A process for the preparation of a dronedarone hydrochloride intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a hydrochloric acid dinedarone intermediate N-(2-n-butyl-3-(4-halogenated benzoyl) benzofuran-5-yl) methanesulfonamide. The preparation method of the hydrochloric acid dinedarone intermediate provided by the application is safe, simple and convenient in operation process, high in product yield and purity, green and environment-friendly, and suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an intermediate N-(2-n-butyl-3-(4-halogen benzoyl) benzofuran-5-yl) methanesulfonamide of dronedarone hydrochloride. BACKGROUND

[0002] Dronedarone hydrochloride, chemically named as 2-n-butyl-3-[4-(3-dibutylamino propoxy) benzoyl]-5-methanesulfonamidobenzofuran hydrochloride, CAS: 141625-93-6, is a new antiarrhythmic drug, which is developed by Sanofi Company in France, registered in the United States and the European Union, and approved for clinical use in China in July 2006. It is mainly used for treating arrhythmia, can effectively reduce the risk of cardiovascular events in patients with atrial fibrillation or atrial flutter, and is suitable for heart rhythm control, maintaining sinus rhythm and slowing the ventricular rhythm of patients with atrial fibrillation and atrial flutter.

[0003] There are many literatures about the synthesis of dronedarone hydrochloride. In the patent EP2617718A1 and the like, 2-n-butyl-5-benzofuranyl methanesulfonamide and 4-halogen benzoyl chloride are subjected to Friedel-Crafts acylation reaction under the catalysis of Lewis acid to prepare N-(2-n-butyl-3-(4-halogen benzoyl) benzofuran-5-yl) methanesulfonamide (I-1), then subjected to Ullmann reaction with 3-(dibutylamino) propan-1-ol under the catalysis of CuI to prepare dronedarone, and finally subjected to salt formation to prepare dronedarone hydrochloride, and the synthetic route is as follows:

[0004]

[0005] When the intermediate I-1 is prepared by the above route, the catalyst used is Lewis acid such as anhydrous SnCl4, FeCl3, TiCl4 or AlCl3 containing metal ions, ① the catalysts in the series have high activity, the reaction is violent, and the reproducibility is poor, and the feeding temperature and the catalyst feeding mode need to be strictly controlled; ② the catalysts in the series will produce a large amount of acid mist during operation, and a large amount of metal salt solid waste and waste liquid containing metal ions will be produced after post-treatment, which causes great pollution to the environment; ③ the Friedel-Crafts acylation reaction for preparing related products will produce various isomerization acylation impurities, which need to be repeatedly refined and purified, so that the operation is complicated and the total yield is reduced.

[0006] Based on the technical problems existing in the preparation of N-(2-n-butyl-3-(4-halogen benzoyl) benzofuran-5-yl) methanesulfonamide (I-1) above, it is still one of the problems to be solved at present to find a process route for producing the intermediate I-1 of dronedarone hydrochloride which is safe, simple in operation process, high in product yield and purity, so as to ensure the production, market supply and quality of dronedarone hydrochloride. SUMMARY

[0007] In view of the problems existing in the preparation of the intermediate N-(2-n-butyl-3-(4-halogen benzoyl) benzofuran-5-yl) methanesulfonamide (I-1) of dronedarone hydrochloride in the prior art, the present application provides a high-efficiency and simple preparation method of the intermediate I-1 of dronedarone hydrochloride.

[0008] The specific technical scheme of the present application is as follows:

[0009] In the first aspect, the present application provides a preparation method of the intermediate I-1 of dronedarone hydrochloride, which comprises the following steps:

[0010] wherein R is H, C 1～6 alkyl, -C6H5, -p-C6H4CH3, -CH2C6H5; X is halogen.

[0011] The preparation method specifically comprises the following steps: iodine and zinc are added into an organic solvent 1, stirred, SM-1 is added, temperature T1 is controlled for reaction, after the reaction is completed, the reaction liquid is reduced to room temperature, an organic solvent 2, SM-2 and a catalyst are added, temperature T2 is controlled for reaction, after the reaction is completed, the target product I-1 is obtained through post-treatment.

[0012] Preferably, T1 is 65-100℃.

[0013] Further preferably, T1 is 70-75℃.

[0014] Preferably, the molar ratio of SM-1 to iodine and zinc is 1:0.02-0.1:1.2-1.8.

[0015] Further preferably, the molar ratio of SM-1 to iodine and zinc is 1:0.05:1.5.

[0016] Preferably, the zinc is zinc powder or zinc scrap; and the zinc powder is particularly preferred.

[0017] Preferably, the organic solvent 1 is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone and N,N-dimethyl acryl urea.

[0018] Preferably, the molar ratio of SM-1 to SM-2 is 1:1.2-1.6.

[0019] Further preferably, the molar ratio of SM-1 to SM-2 is 1:1.4.

[0020] Preferably, the molar ratio of SM-1 to catalyst is 1:2%-10%.

[0021] Further preferably, the molar ratio of SM-1 to catalyst is 1:5%.

[0022] Preferably, the SM-2 is one of 4-fluorobenzoic acid-(S)-thiomethyl ester, 4-fluorobenzoic acid-(S)-thioethyl ester, 4-chlorobenzoic acid-(S)-thiomethyl ester, 4-chlorobenzoic acid-(S)-thioethyl ester, 4-bromobenzoic acid-(S)-thiomethyl ester, 4-bromobenzoic acid-(S)-thioethyl ester, 4-iodobenzoic acid-(S)-thiomethyl ester, and 4-iodobenzoic acid-(S)-thioethyl ester.

[0023] Preferably, T2 is 15-50°C.

[0024] Further preferably, T2 is 40-50°C.

[0025] Preferably, the catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2.

[0026] Preferably, the organic solvent 2 is one or more of toluene, dichloromethane, chloroform, and tetrahydrofuran.

[0027] Preferably, the reaction is carried out under inert gas protection.

[0028] Further preferably, the inert gas is one or a combination of argon and nitrogen; and particularly preferably, the inert gas is argon.

[0029] In a preferred embodiment, the post-treatment step is as follows: the reaction solution is filtered through celite, the filtrate is poured into dilute hydrochloric acid for quenching, an organic solvent is extracted, the organic phase is washed with saturated brine, and the organic phase is concentrated to dryness under reduced pressure to obtain the target product I-1.

[0030] Preferably, the dilute hydrochloric acid is 0.5-2 mol / L, and particularly preferably, the dilute hydrochloric acid is 1 mol / L.

[0031] Preferably, the organic solvent is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, and particularly preferably, the organic solvent is dichloromethane.

[0032] Compared with the prior art, the present application provides a new route for synthesizing a new intermediate of the hydrochloric acid dinedarone, which is simple and efficient, has high yield and purity, is green and environment-friendly, and is suitable for industrial production. DETAILED DESCRIPTION

[0033] The present application is further illustrated by the following examples, it should be understood that the examples of the present application are only used to illustrate the present application, but not limit the present application, so, the simple improvement of the present application under the method of the present application is within the scope of the present application.

[0034] In the following examples, various processes and methods not described in detail are conventional methods known in the art.

[0035] Example 1

[0036]

[0037] Under the condition of argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) and stirred, then SM-1 (34.62 g) was added and reacted at 70-75℃, after the reaction was detected to be completed, the reaction liquid was cooled to room temperature, then toluene (300 ml), 4-fluorobenzoic acid-(S)-thiomethyl ester (23.83 g) and Pd(dppf)Cl2 (3.66 g) were added and reacted at 45-50℃, after the reaction was detected to be completed, the reaction liquid was filtered through diatomite, the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-fluorobenzoyl) benzofuran-5-yl) methanesulfonamide, with a yield of 87.4% and HPLC purity of 99.87%.

[0038] Example 2

[0039]

[0040] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction liquid was cooled to room temperature, tetrahydrofuran (300 ml), 4-fluorobenzoic acid-(S)-thioethyl ester (22.11 g) and Pd(dppf)Cl2(1.46 g) were added, and the reaction was continued at 40-45°C. After the reaction was completed, the reaction liquid was filtered through celite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching. The chloroform (1000 ml x 3) was extracted, and the saturated brine (1000 ml x 2) was washed. The organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl) methanesulfonamide, with a yield of 80.3% and an HPLC purity of 99.80%.

[0041] Example 3

[0042]

[0043] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction liquid was cooled to room temperature, tetrahydrofuran (300 ml), 4-fluorobenzoic acid-(S)-thioethyl ester (22.11 g) and Pd(dppf)Cl2(1.46 g) were added, and the reaction was continued at 40-45°C. After the reaction was completed, the reaction liquid was filtered through celite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching. The chloroform (1000 ml x 3) was extracted, and the saturated brine (1000 ml x 2) was washed. The organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl) methanesulfonamide, with a yield of 80.3% and an HPLC purity of 99.80%.

[0044] Example 4

[0045]

[0046] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 55-60°C. After the reaction was completed, the reaction liquid was cooled to room temperature, and then toluene (300 ml), 4-fluorobenzoic acid-(S)-thiomethyl ester (23.83 g) and Pd(dppf)Cl2(3.66 g) were added, and the reaction was continued at 45-50°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, and extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 70.2% and an HPLC purity of 98.69%.

[0047] Example 5

[0048]

[0049] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 55-60°C. After the reaction was completed, the reaction liquid was cooled to room temperature, and then toluene (300 ml), 4-fluorobenzoic acid-(S)-thiomethyl ester (23.83 g) and Pd(dppf)Cl2(3.66 g) were added, and the reaction was continued at 45-50°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, and extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 70.2% and an HPLC purity of 98.69%.

[0050] Example 6

[0051]

[0052] Under argon protection, iodine (1.90 g) and zinc dust (14.71 g) were added into N,N-dimethylacetamide (300 ml) and stirred, then SM-1 (51.93 g) was added and the reaction was carried out at 70-75°C, after the reaction was completed, the reaction liquid was cooled to room temperature, tetrahydrofuran (300 ml), 4-chlorobenzoic acid-(S)-thioethyl ester (48.16 g) and Pd(dppf)Cl2(10.98 g) were added, and the reaction was continued at 45-50°C, after the reaction was completed, the reaction liquid was filtered through celite, the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, methyl tert-butyl ether (1000 ml x 3) was used for extraction, saturated brine (1000 ml x 2) was used for washing, and the organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-chlorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 79.1% and an HPLC purity of 99.75%.

[0053] Example 7

[0054]

[0055] Under argon protection, iodine (1.90 g) and zinc dust (14.71 g) were added into N,N-dimethylacetamide (300 ml) and stirred, then SM-1 (51.93 g) was added and the reaction was carried out at 70-75°C, after the reaction was completed, the reaction liquid was cooled to room temperature, tetrahydrofuran (300 ml), 4-chlorobenzoic acid-(S)-thioethyl ester (48.16 g) and Pd(dppf)Cl2(10.98 g) were added, and the reaction was continued at 45-50°C, after the reaction was completed, the reaction liquid was filtered through celite, the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, methyl tert-butyl ether (1000 ml x 3) was used for extraction, saturated brine (1000 ml x 2) was used for washing, and the organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-chlorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 79.1% and an HPLC purity of 99.75%.

[0056] Example 8

[0057]

[0058] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 80-85°C. After the reaction was completed, the reaction liquid was cooled to room temperature, and then toluene (300 ml), 4-chlorobenzoic acid-(S)-thiomethyl ester (26.13 g) and Pd(dppf)Cl2(3.66 g) were added, and the reaction was continued at 40-45°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, and extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-chlorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 77.4% and an HPLC purity of 99.75%.

[0059] Example 9

[0060]

[0061] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 80-85°C. After the reaction was completed, the reaction liquid was cooled to room temperature, and then toluene (300 ml), 4-chlorobenzoic acid-(S)-thiomethyl ester (26.13 g) and Pd(dppf)Cl2(3.66 g) were added, and the reaction was continued at 40-45°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, and extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-chlorobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 77.4% and an HPLC purity of 99.75%.

[0062] Example 10

[0063]

[0064] Under argon protection, iodine (2.54 g) and zinc powder (19.61 g) were added into N,N-dimethylformamide (500 ml) with stirring, SM-1 (69.25 g) was added, and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction liquid was cooled to room temperature, toluene (400 ml), 4-iodobenzoic acid-(S)-thiomethyl ester (77.87 g) and Pd(dppf)Cl2(7.32 g) were added, and the reaction was continued at 25-30°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching. The product was extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-iodobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 72.2% and an HPLC purity of 97.36%.

[0065] Example 11

[0066]

[0067] Under argon protection, iodine (2.54 g) and zinc powder (19.61 g) were added into N,N-dimethylformamide (500 ml) with stirring, SM-1 (69.25 g) was added, and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction liquid was cooled to room temperature, toluene (400 ml), 4-iodobenzoic acid-(S)-thiomethyl ester (77.87 g) and Pd(dppf)Cl2(7.32 g) were added, and the reaction was continued at 25-30°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching. The product was extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-iodobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 72.2% and an HPLC purity of 97.36%.

[0068] Example 12

[0069]

[0070] Under the condition of nitrogen protection, iodine (5.08 g) and zinc powder (16.34 g) were added into N, N-dimethylacrylamide (300 ml) and stirred, then SM-1 (34.62 g) was added and reacted at 70-75°C, after the reaction was detected to be completed, the reaction liquid was cooled to room temperature, dichloromethane (300 ml), 4-bromobenzoic acid-(S)-thiomethyl ester (32.36 g) and Pd(dppf)Cl2(3.66 g) were added and reacted at 40-45°C, after the reaction was detected to be completed, the reaction liquid was filtered through diatomite, the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, chloroform (1000 ml x 3) was used for extraction, saturated brine (1000 ml x 2) was used for washing, and the organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-bromobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 74.6% and an HPLC purity of 99.69%.

[0071] Example 13

[0072]

[0073] Under the condition of nitrogen protection, iodine (5.08 g) and zinc powder (16.34 g) were added into N, N-dimethylacrylamide (300 ml) and stirred, then SM-1 (34.62 g) was added and reacted at 70-75°C, after the reaction was detected to be completed, the reaction liquid was cooled to room temperature, dichloromethane (300 ml), 4-bromobenzoic acid-(S)-thiomethyl ester (32.36 g) and Pd(dppf)Cl2(3.66 g) were added and reacted at 40-45°C, after the reaction was detected to be completed, the reaction liquid was filtered through diatomite, the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching, chloroform (1000 ml x 3) was used for extraction, saturated brine (1000 ml x 2) was used for washing, and the organic phase was concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-bromobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 74.6% and an HPLC purity of 99.69%.

[0074] Example 14

[0075]

[0076] Under argon protection, iodine (1.27 g) and zinc powder (9.81 g) were added into N, N-dimethylacetamide (300 ml) with stirring, SM-1 (34.62 g) was added, and the reaction was carried out at 70-75°C. After the reaction was completed, the reaction liquid was cooled to room temperature, and then toluene (300 ml), 4-bromobenzoic acid-(S)-thioethyl ester (34.32 g) and Pd2(dba)3 (4.58 g) were added. The reaction was continuously carried out at 45-50°C. After the reaction was completed, the reaction liquid was filtered through diatomite, and the filtrate was poured into 1 mol / L dilute hydrochloric acid (3 L) for quenching. The product was extracted with dichloromethane (1000 ml x 3), washed with saturated brine (1000 ml x 2), and concentrated to dryness under reduced pressure to obtain N-(2-n-butyl-3-(4-bromobenzoyl)benzofuran-5-yl)methanesulfonamide, with a yield of 76.3% and an HPLC purity of 99.76%.

Claims

1. A process for the preparation of an intermediate of dronedarone hydrochloride, characterized in that, The method comprises the following steps: wherein R is H, C 1～6 alkyl, -C6H5, p -C6H4CH3, -CH2C6H5; X is halogen; comprising the following steps: iodine, zinc are added into organic solvent 1, stirring, SM-1 is added, temperature T1 is controlled for reaction, after the reaction is completed, the reaction liquid is reduced to room temperature, then organic solvent 2, SM-2 and catalyst are added, temperature T2 is continuously controlled for reaction, after the reaction is completed, the target product I-1 is prepared through post-treatment; the T1 is 65-100 DEG C; the T2 is 40-50 DEG C; the molar ratio of SM-1, iodine and zinc is 1:0.02-0.1:1.2-1.8; the catalyst is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2 and Pd(dppf)Cl2.

2. The production method according to claim 1, wherein The T1 is 70-75°C.

3. The production method according to claim 1, wherein said organic solvent 1 is selected from one or more of dimethyl sulfoxide, N , N - dimethylformamide, N , N - dimethylacetamide, N - methylpyrrolidone, N,N - dimethylpropylene urea.

4. The production method according to claim 1, wherein The SM-1 and the catalyst are in a feed molar ratio of 1:2%-10%.

5. The production method according to claim 1, wherein The organic solvent 2 is selected from one or more of toluene, dichloromethane, chloroform, tetrahydrofuran.

6. The production method according to claim 1, wherein The SM-2 is selected from one of 4-fluorobenzoic acid-( S )-thiomethyl ester, 4-fluorobenzoic acid-( S )-thioethyl ester, 4-chlorobenzoic acid-( S )-thiomethyl ester, 4-chlorobenzoic acid-( S )-thioethyl ester, 4-bromobenzoic acid-( S )-thiomethyl ester, 4-bromobenzoic acid-( S )-thioethyl ester, 4-iodobenzoic acid-( S )-thiomethyl ester, 4-iodobenzoic acid-( S )-thioethyl ester.

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