JPH05125072A - Production of 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4h-1-benzopyran-4-one derivative or its salt - Google Patents

Abstract

PURPOSE:To industrially obtain the subject compound useful as an antiinflammatory agent, etc., in a high yield by reacting a specific benzene derivative with a halogenating agent, aminating the obtained compound, reacting the aminated compound with a specific compound and subsequently cyclizing the obtained compound. CONSTITUTION:A benzene derivative of formula I [R<1> is (halogenated) phenyl; R<2> is lower alkyl] is reacted with a halogenating agent, and the obtained compound of formula II (X is halogen) is subjected to am aminatination reaction comprising reaction with hexamethylene tetramine and hydrolysis of the reactional product. The obtained compound salt of formula III is reacted with a compound of formula IV [R<3> 1s (halogen-substituted)acyl] or its reactive derivative, and the produced compound of formula V or its salt is cyclized in the presence of a cyclization condensation agent such as N,N- dimethylformamide dimethylacetal to obtain the objective compound of formula V1.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for industrially producing a 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one derivative or a salt thereof which is useful as an anti-inflammatory agent. Regarding

[0002]

2. Description of the Related Art A method for producing a 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one derivative or a salt thereof useful as an anti-inflammatory agent is disclosed in JP-A-2-49778. It is disclosed in the official gazette. However, the various methods described in the publication are not sufficient as an industrial production method of a compound in which an acylamino group is introduced at the 3-position of 4H-1-benzopyran-4-one, including a step of low yield. It was Also, among those methods,
A method for obtaining the above target compound by subjecting an intermediate, N-acylaminomethyl = 2-hydroxy-4-lower alkylsulfonylamino-5-phenoxyphenyl = ketone, to a cyclization reaction is described.

[0003]

Under such circumstances, 3
It has been desired to develop an industrial production method for obtaining an -acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one derivative or a salt thereof in a high yield.

[0004]

The inventors of the present invention have disclosed in
Among the manufacturing methods disclosed in Japanese Patent Publication No. 49778, the general formula [5]

[Chemical 7] [In the formula, R ¹ represents a phenyl group which may be substituted with a halogen atom; R ² represents a lower alkyl group; and R ³ represents an acyl group which may be substituted with a halogen atom. The compound represented by the formula or a salt thereof is subjected to a ring-forming reaction to give the desired compound of the general formula [6]

[Chemical 8] 3-Acylamino-6-represented by "wherein R ¹ , R ² and R ³ have the same meanings as described above."
Phenyloxy-7-alkylsulfonylamino-4H
The method for obtaining the -1-benzopyran-4-one derivative or its salt is considered to be an industrially advantageous method, and various methods for producing the compound of the general formula [5] or its salt were investigated.

As a result,

[Formula 1] “In the formula, X represents a halogen atom; R ¹ , R ² and R
Each ³ has the same meaning as described above. The compound of the general formula [5] or a salt thereof can be obtained in a high yield by the method represented by the formula [10], and the obtained compound of the general formula [5] or a salt thereof is subjected to a ring forming reaction known per se The present invention found that a 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one derivative or a salt thereof can be industrially advantageously produced in high yield. Was completed.

The present invention will be described in detail below. In the present specification, unless otherwise specified, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and the lower alkyl group means, for example, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, te
rt- butyl and C ₁ ~ ₅ alkyl group such as pentyl;
The acyl group refers to, for example, formyl or acetyl, a C ₂ ~ ₈ alkanoyl groups such as propionyl and butyryl, respectively.

The present invention is shown by the following manufacturing routes.

[Formula 2] "In the formula, R ¹ , R ² , R ³ and X have the same meanings as described above."

The salt of the compound of the general formula [3] includes salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with carboxylic acids such as oxalic acid; salts with sulfonic acids such as p-toluenesulfonic acid. Is mentioned. The salts of the compounds of the general formulas [5] and [6] include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; amines such as triethylamine and pyridine. And a salt with an amino acid such as lysine and arginine.

Next, the present invention will be described in detail according to the above manufacturing route. (1) The compound of general formula [2] can be obtained by reacting the compound of general formula [1] with a halogenating agent in a solvent. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane. ;; and ethers such as dioxane, etc., which may be appropriately mixed and used. Examples of the halogenating agent used in this reaction include chlorine, bromine, sulfuryl chloride, pyridinium hydrobromide perbromide and benzyltrimethylammonium tribromide. This reaction is preferably carried out in the presence of a hydrogen halide gas such as hydrogen chloride and hydrogen bromide. The amount of the halogenating agent used is 0.1 to 3 with respect to the compound of the general formula [1].
It is 0 times the mole. The reaction temperature and reaction time of this reaction are usually from -20 to 40 ° C and from 0.5 to 10 hours. The compound of the general formula [1] may be produced, for example, by the method described in JP-A-2-49778.

(2) The compound of the general formula [3] can be obtained by subjecting the compound of the general formula [2] to an amination reaction. As the amination reaction, the compound of the general formula [2] is reacted with, for example, a) hexamethylenetetramine and then hydrolyzed. B) After reacting with an azide reagent such as sodium azide, There are various amination reactions such as reduction, c) reaction with an alkali metal salt of imide such as potassium salt of phthalimide, followed by hydrolysis, and d) reaction with ammonia gas. Of these, an amination reaction in which hydrolysis is carried out after the reaction with hexamethylenetetramine of a) is particularly preferable is preferable, and this reaction will be specifically described below.

This reaction is carried out in a solvent. The solvent used is not particularly limited as long as it does not adversely influence the reaction, but for example, halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane;
Examples thereof include ethers such as dioxane; ketones such as acetone; esters such as ethyl acetate; and nitrites such as acetonitrile, which may be used in an appropriate mixture. The amount of hexamethylenetetramine used is 0.9 to 1.3 times the mol of the compound of the general formula [2]. The reaction temperature and reaction time for this reaction are usually 20
At ~ 40 ° C, 0.5 to 24 hours. In carrying out this reaction, sodium iodide, potassium iodide, or the like may be added as a reaction accelerator, and the addition amount is 0.1 to 1.5 times the mol of the compound of the general formula [2]. Then, hydrolysis is carried out in the presence of an acid to obtain a salt of the compound of general formula [3]. Examples of the acid used for this hydrolysis include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid; organic carboxylic acids such as oxalic acid. Can be mentioned. The reaction temperature and reaction time for this hydrolysis are usually 10 to 50 ° C. and 1 to 24 hours. The obtained salt of the compound of the general formula [3] may be converted into another salt of the compound of the general formula [3] with another acid.

(3) by reacting a salt of the compound of general formula [3] with a compound of general formula [4] or a reactive derivative thereof in a solvent in the presence or absence of a deoxidizing agent,
A compound of the general formula [5] or a salt thereof can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; ethers such as dioxane; Examples thereof include ketones such as acetone; esters such as ethyl acetate; nitriles such as acetonitrile; and water, which may be appropriately mixed and used. Specific examples of the compound of the general formula [4] include carboxylic acids such as formic acid, acetic acid, propionic acid and butyric acid. In addition, examples of the reactive derivative of the compound of the general formula [4] include active ester, acid chloride, active acid amide, acid anhydride and mixed acid anhydride, and specifically, for example, ethyl formate. , Acetic anhydride, acetyl chloride, propionyl chloride, mixed acid anhydride of formic acid and acetic acid,
Examples thereof include mixed acid anhydrides of formic acid and methanesulfonic acid. The amount of the compound of the general formula [4] or its reactive derivative used is 1 to 5 times mol of the salt of the compound of the general formula [3]. The reaction temperature and reaction time of this reaction are usually from -30 to 30 ° C and from 0.5 to 10 hours. In this reaction, as a deoxidizing agent optionally used, for example, organic bases such as triethylamine and pyridine;
Carbonates such as potassium carbonate and sodium hydrogen carbonate; salts of carboxylic acids such as sodium formate and sodium acetate; and alkali hydroxides such as sodium hydroxide and potassium hydroxide. The amount of the deoxidizer used is 1 to 1.5 times the mol of the salt of the compound of the general formula [4].

(4) The compound of the general formula [6] or a salt thereof can be obtained by subjecting the compound of the general formula [5] or a salt thereof to a cyclization reaction. A cyclizing condensing agent is used in this cyclization reaction, and examples of the cyclizing condensing agent include N, N-dimethyl such as N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal. Formamide di-lower alkyl acetal; N, N-dimethylformamide dicyclohexyl acetal; Combination of orthoformate ester such as methyl orthoformate and ethyl orthoformate with pyridine or acetic anhydride; Combination of phosphorus oxychloride and N, N-dimethylformamide Vilsmeier reagent; and a combination of a mixed acid anhydride of formic acid and acetic acid and sodium formate, etc. may be mentioned, and these may be prepared and used in the reaction system. This reaction can also be carried out in a solvent, and the solvent used is not particularly limited as long as it does not adversely influence the reaction, but for example, amides such as N, N-dimethylformamide;
Alcohols such as methanol; halogenated hydrocarbons such as methylene chloride; ethers such as dioxane and tetrahydrofuran; esters such as methyl acetate and ethyl acetate; and nitriles such as acetonitrile. Can be mentioned. Further, by using an excessive amount of the cyclocondensation agent, it can also serve as a solvent. In this reaction, glacial acetic acid or the like may be added to suppress side reactions. The amount of the cyclized condensing agent used is 1 to 10 times the mol of the compound of the general formula [5] or a salt thereof. The reaction temperature and reaction time for this reaction are usually from -30 to 150.
C., preferably 10 to 100.degree. C., for 1 to 24 hours.

Compounds of the general formulas [1] and [2]; salts of the compounds of the general formula [3]; and general formulas [5] and [6] or salts thereof in the above-mentioned production method, isomers (for example, Optical isomers, geometric isomers, tautomers, etc.), all of these isomers can be used, and all hydrates, solvates and various crystalline forms can be used. can do. Thus obtained compounds of the general formula of the present invention or salts thereof are extracted,
It can be isolated and purified according to a conventional method such as crystallization, recrystallization and column separation.

【Example】

Next, the present invention will be described with reference to examples, but the present invention is not limited thereto. Also,
The wave number in IR shows the absorption of carbonyl, and [] in the table and the sentence shows a recrystallization solvent.

Example 1 45 ml of methanol containing 11 g of hydrogen chloride and 160 ml of methylene chloride
10 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was dissolved in the mixed solution of and cooled to -10 ° C. Add -10 to -5 to this solution.
While maintaining the temperature at 5.5 ° C., 5.5 g of bromine was added dropwise over 1 hour with stirring. After stirring for another 2 hours at the same temperature, the reaction mixture is poured into 70 ml of an aqueous solution of 3.5 g of sodium thiosulfate. this
After raising the temperature to 25 to 30 ° C., the organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure and washing the obtained solid with a small amount of methylene chloride,
If dried, (2-hydroxy-4-methylsulfonylamino-5-phenoxy) phenacyl bromide 11.4 g
(Yield 91.9%) is obtained. Melting point: 165-166 ° C IR (KBr) cm ^-1 ; 1641 NMR (CDCl ₃ ) δ value; 3.11 (3H, s), 4.17 (2H, s), 6.90-7.56 (8
H, m), 11.85 (1H, s)

Similarly, the compounds shown in Table 1 are obtained. In addition, R ¹ and R ² in Table 1 are respectively expressed by the following equations.

[Chemical 9] The substituents of the compound represented by are shown below.

[0018]

[Table 1]

Example 2 10 g of (2-hydroxy-4-methylsulfonylamino-5-phenoxy) phenacyl bromide was dissolved in 300 ml of methylene chloride, and 3.85 g of hexamethylenetetramine was added to this solution at 25 to 30 ° C. Stir for 2 hours. The precipitated crystals were collected by filtration, washed with 30 ml of methylene chloride and dried to give (2-hydroxy-4-methylsulfonylamino-
12.8 g (yield 94.8%) of 5-phenoxy) phenacyl hexamethylenetetramonium bromide is obtained. Melting point; 176-177 ° C IR (KBr) cm ^-1 ; 1652 NMR (DMSO-d ₆ ) δ value; 3.13 (3H, s), 4.58 (8H, bs), 5.40 (6H, b)
s), 6.90-7.55 (7H, m), 9.70 (1H, bs), 11.20 (1H, bs)

In the same manner, the compounds shown in Table 2 are obtained. Incidentally, R ¹ and R ² in Table 2, the following respective formulas

[Chemical 10] The substituents of the compound represented by are shown below.

[0021]

[Table 2]

Example 3 8.86 g of 63.2% sulfuric acid was added to a mixed solution of 40 ml of methanol and 6.74 ml of water.
Is dripped. To this, 10 g of (2-hydroxy-4-methylsulfonylamino-5-phenoxy) phenacylhexamethylenetetramonium bromide is added, and the mixture is stirred at 30 ° C. for 5 hours. Further, the mixture is stirred at 10 to 15 ° C for 2 hours and then the precipitated crystals are collected by filtration. After sequentially washing with water and acetonitrile and drying, 6.35 g (yield 89.1%) of 1/2 sulfate of aminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone is obtained. Melting point: 225-226 ° C IR (KBr) cm ^-1 ; 1648 NMR (CF ₃ CO ₂ D) δ value: 3.32 (3H, s), 4.65 (2H, s), 6.98-7.57
(7H, m), 11.28 (5H, bs)

In the same manner, the compounds shown in Table 3 are obtained. In addition, R ¹ and R ² in Table 3 are respectively expressed by the following equations.

[Chemical 11] The substituents of the compound represented by are shown below.

[0024]

[Table 3]

Example 4 After adding 4.5 g of acetic anhydride to 5.1 g of 98% formic acid, the mixture was stirred at 40 to 45 ° C. for 2 hours (solution A). Meanwhile, 40 ml of acetonitrile
To this, 10 g of aminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone 1/2 sulfate is added, and the mixture is cooled to -10 ° C. Solution A prepared above is added to this suspension, and then 3.67 g of triethylamine is added dropwise over 30 minutes with stirring. After stirring at 0 ° C for 2 hours, add 100 ml of water and stir at 5-10 ° C for 3 hours. The precipitated crystals were collected by filtration, washed successively with water and isopropanol, and dried to give formylaminomethyl = 2.
8.22 g (yield 87.0%) of -hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone is obtained. Melting point; 173-174.5 ° C IR (KBr) cm ^-1 ; 1664, 1639 NMR (DMSO-d ₆ ) δ value; 3.09 (3H, s), 4.55 (2H, d, J = 5.4Hz), 6.
90-7.50 (7H, m), 8.13 (1H, s), 8.15 (1H, t, J = 5.4Hz), 9.68 (1
H, S), 11.22 (1H, s)

In the same manner, the compounds shown in Table 4 are obtained. Note that R ¹ in Table 4 is the following formula

[Chemical 12] The substituents of the compound represented by are shown below.

[0027]

[Table 4]

Example 5 Acetic anhydride and aminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone
Acetylaminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone is obtained in the same manner as in Example 4 using 1/2 sulfate. Melting point; 191-192 ° C [ethanol] IR (KBr) cm ^-1 ; 1677,1645 NMR (DMSO-d ₆ ) δ value; 1.87 (3H, s), 3.08 (3H, s), 4.45 (2H, d,
J = 5.8Hz), 6.89-7.50 (7H, m), 8.01 (1H, t, J = 5.8Hz), 9.67 (1
H, s), 11.27 (1H, s)

Example 6 To 150 ml of N, N-dimethylformamide, 40.9 g of N, N-dimethylformamide dimethylacetal was added, and 10 to 1 was added.
Cool to 5 ° C. To this, 8.24 g of glacial acetic acid and 50.0 g of formylaminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone are sequentially added, and the mixture is stirred at 15 to 20 ° C. for 5 hours. To the reaction suspension, 250 ml of methylene chloride was added and uniformly dissolved, and then added dropwise to 500 ml of water. The pH is adjusted to 5.0 and the precipitated crystals are collected by filtration. The obtained precipitated crystals are washed successively with methylene chloride, water and ethanol and then dried. Then, the crystals obtained were dissolved in water-containing acetone using 7.1 g of potassium hydroxide,
Neutralize with 2N hydrochloric acid and collect the crystals by filtration. The obtained crystals are washed with water and dried to give 3-formylamino-7-
Methylsulfonylamino-6-phenoxy-4H-1-
44.4 g (yield 86.4%) of benzopyran-4-one are obtained. Melting point: 236-238 ° C IR (KBr) cm ^-1 ; 1680,1615 NMR (DMSO-d ₆ ) δ value; 3.24 (3H, s), 7.09-7.62 (5H, m), 7.35
(1H, s), 7.72 (1H, s), 8.36 (1H, s), 9.28 (1H, s), 9.79 (1H,
s), 10.04 (1H, s)

In the same manner, the following compounds and the compounds shown in Table 5 are obtained. 3-Acetylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one Melting point; 254-256 ° C IR (KBr) cm ^-1 ; 1665,1615 NMR (DMSO-d ₆ ) δ value; 2.12 (3H, s), 3.22 (3H, s), 7.05-7.61
(5H, m), 7.35 (1H, s), 7.71 (1H, s), 9.18 (1H, s), 9.18 (1H,
s), 9.99 (1H, s) Note that R ¹ in Table 5 is the following formula

[Chemical 13] The substituents of the compound represented by are shown below.

[0031]

[Table 5]

[0032]

According to the method of the present invention, 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-, which is useful as an anti-inflammatory agent, is obtained.
The on-derivative or a salt thereof can be industrially produced in high yield.

Claims (1)

[Claims] 1. A general formula: A halogenating agent is reacted with a benzene derivative represented by the formula: "wherein R ¹ represents a phenyl group which may be substituted with a halogen atom; R ² represents a lower alkyl group." Chemical 2] A compound represented by the formula: "wherein X is a halogen atom; R ¹ and R ² have the same meanings as defined above." Then, the compound is subjected to an amination reaction to give a compound represented by the general formula: Chemical 3] A salt of the compound represented by the formula: wherein R ¹ and R ² have the same meanings as described above. A compound represented by the formula "wherein R ³ represents an acyl group which may be substituted with a halogen atom" or a reactive derivative thereof is reacted to give a compound represented by the general formula: A compound represented by the formula "wherein R ¹ , R ² and R ³ have the same meanings as defined above" or a salt thereof, and then the compound or salt thereof is subjected to a ring-forming reaction. And the general formula 3-Acylamino-6-represented by "wherein R ¹ , R ² and R ³ have the same meanings as described above."
Phenyloxy-7-alkylsulfonylamino-4H
A method for producing a -1-benzopyran-4-one derivative or a salt thereof.