JPH05279305A - Production of 3'-amino-2'-hydroxyacetophenone - Google Patents

Abstract

PURPOSE:To obtain 3'-amino-2'-hydroxyacetophenone useful as an intermediate for pharmaceuticals with decreased number of steps in high selectivity at a low cost without necessitating the purification by column chromatography. CONSTITUTION:The objective compound of formula I or its acid addition salt useful as an intermediate for the compound of formula IV (agent for the treatment of allergic diseases caused by leucotriene) is produced on an industrial scale at a low cost by acetylating a compound of formula III (X is halogen, preferably Cl) or its acid addition salt with an acetylation agent (e.g. acetic anhydride or acetyl chloride) in the presence of e.g. an inert organic solvent or without using a solvent preferably under anhydrous condition at a temperature between room temperature and the refluxing temperature in the presence of a catalyst, treating the acetylated product with an acid, optionally converting the product to an acid addition salt to obtain a compound of formula II, subjecting the compound to hydrogenative decomposition in hydrogen atmosphere with a weak alkali in the presence of a catalyst in e.g. an inert solvent in the presence or absence of water at 0-200 deg.C and, as necessary, converting the product into an acid addition salt.

Description

Detailed Description of the Invention

[0001]

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

[Chemical 4] (In the formula, X represents a halogen atom) 3 '.
-Amino-2'-hydroxyacetophenone and a method for producing an acid addition salt thereof.

[0002]

The compound represented by the formula (I) is useful as a therapeutic agent for various allergic diseases caused by leukotrienes.

[Chemical 5] Is an important intermediate for the preparation of 8- [4- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran.

JP-A-62-50977 discloses that a drug represented by the formula (IV) is produced by the following reaction process formula 1.

[0004]

[Chemical 6]

[0005]

[Chemical 7]

The compound represented by the formula 1 has hitherto been produced by a conventional method according to the following reaction process formula 2.

[0007]

[Chemical 8]

Further, in JP-A-3-95144, 3'-amino-2'-hydroxyacetophenone represented by the formula (I) is produced by the routes shown in the following reaction process formulas 3, 4 and 4A. Is disclosed.

[0009]

[Chemical 9] (In the formula, X ^a represents ^a halogen atom.)

[0010]

[Chemical 10]

[0011]

[Chemical 11]

Further, Japanese Patent Application Laid-Open No. 3-77852 discloses that water /
3 ′ of formula (I) in reduction with an organic solvent two-phase system
A method of making -amino-2'-hydroxyacetophenone is disclosed.

[0013]

[Chemical formula 12] (In the formula, X ^a represents ^a halogen atom.)

[0014]

However, none of the methods can be said to be satisfactory in terms of labor, time and cost as an industrial manufacturing method. First, the methods of reaction schemes 2 and 4 have the drawback that the nitration occurs at both the ortho and para positions, resulting in a very poor yield of the required compound 1 . Further, it is difficult to separate the compounds 1 and 1 ', and there is a drawback that they can be separated only by a column chromatography method which is not preferable as an industrial production method. Reaction process formulas 3 and 5
The method (1) does not have the above-mentioned drawbacks, but has the drawback that the number of steps is complicated and the compound 9 as a raw material is expensive.

[0015]

DISCLOSURE OF THE INVENTION The inventors of the present invention have developed an industrial 3'-amino-2'-hydroxyacetophenone which can obtain only the required ortho compound, has a small number of steps, and has a low production cost. As a result of repeated studies on the production method, it was found that the objective was achieved by the route shown in the following reaction process formula A, and the present invention was completed.

[0016]

[Chemical 13] (In the formula, X represents a halogen atom.)

According to the method of the present invention, the formula (III) to the formula (I
Acetylation to I) occurs only at the ortho position, and the number of steps is two, and the yield is good. It is also the most cost effective method compared to the conventional method. Furthermore, when the acid addition salt is produced, it is isolated in the form of crystals, so that separation and purification by column chromatography becomes unnecessary. The 3'-amino-2'-hydroxyacetophenone produced by the present invention is disclosed in JP-A-3-95144.
The compound represented by the formula (IV), which is useful as a medicine, is obtained by the method represented by the reaction scheme 5 in the specification.

[0018]

The present invention has the formula (III)

[0019]

[Chemical 14] (In the formula, X represents a halogen atom.)

A compound represented by: or an acid addition salt thereof,
Acetylation reaction, acid treatment, conversion to acid addition salt if necessary, formula (II)

[0021]

[Chemical 15] (In the formula, X represents a halogen atom.)

A compound represented by the formula (I) is characterized in that the compound represented by

[0023]

[Chemical 16] (In the formula, X represents a halogen atom.)

The present invention relates to a method for producing 3'-amino-2'-hydroxyacetophenone or an acid addition salt thereof represented by: Examples of the halogen atom represented by X include a fluorine, chlorine, bromine and iodine atom, but a chlorine atom is preferable.

Explaining the present invention in detail, the acetylation reaction of the compound represented by the formula (III) can be carried out, for example, by using an inert organic solvent [halogenated hydrocarbon (chlorobenzene, dichlorobenzene, trichlorobenzene, tetrachlorobenzene, tetrachlorobenzene, tetrachloride Carbon, tetrachloroethane, methylene chloride, etc.), nitrobenzene carbon disulfide, etc.] or without solvent (aluminum chloride, aluminum bromide, tin tetrachloride, ferric chloride, boron trichloride, phosphorus pentachloride, trifluoride) Boron chloride, zinc chloride, titanium tetrachloride, etc.) in the presence of acetic anhydride or an acetylating agent such as acetyl chloride at room temperature to reflux temperature. This reaction is preferably carried out under anhydrous conditions, and may be carried out under an atmosphere of argon or nitrogen.

The compound represented by the formula (II) can be obtained by treating the compound obtained by the above acetylation reaction with an acid. The acid treatment is carried out with an organic solvent miscible with water [ether type (tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc.), alcohol type (methanol, ethanol, 2-propanol). Etc.), a ketone system (acetone, methyl ethyl ketone, phenyl methyl ketone, etc.), a nitrile system (acetonitrile, etc.), and the like in the presence of an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, etc.).

The hydrogenolysis reaction of the compound represented by the formula (II) is carried out by, for example, insoluble organic solvent [ether system (tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc. ),
Alcohol type (methanol, ethanol, 2-propanol etc.), hydrocarbon type (pentane, hexane, isooctane, cyclohexane etc.), benzene type (benzene, toluene, xylene etc.), ketone type (acetone, methyl ethyl ketone, phenyl methyl ketone etc.) , Nitriles (acetonitrile, etc.), amides (hexamethylenephosphoramide, dimethylformamide, dimethylimidazolidinone, etc.), acetic acid, ethyl acetate, etc.] in a hydrogen atmosphere (normal pressure or pressure) with or without water. Pressure) in the presence of a catalyst (palladium black, palladium carbon, palladium, palladium dioxide, palladium hydroxide, platinum black, nickel, Raney-nickel, etc.), a weak alkali (sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, etc.). )
Is carried out at a temperature of 0 to 200 ° C.

In the present invention, the compounds represented by the formula (II) and the formula (I) can be produced in the form of acid addition salts. The acid addition salt facilitates recrystallization and facilitates purification and storage. Each compound can be converted into its acid addition salt by adding an excess amount of the corresponding hydrohalic acid in an organic solvent miscible with water [the same as above], or by concentrating the resulting precipitate by filtration. Done.

The solvent used in each reaction of the present invention may be used alone or, if necessary, may be used as a mixed solvent of two or more kinds. The product of each reaction may be subjected to isolation, washing, drying, and purification in each step before being subjected to the next reaction, or these operations may not be performed at all or only necessary operations may be performed. You may proceed to the next step.

[0030]

EFFECTS OF THE INVENTION The method for producing a compound represented by the formula (I) according to the present invention comprises: (1) the desired compound being selectively obtained, (2) a small number of steps, (3) a column It is an industrially superior method in that it does not require purification by chromatography, and (4) the manufacturing cost is low.

[0031]

The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Example 1 Synthesis of 3'-amino-5'-chloro-2'-hydroxyacetophenone hydrochloride

[Chemical 17]

Aluminum chloride (6.67 g) was added to 1, 2,
Add to room temperature with stirring in 4-trichlorobenzene (10 ml). The reaction mixture was heated to 120 ° C. 2-amino-4-chlorophenol hydrochloride (1.80
g) was added to the above suspension. Used to wash the vessel with 1,2,3-trichlorobenzene (5 ml). Acetic anhydride (2.0 ml) was added dropwise to this suspension over 20 minutes. These mixtures were stirred at 120 ° C. for 1 hour 30 minutes. The mixture was cooled to about 100 ° C. and poured into a mixture of concentrated hydrochloric acid and water. The product was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid and concentrated. 2N hydrochloric acid was added to a 2-propanol solution of the residue, and the mixture was heated under reflux for 6 hours. The solution cooled to room temperature was concentrated under reduced pressure to remove 2-propanol and water to obtain crystals. Ethyl acetate was added to the residue and suction filtration was performed to collect crystals. The crystals were washed with ethyl acetate and dried under reduced pressure to give the title compound (1.75 g) having the following physical data. Yield 79%. TLC (free amine form): Rf 0.71 (hexane: ethyl acetate = 1: 1); IR (KBr): ν 2839, 1646, 1455, 1293, 1258c
m ^-1 .

Example 2 Synthesis of 3'-amino-2'-hydroxyacetophenone hydrochloride

[Chemical 18]

The compound (1.11 g) synthesized in Example 1 was treated with 2-propanol (15 m) at 25 ° C. under a hydrogen atmosphere at atmospheric pressure.
In l), hydrogenolysis was carried out for 5 hours using palladium-carbon (56 mg, 5%) and sodium acetate trihydrate (1.70 g). After the reaction was completed, the solid was removed by filtration.
The filtrate was adjusted to acidic with concentrated hydrochloric acid (0.45 ml) to precipitate crystals. The crystals were collected by filtration, washed with 2-propanol and dried under reduced pressure to give the title compound (7
20 mg) was obtained. Secondary crystals from the filtrate (160m
g) was obtained. Yield 94%. TLC (free amine form): Rf 0.61 (hexane: ethyl acetate = 1: 1); IR (KBr): ν 2835, 1648, 1447, 1295, 783 c
m ^-1 .

Claims (1)

[Claims] 1. Formula (III): The compound represented by the formula (wherein X represents a halogen atom) or an acid addition salt thereof is subjected to an acetylation reaction and subjected to an acid treatment, and if necessary, converted to an acid addition salt. 2] (Wherein X represents a halogen atom), and the compound is subjected to a hydrogenolysis reaction,
If necessary, the compound of formula (I) is characterized in that it is converted into an acid addition salt. (In the formula, X represents a halogen atom) 3 '.
-A method for producing amino-2'-hydroxyacetophenone or an acid addition salt thereof.