A silodosin intermediate and a process for its preparation

Abstract

The application provides a silodosin intermediate and a preparation method thereof, and relates to the technical field of medicine preparation. The method comprises the following steps: S1, propyl 3-(indolin-1-yl)benzoate is used as raw material, and a substitution reaction is performed on the raw material with a bromine reagent to obtain propyl 3-(5.7-dibromo-indolin-1-yl)benzoate; S2, the propyl 3-(5.7-dibromo-indolin-1-yl)benzoate is subjected to a substitution reaction to obtain propyl 3-(7-cyano-5-bromo-indolin-1-yl)benzoate; S3, the propyl 3-(7-cyano-5-bromo-indolin-1-yl)benzoate is subjected to nucleophilic addition ring opening with propylene oxide to obtain propyl 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoate; and S4, the propyl 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoate is subjected to oxidation to generate propyl 3-(7-cyano-5-(2-oxo-propyl)indolin-1-yl)benzoate. According to the synthesis method, all raw materials are easy to obtain, no high-risk and high-pollution reagents are used, the method is safe and environmentally friendly, the prepared silodosin intermediate has high purity and high yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a silodosin intermediate and its preparation method. Background Technology

[0002] Benign prostatic hyperplasia (BPH), or enlarged prostate, is a common disease among elderly men, characterized by non-malignant enlargement of the prostate gland. More than 50% of men aged 60 and over suffer from this condition. The exact cause is not fully understood, but it is generally believed to be related to imbalances in the secretion and metabolism of sex hormones and cholesterol. Some believe that in older men, the pituitary-gonadotropin-testis pathway weakens or endogenous changes lead to testicular degeneration, decreased sexual function, lower testosterone levels, and increased connective tissue in the prostate, resulting in changes in glandular epithelium and prostate enlargement. The enlarged prostate can compress the urethra, causing bladder obstruction and even blockage of the bladder outlet. The human prostate contains α1A-adrenergic receptors; activation of these receptors can exacerbate urethral obstruction and difficulty urinating. Clinically, silodosin is mainly used to treat this disease. Its chemical name is 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide.

[0003] Silodosin is an α1-receptor antagonist invented by Kissei Pharmaceutical Co., Ltd. of Japan. Kissei, in collaboration with Daiichi Sankyo, applied for and received marketing approval in Japan in May 2006 under the brand name Urief(R). Kissei also licensed silodosin to Watson Pharmaceuticals in the United States, which recently applied for FDA approval in August 2008.

[0004] Several studies have reported the use of propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate as an intermediate in a multi-step reaction to prepare silodocine, as shown in reaction formula 1:

[0005]

[0006] Currently, there are many synthetic routes for propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, and the relevant literature and patents mainly include the following. One is the synthetic route reported by Japanese patent JP2001199956, which uses indoline, benzoyl chloride, etc. as starting materials, as shown in synthetic route 1. This synthetic route is long, has a relatively low yield, uses POCl3, easily generates phosphorus-containing wastewater, which is environmentally unfriendly, and uses nitrobenzene as an easily explosive reagent, making it unsuitable for industrial production.

[0007] Synthesis Route 1:

[0008]

[0009] Secondly, patent CN102675182 also uses indoline as a starting material. After nitrogen alkylation, it uses phosphorus oxychloride and DMF to make Vilsmeier reagent for aldehyde alkylation reaction, followed by halogenation reaction to synthesize compound 4. Then, it is reduced to obtain compound 5, and finally cyanided to obtain compound IV, namely compound 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate. This route is relatively complicated. In addition, it uses nitrate ethane as a hazardous reagent, and the use of cyanide will produce the highly toxic substance hydrogen cyanide, which is not suitable for industrial production.

[0010] Third, patent CN115838349B reported a synthetic route using 5-bromoindoline and chloropropyl benzoate as raw materials, as shown in synthetic route 2. This synthetic route also uses phosphorus oxychloride and DMF to make Vilsmeier reagent for aldehyde reaction. The post-processing is relatively dangerous and generates a large amount of phosphorus wastewater, which is not conducive to environmental protection. At the same time, the precious metal Pd is used in the cyanidation and oxidation process, which increases the cost of industrial production.

[0011] Synthesis Route 2:

[0012]

[0013] In summary, existing synthetic routes for silodosin intermediates are lengthy and involve the use of phosphorus oxychloride, which easily generates phosphorus-containing wastewater and is detrimental to environmental protection. The use of nitroethane as a reactive explosive agent increases the danger of actual operation, and the use of the precious metal palladium reagent increases economic costs. For these reasons, it is urgent to develop a green, economical, environmentally friendly, and safe synthetic route for silodosin intermediates, and it has broad application prospects. Summary of the Invention

[0014] (a) Technical problems to be solved

[0015] To address the shortcomings of existing technologies, this invention provides a silodosine intermediate and its preparation method, solving the technical problem that existing preparation methods use highly hazardous and polluting reagents, which is detrimental to safety and environmental protection.

[0016] To achieve the above objectives, the present invention provides the following technical solution:

[0017] A method for preparing propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, an intermediate of silodosin, is shown below:

[0018]

[0019] Includes the following steps:

[0020] S1. Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate and solvent were mixed evenly, and a bromine reagent was added in batches at low temperature to carry out a substitution reaction. Then, the mixture was stirred at room temperature to obtain propyl 3-(5,7-dibromo-indoline-1-yl)benzoate.

[0021] S2. Under nitrogen protection, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate, cuprous cyanide and reaction solvent were mixed evenly, and the temperature was raised to react, to obtain propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate.

[0022] S3. Under nitrogen protection, propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate, reaction solvent, and catalyst were added sequentially to a container. The temperature was lowered to -80 to -25°C, and propylene oxide was added to obtain compound III, propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate.

[0023] S4. Under nitrogen protection, compound III 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate, acyl chloride, and reaction solvent undergo an oxidation reaction at low temperature. The reaction is monitored until the starting material spot disappears to obtain compound IV 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate.

[0024] Furthermore, S1 specifically includes the following steps:

[0025] Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate and solvent were mixed thoroughly, and a bromine reagent was added in portions at low temperature to induce a substitution reaction, yielding propyl 3-(5,7-dibromo-indoline-1-yl)benzoate.

[0026] The reaction equation is shown below:

[0027]

[0028] Further, in step S1, the molar ratio of propyl 3-(indoline-1-yl)benzoate to the brominating agent is 1:2-3.5; the solvent is dichloromethane or ethyl acetate, and the mass ratio of propyl 3-(indoline-1-yl)benzoate to solvent volume is 1g:10-30ml;

[0029] Furthermore, the brominating reagent is selected from any one of Br2, PBr3, and NBS, with NBS being preferred. The substitution reaction temperature is 0-50℃, preferably 0-25℃; the reaction time is 1-8h, preferably 3-5h.

[0030] Furthermore, after step S1, the reaction solution is further processed, specifically including the following steps: after the reaction is complete, the organic layer is washed with water, the organic layer is separated, the aqueous layer is extracted, the organic layers are combined, and the solution is concentrated to dryness to obtain the product.

[0031] Furthermore, S2 specifically includes the following steps:

[0032] Take propyl 3-(5,7-dibromo-indoline-1-yl)benzoate and cyanide reagent, add them to the reaction solvent and mix well. Then start the reaction to obtain propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate with structural formula II.

[0033] The reaction equation is shown below:

[0034]

[0035] Further, the reaction solvent in step S2 is DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone) or DMAc (N,N-dimethylacetamide), preferably DMF;

[0036] Further, the molar ratio of propyl 3-(5,7-dibromo-indoline-1-yl)benzoate to the cyaniding reagent is 1:1.1-2.0;

[0037] Furthermore, the cyaniding agent is selected from any one of zinc cyanide, cuprous cyanide, and potassium ferrocyanide, preferably cuprous cyanide;

[0038] Furthermore, the reaction temperature is 100-180℃, preferably 110-130℃; the reaction time is 1-24h, preferably 12-17h.

[0039] Furthermore, after step S2, the process includes a post-treatment of propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate, specifically including the following steps: adding water, cooling to room temperature, filtering, extracting the aqueous layer with dichloromethane, combining the organic layers, concentrating to dryness, and obtaining the product.

[0040] Furthermore, S3 specifically includes the following steps:

[0041] 3-(7-cyano-5-bromo-indoline-1-yl)propyl benzoate, solvent, and catalyst were added sequentially to a container under nitrogen protection. The mixture was cooled to -80 to -25°C, and propylene oxide was added all at once. After the addition was complete, the reaction was allowed to proceed at room temperature. The reaction was quenched with saturated ammonium chloride solution, and the pH was adjusted to yield 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate. The reaction equation is shown below:

[0042]

[0043] Furthermore, the reaction solvent in step S3 is methylpyrrolidone;

[0044] Furthermore, the molar ratio of propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate to propylene oxide is 1:1-5.0;

[0045] Furthermore, the catalyst is a mixture of nickel iodide hexahydrate, bipyridine, pyridine, potassium iodide, and zinc powder;

[0046] Further, the molar ratio of propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate to nickel iodide hexahydrate, bipyridine, pyridine, potassium iodide, and zinc powder is 1:0.1-1.0: 0.1-1.0: 0.1-1.0: 1.5-5.0, preferably 1:0.1-0.2: 0.1-0.2: 0.2-0.3: 0.1-0.25: 2.0-3.0;

[0047] Furthermore, the feeding temperature is -80℃ to 10℃, preferably -80℃ to 0℃; the reaction temperature is 0-25℃;

[0048] Furthermore, after step S3, the process also includes post-treatment of propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate, specifically including the following steps: after the reaction is complete, saturated ammonium chloride solution is added for quenching, dichloromethane is added for extraction, the organic layers are combined, the organic layers are washed with water, and the mixture is concentrated to obtain the product.

[0049] Furthermore, S4 specifically includes the following steps:

[0050] Propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate, acyl chloride, and reaction solvent were subjected to an oxidation reaction at low temperature. The reaction was monitored until the starting material spot disappeared, yielding compound IV, propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate.

[0051] The reaction equation is shown below:

[0052]

[0053] Furthermore, the reaction solvent in step S4 is dichloromethane;

[0054] Furthermore, the acyl chloride is any one of oxalyl chloride, phosphorus oxychloride, and thionyl chloride, preferably oxalyl chloride;

[0055] Further, the molar ratio of propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate to acyl chloride is 1:1-2.5; the reaction temperature is -20-30℃, preferably -20-10℃; and the reaction time is 12-48h, preferably 24-30h.

[0056] Furthermore, after step S4, the process includes post-treatment of compound IV, propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, specifically including the following steps: reducing the pressure to remove the solvent, adding dichloromethane and stirring to dissolve, washing the organic layer with water, concentrating part of the solvent, cooling, crystallizing, filtering, and drying to obtain propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate.

[0057] This invention provides a silodosine intermediate and its preparation method. Compared with the prior art, it has the following advantages:

[0058] This invention proposes a method for preparing a silodoxine intermediate. Using propyl 3-(indoline-1-yl)benzoate as a raw material, it is substituted with a bromine reagent to prepare propyl 3-(5,7-dibromo-indoline-1-yl)benzoate. Following a substitution reaction, propyl 3-(5-bromo7-cyano-indoline-1-yl)benzoate is obtained. This propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate then undergoes a substitution reaction with propylene oxide. After ring-opening with propylene oxide, propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate is obtained. Propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate is oxidized to generate the key intermediate 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate. The present invention provides a novel synthetic route for propyl benzoate, and all the raw materials and reagents used are easy to obtain or prepare. It does not use highly dangerous or polluting reagents, making it safe and environmentally friendly. The reaction conditions are mild, and the operation is convenient and controllable. The prepared silodosin intermediate has good purity and high yield, and has obvious cost advantages. It is suitable for industrial production and also provides a new approach for the preparation of silodosin. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0060] This application provides a method for preparing silodosin intermediates, which solves the technical problems of existing preparation methods using highly hazardous and polluting reagents, making them unsafe and environmentally unfriendly.

[0061] The technical solution in this application is to solve the above-mentioned technical problems, and the general idea is as follows:

[0062] A method for preparing propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, an intermediate of silodosin, includes the following steps:

[0063]

[0064] To better understand the above technical solution, the following will provide a detailed explanation of the technical solution in conjunction with specific implementation methods. Example

[0065] This embodiment provides a method for preparing a silodosine intermediate, which specifically includes the following steps:

[0066] Synthesis of S1, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (Formula I),

[0067] The reaction equation is shown below:

[0068]

[0069] Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate (2.81 g, 10 mmol) and dichloromethane (28 mL) were added sequentially to a four-necked flask. Bromine (3.20 g, 20 mmol) was added in portions at low temperature. After the addition was complete, the temperature was controlled at 25 °C and the reaction was carried out for 3 h. The mixture was washed with water, the organic layer was separated, and the aqueous layer was extracted with 20 mL of dichloromethane. The organic phases were combined and concentrated to dryness to obtain off-white propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (3.95 g, yield 90%, purity 98%), which was used directly in the next step.

[0070] 1 H NMR (400 MHz, CDCl3) δ= 8.54 (s, 1H), 8.17 (m, 1H), 7.65 –7.57 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.12 (m, 2H), 4 .34 (t, J =6.5 Hz, 2H), 3.42 (t, J = 8.4 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 8.4 Hz, 2H), 2.15 (m, 2H). 13C NMR (150 MHz, CDCl3) δ=171.5, 150.4, 150.1, 133.8, 132.1, 129.2, 128.0, 125.4, 121.6, 116.5, 113.0,55.2, 52.4, 32.8, 28.7, 22.3.

[0071] Synthesis of S2,3-(5-bromo-7-cyano-indoline-1-yl)benzoate (Formula II)

[0072] The reaction equation is shown below:

[0073]

[0074] To a four-necked flask, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (4.36 g, 10 mmol), cuprous cyanide (1.34 g, 15 mmol), and DMF (15 mL) were added sequentially. The mixture was stirred at room temperature for 20 min, then heated to 110 °C and reacted for 15 h. After the reaction was complete, 50 mL of water was added, and the mixture was cooled to room temperature. The solid residue was filtered off, and the aqueous layer was extracted with 50 mL x 3 dichloromethane. The organic layers were combined and concentrated to dryness to obtain a light yellow solid, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.35 g, yield 87%, purity 97.5%), which was used directly in the next step.

[0075] 1 H NMR (400 MHz, CDCl3) δ= 8.72 (s, 1H), 8.14 (m, 1H), 7.62 –7.45 (m, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.10 (m, 2H), 4 .32 (t, J =6.5 Hz, 2H), 3.45 (t, J = 8.3 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 8.3 Hz, 2H), 2.15 (m, 2H).

[0076] 13 C NMR (150 MHz, CDCl3) δ= 172.2, 153.6, 148.2, 134.7, 132.0, 131.2,127.4, 124.4, 121.7, 120.5, 116.1, 101.5, 58.3, 53.4, 32.2, 28.5, 22.0.

[0077] Synthesis of S3, 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate (Formula III)

[0078] The reaction equation is shown below:

[0079]

[0080] To a round-bottom flask, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.85 g, 10 mmol), methylpyrrolidone (60 ml), nickel iodide hexahydrate (0.33 g, 1 mmol), bipyridine (0.16 g, 1 mmol), pyridine (0.16 g, 2 mmol), potassium iodide (0.42 g, 2.5 mmol), and zinc powder (1.3 g, 20 mmol) were added sequentially. Under nitrogen protection, the mixture was cooled to -70°C, and propylene oxide (1.16 g, 20 mmol) was added all at once. After the addition was complete, the reaction was maintained at 25°C. TLC was used to monitor the reaction until complete. The reaction was quenched with 20 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 30 mL of dichloromethane three times. The organic layers were combined, washed with water, and concentrated to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl) 3.10 g of propyl benzoate, yield 85%.

[0081] 1 H NMR (400 MHz, CDCl3) δ= 8.45 (m, 1H), 8.00 (m, 1H), 7.65 –7.52 (m, 1H), 7.29(t, J = 7.6 Hz, 2H), 7.13 (m, 2H), 6 .12 (s, 1H), 4.43 (m, 1H), 4.37 (t, J = 6.5 Hz, 2H), 3.42 (t, J = 8.2 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H), 2.95 (td, J = 8 .7, 1.1 Hz, 2H), 2.55 (t,J = 8.2 Hz, 2H), 2.05 (m, 2H), 1.63 (m, 3H).

[0082] 13C NMR (150 MHz, CDCl3) δ=171.9, 150.4, 146.2, 135.1, 133.4, 132.3,129.5, 127.2, 124.1, 123.7, 117.6, 100.5, 68.4, 57.3, 53.4, 47.3, 32.5, 29.0, 22.5, 21.0.

[0083] Synthesis of S4, 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate (Formula IV)

[0084] The reaction equation is shown below:

[0085]

[0086] To a four-necked round-bottom flask, propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate (3.64 g, 10 mmol), oxalyl chloride (1.27 g, 10 mmol), DMSO (2.34 g, 30 mmol), and dichloromethane (12 mL) were added sequentially. The temperature was controlled at 10 °C, and the reaction was carried out for 24 h. The reaction was monitored by TLC to ensure the starting materials were completely reacted (PE:EA = 1:1). The solvent was removed under reduced pressure, and 30 mL of dichloromethane was added. The mixture was stirred to dissolve the solvent, and 50 mL of water was added to wash the organic layer. The organic layer was separated, and part of the solvent was concentrated. The mixture was cooled to -5 °C to allow crystallization. The crystals were filtered and dried to obtain 3.15 g of propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, with a yield of 87% and a purity of 99%.

[0087] 1 H NMR (400 MHz, CDCl3) δ= 8.67 (m, 1H), 8.05 (m, 1H), 7.62 –7.55 (m, 1H), 7.26 (t, J = 7.6 Hz, 2H), 7.10 (m, 2H), 4 .32 (t, J =6.5 Hz, 2H), 3.45 (t, J = 8.4 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.97 (td, J = 8.8, 1.2 Hz, 2H), 2.85 (t , J = 8.4 Hz, 2H), 2.15 (m, 2H), 1.75 (s, 3H).

[0088] 13C NMR (150 MHz, CDCl3) δ= 205.4,174.2, 155.3, 150.9, 136.7,133.1,131.7, 128.4, 127.2, 123.4, 121.5, 116.7, 102.3, 58.2, 55.8, 50.5, 35.3,30.2, 27.4, 21.2. Example

[0089] This embodiment provides a method for preparing a silodosine intermediate, which specifically includes the following steps:

[0090] Synthesis of S1, 3-(5,7-dibromo-indoline-1-yl)benzoate (Formula I)

[0091] The reaction equation is shown below:

[0092]

[0093] Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate (2.81 g, 10 mmol) and ethyl acetate (84 mL) were added sequentially to a four-necked flask. The temperature was controlled at 0 °C. NBS (6.23 g, 35 mmol) was added in portions. After the addition was complete, the mixture was reacted at 0 °C for 5 h. The mixture was washed with water, and the organic layer was separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The organic phases were combined and concentrated to dryness to obtain a white propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (3.82 g, yield 87%, purity 98%), which was directly used in the next step.

[0094] Synthesis of S2,3-(5-bromo-7-cyano-indoline-1-yl)benzoate (Formula II)

[0095] The reaction equation is shown below:

[0096]

[0097] To a four-necked flask, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (4.36 g, 10 mmol), zinc cyanide (1.34 g, 15 mmol), and DMAC (15 mL) were added sequentially. The mixture was stirred at room temperature for 30 min, then heated to 130 °C and reacted for 17 h. After the reaction was complete, 50 mL of water was added, and the mixture was cooled to room temperature. The solid residue was filtered off, and the aqueous layer was extracted with 100 mL x 3 dichloromethane. The organic layers were combined and concentrated to dryness to obtain a light yellow solid, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.31 g, yield 86%, purity 97%), which was used directly in the next step.

[0098] Synthesis of S3, 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate (Formula III)

[0099] The reaction equation is shown below:

[0100]

[0101] In a round-bottom flask, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.85 g, 10 mmol), methylpyrrolidone (60 ml), nickel iodide hexahydrate (0.66 g, 2 mmol), bipyridine (0.32 g, 2 mmol), pyridine (0.24 g, 3 mmol), potassium iodide (0.17 g, 1 mmol), and zinc powder (1.95 g, 30 mmol) were added sequentially. The mixture was protected with nitrogen and cooled to -80°C. Propylene oxide (2.9 g, 50 mmol) was added all at once. After the addition was complete, the reaction was maintained at 0°C. TLC was used to monitor the reaction until complete. The reaction was quenched with 40 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 60 mL of dichloromethane three times. The organic layers were combined, washed with water, and concentrated to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl) 3.02 g of propyl benzoate, yield 83%.

[0102] Synthesis of S4, 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate (Formula IV)

[0103] The reaction equation is shown below:

[0104]

[0105] To a four-necked round-bottom flask, propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate (3.64 g, 10 mmol), phosphorus oxychloride (3.83 g, 25 mmol), DMSO (2.34 g, 30 mmol), and dichloromethane (20 mL) were added sequentially. The temperature was controlled at -20 °C, and the reaction was carried out for 30 h. The reaction was monitored by TLC to ensure the starting material was completely reacted (PE:EA = 1:1). The solvent was removed under reduced pressure, and 30 mL of dichloromethane was added. The mixture was stirred to dissolve the solvent, and 50 mL of water was added to wash the organic layer. The organic layer was separated, and part of the solvent was concentrated. The mixture was cooled to -5 °C to allow crystallization. The crystals were filtered and dried to obtain 3.09 g of propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, with a yield of 85% and a purity of 98%. Example

[0106] This embodiment provides a method for preparing a silodosine intermediate, which specifically includes the following steps:

[0107] Synthesis of S1, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (Formula I),

[0108] Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate (2.81 g, 10 mmol) and dichloromethane (56 mL) were added sequentially to a four-necked flask. Phosphorus tribromide (6.77 g, 25 mmol) was added in portions at low temperature. After the addition was complete, the temperature was controlled at 10 °C and the reaction was carried out for 4 h. The mixture was washed with water, the organic layer was separated, and the aqueous layer was extracted with 30 mL of dichloromethane. The organic phases were combined and concentrated to dryness to obtain off-white propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (3.82 g, yield 87%, purity 98%), which was used directly in the next step.

[0109] Synthesis of S2,3-(5-bromo-7-cyano-indoline-1-yl)benzoate (Formula II)

[0110] To a four-necked flask, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate (4.36 g, 10 mmol), potassium ferrocyanide (5.53 g, 15 mmol), and NMP (10 mL) were added sequentially. The mixture was stirred at room temperature for 20 min, then heated to 120 °C and reacted for 14 h. After the reaction was complete, 100 mL of water was added, and the mixture was cooled to room temperature. The solid residue was filtered off, and the aqueous layer was extracted with 50 mL x 3 dichloromethane. The organic layers were combined and concentrated to dryness to obtain a light yellow solid, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.23 g, yield 84%, purity 97%), which was used directly in the next step.

[0111] Synthesis of S3, 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate (Formula III)

[0112] In a round-bottom flask, propyl 3-(5-bromo-7-cyano-indoline-1-yl)benzoate (3.85 g, 10 mmol), methylpyrrolidone (20 ml), nickel iodide hexahydrate (0.50 g, 1.5 mmol), bipyridine (0.23 g, 1.5 mmol), pyridine (0.20 g, 2.5 mmol), potassium iodide (0.33 g, 2 mmol), and zinc powder (1.63 g, 25 mmol) were added sequentially. The mixture was protected with nitrogen and cooled to 0°C. Propylene oxide (1.76 g, 30 mmol) was added all at once. After the addition was complete, the reaction was maintained at 10°C. TLC was used to monitor the reaction until complete. The reaction was quenched with 40 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 40 mL of dichloromethane three times. The organic layers were combined, washed with water, and concentrated to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl) 2.95g of propyl benzoate, yield 81%.

[0113] Synthesis of S4, 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate (Formula IV)

[0114] To a four-necked round-bottom flask, propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate (3.64 g, 10 mmol), thionyl chloride (3.57 g, 30 mmol), DMSO (2.34 g, 30 mmol), and dichloromethane (20 mL) were added sequentially. The temperature was controlled at 0 °C, and the reaction was carried out for 30 h. The reaction was monitored by TLC to ensure the starting material was completely reacted (PE:EA = 1:1). The solvent was removed under reduced pressure, and 40 mL of dichloromethane was added. The mixture was stirred to dissolve the solvent, and 50 mL of water was added to wash the organic layer. The organic layer was separated, and part of the solvent was concentrated. The mixture was cooled to -5 °C to allow crystallization. The crystals were filtered and dried to obtain 3.08 g of propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, with a yield of 85% and a purity of 99%.

[0115] In summary, compared with existing technologies, it has the following beneficial effects:

[0116] This invention provides a method for preparing silodosine intermediates. The method uses readily available and environmentally friendly raw materials, has a novel route and a short synthetic line, and produces silodosine intermediates with good purity, high yield and low cost.

[0117] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0118] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a silodosine intermediate, characterized in that, The synthesis route is shown below: ， The preparation method of compound IV, propyl 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)benzoate, includes the following steps: Using S1 and 3-(indoline-1-yl)propyl benzoate as raw materials, a substitution reaction is carried out with a brominating reagent to obtain 3-(5,7-dibromo-indoline-1-yl)propyl benzoate. S2,3-(5,7-dibromo-indoline-1-yl)benzoate propyl ester is given by a substitution reaction to 3-(7-cyano-5-bromo-indoline-1-yl)benzoate propyl ester; S3, propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate undergoes nucleophilic addition ring-opening with propylene oxide to give propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate; S4, 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate is oxidized to produce compound IV, 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate; The S2 step includes the following steps: under nitrogen protection, propyl 3-(5,7-dibromo-indoline-1-yl)benzoate, a cyaniding reagent, and a reaction solvent are mixed evenly and the mixture is heated to obtain propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate; the reaction solvent is selected from DMF, NMP, or DMAC; the molar ratio of propyl 3-(5,7-dibromo-indoline-1-yl)benzoate to the cyaniding reagent is 1:1.1-2.0; the cyaniding reagent is selected from any one of zinc cyanide, cuprous cyanide, and potassium ferrocyanide; the reaction temperature is 100-180℃; and the reaction time is 1-24h.

2. The method for preparing a silodosine intermediate according to claim 1, characterized in that, S1 specifically includes the following steps: Under nitrogen protection, propyl 3-(indoline-1-yl)benzoate and solvent were mixed evenly, and a bromine reagent was added in batches at low temperature to undergo a substitution reaction to obtain propyl 3-(5,7-dibromo-indoline-1-yl)benzoate.

3. The method for preparing a silodosine intermediate according to claim 1, characterized in that, S1 satisfies at least one of the following conditions: The molar ratio of propyl 3-(indoline-1-yl)benzoate to the brominating reagent is 1:2-3.5; The solvent is selected from dichloromethane or ethyl acetate; The mass-to-volume ratio of propyl 3-(indoline-1-yl)benzoate to solvent is 1 g: 10-30 ml.

4. The method for preparing a silodosine intermediate according to claim 1, characterized in that, S3 specifically includes the following steps: Under nitrogen protection, propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate, solvent, and catalyst were added sequentially to a container. Under nitrogen protection, the temperature was lowered to -80 to -25°C, and propylene oxide was added. After the addition was complete, the reaction was carried out at room temperature to obtain propyl 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoate.

5. The method for preparing a silodosine intermediate according to claim 1, characterized in that, S3 satisfies at least one of the following conditions: The reaction solvent is methylpyrrolidone; The molar ratio of propyl 3-(7-cyano-5-bromo-indoline-1-yl)benzoate to propylene oxide is 1:1-5.

0.

6. The method for preparing a silodosine intermediate according to claim 1, characterized in that, S4 specifically includes the following steps: Under nitrogen protection, compound III 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)propyl benzoate, acyl chloride, and reaction solvent were subjected to an oxidation reaction at low temperature to obtain compound IV 3-(7-cyano-5-(2-oxopropyl)indoline-1-yl)propyl benzoate.

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