JP2973143B2 - Process for producing 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one or a salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an industrial process 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. About.

[0002]

2. Description of the Related Art A method for producing 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one or a salt thereof useful as an anti-inflammatory agent is disclosed in JP-A-2-49778. Is disclosed. However, since the various methods described in the publication include long steps and low yield steps, particularly, 4H-1-benzopyran-4-
It was not sufficient as an industrial production method of a compound having an acylamino group introduced at the 3-position of ON. In these methods, the above-mentioned target compound is obtained by subjecting an intermediate, N-acylaminomethyl = 2-hydroxy-4-lower alkylsulfonylamino-5-phenoxyphenyl = ketone, to a ring-forming reaction. The method of obtaining is described. On the other hand, as a method for directly introducing an acylaminoacetyl group into a benzene derivative, (a) a method by a so-called Friedel-Crafts reaction using an N-acylglycine derivative, for example, an acylaminoacetic acid halide { Journal of American Chemical Society [J. Am. Chem. Soc., 103 , 6157-6163 (19
81)], and Journal of Organic Chemistry [J. Org. Chem., 50 , 3481-3484 (1985)}.

[0003]

SUMMARY OF THE INVENTION 3-Acylamino-6
-Phenyloxy-7-alkylsulfonylamino-4
In an industrial process for producing H-1-benzopyran-4-one or a salt thereof, it has been desired to develop a process for obtaining the desired product in a small number of steps and in a high yield.

[0004]

Means for Solving the Problems The present inventors have disclosed Japanese Patent Laid-Open No.
Among the production methods disclosed in Japanese Patent Publication No. 49778, general formula [3a]

Embedded image Wherein R ¹ is a phenyl group optionally substituted with a halogen atom; R ² is a lower alkyl group; R ⁴ is an acyl group or a hydrogen atom optionally substituted with a halogen atom; Or a salt thereof, which is subjected to a ring-forming reaction to obtain the desired general formula [4].

Embedded image Wherein R ⁵ is an acyl group which may be substituted with a halogen atom; R ¹ and R ² have the same meanings as described above, respectively. -Alkylsulfonylamino-4H-1
The method of obtaining -benzopyran-4-one or a salt thereof was considered to be an industrially advantageous method, and various methods for producing a compound of the general formula [3a] or a salt thereof were examined.

The above method (a) as a method for directly introducing an acylaminoacetyl group into a benzene derivative usually has a low yield. On the other hand, the method (a) in which a trifluoroacetyl group is directly introduced into a benzene derivative has a relatively high yield, but is extremely disadvantageous industrially. Further, as a benzene derivative, a compound represented by the general formula [1]:

Embedded image Wherein 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 a hydrogen atom or a lower alkyl group. When the reaction is carried out using, a compound having an acylaminoacetyl group introduced at the desired substitution position is obtained, while the phenyl group which may be substituted with a halogen atom of R ¹ is substituted at the para position (4 position). A large amount of a compound into which an acylaminoacetyl group has been introduced can be obtained, and the desired compound represented by the general formula [3]

Embedded image Cannot be obtained in high yield.

Under these circumstances, the compound of the general formula [1] is added to the compound of the general formula [2].

Embedded image When a nitrile derivative or a salt thereof represented by “wherein R ⁴ represents an acyl group or a hydrogen atom which may be substituted with a halogen atom” is reacted, unexpectedly, the compound represented by the general formula [3] It has been found that a compound represented by the formula or a salt thereof can be obtained in a high yield, and the present invention has been completed.

Hereinafter, the present invention will be described in detail. In the present specification, unless otherwise specified, a halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a lower alkyl group includes, for example, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, te
rt- butyl and C ₁ ~ ₅ alkyl group such as pentyl; Acyl groups, e.g., C _2, such as formyl or acetyl, propionyl and butyryl group
~ ₈ alkanoyl groups respectively.

The present invention is shown by the following manufacturing route.

(Equation 1) "In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meaning as described above."

The salt of the compound of the general formula [2] includes, for example, salts with mineral acids such as hydrochloride, sulfate and hydrogensulfate, among which hydrochloride is most preferred.
Salts of the compound of the general formula [3] include salts with mineral acids such as hydrochlorides and sulfates; salts with carboxylic acids such as oxalates; salts with sulfonic acids such as p-toluenesulfonate Salts. As the salt of the compound of the general formula [4],
Salts with alkali metals such as sodium and potassium;
Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with amines such as triethylamine and pyridine; and salts with amino acids such as lysine and arginine.

Next, the present invention will be described in detail according to the manufacturing route. (1) The compound of the general formula [1] is reacted with a compound of the general formula [1] in a solvent in the presence of a Lewis acid or in the presence of a Lewis acid and an acid gas.
By reacting with the compound of the formula (I) or a salt thereof, the compound of the general formula [3] 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.
Nitrobenzenes; nitro compounds such as nitromethane and nitroethane; sulfolane; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; esters such as diethyl oxalate and ethyl acetate; and nitriles such as acetonitrile. And these may be appropriately mixed and used. Preferred solvents include a mixture of a nitro compound such as nitrobenzene, nitromethane or nitroethane and a halogenated hydrocarbon such as methylene chloride. Examples of the Lewis acid used in this reaction include aluminum chloride, aluminum bromide, zinc chloride,
Examples include tin chloride and titanium chloride, with aluminum chloride being particularly preferred. If no acid gas is used, use boron tribromide or boron trichloride as the Lewis acid,
Further, aluminum chloride or aluminum bromide may be added. Examples of the acidic gas used in this reaction include hydrogen chloride and hydrogen bromide. The amount of the compound of the general formula [2] or a salt thereof is 0.3 to 3 times the molar amount of the compound of the general formula [1]. It is 1.1 to 5 times mol, and preferably 1.1 to 4 times mol. The amount of the acid gas used is 1 to 20 times, preferably 1 to 4 times the mol of the general formula [2] or a salt thereof. This reaction is usually performed at 10 to 40 ° C, preferably 20 to 35 ° C.
Will be implemented. The reaction time can be appropriately selected depending on the Lewis acid to be used, the amount of the acidic gas to be introduced, the reaction temperature, and the organic solvent to be used, but is usually 4 to 20 hours. In this reaction, sodium chloride, potassium chloride, ammonium chloride or the like can be added to adjust the reaction rate. In this reaction, the resulting compound is hydrolyzed to lead to the compound of the general formula [3]. The compound of the general formula [1] can be prepared, for example, by the method described in JP-A-2-49778, and the compound of the general formula [2] or a salt thereof can be prepared, for example, by the method described in Chemical
Pharmaceutical Bulletin [Chem.Pharm.Bul
l, 13 , 1319-1325 (1965)].

(2) A compound of the general formula [4] or a salt thereof can be obtained by subjecting the compound of the general formula [3] or a salt thereof to a ring-forming reaction. A cyclizing condensing agent is used in the ring forming reaction. 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 such as methyl or ethyl orthoformate with pyridine or acetic anhydride; Vilsmeier by combination of phosphorus oxychloride and N, N-dimethylformamide A reagent; or a combination of a mixed acid anhydride of formic acid and acetic acid and sodium formate, each of which may be prepared and used in a reaction system.
This reaction can be carried out in a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, amides such as N, N-dimethylformamide; methanol Alcohols such as methylene chloride; ethers such as dioxane and tetrahydrofuran; esters such as methyl acetate and ethyl acetate; and nitriles such as acetonitrile. Also,
By using an excess amount of the cyclizing condensing agent, it can be used also as a solvent. In this reaction, glacial acetic acid or the like may be added to suppress a side reaction. The amount of the cyclizing condensing agent used is 1 to the compound of the general formula [3] or a salt thereof.
It is about 10 times mol. The reaction temperature and reaction time in this reaction are usually -30 to 150 ° C, preferably 10 to 100 ° C.
It takes 1 to 24 hours.

The compound of the general formula [3] wherein R ³ is a lower alkyl group or a salt thereof can be prepared by the usual dealkylation,
For example, after performing dealkylation by the method described in Chemical Pharmaceutical Bulletin [Chem. Pharm. Bull., 31 , 4178-4180 (1983)], a ring-forming reaction may be performed. Further, the compound of the general formula [3] or a salt thereof in which R ⁴ is a hydrogen atom is subjected to a known acylation reaction, and if necessary, to the above-described dealkylation reaction, and then to a ring formation reaction. I should do it. General formula [1] in the above-mentioned production method
In the compound of the formula, the compounds of the general formulas [2], [3] and [4] or salts thereof, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present,
All these isomers can be used, and all hydrates, solvates and various crystal forms can be used. The thus-obtained compound of the general formula [3] or [4] of the present invention or a salt thereof may be isolated and purified according to a conventional method such as extraction, crystallization, recrystallization and column separation. Can be.

【Example】

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

Example 1 Anhydrous aluminum chloride 10 in 300 ml of nitrobenzene
After 9.1 g was added in portions, 37.9 g of aminoacetonitrile / hydrochloride was added, and the mixture was stirred for 1 hour while maintaining 40 ° C. After cooling the reaction mixture to 10-15 ° C, 3
100 g of methylsulfonylamino-4-phenoxyanisole are added. Then, under stirring, 30 g of hydrogen chloride gas is introduced into the reaction mixture over 10 hours while maintaining 25 to 30 ° C. The reaction mixture is added dropwise to 500 ml of 2N hydrochloric acid, and the mixture is stirred at 25 to 30 ° C. for 1 hour and further at 10 ° C. for 1 hour. The obtained precipitated crystals are washed successively with ethyl acetate, water and isopropyl alcohol, and then dried, and aminomethyl-2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone / hydrochloride / 1/2 hydrate 121.5 g (yield 90.0
%). Melting point: 167.0-169.5 ° C (decomposition) IR (KBr) cm ^-1 ; 1675 NMR (DMSO-d ₆ ) δ value: 3.17 (3H,
s), 3.97 (3H, s), 4.25 (2H, s),
6.91-7.54 (7H, m), 8.50 (4H, b
s)

Similarly, compounds shown in Tables 1 and 2 are obtained. Note that R ¹ , R ³ and R in Tables 1 and 2 are represented by the following formulas, respectively.

Embedded image Represents a substituent of the compound represented by

[0016]

[Table 1]

[0017]

[Table 2]

Example 2 41.2 g of sodium formate and 36.6 g of pivalic acid chloride are sequentially added to 300 ml of acetone, and vigorously stirred at room temperature for 5 to 6 hours. Then, 100 g of aminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone / hydrochloride / 1/2 hydrate is added, and the mixture is stirred at room temperature for 3 hours. 900 ml of water is added dropwise to the reaction suspension, and the precipitated crystals are collected by filtration. The obtained precipitated crystals were washed with water and isopropyl alcohol in that order, dried, and then dried with formylaminomethyl
There are obtained 87.0 g (91.0% yield) of 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. Melting point: 153-154 ° C IR (KBr) cm ^-1 ; 1679,1655 NMR (DMSO-d ₆ ) δ value; 3.13 (3H, s), 3.94 (3H, s), 4.47 (2H, d,
J = 5.4Hz), 6.90-7.81 (7H, m), 8.12 (1H, s), 8.15 (1H, t, J = 5.
4Hz), 9.74 (1H, s)

Similarly, the compounds shown in Table 3 are obtained. Note that R ¹ in Table 3 is represented by the following equation:

Embedded image Represents a substituent of the compound represented by

[0020]

[Table 3]

EXAMPLE 3 70.5 g of anhydrous aluminum chloride was added to 300 ml of acetonitrile for 20 minutes.
Add in portions while maintaining the temperature below ° C. Then, 100 g of formylaminomethyl = 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone and 43.6 g of sodium iodide are sequentially added, and the mixture is stirred for 3 hours while maintaining 20 ° C. The reaction suspension is dropped into 900 ml of a 1% aqueous solution of sodium sulfite, cooled to 10 ° C., and the precipitated crystals are collected by filtration. The obtained precipitated crystals are washed with water and ethanol in that order and then dried to obtain 91.5 g (yield 95.0%) of formylaminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone. Melting point: 173.0-174.5 ° C IR (KBr) cm ^-1 ; 1664,1639 NMR (DMSO-d ₆ ) δ value: 3.09 (3H, s), 4.55 (2H, d, J = 5.4 Hz), 6.
90-7.50 (7H, m), 8.14 (1H, s), 8.15 (1H, t, J = 5.4Hz), 9.68 (1
H, s), 11.22 (1H, s)

Similarly, the following compounds and the compounds shown in Table 4 are obtained. Acetylaminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone 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)

Note that R ¹ in Table 4 is represented by the following formula:

Embedded image Represents a substituent of the compound represented by

[0024]

[Table 4]

Example 4 3-Methylsulfonylamino-4 in 200 ml of methylene chloride
-50 g of phenoxyanisole are added, followed by 22.7 g of anhydrous aluminum chloride at 5-10 ° C. After introducing 39.9 g of boron trichloride gas into the reaction mixture, the mixture is stirred at 20 to 25 ° C. for 5 hours. 68.7 g of trichloroacetaminoacetonitrile is added to the reaction mixture, and the mixture is stirred at 20 to 25 ° C for 20 hours. After the reaction mixture is added dropwise to a mixture of 200 ml of ethyl acetate and 500 ml of 4N hydrochloric acid, the mixture is stirred at 15 to 20 ° C. for 30 minutes, and the precipitated crystals are collected by filtration. The obtained precipitated crystals were washed with water and ethanol in that order, dried, and trichloroacetylaminomethyl = 2.
58.3 g (71.0% yield) of -hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone are obtained. Melting point: 232-233 ° C IR (KBr) cm ^-1 ; 1720,1649 NMR (DMSO-d ₆ ) δ value: 3.09 (3H, s), 4.58 (2H, d, J = 5.9 Hz), 6.
91-7.50 (7H, m), 9.01 (1H, t, J = 5.9Hz), 9.69 (1H, s), 11.19
(1H, s)

Example 5 N, N-dimethylformamide dimethyl acetal (40.9 g) was added to N, N-dimethylformamide (150 ml).
Cool to 5 ° C. 8.24 g of glacial acetic acid and 50.0 g of formaminomethyl = 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl = ketone are sequentially added to the mixture, and the mixture is stirred at 15 to 20 ° C. for 5 hours. 250 ml of methylene chloride was added to the reaction suspension, and the solution uniformly dissolved was added to 500 ml of water.
After the addition, the pH is adjusted to 5.0. The precipitated crystals are collected by filtration,
After washing sequentially with methylene chloride, water and ethanol,
dry. Next, the obtained crystals are dissolved in aqueous acetone with caustic potash, neutralized and crystallized with hydrochloric acid, and the crystals are collected by filtration. The obtained crystals are washed with water and dried to obtain 44.4 g (yield 86.4%) of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. 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
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 represented by the following formula:

Embedded image Represents a substituent of the compound represented by

[0029]

[Table 5]

Example 6 Trichloroacetylaminomethyl 2-hydroxy-4
-Methylsulfonylamino-5-phenoxyphenyl =
10 g of ketone are dissolved in 30 ml of N, N-dimethylformamide and cooled to 10-15 ° C. 4.95 g of N, N-dimethylformamide dimethyl acetal was added to this solution, and 20
Stir at 2525 ° C. for 15 hours. The reaction mixture is added dropwise to 50 ml of 1N hydrochloric acid, and the precipitated crystals are collected by filtration. The precipitate was washed with water and recrystallized from acetonitrile to give 3-trichloroacetylamino-7-methylsulfonylamino-6-phenoxy-
7.24 g of 4H-1-benzopyran-4-one (70.9 yield)
%). Melting point: 216-217 ° C IR (KBr) cm ^-1 ; 1715,1635 NMR (DMSO-d ₆ ) δ value: 3.24 (3H, s), 7.09-7.62 (5H, m), 7.33
(1H, s), 7.77 (1H, s), 8.84 (1H, s), 9.88 (1H, s), 10.08 (1H, s
s)

[0031]

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

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-2-268178 (JP, A) JP-A-2-49778 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 311/00-311/22

Claims (1)

(57) [Claims] (1) (1)-General formula Wherein, 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 a hydrogen atom or a lower alkyl group, respectively. The derivative has the general formula Wherein R ⁴ represents an acyl group or a hydrogen atom which may be substituted by a halogen atom, and a nitrile derivative represented by the formula: Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, respectively, and a salt thereof, and the compound or a salt thereof is subjected to a ring-forming reaction. A general formula characterized by the following: Wherein R ⁵ is an acyl group which may be substituted with a halogen atom; R ¹ and R ² have the same meanings as described above, respectively. 7-alkylsulfonylamino-4H-
A method for producing 1-benzopyran-4-one or a salt thereof.