A preparation method of 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid

Abstract

The present invention provides a method for preparing 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid. Specifically, by selecting a solvent and optimizing reaction conditions, the process of post-treatment of the intermediate is avoided, which is more environmentally friendly and more suitable for industrialization.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing a compound 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I). Background Art

[0002] Clofentacil and its meglumine salt are used to delay nerve damage caused by transthyretin amyloidosis (a genetic disease in which fibers of a protein called amyloid accumulate in peripheral tissues of the body, including around nerves) and are used to treat adult patients in the early stages (stage 1) of the neurological disease. Clofentacil, chemically known as 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid, has a molecular formula of C 14 H 7 Cl 2 NO 3 , molecular weight is 308.12, structural formula I is as follows:

[0003]

[0004] The patent publication number CN101413143B discloses a synthetic route for clofentazone, which uses 3,5-dichlorobenzoyl chloride and 4-amino-3-hydroxybenzoic acid as starting materials, wherein the intermediate 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid is reacted with TMSCH 2 After esterification, column chromatography purification is required, which makes large-scale industrial production difficult.

[0005] Literature: Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (24), using 4-amino-3-hydroxybenzoic acid as the starting material, this route prepares clofentoxime by a method of protecting the carboxyl group with methyl ester, forming a salt, condensing, demethylating, and cyclizing. The method of protecting the carboxyl group with methyl ester and demethylating increases the process steps and the cost is relatively high.

[0006] The patent with publication number WO2019175263 discloses a method for synthesizing clofazolin, which uses 3.5-dichlorobenzoic acid as the starting material, and obtains the key intermediate 4-(3,5-dichlorobenzamide)-3-hydroxybenzoic acid through substitution and condensation, and then cyclizes to synthesize clofazolin. The synthetic route of this application purifies the key intermediate 4-(3,5-dichlorobenzamide)-3-hydroxybenzoic acid, adds a post-treatment process, and increases the number of reaction steps in the synthetic route, making the operation complicated and the cost high. Summary of the invention

[0007] The present application provides a method for preparing a compound 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I), the route of which is as follows:

[0008]

[0009] Step (A): 3,5-dichlorobenzoic acid reacts with an organic solvent and an acylating agent to obtain a reaction solution of 3,5-dichlorobenzoyl chloride;

[0010] Step (B): adding the obtained reaction solution containing 3,5-dichlorobenzoyl chloride to a solvent containing 4-amino-3-hydroxybenzoic acid to carry out a reaction to obtain a reaction solution of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid;

[0011] Step (C): adding a base to the obtained reaction solution containing 4-(3,5-dichlorobenzamide)-3-hydroxybenzoic acid, then adding methanesulfonic acid, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, and then adding a benzene series substance to react at 100° C. or above. After the reaction is completed, directly cooling and filtering or cooling and adding an alcohol solvent for crystallization, filtering, and obtaining 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I).

[0012] The organic solvent in step (A) is selected from one or more of toluene, tetrahydrofuran, dichloromethane or dimethylformamide; preferably one or more of toluene, tetrahydrofuran or dimethylformamide; more preferably one or two of tetrahydrofuran and dimethylformamide; most preferably tetrahydrofuran.

[0013] The acylating agent in step (A) is selected from thionyl chloride or oxalyl chloride, preferably thionyl chloride.

[0014] The solvent in step (B) is selected from one or more of benzene, tetrahydrofuran, dichloromethane or water; preferably one or more of tetrahydrofuran, dichloromethane or water; more preferably one or more of tetrahydrofuran or water.

[0015] In the step (C), the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium bicarbonate or sodium carbonate; preferably triethylamine.

[0016] The amount of the base used in the step (C) is 1-4 equivalents of 4-amino-3-hydroxybenzoic acid.

[0017] The benzene series compound in step (C) is selected from toluene or xylene, preferably toluene.

[0018] The alcohol solvent in step (C) is selected from one or more of methanol, ethanol, isopropanol, n-propanol or n-butanol; preferably isopropanol, ethanol or methanol; most preferably isopropanol.

[0019] The amount of methanesulfonic acid, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate used in step (C) should be 1.0-5.0 equivalents of 4-amino-3-hydroxybenzoic acid.

[0020] The temperature in step (C) is lowered to below 70°C; preferably, to below 30°C; more preferably, to 0-10°C.

[0021] The beneficial effects of the present invention are as follows: the present invention prepares the compound 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I) by a one-pot method, avoids the intermediate post-treatment process, and the final product has high yield and purity, which is suitable for industrial application. DETAILED DESCRIPTION

[0022] The present invention will be described in more detail below, but the following examples do not limit the scope of the present invention in any way. In addition, reaction conditions such as solvent, reaction temperature, reaction time, etc. are not limited to the following examples.

[0023] abbreviation:

[0024] THF: Tetrahydrofuran

[0025] DMF: dimethylformamide

[0026] HPLC determination method:

[0027] Chromatographic column: Waters Atiantis T3;

[0028] Mobile phase: A: 0.05% potassium dihydrogen phosphate solution; B: acetonitrile

[0029] Column temperature: 30°C;

[0030] Flow rate: 1.0 ml / min;

[0031] Detection wavelength: 250nm;

[0032] Injection volume: 10 μl;

[0033] Gradient elution;

[0034] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 5 80 20 6 65 35 20 60 40 45 30 70 50 40 60 50.1 90 10 58 90 10

[0035] Embodiment 1:

[0036] 4.20 g 3,5-dichlorobenzoic acid (1.12 eq), 30 ml THF, 3.40 g thionyl chloride (1.46 eq) and a catalytic amount of DMF were added to the reaction bottle in sequence. After the addition was completed, the temperature was controlled at 70-80° C. and the reaction was carried out for 2 h.

[0037] Take another reaction bottle and add 3.00g 4-amino-3-hydroxybenzoic acid (1.0eq), 30ml THF, 3ml water, control the temperature at 0-20℃, stir and dissolve; add the obtained 3,5-dichlorobenzoyl chloride reaction solution to the 4-amino-3-hydroxybenzoic acid system, react at 20-30℃ for 2h, add 7.28g triethylamine (3.67eq), 3.84g methanesulfonic acid (2.04eq), 30ml toluene to the reaction system, gradually increase the temperature to 105-115℃, react for about 20h, cool to 0-10℃, add 12ml isopropanol to crystallize, filter, rinse with 4ml isopropanol, dry the filter cake to obtain 5.70g sample. Formula (I) (liquid phase purity 98.09%)

[0038] MS (EI) m / z theoretical value: 306.98, detected value [M+H] + :307.99;

[0039] 1 H NMR (300MHz, DMSO): 8.15 (s, 1H), 7.96 (d, J = 9.9Hz, 3H), 7.85–7.71 (m, 2H);

[0040] 13 CNMR (75MHz, DMSO): 166.45, 161.63, 149.77, 144.40, 134.98, 131.38, 128.79, 128.62, 126.28, 125.53, 119.71, 111.94.

[0041] Embodiment 2:

[0042] 4.12 g 3,5-dichlorobenzoic acid (1.1 eq), 15 ml dichloromethane and 3.29 g oxalyl chloride (1.32 eq) were added to the reaction bottle in sequence. After the addition was completed, the temperature was controlled at 20-30° C. and the reaction was carried out for 4 h.

[0043] Take another reaction bottle and add 3.00g 4-amino-3-hydroxybenzoic acid (1.0eq), 15ml dichloromethane, control the temperature at 0-20℃, stir and dissolve; add the obtained 3,5-dichlorobenzoyl chloride reaction solution to the 4-amino-3-hydroxybenzoic acid system, react at 20-30℃ for 2h, add 30ml toluene, 7.93g triethylamine (4eq), 1.88g methanesulfonic acid (1.0eq) to the reaction bottle, heat to 100-110℃, react for about 24h, cool to 20-30℃, add 18ml methanol for crystallization, filter, rinse with 6ml methanol, dry the filter cake to obtain 5.20g sample. Formula (I) (liquid phase purity 97.99%)

[0044] Embodiment 3:

[0045] 4.12 g 3,5-dichlorobenzoic acid (1.1 eq), 15 ml toluene and 3.33 g thionyl chloride (1.43 eq) were added to the reaction bottle in sequence. After the addition was completed, the temperature was controlled at 75-95° C. and the reaction was carried out for 4 h.

[0046] Take another reaction bottle and add 3.00g 4-amino-3-hydroxybenzoic acid (1.0eq), 30ml THF, control the temperature at 0-20℃, stir and dissolve; add the obtained 3,5-dichlorobenzoyl chloride reaction solution to the 4-amino-3-hydroxybenzoic acid system, react at 20-30℃ for 2h, add 30ml toluene, 2.71g potassium carbonate (1.0eq), 3.96g N,N-diisopropylethylamine (2eq), 6.75g p-methanebenzenesulfonic acid (2.0eq) to the reaction bottle, heat to 110-120℃, react for about 24h, then cool to below 70℃, filter directly, and dry the filter cake to obtain 5.08g sample. Formula (I) (liquid phase purity 98.99%)

[0047] Embodiment 4:

[0048] 4.20 g 3,5-dichlorobenzoic acid (1.12 eq), 30 ml THF, 3.40 g thionyl chloride (1.46 eq) and a catalytic amount of DMF were added to the reaction bottle in sequence. After the addition was completed, the temperature was controlled at 70-80° C. and the reaction was carried out for 2 h.

[0049] Take another reaction bottle and add 3.00g 4-amino-3-hydroxybenzoic acid (1.0eq), 30ml THF, 3ml water, control the temperature at 0-20℃, stir and dissolve; add the obtained 3,5-dichlorobenzoyl chloride reaction solution to the 4-amino-3-hydroxybenzoic acid system, react at 20-30℃ for 2h, add 1.98g triethylamine (1.0eq), 3.84g methanesulfonic acid (2.04eq), 30ml toluene to the reaction system, gradually increase the temperature to 105-115℃, react for about 20h, then cool to 0-10℃, add 12ml isopropanol for crystallization, filter, rinse with 4ml isopropanol, and dry the filter cake to obtain 5.59g sample. That is, formula (I) (liquid phase purity 98.33%).

Claims

1. A method for preparing a compound 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I), the route is as follows: Step (A): 3,5-dichlorobenzoic acid reacts with an organic solvent and an acylating agent to obtain a reaction solution of 3,5-dichlorobenzoyl chloride; the organic solvent in the step (A) is selected from one or more of toluene, tetrahydrofuran, dichloromethane or dimethylformyl; the acylating agent in the step (A) is selected from thionyl chloride or oxalyl chloride; Step (B): adding the obtained reaction solution containing 3,5-dichlorobenzoyl chloride to a solvent containing 4-amino-3-hydroxybenzoic acid to react to obtain a reaction solution of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid; wherein the solvent in step (B) is selected from one or more of benzene, tetrahydrofuran, dichloromethane or water; Step (C): adding a base to the obtained reaction solution containing 4-(3,5-dichlorobenzamide)-3-hydroxybenzoic acid, then adding methanesulfonic acid, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate, heating, then adding a benzene series to react at 100° C. or above, and after the reaction is completed, directly cooling and filtering or cooling and adding an alcohol solvent for crystallization, filtering, and obtaining 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid (I); wherein the base in the step (C) is selected from triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium bicarbonate or sodium carbonate wherein the benzene series in step (C) is selected from toluene or xylene; wherein the amount of the base in step (C) is 1-4 equivalents of 4-amino-3-hydroxybenzoic acid; wherein the alcohol solvent in step (C) is selected from one or more of methanol, ethanol, isopropanol, n-propanol or n-butanol; wherein the amount of methanesulfonic acid, p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate in step (C) should be 1.0-5.0 equivalents of 4-amino-3-hydroxybenzoic acid; wherein the cooling in step (C) is below 70°C.

2. The preparation method according to claim 1, characterized in that: The organic solvent in step (A) is one or more of toluene, tetrahydrofuran or dimethylformamide.

3. The preparation method according to claim 2, characterized in that: The organic solvent in step (A) is one or two of tetrahydrofuran and dimethylformamide.

4. The preparation method according to claim 3, characterized in that: The organic solvent in step (A) is tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that: The acylating agent in the step (A) is thionyl chloride.

6. The preparation method according to claim 1, characterized in that: The solvent in step (B) is one or more of tetrahydrofuran, dichloromethane or water.

7. The preparation method according to claim 6, characterized in that: The solvent in step (B) is one or both of tetrahydrofuran and water.

8. The preparation method according to claim 1, characterized in that: In the step (C), the base is triethylamine.

9. The preparation method according to claim 1, characterized in that: The benzene series compound in the step (C) is toluene.

10. The preparation method according to claim 1, characterized in that: The alcohol solvent in step (C) is isopropanol, ethanol or methanol.

11. The preparation method according to claim 10, characterized in that: The alcohol solvent in step (C) is isopropanol.

12. The preparation method according to claim 1, characterized in that: The temperature in step (C) is lowered to below 30°C.

13. The preparation method according to claim 12, characterized in that: The temperature in step (C) is lowered to 0-10°C.

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