A process for the preparation of a key intermediate of silodosin

Abstract

The application discloses a preparation method of a silodosin key intermediate and belongs to the technical field of drug chemical synthesis. The silodosin key intermediate is prepared from indoline as raw material through halogenation, cyanation, N-benzoylpropylamine protection, substitution, amination, reduction and salt formation, and the silodosin key intermediate is compound 1. The synthesis line is novel, the raw reagents are easy to obtain or prepare, high-risk and high-pollution reagents are not used, the method is safe, environment-friendly, mild in reaction condition, easy and controllable to operate, the prepared silodosin key intermediate is good in purity, high in yield and high in atom utilization rate, and the industrial production problem of silodosin can be practically solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for preparing a key intermediate of silodosin. Background Technology

[0002] Sildosin, chemically named 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide, is an α1A receptor antagonist developed by Kissei Pharmaceutical Co., Ltd. of Japan. It was first launched in Japan in May 2006 and officially launched in the United States in October 2008 under the brand name Urief. Preclinical studies have shown that its selectivity for the urethra is 12 times higher than that of prazosin and 7.5 times higher than that of tamsulosin. Its structural formula is as follows:

[0003]

[0004] The synthesis of silodosine mainly involves a multi-step reaction from the key intermediate compound I, as shown in the following reaction formula:

[0005]

[0006] The core of research on silodosine lies in the construction of the key intermediate compound I, and the main synthetic routes currently include the following:

[0007] Synthetic Route 1: Patents JP2001199956 and WO2015 / 010594 disclose a method using indoline and 3-chloropropyl benzoate as raw materials, involving a Vilsmeier-Haack formylation reaction, CC coupling addition, reduction, followed by formylation, cyanation, addition, reduction, and salt formation to obtain the key intermediate compound I. This synthetic route has many steps, low yield, and uses the Vilsmeier-Haack formylation process twice, generating a large amount of phosphide, which has a significant environmental impact. Furthermore, the reduction process uses Pd as a catalyst, resulting in high production costs and limiting its large-scale industrial production.

[0008] Synthetic Route Two: Patent WO2011 / 030356 discloses a method using 7-cyano-substituted indoline derivatives and D-alanine as starting materials, proceeding sequentially through Friedel-Crafts reaction, trifluoroacetic acid-catalyzed reduction, diazotization, Pd-BaSO4-catalyzed reduction, Boc anhydride protection, deprotection, and salt formation to obtain the target chiral compound. This synthetic route still involves many steps, uses the highly toxic trifluoroacetic acid as a catalyst, incorporates a diazotization process which poses significant safety risks, and also uses Pd as a catalyst in the reduction process. Furthermore, the first Friedel-Crafts reaction step is prone to racemization. All of these factors greatly increase production costs and make it unsuitable for industrial-scale production.

[0009] Synthetic Route 3: Patent CN107056675B discloses using N-acetylindoline derivative 2 as a starting material, followed by elimination, addition with potassium phthalimide, addition with propyl 3-chlorobenzoate, reduction catalyzed by triethylsilane and trifluoroformic acid, VH reaction, cyanation, hydrazine hydrolysis, and salt formation to obtain the target molecule. This synthetic route has 8 steps and is relatively long.

[0010] Although it avoids the use of the expensive metal Pd and avoids chiral separation, it has commercial potential. However, the starting material 2 is expensive and there is no commercialization route. Moreover, it uses highly toxic substances such as trifluoroacetic acid, hydrogen amine hydrochloride, and hydrazine hydrate multiple times. In particular, the VH reaction produces a large amount of acidic phosphine wastewater pollution, which greatly increases the production cost.

[0011] Synthetic Route 4: Patent US5387603 discloses the silodoxine compound and its basic synthetic route. Using indoline as a starting material, after acetyl protection, it undergoes Friedel-Crafts acylation with propionyl chloride, followed by halogenation with concentrated sulfuric acid / hydrobromic acid to obtain a haloketone. The haloketone is then reduced to carbonyl via a triethylsilane / trifluoroacetic acid system. The resulting haloproduct is subsequently nitrated, reduced, and reacted with Sandmeyer to introduce a cyano group at the 7-position of the indoline. The cyanoproduct reacts with sodium azide, followed by palladium / barium sulfate reduction and chiral resolution to obtain propylamine with the R configuration. This is then condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate. The resulting product has its amino group protected with Boc, and then undergoes deacetylation, oxidative hydrolysis, benzoyloxypropylation, debenzoylation, and deBoc protection to obtain silodoxine. This route is lengthy, involves numerous protection and deprotection steps, has a low overall yield, requires hazardous reactions such as nitration, azidation, and cyanation, and the process conditions are difficult to control, resulting in high production costs and significant safety risks.

[0012] Synthetic Route 5: Patent CN114751852A reports a route using indoline as a starting material, which involves sequential cyanolation, bromination, N-2-(3-bromopropoxy)tetrahydro-2H-pyran protection, -75°C, n-butyllithium catalytic substitution, addition with phthalimide or its potassium salt, hydrazolysis, deprotection, amino-BOC protection, esterification, deBOC removal, and salt formation to obtain the target product. This route is lengthy and has an extremely low overall yield. The addition process of compound 3 with epichlorohydrin involves an ultra-low temperature reaction at -75°C, which greatly increases energy consumption and limits production capacity. The reaction process uses N-2-(3-bromopropoxy)tetrahydro-2H-pyran as an amino protecting agent, which is then removed to prepare benzoic acid esters, resulting in very low atom utilization. The use of highly toxic hydrazine hydrate to hydrolyze compounds 5 and 6 also greatly increases production risks.

[0013] In summary, there are currently many synthetic routes for silodosine key intermediate I. These synthetic methods are difficult to scale up for industrial production due to various factors, such as long synthetic routes resulting in low yields, the use of expensive catalysts, the use of hazardous reagents, or the occurrence of racemization leading to high separation and purification costs. Therefore, there is an urgent need and broad prospects for developing green, environmentally friendly, high-yield, low-cost, and highly atom-utilized silodosine key intermediates. Summary of the Invention

[0014] The purpose of this invention is to provide a method for preparing a key intermediate of silodosine, in order to solve the following technical problems: shortening the synthetic route, increasing the yield of key intermediate I of silodosine, reducing the synthesis cost, and improving the atom utilization rate.

[0015] The objective of this invention can be achieved through the following technical solutions:

[0016] A method for preparing a key intermediate of silodosine, the synthetic route is as follows:

[0017]

[0018] Where X is any one of chlorine, bromine, and iodine, and R is any one of bromine, chlorine, and p-toluenesulfonyl;

[0019] Includes the following steps:

[0020] Step S1: Under nitrogen protection, indoline was added to acetonitrile solvent, cooled to 0-5℃, and a halogenating reagent was added dropwise. The mixture was heated to 20-25℃ to react. Water was added and the mixture was filtered to remove insoluble matter. Dichloromethane was added, and the mixture was extracted. The organic layer was separated, dried, and partially concentrated under reduced pressure to remove solvent. The mixture was cooled, crystallized, filtered, and dried to obtain compound 2. Compound 2 was obtained by halogenating indoline with a halogen source. The reaction equation is shown below:

[0021]

[0022] Step S2: Under nitrogen protection, compound 2 was added to acetonitrile solvent, and the mixture was cooled for the first time. A 1M BCl3 solution in toluene was added dropwise. After the addition was complete, the temperature was raised to 20-25°C, and the mixture was stirred for 30 minutes. The temperature was then raised again for the first reflux reaction. A second cooling was performed, and methyl thiocyanate was added. A second reflux reaction was carried out. A third cooling was performed, and a methanol solution of alkali was slowly added dropwise. A final heating and a final reflux reaction were carried out. Insoluble matter was filtered off, the solvent was concentrated under reduced pressure, water was added, and the mixture was extracted with toluene. The organic layers were combined, dried, filtered, and partially concentrated to remove the solvent. The mixture was cooled, crystallized, filtered, and dried to obtain compound 3. Compound 2 undergoes a substitution reaction with methyl thiocyanate to obtain compound 3. The reaction equation is shown below:

[0023]

[0024] Step S3: Add the base, compound 3, and propyl benzoate derivative A sequentially to the solvent, heat the mixture to quench the reaction, extract the organic layer, and perform post-treatment to obtain compound 4. The reaction equation is shown below:

[0025] The reaction equation is shown below:

[0026]

[0027] Step S4: Under nitrogen protection, compound 4 was added to the solvent, cooled, and n-butyllithium was added dropwise. After the addition was complete, (S)-propylene oxide was added dropwise with stirring. After the addition was complete, the mixture was stirred for 0.5 h, and boron trifluoride diethyl ether solution was added dropwise to carry out the reaction. The reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water, and the organic layer was separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent was concentrated. Acetonitrile was added, the mixture was heated to dissolve, cooled to crystallize, filtered, and dried to obtain compound 5. Compound 4 reacts with (S)-propylene oxide under the catalysis of n-butyllithium to generate compound 5. The reaction equation is shown below:

[0028]

[0029] Step S5: Under nitrogen protection, compound 5 was added to a solvent, followed by phthalimide and triphenylphosphine. The mixture was cooled, and DIAD (diisopropyl azodicarbonate) was added dropwise. The reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated to dryness, and acetonitrile was added. The mixture was heated to dissolve the compounds, cooled to crystallize, filtered, and dried to obtain compound 6. Compound 5 reacts with phthalimide to give compound 6. The reaction equation is shown below:

[0030]

[0031] Step S6: Compound 6 was added to the solvent isopropanol, a reducing agent was added, and the mixture was stirred at 20-25°C. The mixture was then cooled, and acetic acid was added dropwise to adjust the pH. The temperature was raised, and the mixture was stirred again. The solvent was concentrated, and the mixture was washed with a 1M hydrochloric acid solution. The organic layer was separated, washed with an aqueous sodium carbonate solution, dried, concentrated, crystallized, and filtered to obtain compound 7. Compound 6 was reduced to obtain compound 7. The reaction equation is shown below:

[0032]

[0033] Step S7: Compound 7 and L-(+)-tartaric acid were added to an aqueous acetone solution, heated, refluxed until the solution was clear, cooled, crystallized, filtered, and dried to obtain a key intermediate compound 1, silodosin. Compound 7 forms a salt with L-(+)-tartaric acid to give compound 1, as shown in the following reaction equation:

[0034]

[0035] Further, in step S1, the ratio of indoline, solvent acetonitrile, and halogenated reagent is 1 mol: 1600-2000 mL: 1-3.5 mol.

[0036] Further, the halogenating agent mentioned in step S1 is any one of N-bromosuccinimide (NBS), bromine, chlorine, and iodine;

[0037] Preferably, the halogenated reagent is N-bromosuccinimide.

[0038] Further, the reaction time in step S1 is 1-18 hours; preferably, the reaction time is 2-5 hours.

[0039] Further, in step S2, the ratio of compound 2, acetonitrile, BCl3, methyl thiocyanate, and alkali is 1 mol: 2000 mL: 1.0-1.5 mol: 1.5-2.5 mol: 1.0-3.0 mol; preferably, the ratio of compound 2, acetonitrile, BCl3, and methyl thiocyanate is 1 mol: 2000 mL: 1.25 mol: 2.0 mol: 2.0 mol.

[0040] Further, the alkali mentioned in step S2 is any one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide, and potassium bicarbonate; preferably, the alkali is potassium carbonate.

[0041] Further, in step S2, the temperature of the first cooling is -10⁻⁵℃; preferably, the temperature of the first cooling is -5⁻⁰℃; the time of the first reflux reaction is 2-10 hours, preferably, the time of the first reflux reaction is 3-5 hours; the temperature of the second cooling is 40-65℃; preferably, the temperature of the second cooling is 50-60℃; the time of the second reflux reaction is 12-36 hours; preferably, the time of the second reflux reaction is 20-28 hours; the temperature of the third cooling is -10⁻⁵℃; preferably, the temperature of the third cooling is -5⁻⁰℃; the temperature of the last heating is 50-80℃; preferably, the temperature of the last heating is 60-70℃; the time of the last reflux reaction is 12-36 hours; preferably, the time of the last reflux reaction is 12-15 hours.

[0042] Further, in step S3, the ratio of compound 3, base, solvent, and propyl benzoate substituted product A is 1 mol: 1.2-2.5 mol: 1500-2000 mL: 1.0-1.5 mol; preferably, the ratio of compound 3, base, solvent, and propyl benzoate substituted product A is 1 mol: 2.5 mol: 1500 mL: 1.25 mol.

[0043] Further, the solvent is acetonitrile, dimethylacetamide, or polyethylene glycol; preferably, the solvent is acetonitrile.

[0044] Further, the alkali is any one of triethylamine, sodium carbonate, and potassium carbonate; preferably, the alkali is triethylamine.

[0045] Furthermore, the reaction temperature in step S3 is 75-140℃; the reaction time is 6-12h.

[0046] Further, in step S3, the propyl benzoate substituted product A is any one of 3-bromopropyl benzoate, 3-chloropropyl benzoate, and 3-p-toluenesulfonylpropyl benzoate; preferably, the propyl benzoate substituted product A is 3-bromopropyl benzoate.

[0047] Further, the solvent in step S4 is any one of acetonitrile, tetrahydrofuran, and ethyl acetate; preferably, the solvent is acetonitrile.

[0048] Further, in step S4, the ratio of compound 4, solvent, n-butyllithium, (S)-propylene oxide, and boron trifluoride ether is 1 mol: 1000-1500 mL: 1.1-1.8 mol: 1.5-2.4 mol: 1.5-3.0 mol; preferably, the ratio of compound 4, solvent, n-butyllithium, (S)-propylene oxide, and boron trifluoride ether is 1 mol: 1500 mL: 1.2 mol: 1.8 mol: 2.0 mol.

[0049] Further, the cooling temperature in step S4 is -80 to -10°C; preferably, the cooling temperature is -35 to -10°C; the reaction temperature is -80 to -10°C; preferably, the reaction temperature is -35 to -10°C; the reaction time is 2-6 hours; preferably, the reaction time is 2-4 hours.

[0050] Further, in step S5, the ratio of compound 5, solvent, phthalimide, triphenylphosphine, and DIAD is 1 mol: 1000 mL: 1.0-1.5 mol: 1.0-1.5 mol: 1.0-1.5 mol; preferably, the ratio of compound 5, solvent, phthalimide, triphenylphosphine, and DIAD is 1 mol: 1000 mL: 1.1 mol: 1.2 mol: 1.1 mol.

[0051] Further, the solvent in step S5 is any one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and tetrahydrofuran; preferably, the solvent is acetonitrile.

[0052] Further, the cooling temperature in step S5 is -10⁻⁵℃; preferably, the cooling temperature is -5⁻⁰℃; the reaction temperature is -10⁻⁵℃, preferably, the reaction temperature is -5⁻⁰℃; the reaction time is 2-8 hours, preferably, the reaction time is 2-5 hours.

[0053] Further, the reducing agent in step S6 is sodium borohydride or lithium aluminum hydride, preferably any one of sodium borohydride.

[0054] Further, in step S6, the ratio of compound 6, isopropanol, and reducing agent is 1 mol: 1000 mL: 1.5-2.5 mol; preferably, the ratio of compound 6, isopropanol, and reducing agent is 1 mol: 1000 mL: 1.8 mol.

[0055] Further, the stirring reaction time in step S6 is 12-36 hours; preferably, the stirring reaction time is 20-24 hours; the cooling temperature is -10 to 10°C; preferably, the cooling temperature is -5 to 0°C; the pH is 4.0-6.0; preferably, the pH is 4.0-5.0; the heating temperature is 70-90°C; preferably, the heating temperature is 80-85°C; the re-stirring time is 2-6 hours; preferably, the re-stirring time is 2-4 hours.

[0056] Further, in step S7, the ratio of compound 7, L-(+) tartaric acid, and acetone aqueous solution is 1 mol: 1.2 mol: 2300 mL.

[0057] Further, in step S7, the volume ratio of acetone to water in the acetone aqueous solution is 1:1.0-2.5; preferably, the volume ratio of acetone to water in the acetone aqueous solution is 1:1.5.

[0058] Further, the cooling temperature in step S7 is 20-40℃; preferably, the cooling temperature is 30-35℃; the crystallization time is 2-8h, preferably, the crystallization time is 4-6h.

[0059] The beneficial effects of this invention are:

[0060] This invention specifically proposes a method for preparing a key intermediate of silodoxine (compound 1). The method uses indoline as a raw material, which is halogenated, then cyano-treated, protected with N-benzoylpropyl ester, substituted, amination, reduced, and salted to obtain silodoxine key intermediate compound 1. The synthetic route of this invention is novel, the raw materials and reagents used are easy to obtain or prepare, and it avoids the use of highly hazardous and polluting reagents, making it safe and environmentally friendly. The reaction conditions are mild, and the operation is convenient and controllable. The prepared silodoxine key intermediate has good purity, high yield, and high atom utilization, with significant cost advantages, making it suitable for industrial production. It also provides a new approach for the preparation of silodoxine. Detailed Implementation

[0061] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0062] Example 1

[0063] A method for preparing a key intermediate compound 1 of silodosine includes the following steps:

[0064]

[0065] Step S1, Synthesis of Compound 2

[0066] Under nitrogen protection, acetonitrile (1000 mL) and indoline (59.5 g, 0.5 mol) were added sequentially to a round-bottom flask. The mixture was cooled to 0 °C, and NBS (90.0 g, 0.50 mol) was added in three portions. After the addition was complete, the mixture was heated to 20 °C and stirred for 2 h. The reaction was monitored by TLC until complete (PE:EA = 1:1). Water (500 mL) was added, and the insoluble matter was filtered off. Dichloromethane (1000 mL) was added for extraction. The organic layer was separated, dried over anhydrous sodium sulfate, and partially dissolved under reduced pressure. The mixture was cooled to 0 °C and allowed to crystallize for 3 h. After filtration, the crystals were dried at 50 °C for 4 h to obtain compound 2 (93.94 g, yield 95%, purity 97%).

[0067] The reaction equation is shown below:

[0068]

[0069] Step S2, Synthesis of Compound 3

[0070] Under nitrogen protection, acetonitrile (100 mL) and compound 2 (19.81 g, 0.1 mol) were added sequentially to a round-bottom flask. The mixture was cooled to -5°C, and a 1M toluene solution of BCl3 (125 mL) was added dropwise. After the addition was complete, the mixture was heated to 20°C and stirred for 30 min. The mixture was then refluxed for 3 h. The mixture was cooled to 50°C, and methyl thiocyanate (14.63 g, 0.20 mol) was added. The mixture was refluxed for 24 h. The mixture was then cooled to -5°C, and potassium carbonate was slowly added dropwise. Methanol solution (148 g - 650 mL) was heated to 60 °C and refluxed for 12 h. The reaction of the starting material was monitored by TLC until complete (PE:EA = 1:1). After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, water (100 mL) was added, toluene (100 mL) was added for extraction, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, some solvent was concentrated, the mixture was cooled to -5 °C, crystallized for 6 h, filtered, and dried at 50 °C to obtain compound 3 (19.41 g, yield 87%, purity 99.3%).

[0071] The reaction equation is shown below:

[0072]

[0073] Step S3, Synthesis of Compound 4

[0074] Under nitrogen protection, acetonitrile (150 mL), 3-chloropropyl benzoate (30.39 g, 0.125 mol), triethylamine (18 mL), and compound 3 (22.31 g, 0.10 mol) were added sequentially to a round-bottom flask. The mixture was heated to 75 °C and refluxed for 6-10 h. The reaction was completed by TLC (PE:EA = 1:1). The mixture was then cooled to room temperature, and ethyl acetate (100 mL) was added. The organic layer was washed sequentially with sodium bicarbonate solution (300 mL), citric acid aqueous solution (300 mL), and brine (200 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and a portion of the solvent was concentrated. Methyl tert-butyl ether was added, and the mixture was cooled to 0 °C and allowed to crystallize for 6-8 h. After filtration, compound 4 (35.06 g, yield 91%, purity 95.2%) was obtained.

[0075] The reaction equation is shown below:

[0076]

[0077] Step S4, Synthesis of Compound 5

[0078] Under nitrogen protection, acetonitrile (100 mL), compound 4 (38.53 g, 0.1 mol) were added sequentially to a round-bottom flask. The temperature was maintained at -35 °C. 48 mL of 2.5 mol / L n-butyllithium solution was added dropwise, and stirring continued. The temperature was maintained at -35 °C. (S)-propylene oxide (16.65 g, 0.18 mol) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 0.5 h. Boron trifluoride diethyl ether (28.39 g, 0.2 mol) was added dropwise, and the reaction was stirred for 3 h. The reaction was then analyzed by TLC. The reaction was completed (PE:EA = 1:1). 50 mL of ammonium chloride aqueous solution was added to quench the reaction. Ethyl acetate (100 mL * 2) was added to extract the aqueous layer twice. The organic layers were combined, washed with 100 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and 75 mL of acetonitrile was added. The mixture was heated to 70 °C, stirred to dissolve, and slowly cooled to 0 °C. Crystallization was allowed to occur for 6 hours. The mixture was filtered, dried at 60 °C, and yielded solid compound 5 (31.34 g, yield 86%, purity 99.7%).

[0079] The reaction equation is shown below:

[0080]

[0081] Step S5, Synthesis of Compound 6

[0082] Under nitrogen protection, acetonitrile (100 mL), compound 5 (36.45 g, 0.1 mol), phthalimide (17.18 g, 0.11 mol), and triphenylphosphine (28.85 g, 0.12 mol) were added sequentially to a round-bottom flask. The mixture was stirred to dissolve the compounds, and the temperature was controlled at -5°C. DIAD (22.24 g, 0.11 mol) was added dropwise, and the reaction was allowed to proceed for 3-5 hours. The reaction was quenched with ammonium chloride aqueous solution (50 mL), and the aqueous layer was extracted twice with ethyl acetate (100 mL * 2). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness. 100 mL of acetonitrile was added, and the mixture was heated to 75°C to dissolve the compounds. The temperature was then slowly lowered to 5°C, and crystallization was allowed to occur for 6 hours. The mixture was filtered, dried, and compound 6 (43.18 g, yield 87.5%, purity 99.1%) was obtained.

[0083] The reaction equation is shown below:

[0084]

[0085] Step S6, Synthesis of Compound 7

[0086] Isopropanol (100 mL), compound 6 (49.36 g, 0.1 mol), and NaBH4 (6.81 g, 0.18 mol) were added sequentially to a round-bottom flask. The mixture was stirred at room temperature for 20 h, and the reaction was completed by TLC (PE:EA = 1:1). The mixture was cooled to -5 °C, and acetic acid was added dropwise to adjust the pH to 4.0. The mixture was stirred for 0.5 h, and the temperature was raised to 80 °C. The mixture was stirred for another 3 h to remove isopropanol. 10 mL of 1 M hydrochloric acid solution was added, and the mixture was stirred for 1.0 h. The organic layer was separated, washed with sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and a portion of the solvent was concentrated. Crystallization was carried out at 0-5 °C for 8 h. The mixture was filtered, dried, and compound 7 (29.80 g, yield 82%, purity 99.7%) was obtained.

[0087] The reaction equation is shown below:

[0088]

[0089] Step S7, Synthesis of Compound 1

[0090] Acetone (110 mL), water (120 mL), compound 7 (36.36 g, 0.1 mol), and L-(+)-tartaric acid (18.01 g, 0.12 mol) were added sequentially to a round-bottom flask. The mixture was heated to reflux and dissolved completely. The mixture was stirred for 1.0 h, then cooled to 30-35 °C and allowed to crystallize for 4-6 h. The mixture was then filtered and dried to obtain compound 1 (34.52 g, yield 95%, purity 99.6%).

[0091] The reaction equation is shown below:

[0092]

[0093] Example 2, Synthesis of Compound 2

[0094] Under nitrogen protection, acetonitrile (500 mL) and indoline (29.8 g, 0.25 mol) were added sequentially to a round-bottom flask. The mixture was cooled to 5 °C, and Br2 (39.96 g, 0.25 mol) was added. After the addition was complete, the mixture was heated to 25 °C and stirred for 3 h. The reaction was monitored by TLC until complete (PE:EA = 1:1). Water (200 mL) was added, followed by extraction with dichloromethane (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and partially dissolved under reduced pressure. The mixture was cooled to 5 °C and allowed to crystallize for 4 h. After filtration, the crystals were dried at 60 °C for 6 h to obtain compound 2 (48.02 g, yield 97%, purity 98.7%).

[0095]

[0096] Example 3: Synthesis of Compound 2

[0097] Under nitrogen protection, acetonitrile (400 mL) and indoline (29.8 g, 0.25 mol) were added sequentially to a round-bottom flask. The mixture was cooled to 0 °C, and Cl2 (61.69 g, 0.87 mol) was introduced. After the addition was complete, the mixture was heated to 20-25 °C and stirred for 7 h. The reaction was monitored by TLC until complete (PE:EA = 1:1). Water (100 mL) was added, followed by extraction with dichloromethane (400 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and partially dissolved under reduced pressure. The mixture was cooled to 0-5 °C and allowed to crystallize for 4 h. After filtration, the crystals were dried at 50-60 °C for 4 h to obtain compound 2 (32.57 g, yield 85%, purity 96.3%).

[0098]

[0099] Example 4: Synthesis of Compound 4

[0100] Under nitrogen protection, dimethylacetamide (DMA, 160 mL), 3-chloropropyl benzoate (29.81 g, 0.15 mol), potassium carbonate (34.55 g, 0.25 mol), tetrabutylammonium bromide (TBAB, 2.3 g, 7.2 mmol), potassium iodide (31.6 g, 0.19 mol), and compound 3 (22.31 g, 0.10 mol) were added sequentially to the reaction flask. The mixture was slowly heated to 140 °C and stirred for 10–12 h. The reaction was completed by TLC. PE:EA = 1:1), the solvent was removed by vacuum evaporation, and the resulting yellow viscous liquid was added dropwise to a mixture of dichloromethane (DCM, 500 mL) and 5 wt% hydrochloric acid aqueous solution (300 mL). After stirring for 15 min, the mixture was allowed to stand and separate into layers. The organic phase was washed successively with saturated sodium bicarbonate solution (600 mL * 2) and saturated sodium chloride solution (600 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 4 (33.91 g, yield 88%, purity 94.7%).

[0101] The reaction equation is shown below:

[0102]

[0103] Example 5: Synthesis of Compound 4

[0104] Under nitrogen protection, polyethylene glycol (PEG-400, 200 mL), 3-chloropropyl benzoate (29.81 g, 0.15 mol), sodium carbonate (17.0 g, 0.16 mol), and compound 3 (22.31 g, 0.10 mol) were added sequentially to a reaction flask. The mixture was slowly heated to 120 °C and stirred for 10 h. The reaction was completed by TLC (PE:EA = 1:1). The solvent was removed by vacuum distillation. The resulting yellow viscous liquid was added dropwise to a mixture of dichloromethane (DCM, 300 mL) and 5 wt% hydrochloric acid aqueous solution (300 mL). After stirring for 15 min, the mixture was allowed to stand and separate into layers. The organic phase was washed sequentially with saturated sodium bicarbonate solution (300 mL * 2) and saturated sodium chloride solution (300 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 4 (34.87 g, yield 90.5%, purity 95.0%).

[0105]

[0106] Example 6: Synthesis of Compound 5

[0107] Under nitrogen protection, acetonitrile (150 mL), compound 4 (34.81 g, 0.1 mol) were added sequentially to a round-bottom flask. The temperature was maintained at -35°C. 65 mL of a 2.5 mol / L n-butyllithium solution was added dropwise. Stirring continued, and the temperature was maintained at -35°C. (S)-epimylochloropropane (18.50 g, 0.20 mol) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 0.5 h. Boron trifluoride diethyl ether (28.39 g, 0.2 mol) was added dropwise, and the reaction was stirred for 3 h. The reaction was then recorded on a TLC plate. The reaction should be completely quenched by adding 80 mL of ammonium chloride aqueous solution (PE:EA = 1:1), and the aqueous layer should be extracted twice by adding ethyl acetate (100 mL * 2). The organic layers should be combined, washed with 100 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and 100 mL of acetonitrile should be added. The mixture should be heated to 70-75 °C, stirred to dissolve, slowly cooled to 0 °C, and allowed to crystallize for 8 hours. After filtration, the mixture should be dried at 60 °C to obtain solid compound 5 (30.61 g, yield 82.2%, purity 99.2%).

[0108] The reaction equation is shown below:

[0109]

[0110] 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 process, method, article, or apparatus.

[0111] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a key intermediate of silodosine, characterized in that, The synthesis route is as follows: Where X is any one of chlorine, bromine, and iodine, and R is any one of bromine, chlorine, and p-toluenesulfonyl; Specifically, the following steps are included: Step S1: Under nitrogen protection, indoline was added to acetonitrile solvent, cooled to 0-5℃, a halogenated reagent was added dropwise, the temperature was raised to 20-25℃, water was added and filtered, dichloromethane was added, extraction was performed, the organic layer was separated, the organic layer was dried, the solvent was removed by vacuum concentration, the temperature was lowered, crystals were precipitated, filtered, and dried to obtain compound 2. The reaction equation is shown below: Step S2: Under nitrogen protection, compound 2 was added to the solvent acetonitrile, and the mixture was cooled for the first time. A 1M BCl3 solution in toluene was added dropwise. After the addition was complete, the temperature was raised to 20-25℃, and the mixture was stirred for 30 min. The temperature was then raised again for the first reflux reaction. The mixture was cooled for the second time, and methyl thiocyanate was added for the second reflux reaction. The mixture was cooled for the third time, and a base methanol solution was added dropwise. The mixture was heated for the last time and then refluxed for the last time. The insoluble matter was filtered off, and the solvent was removed by concentration under reduced pressure. Water was added, and the mixture was extracted with toluene. The organic layers were combined, dried, filtered, concentrated to remove some of the solvent, cooled, crystallized, filtered, and dried to obtain compound 3. The reaction equation is shown below: Step S3: Add the base, compound 3, and propyl benzoate derivative A sequentially to the solvent acetonitrile, heat the mixture for 6-12 hours, quench the reaction, extract the organic layer, and perform post-treatment to obtain compound 4. The reaction equation is shown below: Step S4: Under nitrogen protection, compound 4 was added to the solvent acetonitrile, cooled to -80℃ to -10℃, and n-butyllithium was added dropwise. After the addition was complete, (S)-epoxypropane was added dropwise with stirring. After the addition was complete, the mixture was stirred for 0.5 h, and boron trifluoride diethyl ether solution was added dropwise to carry out the reaction. The reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water, and the organic layer was separated. The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and acetonitrile was added. The mixture was heated to dissolve, cooled to crystallize, filtered, and dried to obtain compound 5. The reaction equation is shown below: Step S5: Under nitrogen protection, compound 5 was added to the solvent acetonitrile, followed by the addition of phthalimide and triphenylphosphine. The mixture was cooled to -10°C to -5°C, and DIAD was added dropwise. After the reaction was initiated, the mixture was quenched with an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated to dryness, and acetonitrile was added. The mixture was heated to dissolve the compound, cooled to allow crystals to precipitate, filtered, and dried to obtain compound 6. The reaction equation is shown below: Step S6: Compound 6 was added to the solvent isopropanol, a reducing agent was added, and the mixture was stirred at 20-25°C. The mixture was then cooled, and acetic acid was added dropwise to adjust the pH. The mixture was heated again, stirred, and concentrated to remove the solvent. A 1M hydrochloric acid solution was added and the mixture was stirred and washed. The organic layer was separated, washed with an aqueous sodium carbonate solution, dried, concentrated, crystallized, and filtered to obtain compound 7. The reaction equation is shown below: Step S7: Compound 7 and L-(+) tartaric acid were added to an aqueous acetone solution, heated, refluxed until the solution was clear, cooled, crystallized, filtered, and dried to obtain a key intermediate compound 1 of silodosin; the reaction equation is shown below: 。 2. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The ratio of indoline, solvent acetonitrile, and halogenated reagent in step S1 is 1 mol: 1600-2000 mL: 1-3.5 mol.

3. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The halogenated reagent in step S1 is any one of N-bromosuccinimide (NBS), bromine, chlorine, and iodine.

4. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The ratio of compound 2, acetonitrile, BCl3, methyl thiocyanate, and alkali used in step S2 is 1 mol: 2000 mL: 1.0-1.5 mol: 1.5-2.5 mol: 1.0-3.0 mol.

5. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The propyl benzoate substitute A in step S3 is any one of 3-bromopropyl benzoate, 3-chloropropyl benzoate, and 3-p-toluenesulfonylpropyl benzoate.

6. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, In step S3, the ratio of compound 3, base, acetonitrile, and propyl benzoate substituted product A is 1 mol: 2.0-5.5 mol: 1000-2000 mL: 1.0-1.5 mol.

7. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, In step S4, the ratio of compound 4, solvent acetonitrile, n-butyllithium, (S)-propylene oxide, and boron trifluoride diethyl ether is 1 mol: 1000-1500 mL: 1.1-1.8 mol: 1.5-2.4 mol: 1.5-3.0 mol.

8. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The ratio of compound 5, solvent acetonitrile, phthalimide, triphenylphosphine, and DIAD in step S5 is 1 mol: 1000 mL: 1.0-1.5 mol: 1.0-1.5 mol: 1.0-1.5 mol.

9. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The ratio of compound 6, isopropanol, and reducing agent in step S6 is 1 mol: 1000 mL: 1.5-2.5 mol.

10. The method for preparing a key intermediate of silodosine according to claim 1, characterized in that, The ratio of compound 7, L-(+) tartaric acid, and acetone aqueous solution in step S7 is 1 mol: 1.2 mol: 2300 mL.

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