Method for preparing dronedarone intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for preparing a dronedarone intermediate. According to the preparation method, 2-butyl-5-nitrobenzofuran-3-carboxylic acid is taken as a starting material and reacts with phenol, then rearrangement is carried out, the dronedarone intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran is obtained, the route is simple, convenient and efficient, the obtained product is high in yield and purity, and the preparation method is green, environmentally friendly and suitable for industrial production. The use of various metal Lewis acid catalysts can be effectively avoided, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a dronedarone intermediate. Background Art

[0002] Dronedarone Hydrochloride, chemically named N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-5-benzofuranyl]methanesulfonamide hydrochloride, is an antiarrhythmic drug developed by Sanofi-Aventis of France. This drug has similar electrophysiological effects to amiodarone hydrochloride, but it does not contain iodine, so it will not cause iodine-related adverse reactions, and is an alternative to the latter. It was first approved by the FDA in July 2009 and was launched in the United States. This product is suitable for cardiac rhythm control, maintaining sinus rhythm and slowing ventricular rhythm in patients with atrial fibrillation and atrial flutter. It is mainly used in the clinical treatment of arrhythmias. The chemical structure of the related compound is as follows:

[0003]

[0004] At present, there are many publicly reported synthetic routes for dronedarone hydrochloride, among which patents FR2665444 (same patents EP0471609A1, US5223510A), EP2428511A1, US5336738A, US5223510A, WO03040120A1, CN102070578A, CN102659726B and documents Org.Process Res.Dev., 2014, 18, 157-162, Org.Process Res.Dev., 2013, 17, 863-868 etc. prepare 2-n-butyl-5-nitrobenzofuran by various routes, then react with 4-methoxybenzoyl chloride (anisyl chloride) by anhydrous SnCl 4 (or FeCl 3 、AlCl 3 ) catalyzes the Friedel-Crafts acylation reaction to obtain 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran, which is then further treated with anhydrous A1Cl 3 The key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) was obtained by catalytic removal of the methyl group of phenol methyl ether, which was then etherified with N-(3-chloropropyl)-di-n-butylamine in the presence of anhydrous potassium carbonate, and then reacted with PtO 2 As catalyst, 3.4atm pressure hydrogen (or Pd / CH 2) reducing the nitro group to the amino group, and then the reduction product reacts with methanesulfonyl chloride in the presence of triethylamine to undergo a methylsulfonylation reaction of the amino group, and finally acidifies with hydrochloric acid to obtain the target product, dronedarone hydrochloride. The synthetic route is as follows:

[0005]

[0006] As can be seen from the above, 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) can be used as a key intermediate for preparing dronedarone hydrochloride, so 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) can directly affect the production, market supply and quality of the drug. Its specific structural formula is as follows:

[0007]

[0008] Meanwhile, patent CN101948455B first reacts 5-nitrosalicylicaldehyde with methyl 2-bromohexanoate, and then produces 2-(2-formyl-4-nitrophenoxy) hexanoic acid by hydrolysis; then, under the action of benzenesulfonyl chloride, 2-n-butyl-5-nitrobenzofuran is produced by ring buckling; in the presence of AlCl 3 Under the action of catalyst, the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) is obtained by Friedel-Crafts acylation reaction with 4-methoxybenzoyl chloride (anisyl chloride) and removal of the methyl protecting group. The synthetic route is as follows:

[0009]

[0010] The literature "Synthesis of Dronedarone Hydrochloride", Chinese Journal of Pharmaceutical Industry, 2011, 42(3), 161-164 and patent CN109970693A use cheap p-nitrophenol as the starting material, react with paraformaldehyde or dimethylformal in the presence of hydrochloric acid to obtain 2-chloromethyl-4-nitrophenol; then react with triphenylphosphine to generate 2-hydroxy-5-nitrobenzyl) triphenylphosphine chloride; react with n-valeryl chloride to obtain 2-butyl-5-nitrobenzofuran; in the presence of AlCl 3 Under the catalytic action, after Friedel-Crafts acylation reaction with 4-methoxybenzoyl chloride (anisyl chloride), it is further reacted with anhydrous A1Cl 3 The key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) is obtained by catalytic removal of the methyl group of phenol methyl ether. The synthetic route is as follows:

[0011]

[0012] In addition, patent CN102153530A uses 2-butyl-5-nitrobenzofuran as a starting material, and reacts with p-acetoxybenzoyl chloride under Lewis acid catalysis to obtain 2-butyl-3-(4-acetoxybenzoyl)-5-nitrobenzofuran, and finally hydrolyzes it with sodium hydroxide to obtain the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I). Among them, the key material p-acetoxybenzoyl chloride is p-hydroxybenzoic acid as a starting material, and reacts with acetic anhydride under concentrated sulfuric acid catalysis to first obtain p-acetoxybenzoic acid, and then reacts with oxalyl chloride or thionyl chloride. The synthetic route is as follows:

[0013]

[0014] The catalyst used in the above route for preparing the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) is an anhydrous SnCl containing metal ions. 4 、FeCl 3 、TiCl 4 or AlCl 3 Lewis acid, ① This series of catalysts has high activity, violent reaction, and poor reproducibility, and requires strict control of the feeding temperature and catalyst feeding method; ② This series of catalysts will produce a large amount of acid mist during operation, and after post-treatment will produce a large amount of metal salt solid waste and waste liquid containing metal ions, causing great pollution to the environment.

[0015] Based on the technical problems existing in the preparation of the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) of dronedarone hydrochloride, a process route for producing the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I) of dronedarone hydrochloride with a safe and simple operation process, high product yield and high purity is studied to ensure the production, market supply and quality of dronedarone hydrochloride, which is still one of the problems that need to be solved at present. Summary of the invention

[0016] Aiming at the many problems existing in the prior art in preparing the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of dronedarone hydrochloride, the present invention provides a new method for preparing the key intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran of dronedarone hydrochloride. The method has mild reaction conditions, a safe and simple operation process, and the obtained target product has high purity and yield.

[0017] The specific technical solutions of the present invention are as follows:

[0018]

[0019] A method for preparing 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran, a key intermediate of dronedarone hydrochloride, comprises the following steps:

[0020] Step 1: Add compound SM to thionyl chloride at room temperature and control the temperature T A After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, dissolved with organic solvent A, and an acid-binding agent and phenol are added, and the temperature is continued to be controlled. B After the reaction is completed, the intermediate compound I-1 is obtained by post-treatment;

[0021] Preferably, the mass volume ratio of SM to thionyl chloride in step 1 is 1:4-10 g / mL, preferably 6 g / mL.

[0022] Preferably, the organic solvent A in step 1 is one of dichloromethane and chloroform, preferably dichloromethane.

[0023] Preferably, the acid binding agent described in step 1 is selected from one of N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and sodium bicarbonate, preferably triethylamine.

[0024] Preferably, the molar ratio of the compound SM to phenol and the acid binding agent in step 1 is 1:1.05-1.3:2.0-4.5, preferably 1:1.1:2.2.

[0025] Preferably, the reaction temperature T in step 1 is A 50~79 ℃, preferably reflux temperature; T B The temperature is 15 to 50°C, preferably 25 to 30°C.

[0026] In a preferred embodiment, after the reaction in step 1 is completed, a post-treatment operation is required, specifically: the reaction solution is poured into purified water, the organic phase is separated, washed with saturated sodium bicarbonate solution, washed with saturated brine, and the organic phase is concentrated to dryness under reduced pressure to obtain intermediate I-1.

[0027] Step 2: Compound I-1, BF 3 ·Et 2 O is added to glacial acetic acid and the temperature is controlled at T C After the reaction is completed, the target compound I is obtained by post-treatment;

[0028] Preferably, the compound I-1 and BF 3 ·Et 2 The molar ratio of O is 1:2.5-5.0, preferably 1:3.0.

[0029] Preferably, the reaction temperature T in step 2 is CIt is 70-100°C, preferably 80-85°C.

[0030] In a preferred embodiment, after the reaction in step 2 is completed, a post-treatment operation is required, specifically: the reaction solution is cooled to room temperature, the reaction is quenched with ice water, extracted with dichloromethane, the organic phases are combined, washed with saturated sodium bicarbonate solution and saturated brine, and the organic phase is concentrated to dryness under reduced pressure and then recrystallized from toluene to obtain the target compound I.

[0031] Compared with the prior art, the present invention provides a novel method for synthesizing dronedarone hydrochloride intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (I), the route is simple and efficient, the yield and purity of the obtained product are both high, and the method is green and environmentally friendly, and the use of various metal Lewis acid catalysts can be effectively avoided, so the method is suitable for industrial production. DETAILED DESCRIPTION

[0032] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0033] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0034] Example 1

[0035] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (158 mL), and the reaction was refluxed under controlled temperature for 4 to 5 h. The reaction solution was concentrated to dryness under reduced pressure and dissolved in dichloromethane (200 mL). A solution of triethylamine (22.26 g, 0.22 mol) and phenol (10.35 g, 0.11 mol) in dichloromethane (50 mL) was added. The reaction was continued at 25 to 30 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL) were washed. The organic phase was concentrated to dryness under reduced pressure to obtain intermediate I-1 with a yield of 98.5% and a HPLC purity of 99.92%.

[0036] Example 2

[0037] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (105 mL), and the reaction mixture was refluxed under controlled temperature for 4 to 5 h. The reaction mixture was then concentrated to dryness under reduced pressure and dissolved in dichloromethane (200 mL). A solution of N,N-diisopropylethylamine (28.45 g, 0.22 mol) and phenol (10.35 g, 0.11 mol) in dichloromethane (50 mL) was added. The reaction mixture was continued to be controlled at 25 to 30 ° C. After the reaction was completed, the reaction mixture was poured into purified water (750 mL), the organic phase was separated, and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL). The organic phase was concentrated to dryness under reduced pressure to obtain intermediate I-1 with a yield of 94.4% and a HPLC purity of 99.70%.

[0038] Example 3

[0039] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (263 mL), and the reaction was refluxed under controlled temperature for 4 to 5 h. The reaction solution was then concentrated to dryness under reduced pressure and dissolved in dichloromethane (200 mL). A solution of pyridine (17.40 g, 0.22 mol) and phenol (10.35 g, 0.11 mol) in dichloromethane (50 mL) was added, and the reaction was continued at a controlled temperature of 25 to 30 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL). The organic phase was concentrated to dryness under reduced pressure to obtain intermediate I-1 with a yield of 95.1% and a HPLC purity of 99.65%.

[0040] Example 4

[0041] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (158 mL). After the temperature was controlled to reflux for 4 to 5 h, the reaction solution was concentrated to dryness under reduced pressure and dissolved with chloroform (200 mL). A solution of triethylamine (20.24 g, 0.2 mol) and phenol (10.35 g, 0.11 mol) in chloroform (50 mL) was added. The temperature was continued to be controlled at 25 to 30 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, washed with saturated sodium bicarbonate solution (100 mL), washed with saturated brine (100 mL), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate I-1 with a yield of 95.0% and a HPLC purity of 99.68%.

[0042] Example 5

[0043] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (158 mL), and the temperature was controlled at 50-55 ° C for 4-5 h. The reaction solution was concentrated to dryness under reduced pressure and dissolved with chloroform (200 mL). A chloroform (50 mL) solution of triethylamine (45.54 g, 0.45 mol) and phenol (10.35 g, 0.11 mol) was added. The temperature was continued to be controlled at 25-30 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL) were washed. The organic phase was concentrated to dryness under reduced pressure to obtain the intermediate I-1 with a yield of 96.3% and a HPLC purity of 99.60%.

[0044] Example 6

[0045] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (158 mL), and the temperature was controlled at 75-79 ° C. After the reaction was carried out for 4-5 h, the reaction solution was concentrated to dryness under reduced pressure, dissolved in chloroform (200 mL), and a chloroform (50 mL) solution of 4-dimethylaminopyridine (26.88 g, 0.22 mol) and phenol (9.88 g, 0.105 mol) was added. After the temperature was controlled at 15-20 ° C, the reaction was completed. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) was washed with saturated brine (100 mL). The organic phase was concentrated to dryness under reduced pressure to obtain the intermediate I-1, with a yield of 95.8% and a HPLC purity of 99.71%.

[0046] Example 7

[0047] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (158 mL), and the temperature was controlled at 45-50 ° C. After the reaction was carried out for 4-5 hours, the reaction solution was concentrated to dryness under reduced pressure, dissolved with chloroform (200 mL), and a solution of sodium bicarbonate (18.48 g, 0.22 mol) and phenol (42.35 g, 0.45 mol) in dichloromethane (100 mL) was added. After the temperature was controlled at 45-50 ° C., the reaction was completed after the reaction was detected, and the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) was washed with saturated brine (100 mL). The organic phase was concentrated to dryness under reduced pressure to obtain the intermediate I-1, with a yield of 96.1% and a HPLC purity of 99.62%.

[0048] Example 8

[0049] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (80 mL), and the temperature was controlled at 45-50 ° C for 4-5 h. The reaction solution was concentrated to dryness under reduced pressure and dissolved in dichloromethane (200 mL). A solution of triethylamine (18.21 g, 0.18 mol) and phenol (9.41 g, 0.1 mol) in dichloromethane (50 mL) was added, and the temperature was continued to be controlled at 10-15 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL) were washed. The organic phase was concentrated to dryness under reduced pressure to obtain the intermediate I-1 with a yield of 85.6% and a HPLC purity of 98.89%.

[0050] Example 10

[0051] At room temperature, compound SM (26.32 g, 0.10 mol) was added to thionyl chloride (315 mL), and the temperature was controlled at 80-82 ° C for 4-5 h. The reaction solution was concentrated to dryness under reduced pressure and dissolved in dichloromethane (200 mL). A solution of triethylamine (47.56 g, 0.47 mol) and phenol (14.12 g, 0.15 mol) in dichloromethane (50 mL) was added, and the temperature was continued to be controlled at 50-55 ° C. After the reaction was completed, the reaction solution was poured into purified water (750 mL), the organic phase was separated, and the saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL) were washed. The organic phase was concentrated to dryness under reduced pressure to obtain intermediate I-1 with a yield of 89.2% and a HPLC purity of 98.45%.

[0052] Preparation of Compound I

[0053] Embodiment 11

[0054] Compound I-1 (16.97 g, 0.05 mol), BF 3 ·Et 2 O (ω=47%,45.30g,0.15mol) was added to glacial acetic acid (100mL), and the temperature was controlled to 80~85℃ for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with ice water (1000mL). The mixture was extracted with dichloromethane (400mL×3), and the organic phases were combined, washed with saturated sodium bicarbonate solution (400mL×2) and saturated brine (400mL). The organic phase was concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the target compound I with a yield of 98.5% and a HPLC purity of 99.95%.

[0055] Example 12

[0056] Compound I-1 (16.97 g, 0.05 mol), BF 3 ·Et2 O (ω=47%,37.75g,0.125mol) was added to glacial acetic acid (100mL), and the temperature was controlled to 70~75℃ for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with ice water (1000mL). The mixture was extracted with dichloromethane (400mL×3), and the organic phases were combined, washed with saturated sodium bicarbonate solution (400mL×2) and saturated brine (400mL). The organic phase was concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the target compound I with a yield of 95.2% and a HPLC purity of 99.72%.

[0057] Embodiment 13

[0058] Compound I-1 (16.97 g, 0.05 mol), BF 3 ·Et 2 O (ω=47%,75.50g,0.22mol) was added to glacial acetic acid (100mL), and the temperature was controlled at 95~100℃ to react. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with ice water (1000mL). The mixture was extracted with dichloromethane (400mL×3), and the organic phases were combined, washed with saturated sodium bicarbonate solution (400mL×2) and saturated brine (400mL). The organic phase was concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the target compound I with a yield of 96.1% and a HPLC purity of 99.60%.

[0059] Embodiment 14

[0060] Compound I-1 (16.97 g, 0.05 mol), BF 3 ·Et 2 O (ω=47%,33.22g,0.11mol) was added to glacial acetic acid (100mL), and the reaction was controlled at 65~70℃. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with ice water (1000mL). The mixture was extracted with dichloromethane (400mL×3), and the organic phases were combined, washed with saturated sodium bicarbonate solution (400mL×2) and saturated brine (400mL). The organic phase was concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the target compound I with a yield of 85.3% and a HPLC purity of 98.87%.

[0061] Embodiment 15

[0062] Compound I-1 (16.97 g, 0.05 mol), BF 3 ·Et 2O (ω=47%,78.52g,0.26mol) was added to glacial acetic acid (100mL), and the temperature was controlled at 100~105℃ to react. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction was quenched with ice water (1000mL). The mixture was extracted with dichloromethane (400mL×3), and the organic phases were combined, washed with saturated sodium bicarbonate solution (400mL×2) and saturated brine (400mL). The organic phase was concentrated to dryness under reduced pressure and recrystallized from toluene to obtain the target compound I with a yield of 88.5% and a HPLC purity of 98.21%.

Claims

1. A method for preparing a dronedarone intermediate, It is characterized in that The preparation method comprises the following steps: Step 1: Add compound SM to thionyl chloride at room temperature and control the temperature T A After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, dissolved with organic solvent A, and an acid-binding agent and phenol are added, and the temperature is continued to be controlled. B After the reaction is completed, the intermediate compound I-1 is obtained by post-treatment; Step 2: Compound I-1, BF 3 ·Et 2 O is added to glacial acetic acid and the temperature is controlled at T C After the reaction is completed, the target compound I is obtained by post-treatment; The reaction route is as follows:

2. The preparation method according to claim 1, It is characterized in that The mass volume ratio of SM to thionyl chloride in step 1 is 1:4-10 g / mL.

3. The preparation method according to claim 1, It is characterized in that The organic solvent A described in step 1 is one of dichloromethane and chloroform.

4. The preparation method according to claim 1, It is characterized in that The acid binding agent described in step 1 is selected from one of N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and sodium bicarbonate.

5. The preparation method according to claim 1, It is characterized in that The molar ratio of the compound SM to the phenol and the acid-binding agent in step 1 is 1:1.05-1.3:2.0-4.

5.

6. The preparation method according to claim 1, It is characterized in that The reaction temperature T in step 1 A It is 50~79℃.

7. The preparation method according to claim 1, It is characterized in that Compound I-1 described in step 2 and BF 3 ·Et 2 The feeding molar ratio of O is 1:2.5-5.

0.

8. The preparation method according to claim 1, It is characterized in that The reaction temperature T in step 2 C It is 70~100℃.

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