A method for preparing benzofuran compounds

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis. The present invention provides a method for preparing benzofuran compounds, which is prepared by using SM-1 and SM-2 as starting materials and obtaining benzofuran compounds under the action of a catalyst. In particular, it is the preparation of dronedarone and its related intermediates. The preparation process of the present invention has mild reaction conditions, simple operation process, high purity and yield compared with the prior art, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing benzofuran compounds. Background Art

[0002] The present invention relates to a method for preparing various benzofuran compounds, and these benzofuran compounds, such as antiarrhythmic drugs like dronedarone, and intermediate compounds required for their synthesis.

[0003] Dronedarone Hydrochloride, with the chemical name N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]methanesulfonamide hydrochloride, is an antiarrhythmic drug developed by Sanofi-Aventis France. This drug has an electrophysiological effect similar to that of Amiodarone Hydrochloride, but it does not contain iodine, so it will not cause iodine-related adverse reactions and is a replacement and updated drug for the latter. It was first launched in the United States in July 2009. This product is applicable to the control of heart rhythm, maintenance of sinus rhythm, and slowing of ventricular rhythm in patients with atrial fibrillation and atrial flutter, and is mainly used clinically for the treatment of arrhythmia. The chemical structural formulas of related compounds are as follows:

[0004]

[0005] There are many references reported on the synthesis of dronedarone hydrochloride. Among them, in patent WO03040120A2, US6828448B2, EP1343777A, EP1351907A, CN102753018A, CN1769262A (CN100371314C), WO03040120A2, WO0248132 A2, CN102666522A, CN103450124B, CN102675267B, CN102653530A and the literature Bioorganic&Medicinal Chemistry, 26(2018)4330-4335, "Synthesis and Process Optimization of Dronedarone Hydrochloride", Chemical Reagents, 2016, 38(1), 73-76, after obtaining 2-butyl-5-benzofuranylmethanesulfonamide through various routes, it reacts with 4-(3-dibutylaminopropoxy)benzoyl chloride under the catalysis of anhydrous A1C13 (or FeCl3, SnCl4) to carry out Friedel-Crafts acylation reaction to obtain dronedarone (I-1), and finally forms a salt with hydrochloric acid to obtain the target product. The synthesis route is as follows:

[0006]

[0007] Patent EP2617718A1 uses 2-n-butyl-5-benzofuranyl methanesulfonamide and 4-halogenated benzoyl chloride to react with FeCl3 to produce Friedel-Crafts acylation to obtain N-(2-n-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl) methanesulfonamide (I-2), and then reacts with 3-(dibutylamino)propan-1-ol to obtain dronedarone through Ullmann reaction under CuI catalysis, and finally forms salt to obtain the target product. The synthetic route is as follows:

[0008]

[0009] In addition, patents FR2665444 (same patents EP0471609A1, US5223510A), EP2428511A1, US5336738A, US5223510A, WO03040120A1, CN102070578A, CN102659726B and documents Org.ProcessRes.Dev.,2014,18,157-162, Org.Process Res. Dev., 2013, 17, 863-868, "Synthesis of Dronedarone Hydrochloride", Chinese Journal of Pharmaceutical Industry, 2011, 42(3), 161-164. 2-n-Butyl-5-nitrobenzofuran is prepared by various routes, and then reacted with 4-methoxybenzoyl chloride (anisyl chloride) to obtain 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran by Friedel-Crafts acylation reaction catalyzed by anhydrous SnCl4 (or FeCl3, AlCl3). Furan (I-3), then demethylated by anhydrous AlCl3 to obtain 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran, followed by etherification with N-(3-chloropropyl)-di-n-butylamine under the action of anhydrous potassium carbonate, and then PtO2 as a catalyst and 3.4atm pressure of hydrogen (or Pd / C-H2) to reduce the nitro group, and the reduction product is then treated with methanesulfonyl chloride under the action of triethylamine to carry out methylsulfonylation of the amino group, and finally acidified with hydrochloric acid to obtain the target product dronedarone hydrochloride. The synthetic route is as follows:

[0010]

[0011] At the same time, patents CN101948455B, WO200128974A2, WO2007140989A2, and CN109970693A use different strategies to prepare 2-n-butyl-5-nitrobenzofuran and 4-methoxybenzoyl chloride, and then obtain the key intermediate I-3 through Friedel-Crafts acylation reaction.

[0012] In addition, Patent CN102153530A uses 4-(chlorocarbonyl)phenyl acetate as a Friedel-Crafts acylation reagent to react with 2-n-butyl-5-nitrobenzofuran to obtain the key intermediate 2-n-butyl-3-(4-acetoxybenzoyl)-5-nitrobenzofuran (I-4), and then hydrolyzes it to obtain the corresponding intermediate for further synthesis of dronedarone hydrochloride. The synthetic route is as follows:

[0013]

[0014] Meanwhile, after obtaining 2-n-butyl-5-nitrobenzofuran by various methods in Patent CN1479706A (FR2817865, CN1295200C, WO2002048078), it first reacts with 4-(3-dibutylaminopropoxy)benzoyl chloride under the catalysis of SnCl4 (or FeCl3) through Friedel-Crafts acylation reaction to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5-nitrobenzofuran (I-5). Then, the nitro group is catalytically hydrogenated and reduced by platinum dioxide, followed by mesylation and formation of hydrochloride to obtain the target compound. The synthetic route is as follows:

[0015]

[0016] In Patent CN102321058B, 2-n-butyl-5-nitrobenzofuran reacts with 4-(3-chloropropoxy)benzoyl chloride under the catalysis of AlCl3 through Friedel-Crafts acylation reaction to obtain 2-n-butyl-3-(4-(3-chloropropoxy)benzoyl)-5-nitrobenzofuran (I-6), and then through N-alkylation, nitro reduction, mesylation, salification and other reactions to obtain the target product. The synthetic route is as follows:

[0017]

[0018] In the literature "Synthesis of Dronedarone Hydrochloride", Chinese Journal of Pharmaceuticals, 2011, 42(12), 881-883, N-(2-n-butylbenzofuran-5-yl)acetamide reacts with 4-(3-chloropropoxy)benzoyl chloride under the catalysis of AlCl3 through Friedel-Crafts acylation reaction to obtain 2-n-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-acetamidobenzofuran (I-7), and then reacts with dibutylamine, removes the acetyl protecting group, and finally the amino group undergoes mesylation reaction and salification reaction to obtain the target product. The synthetic route is as follows:

[0019]

[0020] Patent CN101993427B first uses N-(2-n-butylbenzofuran-5-yl)acetamide and 4-methoxybenzoyl chloride (anisoyl chloride) to prepare 2-n-butyl-3-(4-methoxybenzoyl)-5-acetamidobenzofuran (I-8) through Friedel-Crafts acylation reaction under the catalysis of SnCl4 (or FeCl3). Then, the target product is obtained through two strategies: one is through reactions such as demethylation, O-alkylation, deacetylation protection group removal, mesylation, and salt formation; the other is through reactions such as deacetylation and methylation, mesylation, O-alkylation, and salt formation. The synthetic route is as follows:

[0021]

[0022] Similarly, patent CN102532074A also uses the same starting materials to first prepare 2-n-butyl-3-(4-methoxybenzoyl)-5-acetamidobenzofuran (I-8) through Friedel-Crafts acylation reaction under the catalysis of SnCl4, and then obtains the target product through similar strategies such as deacetylation protection group removal, mesylation, demethylation, O-alkylation, and salt formation. The synthetic route is as follows:

[0023]

[0024] Patent CN105452232A uses 2-n-butyl-5-bromobenzofuran as the starting material and 4-fluorobenzoyl chloride to first prepare 2-n-butyl-3-(4-fluorobenzoyl)-5-bromobenzofuran (I-9) through Friedel-Crafts acylation reaction under the catalysis of AlCl3. Then, it reacts with N-protected methanesulfonamide to introduce the methanesulfonamide group, and then undergoes O-alkylation reaction to form an ether to introduce the (di-n-butylamino)propoxy side chain. Finally, the N-protecting group is removed and salt formation is carried out to obtain the target product. The synthetic route is as follows:

[0025]

[0026] Patent WO2013178337A1 discloses using 2-n-butyl-5-benzofuranylmethanesulfonamide as the raw material, through chlorination or bromination, and then reacting with magnesium to prepare a Grignard reagent, which undergoes a Grignard reaction with 4-(3-di-n-butylaminopropoxy)-N,N-dimethylbenzamide, and dronedarone is obtained after treatment. The reaction operation requires anhydrous and anaerobic operation, and the reaction conditions are demanding. At the same time, due to the strong activity of the Grignard reagent, it is extremely easy to react with the active hydrogen in its own sulfonamide group and then couple, resulting in low purity and yield of this intermediate, which is not suitable for industrial production. The reaction route is as follows:

[0027]

[0028] In summary, it can be seen that the preparation of dronedarone (I-1) and its related intermediates (I-2 to I-9) from 2-butyl-5-substituted benzofuran (SM-1) and 4-substituted benzoyl chloride (SM-2) through the Friedel-Crafts acylation reaction catalyzed by Lewis acid is a very feasible strategy and is widely used in this field. Therefore, the compounds related to I-1 to I-9 directly affect the production, market supply, and quality of dronedarone hydrochloride drugs. The relevant chemical structural formulas are as follows:

[0029]

[0030] However, currently, when preparing dronedarone (I-1) and its related intermediates (I-2 to I-9) from 2-butyl-5-substituted benzofuran (SM-1) and 4-substituted benzoyl chloride (SM-2), the catalysts used are all Lewis acids containing metal ions, such as anhydrous SnCl4, FeCl3, or AlCl3, etc. However, this series of catalysts will have the following problems when applied:

[0031] ① This series of catalysts has high activity, the reaction is violent, and it is extremely easy to generate isomeric impurities of abnormal substitution. Therefore, it is necessary to strictly control the feeding temperature and the catalyst feeding method, and the operation reproducibility is poor;

[0032] ② This series of catalysts will produce a large amount of flocculent precipitates during post-treatment. On the one hand, it will adsorb a large amount of products, resulting in a reduction in yield. On the other hand, it will also greatly extend the filtration operation time, which is not only cumbersome in operation but also increases the production cycle;

[0033] ③ This series of catalysts will produce a large amount of acid mist during operation and a large amount of metal salt solid waste and metal ion-containing waste liquid after post-treatment. This series of "three wastes" causes great pollution to the environment.

[0034] In view of the many deficiencies in the current preparation of dronedarone (I-1) and its related intermediates (I-2 to I-9) from 2-butyl-5-substituted benzofuran (SM-1) and 4-substituted benzoyl chloride (SM-2), therefore, researching and finding a preparation process for dronedarone and its related intermediates that is simple in operation, mild in reaction conditions, safe and simple in the operation process, and has high product yield and purity is still a problem that needs to be solved currently. Summary of the Invention

[0035] In view of the many problems existing in the preparation of benzofuran compounds in the current prior art, the present invention provides a method for preparing benzofuran compounds. In particular, a method for preparing dronedarone and its related intermediates. This method has mild reaction conditions, is safe and simple in the operation process, and the target products obtained have high purity and yield.

[0036] The specific technical solution of the present invention is as follows:

[0037]

[0038] Among them, in a preferred embodiment, R1 is C 1～4 alkyl, hydrogen, halogen, -NO2, -CN, -NH-C(O)R, -NH-S(O)2R;

[0039] R2 is C 1～4 alkyl, hydrogen, halogen, -O-C(O)R, -OR, -OCH2CH2CH2N(CH2CH2CH2CH3)2;

[0040] R3 is methyl, ethyl, n-propyl, isopropyl;

[0041] R represents C 1～4 alkyl or C 1～4 alkyl substituted by one or more halogen atoms.

[0042] In a preferred embodiment, R1 is -Br, -NO2, -NH-C(O)CH3, -NH-S(O)2CH3;

[0043] R2 is halogen, -O-C(O)CH3, -OCH3, -OCH2CH2CH2N(CH2CH2CH2CH3)2, -O(CH3)2CH2Cl;

[0044] R3 is methyl, ethyl, n-propyl, isopropyl.

[0045] In a further preferred embodiment, R1 is -NH-S(O)2CH3;

[0046] R2 is -OCH2CH2CH2N(CH2CH2CH2CH3)2;

[0047] R3 is methyl, ethyl, n-propyl, isopropyl; more preferably, R3 is methyl.

[0048] The present invention provides a method for preparing a benzofuran compound, which specifically includes the following steps:

[0049] Control the temperature, add the catalyst and SM-2 into the reaction solvent, stir and mix evenly, then control the temperature and add SM-1. After adding, control the temperature until the reaction is completed, pour the reaction solution into ice water, adjust the pH to 8-9 with alkali, extract with an extractant, wash with purified water, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product. Among them, SM-1 and SM-2 are the compounds defined above.

[0050] Preferably, the reaction solvent is one or a combination of tetrahydrofuran, acetone, and acetonitrile.

[0051] Preferably, the catalyst is one or a combination of phosphorus oxychloride (POCl3), thionyl chloride (SOCl2), and oxalyl chloride [(COCl)2], and phosphorus oxychloride is particularly preferred.

[0052] Preferably, the base is one of NaOH, KOH, and LiOH.

[0053] Preferably, the extractant is one of dichloromethane, chloroform, and ethyl acetate.

[0054] Preferably, the SM-1 can be directly added or added in the form of a tetrahydrofuran solution.

[0055] Preferably, the molar ratio of the feed of SM-2 to SM-1 and the catalyst is 1:1.2 - 1.4:1.3 - 1.5, and 1:1.3:1.4 is particularly preferred.

[0056] Preferably, the temperature controlled when adding SM-1 and SM-2 is -5 to 10°C, and the reaction temperature is 60 to 66°C.

[0057] Preferably, the SM-2 can be prepared by the prior art or prepared by reacting an acyl chloride with a low molecular weight dialkylamine having a corresponding structure.

[0058] In the present invention, the reaction system needs to be isolated from moisture, which can be achieved by adding a drying tube containing calcium chloride to the reaction device.

[0059] Advantages of the present invention:

[0060] 1. The present invention provides a simple and efficient method for preparing dronedarone or its intermediate. The entire synthesis method is easy to operate and suitable for industrial production.

[0061] 2. The present invention uses inexpensive phosphorus oxychloride, thionyl chloride, or oxalyl chloride to replace anhydrous SnCl4, FeCl3, or AlCl3 as the catalyst. The post-treatment is simple, which can effectively avoid the problems of generating more "three wastes", reducing the yield, and complicated post-treatment when using metal Lewis acid catalysis. At the same time, the production cost is also effectively reduced.

[0062] 3. The reaction completed through this system can effectively reduce the generation of regioisomers, and the yield and purity of the obtained product are both relatively high. Specific embodiments

[0063] The present invention will be 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 limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope claimed by the present invention.

[0064] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0065] Synthesis of I-1:

[0066]

[0067] ESI-HRMS (m / z): 557.3046 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.23 (dd, J = 8.8, 2.2 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.21 (t, J = 6.2 Hz, 2H), 3.21~3.23 (m, 2H), 3.04~3.07 (m, 4H), 2.89 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.23~2.25 (m, 2H), 1.68~1.71 (m, 4H), 1.65~1.68 (m, 2H), 1.32~1.35 (m, 4H), 1.23~1.25 (m, 2H), 0.92 (t, J = 7.2 Hz, 6H), 0.81 (t, J = 7.4 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 189.13, 164.6, 8 162.16, 150.35, 134.20, 131.35, 131.11, 127.28, 118.87, 116.31, 114.44, 113.29, 111.58, 65.31, 51.68, 48.74, 38.58, 29.39, 27.15, 24.81, 22.87, 21.55, 19.48, 13.43, 13.32.

[0068] Example 1

[0069] 4-(3-(Dibutylamino)propoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 33.45 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-1) with a yield of 93.3% and an HPLC purity of 99.85%.

[0070] Example 2

[0071] 4-(3-(Dibutylamino)propoxy)-N,N-dipropylbenzamide (SM-2, R3 = n-Pr, 39.06 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (23.00 g, 0.15 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-1) with a yield of 92.9% and an HPLC purity of 99.82%.

[0072] Example 3

[0073] 4-(3-(Dibutylamino)propoxy)-N,N-diisopropylbenzamide (SM-2, R3 = i-Pr, 39.06 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (19.93 g, 0.13 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, (34.75 g, 0.13 mol). After addition, the reaction was carried out at a controlled temperature of 66 °C. After detecting the completion of the reaction, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-1) with a yield of 92.1% and an HPLC purity of 99.79%.

[0074] Example 4

[0075] 4-(3-(Dibutylamino)propoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 33.45 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and SOCl2 (16.65 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 37.43 g, 0.14 mol) was added. After addition, the reaction was carried out at a controlled temperature of 66 °C. After detecting the completion of the reaction, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-1) with a yield of 93.4% and an HPLC purity of 99.75%.

[0076] Example 5

[0077] 4-(3-(Dibutylamino)propoxy)-N,N-diethylbenzamide (SM-2, R3 = Et, 36.26 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and (COCl)2 (17.77 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 32.08 g, 0.12 mol) was added. After addition, the reaction was carried out at a controlled temperature of 60 °C. After detecting the completion of the reaction, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-1) with a yield of 91.8% and an HPLC purity of 99.80%.

[0078] Synthesis of I-2-1:

[0079]

[0080] ESI-HRMS (m / z): 390.1172 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 9.62 (s, 1H), 7.85 (dd, J = 8.0, 5.8 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.25 (d, J = 5.1 Hz, 1H), 7.20 (dd, J = 8.6, 1.8 Hz, 1H), 2.86 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 1.61~1.65 (m, 2H), 1.23~1.27 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ: 189.43, 170.35, 166.21, 150.45, 134.46, 132.41, 132.29, 121.44, 118.35, 117.24, 115.86, 115.21, 114.36, 42.17, 30.62, 29.17, 22.18, 13.96。

[0081] Example 6

[0082] 4-Fluoro-N,N-dimethylbenzamide (SM-2, R2 = F, R3 = Me, 16.72 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0~5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0~5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8~9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml×3), washed with purified water (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-2-1) with a yield of 89.5% and an HPLC purity of 99.89%.

[0083] Synthesis of I-2-2:

[0084]

[0085] ESI-HRMS (m / z): 406.0877 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 9.62 (s, 1H), 7.85 (dd, J = 8.0, 5.8 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.25 (d, J = 5.1 Hz, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 1H), 2.88 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 1.62~1.66 (m, 2H), 1.22~1.27 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 189.60, 172.35, 150.74, 138.90, 135.32, 132.26, 130.35, 128.47, 121.21, 118.47, 117.40, 115.86, 115.01, 41.15, 30.81, 28.17, 22.18, 15.14.

[0086] Example 7

[0087] 4-Chloro-N,N-dimethylbenzamide (SM-2, R2 = Cl, R3 = Me, 18.36 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0~5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0~5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8~9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-2-2) with a yield of 88.9% and an HPLC purity of 99.78%. Synthesis of I-2-3:

[0088]

[0089] ESI-HRMS (m / z): 450.0372, 452.0350 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.85 (dd, J = 8.0, 5.8 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.25 (d, J = 5.1 Hz, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 1H), 2.86 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 1.62 - 1.66 (m, 2H), 1.22 - 1.27 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 189.56, 173.25, 150.75, 136.97, 132.41, 131.61, 131.45, 127.53, 120.20, 118.44, 117.39, 115.98, 115.24, 44.15, 30.01, 29.17, 22.18, 13.02.

[0090] Example 8

[0091] 4-Bromo-N,N-dimethylbenzamide (SM-2, R2 = Br, R3 = Me, 22.81 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After the addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-2-3) with a yield of 89.2% and an HPLC purity of 99.87%.

[0092] Synthesis of I-2-4:

[0093]

[0094] ESI-HRMS (m / z): 398.0234 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.85 (dd, J = 8.0, 5.8 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.26 (d, J = 5.1 Hz, 1H), 7.20 (dd, J = 8.8, 1.9 Hz, 1H), 2.87 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 1.62 - 1.66 (m, 2H), 1.22 - 1.27 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 190.13, 174.26, 150.74, 136.91, 136.74, 132.86, 132.42, 120.21, 118.56, 117.28, 115.98, 115.21, 93.26, 42.14, 29.76, 29.17, 22.18, 14.05.

[0095] Example 9

[0096] 4-Iodo-N,N-dimethylbenzamide (SM-2, R2 = I, R3 = Me, 27.51 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)methanesulfonamide (SM-1, 34.75 g, 0.13 mol) was added. After addition, the reaction was carried out at 60 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-2-4) with a yield of 88.6% and an HPLC purity of 99.76%.

[0097] Synthesis of I-3:

[0098]

[0099] ESI-HRMS (m / z): 354.1338 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 8.33 - 8.34 (m, 1H), 8.22 (dd, J = 8.8, 2.6 Hz, 1H), 7.82 - 7.84 (m, 2H), 7.54 - 7.58 (m, 1H), 6.98 - 7.02 (d, J = 9.3 Hz, 2H), 3.12 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 1.72 - 1.82 (m, 2H), 1.30 - 1.42 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 180.42, 173.28, 162.90, 151.04, 132.58, 130.36, 129.02, 127.45, 127.08, 122.05, 118.44, 113.20, 112.94, 56.17 29.83, 29.26, 22.23, 14.13.

[0100] Example 10

[0101] 4-(Methoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 17.92 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuous stirring and mixing, the temperature was controlled at 0 - 5 °C, and 2-n-butyl-5-nitrobenzofuran (SM-1, R1 = NO2, 28.50 g, 0.13 mol) was added. After the addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-3) with a yield of 91.2% and an HPLC purity of 99.83%.

[0102] Synthesis of I-4:

[0103]

[0104] ESI-HRMS (m / z): 382.1287 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 8.32 - 8.35 (m, 1H), 8.11 (dd, J = 8.6, 2.5 Hz, 1H), 7.78 - 7.81 (m, 3H), 7.41 (d, J = 7.6 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.27 (s, 3H), 1.77 - 1.64 (m, 2H), 1.40 - 1.26 (m, 2H), 0.97 (t, J = 7.8 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 185.63, 173.25, 169.71, 159.44, 154.10, 140.41, 134.73, 132.12, 125.70, 121.48, 121.38, 120.29, 118.44, 112.65, 29.81, 29.17, 22.18, 20.89, 14.02.

[0105] Example 11

[0106] 4-(Acetoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 20.72 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and 2-n-butyl-5-nitrobenzofuran (SM-1, R1 = NO2, 28.50 g, 0.13 mol) was added. After the addition was complete, the reaction was carried out at 66 °C. After detecting that the reaction was complete, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-4) with a yield of 90.3% and an HPLC purity of 99.79%.

[0107] Synthesis of I-5:

[0108]

[0109] ESI-HRMS (m / z): 509.3012 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 8.38 (d, J = 6.8 Hz, 1H), 8.23 (dd, J = 9.0, 2.3 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 6.9 Hz, 2H), 2.51 - 2.38 (m, 4H), 2.03 - 1.91 (m, 2H), 1.83 - 1.72 (m, 2H), 1.48 - 1.40 (m, 4H), 1.38 - 1.29 (m, 6H), 0.91 (t, J = 7.2 Hz, 9H); 13 13C NMR (101 MHz, DMSO-d6) δ: 188.47, 167.25, 163.20, 159.30, 140.64, 132.69, 130.75, 125.94, 120.16, 118.69, 117.34, 114.48, 111.33, 66.62, 53.95, 50.38, 29.90, 29.81, 29.17, 28.05, 27.05, 22.18, 20.53, 14.02, 13.62.

[0110] Example 12

[0111] 4-(3-(Dibutylamino)propoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 33.45 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and 2-butyl-5-nitrobenzofuran (SM-1, R1 = NO2, 28.50 g, 0.13 mol) was added. After the addition was complete, the reaction was carried out at 66 °C. After detecting that the reaction was complete, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-5) with a yield of 93.2% and an HPLC purity of 99.76%.

[0112] Synthesis of I-6:

[0113]

[0114] ESI-HRMS (m / z): 412.1260 [M + H] + ;1 1H NMR (400 MHz, DMSO-d6) δ: 8.30 (m, 2H), 7.97 (m, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 4.26 (t, J = 6.4 Hz; 2H), 3.86 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 6.5 Hz, 2H), 2.24 - 2.27 (m, 2H), 1.70 - 1.73 (m, 2H), 1.25 - 1.28 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 184.58, 174.26, 162.18, 160.42, 140.42, 132.28, 132.05, 125.72, 121.26, 120.13, 118.44, 113.86, 111.65, 67.45, 41.76, 30.53, 29.81, 29.17, 22.18, 14.02.

[0115] Example 13

[0116] 4-(3-Chloropropoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 24.17 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and 2-n-butyl-5-nitrobenzofuran (SM-1, R1 = NO2, 28.50 g, 0.13 mol) was added. After addition, the reaction was carried out at 60 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-6) with a yield of 94.3% and an HPLC purity of 99.73%.

[0117] Synthesis of I-7:

[0118]

[0119] ESI-HRMS (m / z): 428.1626 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 7.80 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.92 (d, J = 8.6 Hz, 2H), 4.20 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.25 - 2.30 (m, 2H), 2.11 (s, 3H), 1.68 - 1.76 (m, 2H), 1.30 - 1.36 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 182.60, 173.32, 170.26, 163.18, 157.66, 133.42, 132.10, 132.06, 124.30, 118.46, 114.95, 113.98, 113.64, 113.29, 67.45, 41.76, 30.53, 29.81, 29.17, 23.80, 22.18, 14.02。

[0120] Example 14

[0121] 4-(3-Chloropropoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 24.17 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)acetamide (SM-1, 30.07 g, 0.13 mol) was added. After the addition was complete, the reaction was carried out at 66 °C. After detecting that the reaction was complete, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-7) with a yield of 87.9% and an HPLC purity of 99.75%.

[0122] Synthesis of I-8:

[0123]

[0124]

[0125] ESI-HRMS (m / z): 366.1798 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 8.06 (s, 1H), 7.75 (d, 2H), 7.70 - 7.54 (m, 2H), 7.09 (d, J = 7.6 Hz, 2H), 3.84 (s, 3H), 3.04 (t, J = 7.4 Hz, 2H), 2.06 (s, 3H), 1.74 - 1.57 (m, 2H), 1.54 - 1.37 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 190.21, 173.25, 170.43, 162.92, 157.73, 133.42, 132.66, 130.42, 124.30, 118.44, 114.95, 113.98, 113.29, 113.20, 56.04, 29.81, 29.17, 23.80, 22.18, 14.02.

[0126] Example 15

[0127] 4-(Methoxy)-N,N-dimethylbenzamide (SM-2, R3 = Me, 17.92 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and N-(2-butylbenzofuran-5-yl)acetamide (SM-1, 30.07 g, 0.13 mol) was added. After the addition was complete, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-8) with a yield of 92.1% and an HPLC purity of 99.74%.

[0128] Synthesis of I-9:

[0129]

[0130] ESI-HRMS (m / z): 375.0392 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ: 7.80 (dd, J = 8.6, 5.5 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.43 - 7.53 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.71 - 1.49 (m, 2H), 1.29 - 1.09 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 187.68, 173.28, 166.01, 153.73, 134.45, 132.29, 128.94, 127.94, 126.38, 118.91, 118.44, 114.36, 113.97, 29.81, 29.15, 22.26, 14.12.

[0131] Example 16

[0132] 4-Fluoro-N,N-dimethylbenzamide (SM-2, R2 = F, R3 = Me, 16.72 g, 0.10 mol) was added to tetrahydrofuran (300 ml). After stirring evenly, the temperature was controlled at 0 - 5 °C, and POCl3 (21.47 g, 0.14 mol) was added. After continuing to stir and mix evenly, the temperature was controlled at 0 - 5 °C, and 2-n-butyl-5-bromobenzofuran (SM-1, R1 = Br, 25.31 g, 0.13 mol) was added. After the addition, the reaction was carried out at 66 °C. After detecting that the reaction was completed, the reaction solution was poured into ice water (1000 ml), and the pH was adjusted to 8 - 9 with sodium hydroxide solution. It was extracted with dichloromethane (300 ml × 3), washed with purified water (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product (I-9) with a yield of 87.6% and an HPLC purity of 99.71%.

Claims

1. A method for preparing benzofuran compounds, characterized in that, Using SM-1 and SM-2 as raw materials, compound I is directly prepared under the action of a catalyst; the route is as follows: ； Among them, R1 is C 1～4 alkyl, hydrogen, halogen, -NO2, -CN, -NH-C(O)R, -NH-S(O)2R; R2 is C 1～4 alkyl, hydrogen, halogen, -O-C(O)R, -OR, -OCH2CH2CH2N(CH2CH2CH2CH3)2; R3 is methyl, ethyl, n-propyl, or isopropyl; R is represented as C 1～4 alkyl or C 1～4 alkyl substituted by one or more halogen atoms; The catalyst is one or a combination of phosphorus oxychloride, thionyl chloride, and oxalyl chloride.

2. The method according to claim 1, characterized in that, Among them, R1 is -Br, -NO2, -NH-C(O)CH3, -NH-S(O)2CH3; R2 is halogen, -O-C(O)CH3, -OCH3, -OCH2CH2CH2N(CH2CH2CH2CH3)2, -O(CH3)2CH2Cl; R3 is methyl, ethyl, n-propyl, or isopropyl.

3. The method according to claim 1 or 2, characterized in that, R1 is -NH-S(O)2CH3; R2 is -OCH2CH2CH2N(CH2CH2CH2CH3)2; R3 is methyl, ethyl, n-propyl, or isopropyl.

4. The method according to claim 1 or 2, characterized in that, R1 is -NH-S(O)2CH3; R2 is -OCH2CH2CH2N(CH2CH2CH2CH3)2; R3 is methyl.

5. The method according to claim 1, characterized in that, Specifically, it includes the following steps: Control the temperature. Add the catalyst and SM-2 into the reaction solvent, stir and mix evenly, then add SM-1 while controlling the temperature. After adding, control the temperature until the reaction ends. Then pour the reaction solution into ice water, adjust the pH to 8-9 with an alkali, extract with an extractant, wash with purified water, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product.

6. The method according to claim 5, characterized in that, The reaction solvent is one or a combination of tetrahydrofuran, acetone, and acetonitrile.

7. The method according to claim 5, wherein The catalyst is phosphorus oxychloride.

8. The method according to claim 5, characterized in that, The molar ratio of the feed of SM-2 to SM-1 and the catalyst is 1:1.2-1.4:1.3-1.

5.

9. The method according to claim 5, wherein The temperature controlled when adding SM-1 and SM-2 is -5-10°C.

10. The method according to claim 5, wherein The reaction temperature of SM-1 and SM-2 is 60-66°C.

11. The method according to claim 5, wherein, The extractant is one of dichloromethane, chloroform, and ethyl acetate.

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