions.

Therefore, based on these findings, when the reduction reaction of the nitro group is completed, the pH after the reaction is returned to near neutral, the catalytic reduction reaction is continued, and the elimination of the chloro group is completed. Then, the present inventors have found that the desired compound represented by the formula (I) can be obtained in high yield, and completed the present invention. JP-A-3-95144 describes that the catalytic reduction can be carried out in the presence or absence of an acid, and JP-A-3-77852 also describes that the use of an acid accelerates the reaction. However, there is no description that the elimination reaction of the chloro group is accelerated under alkaline conditions. Furthermore, these facts were completely unexpected for the inventors.

[0017]

The present invention relates to a compound of the formula (II)

[0018]

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In the catalytic reduction reaction for reducing the nitro group and removing the chloro group of the compound represented by the following formula:
(I) at the beginning of the reaction, under neutral or acidic conditions,
(Ii) the formula (I) wherein the pH of the reaction solution is returned to around neutral when the reduction of the nitro group is almost completed, and the catalytic reduction reaction is carried out continuously.

[0020]

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The present invention relates to a method for producing the compound represented by In order to carry out the catalytic reduction of the present invention under neutral conditions, an inert solvent [for example, halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, hexachloroethane, etc.), ethers (tetrahydrofuran, tetrahydrofuran, etc.)] Pyran, dioxane, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, methyl ethyl ether, etc.), alcohols (methanol, ethanol, propanol, isopropanol, etc.), hydrocarbons (pentane, hexane, octane, cyclohexane, etc.), ketones ( Acetone, methyl ethyl ketone, phenyl methyl ketone, etc.), N, N-dimethylformamide (hereinafter abbreviated as DMF), acetic acid, ethyl acetate, or a mixed solvent of two or more thereof.
Medium, hydrogenation catalyst (for example, palladium carbon, palladium black, palladium, palladium chloride, palladium hydroxide,
In the presence of platinum dioxide, nickel, Raney nickel, etc.)
The reaction is carried out at 0 ° C. to 50 ° C., preferably at room temperature, in hydrogen gas at normal pressure or under pressure.

In order to carry out the reaction under acidic conditions, an inorganic acid (eg, hydrochloric acid, sulfuric acid, etc.) or an organic acid (eg, acetic acid, p-
The above reduction reaction may proceed in the presence of toluenesulfonic acid, formic acid, etc.). When performed under acidic conditions, the reduction reaction of the nitro group is promoted. Completion of the reduction reaction of the nitro group can be confirmed by thin layer chromatography or the like. When the reduction reaction of the nitro group is almost completed, the pH of the reaction solution is returned to around neutral (pH 6 to 8). Neutralization of the reaction solution is performed by using a hydroxide, carbonate, hydrogencarbonate or acetate of an alkali metal or alkaline earth metal (for example, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium acetate, etc.) or an organic amine ( Triethylamine, etc.).

The compound represented by the formula (II) is disclosed in
It can be produced by the method described in -95144.

[0024]

The method of the present invention is an industrially superior method that can obtain the target compound in good yield without isolating the product on the way and without changing the solvent or catalyst (can be performed in one batch). It is.

[0025]

EXAMPLES The present invention will now be described in detail with reference to Examples and Examples, but the present invention is not limited thereto. Reference Example 1 4-chlorophenyl acetate

[0026]

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Concentrated sulfuric acid (0.05m) in acetic anhydride (11.3ml)
1) and stirred at 25 ° C. To this was slowly added p-chlorophenol (12.856 g). It generated a little heat, but was stirred for 3 hours. Then n
-Hexane (50 ml) was added for dilution, and water (50 m
Washed twice in l). After drying over anhydrous magnesium sulfate and concentrating, the title compound having the following physical data (16.96 g)
Was obtained as a crude product. TLC: Rf 0.46 (benzene). Reference Example 2 2'-hydroxy-5 'chloroacetophenone

[0028]

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In a reaction vessel equipped with a calcium chloride tube, o-
Dichlorobenzene (40 ml) and aluminum chloride (2
0 g), and the mixture was stirred and heated to 130 ° C. The acetate body (16.96 g produced in Reference Example 1) was slowly added dropwise thereto. After the addition, the mixture was further reacted at 130 ° C. for 1 hour, and then allowed to cool. Next, the reaction solution was concentrated hydrochloric acid (20 m
1) and transferred to ice (80 ml) with stirring, and extracted with methylene chloride (40 ml). The aqueous layer was further extracted by adding 2N hydrochloric acid (40 ml) and methylene chloride (40 ml). Next, the organic layers were combined and 2N hydrochloric acid (40
ml) and water (40 ml), dried over anhydrous magnesium sulfate and concentrated. Methanol (20 ml) was added to the obtained crude product, the mixture was stirred, seed crystals were added, and the mixture was cooled to precipitate crystals. The title compound (5.76
g) was obtained. Further, ethanol (10 ml) was added to the mother liquor, stirred, seed crystals were added, and the mixture was cooled to obtain the title compound (3.65 g) as secondary crystals. The title compound had the following physical data. TLC: Rf 0.65 (benzene) NMR (CDCl 3) 200 MHz δ 12.14 (s, H), 7.69 (d, H, J = 2.4 Hz), 7.42
(Dd, H, J = 9, 2.4 Hz) 6.94 (d, H, J = 9H
z), 2.63 (s, 3H) Reference Example 3 5'-chloro-3'-nitro-2'-hydroxylacetophenone

[0030]

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A reaction vessel equipped with a calcium chloride tube was charged with a solution (5 ml) of an acetophenone compound (1.706 g prepared in Reference Example 2) in dichloroethane, and methanesulfonic acid (1 ml) was added thereto, and the mixture was stirred at 0 ° C. And cooled.
Next, concentrated nitric acid (1.5 ml) was slowly added. 30
After stirring for minutes, n-hexane (10 ml) was added and the mixture was stirred, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound (1.70 g) having the following physical data. TLC: Rf 0.30 (benzene) NMR (CDCl 3) 200 MHz δ 12.84 (s, H), 8.19 (d, H, J = 2.6 Hz), 8.01
(D, H, J = 2.6 Hz) 2.73 (s, 3H) Example 1 3'-amino-2'-hydroxyacetophenone hydrochloride

[0032]

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A solution of a chloronitrophenol compound (216 mg produced in Reference Example 3) in isopropanol (3.5 m
5) palladium on carbon (10 mg)
For 3 hours under a hydrogen atmosphere. After confirming disappearance of the spot of the raw material by TLC, sodium acetate trihydrate (204 mg) was added, and the mixture was further stirred under a hydrogen atmosphere for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered off, and concentrated hydrochloric acid was added to the filtrate to precipitate crystals.
The crystals were collected by filtration and washed with ethyl acetate to give the title compound (170 mg) having the following physical data. TLC: Rf0.55 (n-hexane: ethyl acetate = 1:
1) NMR (CD3OD) 200 MHz δ 8.05 (dd, H, J = 8, 1.5 Hz), 7.63 (dd, H, J
= 8,1.5 Hz), 7.11 (dd, H, J = 8.8 Hz), 2.7
1 (s, 3H)

Claims (1)

(57) [Claims] 1. A compound of the formula (II) In the catalytic reduction reaction for the reduction of the nitro group and the elimination of the chloro group of the compound represented by the formula (i), the reaction is carried out under neutral or acidic conditions at the start of the reaction, and (ii) the reduction of the nitro group is almost completed. At the time of the reaction, the pH of the reaction solution is returned to around neutral, and the catalytic reduction reaction is carried out continuously. A method for producing a compound represented by the formula: