KR810001251B1 - Process for preparing 3-(tetrazol-5-yl)-1-azaxanthon derivatives - Google Patents

Abstract

Title compd. (I; R1 = H, amino, hydroxyl; R2 = alkyl, alkoxyl, H, nitro, carboxyl, hydroxyl, butadienyl, amino; m = 0,1,2), having anti-allergic activity, were prepd. by reacting compd.(II) with hydrazoic acid or its salts. Thus, 7-isopropyl-3-cyano-1-azaxanthone 0.50 g, sodium azide 0.362 g and ammonium chloride 0.282 g were dissolved in the dimethyl-formamide 50 ml. The soln. was stirred for 2 hr at 120oC and solvent was eliminated. Water 5 ml and 5 % sodium nitrite 5 ml were added in the residue, and then acidified with 10 % CHl to give I.

Description

Process for preparing 3- (tetrazol-5-yl) -1-azaxanthone derivative

The present invention relates to a method for preparing 3- (tetrazol-5-yl) -1-azaxanthone and derivatives thereof, the compound having excellent pharmacological action such as anti-allergic action and bronchodilator action.

Wherein R ₁ is hydrogen, amino or hydroxyl, R ₂ is alkyl, alkoxy, halogen, nitro, carboxyl, hydroxyl, butadienylene (-CH = CH-CH forming a benzene ring with adjacent carbon atoms = CH-), an amino group which is not substituted at all or is substituted by at least one alkali group, and m is 0, 1 or 2.

The target compound of formula (I) is prepared by reacting the following compound of formula (II) with hydrazoic acid or a salt thereof.

(Wherein R ₁ , R ₂ and m have the same meaning as above).

Substituent represented by R <_2> in each structural formula mentioned above means substituted at one or two positions of 6-, 7-, 8-, or 9-position of an ataxanthone ring.

In the general formulas (I) and (II), the alkyl group represented by R ₂ means any one of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Representative examples of alkyla include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, cyclopentyl and cyclohexyl. Of these, lower alkyl having 1 to 3 carbon atoms is suitable for practical purposes.

Alkoxy groups have from 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy and butoxy.

Halogen may be chlorine, cancelled, oxo or fluorine.

The amino group, which is not substituted at all or is substituted by at least one alkyl group, is a mono- or dialkyl substituted amino group having 1 to 3 carbon atoms with an amino group and its alkyl component, for example methylamino, ethylamino, propylamino, iso Propylamino, dimethylamino, diethylamino or dipropylamino group.

Compound (I) of the present invention can be prepared by reacting compound (II) with hydrazoic acid or a salt thereof. Examples of the salts of hydrazonic acid described above include salts of hydrazonic acid with alkali metals (lithium azide, sodium azide, potassium azide), salts of hydrazonic acid with alkaline earth metals (e.g., magnesium azide, Calcium azide, barium azide and strontium azide), salts of hydrazoic acid with other metals (e.g., aluminum azide, tin azide, zinc azide, titanium azide, etc.) and ammonia And organic bases such as aniline. The salts of hydrazoic acid can be used alone or in combination with other compounds. For example, alkali azide metals (eg, sodium azide) can be used with Lewis acids (eg, aluminum chloride, stannic chloride, zinc chloride or titanium chloride) or ammonium chloride. In the reaction system, alkali metal salts of hydrazoic acid can be converted to different azides corresponding to the cations of comparable compounds, namely aluminum azide, tin azide, zinc azide, titanium azide, ammonium azide, and the like. Different azide is then reacted with the raw compound (II). Among the hydrazoic acids, salts thereof, and combinations of these salts with other compounds, combinations of sodium azide with ammonium chloride are suitable.

In general, the reaction is preferably carried out in an organic solvent. Examples of the organic solvent include hydrocarbons such as benzene, toluene and petroleum ether, ethers such as tetrahydrofuran, dioxane, ethyl ether and ethylene glycol diethyl ether, acetonitrile and dimethylform. Amide, formamide, dimethyl sulfoxide, etc. are mentioned. On the other hand, temperature, time and other reaction conditions are not very important, but it is generally advantageous to carry out this reaction at a temperature between room temperature and about 150 ° C. for about 1 hour to about 2 days.

When a salt such as hydrazoic acid is used in the reaction, the target compound (I) is obtained in the form of a salt corresponding to the salt of hydrazoic acid to be used, which is due to the acidity of the tetrazole ring. This salt can be easily transformed into the target compound (1) having its own free tetrazole ring after treatment with a suitable acid (for example, a mineral acid such as hydrochloric acid or sulfuric acid). Compound (I) is reacted with any one of organic amines, alkali metal hydroxides, ammonia or other reagents in a conventional manner, ie in a suitable solvent to produce the corresponding salts of the compound. Examples of such salt-forming reagents include ethanolamine, diethanolamine, dl-methylephedrine, 1- (3,5-dihydroxyphenyl) -L-isopropylaminoethanol, isoproterenol, dextrome Organic amines such as torpane, hetrazan (diethylcarbazine), diethylamine and triethylamine, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and ammonia.

The compound (I) thus obtained has an antiallergic action and is useful as a drug for the prophylactic light treatment of allergic diseases such as allergic asthma, allergic coat infection and fever fever.

When either compound (I) or salts thereof is used for the prophylaxis or treatment of the aforementioned allergic diseases, it is in tablet, capsule, powder, liquid form orally in an amount of about 1 to about 500 mg per day for adults. May be administered. It may also be administered by other routes, such as, for example, injection solutions, aerosol inhalants, ointments, and the like.

The compound of general formula (II) can be manufactured by the following method. That is, a compound of formula (IV), which may be prepared by the method described in Pharmacopoeia 20, 141 (1977) or by a similar method.

(Wherein m and R ² have the same meanings as above) are reacted with water in the presence of a base to prepare a compound of formula (III).

(Wherein m and R ₂ have the same meanings as above).

Examples of bases used in this reaction include primary amines (e.g. ethylamine, n-propylamine, n-butylamine, benzylamine and aniline), secondary amines (e.g. dimethylamine, diethylamine, dipropylamine, Dibutylamine, morpholine, piperidine and pyrrolidine) and spadeamine (e.g. triethylamine), heterocyclic bases (e.g. imidazole, 2-methylimidazole, pyridine) and inorganic bases (e.g. Aqueous ammonia solution, ammonium acetate, ammonium carbonate, sodium carbonate and sodium bicarbonate). These bases can be used in arbitrary ratios with each other in a large amount from a catalytic amount.

In general, this reaction is suitably carried out in a solvent miscible with water. Examples of this solvent include organic acids such as dimethylformamide, dimethyl sulfoxide, hexamethyl phosphate triamide, edible acid, acetic acid and propionic acid, and ethers such as tetrahydrofuran and dioxane.

On the other hand, although the temperature, time and other conditions of the reaction are not critical, it is generally beneficial to carry out the reaction at a temperature between room temperature and about 100 ° C. for a time between several minutes and about 3 hours.

Compound (III) thus obtained is represented by the general formula (IV).

R ₃ -CN (Ⅴ)

Wherein R ₃ is HC≡C-, NC-CH _2- , R ₄ OCOCCH ₂ (R ₄ is an alkyl group having 1 to 3 carbon atoms) or XOG-CH _2- (X is halogen) And R ₄ OCOCCH ₂ as R ₃ in the reaction. Examples of compound (V) include methylcyanoacetate, ethylcyanoacetate and propylcyanoacetate. have.

The reaction of compound (III) with compound (V) wherein R ₃ is HC≡C-, NC-CH ₂ -or R ₄ OCOCH ₂ -can be carried out in the presence or absence of a base. Examples of this base include primary amines (e.g. ethylamine, n-propylamine, n-butylamine, benzylamine and aniline), secondary amines (e.g. dimethylamine, diethylamine, dipropylamine, dibutylamine, Organic amines such as morpholine, piperidine and pyrrolidine), tertiary amines (e.g. triethylamine) and heterocyclic amines (e.g. imidazole, 2-methylimidazole and pyridine), aqueous ammonia solution, ammonium acetate And inorganic bases such as sodium carbonate and sodium bicarbonate. This base can be used in an arbitrary ratio in large quantities from a catalytic amount.

In general, it is preferable to perform this reaction in an organic solvent. Examples of such organic solvents include ethers such as dimethylformamide, dimethyl sulfoxide, formamide, hexamethyl phosphate amide, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, propanol and butanol, ethyl acetate and methyl propionate, and the like. And esters such as acetone and methyl ethyl ketone.

Although the temperature, time and other conditions of the reaction are not critical, it is advantageous to run this reaction at a temperature between room temperature and about 180 ° C. for a time between several minutes and about 24 hours.

Compound (II) can also be prepared by reacting a compound of formula (III) with compound (V) wherein R ₃ is XOC-CH ₂ -ie cyanoacetyl halide in the presence of substituted formamide. As the cyanoacetyl halide used in this reaction, cyanoacetyl chloride, cyanoacetyl embrittlement, cyanoacetyl oxide, cyanoacetyl fluoride and the like can be used.

Substituted formamides used in this reaction were N, N-dimethylformamide, N, N-dimethylformamide, N, N-dipropylformamide, N-methyl-N-ethylformamide, N-methyl-N-phenyl Alkyl or aryl-substituted formamide, such as formamide and N, N- diphenylformamide, etc. are mentioned. This reaction can be carried out using substituted formamide alone, i.e., as a reaction solvent, and this reaction can be carried out in a mixture of the above-mentioned substituted formamide with other solvents which do not inhibit the reaction as necessary. The above-mentioned solvents include hydrocarbons (e.g. benzene, toluene, xylene and petroleum ether), ethers (e.g. tetrahydrofuran, dioxane, ethyl ether and ethyleneglycol dimethyl ether), halogenated hydrocarbons (e.g. chloroform, dichloromethane, Any of conventional organic solvents, such as dichloroethane and tetrachloroethane), esters (for example, ethyl acetate, methyl acetate, and butyl acetate), acetonitrile, and dimethyl sulfoxide, can be used. The proportion of cyanoacetyl halide used in the preparation of compound (II) is usually between about 1 to 10 molar equivalents based on the starting compound (III). On the other hand, the temperature, time, and other conditions of the reaction are not particularly important, but the reaction is usually performed at about 20 to about 120 ° C. for about 30 minutes to about 2 days. The ratio of the above-mentioned substituted formamide is not particularly important, but is used at a ratio of about 2 or more molar equivalents based on the starting compound (III).

In the case of preparing the raw material compound (II) of the reaction by the above method, the compound (II) wherein R ₁ is a hydroxyl group also contains a compound (II) wherein R ₁ is an amino group in an aqueous solution of an acid (for example, acetic acid or hydrochloric acid). It is prepared by reacting with an alkali salt of nitrous acid (for example, sodium nitrite or potassium nitrite).

The present invention is explained in more detail with reference to the following Examples and Examples.

Reference Example 1

A mixture of 2 ml of morpholine, 3 ml of dimethylformamide and 10 ml of water was warmed up to 60 ° C., and 1.71 g of 4-oxo-4H-1-benzopyran-3-carbonitrile pulverized with stirring was added for at least 5 minutes. The mixture was further maintained at this temperature and then filtered to recover the precipitate, rinsed with water, recrystallized with acetic acid and washed with chloroform. 1.3 g of 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehyde was obtained by the above method. Melting point 252-255 degreeC (decomposition).

NMR (DMSO-d6) δ: 10.19 (1H, s), 9.67 (about 1.5H, Browood s), 8.11 (1H, dd, J = 2.8 Hz), 7.97-7.80 (3H, m).

Elemental Analysis: C ₁₀ H ₇ NO ₃

Calculated Value: C, 63.49 H, 3.73 N, 7.41

Found: C, 63.59 H, 3.44 N. 7.45

In the same manner as above, the following compounds were synthesized.

Reference Example 2

After stirring the mixture with 217 mg of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-carboxaldehyde, 300 mg of maltononitrile, 5 ml of ethanol and 0.5 ml of piperidine under reflux for 15 minutes and cooling Filtration gave a slightly soluble product which was recrystallized from dimethylformamide. 160 mg of 2-amino-7-ethyl-1- azaxanthone-3-carbonitrile was obtained as a colorless needle by the said method. Melting point above 300 ℃.

Infrared absorption spectrum (Nujol) cm ^-1 : 3325, 3125, 2225, 1660.

Nuclear Magnetic Resonance Spectrum (CF ₃ COOD) δ: 9.07 (1H, s), 8.16 (1H, d, J = 2Hz), 7.88 (1H, dd), 7.63 (1H, d, J = 9Hz), 2.92 (2H , q, J = 7 Hz), 1.39 (3H, t, J = 7 Hz).

Elemental Analysis: C ₁₅ H ₁₁ N ₃ O ₂

Calculated value: C, 67.91; H, 4.18; N, 15.84

Found: C, 67.75; H, 4.01; N, 16.00

The following compounds were prepared in a similar manner to the above.

Reference Example 3

1.82 g of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde was dissolved in 140 ml of dimethylformamide, followed by addition of 3.5 g of cyanoacetyl chloride. The mixture was reacted with constant stirring at 60 ° C. for 3 hours. The solvent was then distilled off under reduced pressure and the residue was chromatographed with silica gel. The target product was recovered from the chloroform eluate and recrystallized from acetonitrile. 1.03 g of 7-ethyl-3-cyano-1-azaxanthone was obtained by the above method. Melting point 183-185 degreeC.

The following compounds were prepared in the same manner as above.

Reference Example 4

To 70 ml of dimethylformamide, 2.2 g of 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehyde was added, followed by 2.5 g of cyanoacetylene. The mixture was stirred at 140 ° C. for 15 hours under stirring, and then the solvent was distilled off under reduced pressure. The residue was chromatographed with silica gel, eluted with chloroform and recrystallized with acetonitrile to give 0.83 g of 3-cyano-1-azaxanthone as crystals. Melting Point 220 ~ 226 ℃

Nuclear Magnetic Resonance Spectrum: (DMSO-d6) δ: 7.4-8.4 (4H, m), 9.10 (1H, d, J = 2Hz), 9.30 (1H, d, J = 2Hz).

Elemental Analysis: C ₁₃ H ₆ N ₂ O ₂

Calculated value: C, 70.27; H, 2.72; N, 12.61

Found: C, 70.12; H, 2.55; N, 12.50

The following compounds were prepared in a similar manner to the above.

Reference Example 5

1.0 g of sodium nitrite was gradually added at 70 ° C to a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid. After 1 hour, 3 ml of water was added to the mixture, which was heated at 70 ° C. for 1 hour more. The solvent was distilled off under reduced pressure, and then water was added to the residue. Filtration gave a yellow precipitate, which was rinsed with water and recrystallized with ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals. Melting point above 300 ℃.

Elemental Analysis: C ₁₆ H ₁₂ N ₂ O ₃

Calculated value: C, 68.56; H, 4. 32; N, 10.00

Found: C, 68.28; H, 4. 34; N, 9.70

Reference Example 6

A mixture of 1.73 g of 2-amino-6-methoxy-4-oxo-4H-1-benzopyran-3-carboxaldehyde, 3.2 ml of ethylcyanoacetate, 80 ml of ethanol and 1.6 ml of piperidine was fixed for 1 hour. Stirring to reflux. 3.2 ml of ethylcyanoacetate and 1.6 ml of piperidine were added to the mixture, and the mixture was further refluxed for 3 hours. After cooling, the precipitate was collected by filtration and recrystallized from chloroform-ethanol (2: 1).

By the above method, 1.91 g of ethyl 2-amino-7-methoxy-1- azaxanthone-3-carboxylate was obtained as a colorless needle. Melting point 286-288 degreeC.

On the other hand, the mother liquor obtained by the above-mentioned filtration was concentrated. The resulting precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was chromatographed with silica gel (14 g), and the elution was performed with chloroform-acetone-acid (9: 1: 0.1), followed by elution with chloroform-acetone-acid (2: 1: 1: 0.1). Both eluates were combined and then concentrated. The residue was recrystallized from dimethylformamide-ethanol to give 75 mg of 2-hydroxy-7-methoxy-1-azaxanthone-3-carbonitrile as a white solid. Melting point above 300 ℃.

IR (Nujol) cm ^-1 : 2250 (CN), 1680, 1640

NMR (CF ₃ CO ₂ D) δ: 9.20 (1H, s), 7.75 (2H, s), 4.10 (3H, s)

Elemental _{analysis: C 14 H 8 N 2 O} 4 · 1 / 4H 2 O

Calculated value: C, 61.76; H, 3.14; N, 10.29

Found: C, 61.76; H, 2.90; N, 10.31

Example 1

0.50 g of 7-isopropyl-3-cyano-1-azaxanthone was dissolved in 50 ml of dimethylformamide, followed by addition of 0.326 g of sodium azide and 0.282 g of ammonium chloride. This reaction was carried out at 120 ° C. for 2 hours under constant stirring. The reaction mixture was then distilled off to remove the solvent and 5 ml of water was added to the residue. The mixture was acidified with 10% HCl and the resulting precipitate was collected, rinsed with water and recrystallized from dimethylformamide. 0.31 g of 7-isopropyl-3- (1H-tetrazol-5-yl) -1-azaxanthone was obtained by the above method. Melting point 275-277 ° C. (foaming).

NMR (DMSO-d ₆ ) δ: 1.30 (6H, d, J = 7), 3.00 (1H, quintet, J = 7), 7.70 (1H, d, J = 8), 7.90 (1H, dd, J ₁ = 2, J ₂ = 8), 8.03 (1H, d, J = 2), 9.15 (1H, d, J = 2), 9.38 (1H, d, J = 2).

In the same manner as above, the following compounds were synthesized.

3- (1H-tetrazol-5-yl) -1-azaxanthone,

7-ethyl-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p. 262-265 ° C. (foaming, decomposition)

7-isopropyl-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone,

7-isopropyl-2-hydroxy-3- (1H-tetrazol-5-yl) -1-azaxanthone,

7,9-dimethyl-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p. 294-298 ° C

7-tert-butyl-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.273-275 ° C (decomposition)

7-isopropoxy-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.271-272 ° C (decomposition)

7-chloro-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C

3- (1H-tetrazol-5-yl) -benzo [h] -1-azaxanthone, m.p. 291 to 293 ° C (decomposition)

9-methoxy-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C

Example 2

Suspend 2.0 g of 6-chloro-2-aminochromone-3-carboxaldehyde in 150 ml of ethanol, and then 1.3 g of malonitrile and 5 ml of piperidine were added. The mixture was reacted under reflux for 2 hours. The reaction mixture was then distilled off under reduced pressure to distill the boiling fraction at 100 ° C. and below. 50 ml of dimethylformamide was added to the residue, followed by 0.5 g of sodium azide and 0.4 g of ammonium chloride. The reaction was performed under stirring at 140 ° C. for 2 hours, and the solvent was distilled off under reduced pressure in the reaction boil. The residue was diluted with water, treated with 6 ml of 10% sodium nitrite and acidified with 10% hydrochloric acid. The produced precipitate was collected by filtration and acidified. The resulting precipitate was collected by filtration, rinsed with water and recrystallized from dimethylformamide. Crystals of 7-chloro-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone were obtained by the above method. Melting point above 300 ℃.

In the same manner as above, the following compounds were synthesized.

7-nitro-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C .;

9-methoxy-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C .;

8-hydroxy-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C .;

Benzo [h] -2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p.> 300 ° C;

7-dimethylamino-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone, m.p. > 300 ° C; And

7,9-dimethyl-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone,

Example 3

0.1 g of diethanolamine was added to a solution of 0.163 g of 7-isopropyl-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthone in 20 ml of methanol, followed by 10 minutes at 60 ° C. Heated during.

After cooling, the separated crystals were obtained, recrystallized with methanol to give 7-isopropyl-2-amino-3- (1H-tetrazol-5-yl) -1-azaxanthonediethanolamine salt as colorless needles. Obtained. Melting point above 300 ℃.

In the same manner as above, the following compounds were synthesized.

7-isopropyl-3- (1H-tetrazol-5-yl) -1-azaxanthone diethanolamine salt, melting point 149-151 degreeC

Claims (1)

Method for preparing 3- (tetrazol-5-yl) -1-azaxanthone of general formula (I) and salts thereof by reacting the following compound of general formula (II) with hydrazoic acid or a salt thereof .

Wherein R ₁ is hydrogen, amino, or hydroxyl, R ₂ is alkyl, alkoxy, hydrogen, nitro, carboxyl, hydroxyl, butadienylene (-CH = CH-CH) which forms a benzene ring with adjacent carbon atoms Is an amino group which is a = CH-) group or not substituted at all or substituted by at least one alkyl group, and m is 0, 1 or 2.