Process for the preparation of a silodosin intermediate

Abstract

The application provides a preparation method of silodosin intermediate, and relates to the technical field of biological medicines.The silodosin intermediate is prepared from compound SM-1 and compound SM-2 through a Friedel-Crafts reaction, an esterification reaction (potassium acetate and / or sodium acetate are used as esterification reagents), a hydrolysis reaction, a reduction reaction, an oxidation reaction, an imine-reduction reaction (condensation reduction reaction) and a reduction reaction.The preparation method provided by the application avoids the use of high-risk and explosive nitroethane or sodium azide, improves the safety of the production process of the silodosin intermediate, and greatly improves the utilization rate of raw and auxiliary materials, so that the total yield of the silodosin intermediate is high, the purity is high, the discharge of three wastes is reduced, the production efficiency is improved, the production cost is low, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a method for preparing a silodosin intermediate. 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-adrenergic receptor antagonist developed by Kissei Pharmaceuticals of Japan. Clinically, it is used to treat symptoms such as dysuria caused by benign prostatic hyperplasia. The structure of silodosin is as follows: .

[0003] Japanese Patent JP2001199956A reports a reaction using indoline as a starting material. The indoline is condensed with 3-chloropropylbenzoate. The condensate then reacts with Vilsmeier-Haack, followed by a Knoevenagel reaction with nitrate ethane to break the olefin bond. This is followed by another Vilsmeier-Haack reaction, and finally, oxime formation with hydroxylamine hydrochloride, followed by dehydration to yield a cyano compound. The cyano compound is oxidized with K₂CO₃ / H₂O₂, and then reductively amination with (R)-α-phenylethylamine [(R)-α-PEA], followed by chiral induction to obtain a key intermediate. The reaction route is as follows: .

[0004] However, this method involves multiple reaction steps, repeatedly using the Vilsmeier-Haack reaction to generate large amounts of phosphorus-containing wastewater, and uses dangerous and explosive nitroethane, posing safety hazards to industrial production.

[0005] European patent EP0600675A1 reports a reaction route using acetylindoline as a starting material, which involves Friedel-Crafts reaction, bromination, reduction, nitration, nitro reduction, diazotization, and Sandmeyer reaction, followed by reaction with sodium azide and subsequent reduction to obtain a key intermediate. The reaction route is as follows: .

[0006] This method involves nitration and azidation reactions, which are highly dangerous in industrial production. Furthermore, it uses highly toxic sodium cyanide for the Sandmeyer reaction, posing a significant threat to human health and the environment.

[0007] Existing technology (Zhu Guorong, Yang Huilin, et al. A new method for synthesizing key intermediates of silodosin, China Pharmaceutical Industry Journal, 2017, 48(8), 1115-1118.) reported a method for obtaining key intermediates from 7-cyanoindoline as a starting material through Friedel-Crafts reaction, reduction, azidation, reduction and resolution. The reaction route is as follows: .

[0008] The method uses sodium azide, which is an explosive substance, posing a danger to industrial production and requiring further optimization.

[0009] Therefore, it is of great significance to provide a method for preparing a key intermediate of silodosine with high safety. Summary of the Invention

[0010] In view of this, the purpose of this invention is to provide a method for preparing silodosin intermediates. The preparation method provided by this invention has high reaction safety, high total yield of silodosin intermediates, low cost, and is suitable for industrial production.

[0011] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing a silodosine intermediate, comprising the following steps: Compound SM-1, compound SM-2, Lewis acid and first organic solvent were mixed and subjected to a Friedel-Crafts reaction to obtain compound XL-1; The compound XL-1, the esterifying agent, and the second organic solvent are mixed and subjected to an esterification reaction to obtain compound XL-2; the esterifying agent includes acetate or benzoate, the acetate includes potassium acetate and / or sodium acetate, and the benzoate includes sodium benzoate and / or potassium benzoate. The compound XL-2 was hydrolyzed under alkaline conditions to obtain compound XL-3; The compound XL-3, triethylsilane, and a third organic solvent were mixed and subjected to a first reduction reaction to obtain compound XL-4. The compound XL-4, the oxidant, and the fourth organic solvent were mixed and subjected to an oxidation reaction to obtain compound XL-5. The compound XL-5, (R)-(+)-α-methylbenzylamine and the fifth organic solvent were mixed to carry out an imine reaction. The resulting imine reaction product, Raney nickel and the sixth organic solvent were mixed and hydrogen gas was introduced to carry out a second reduction reaction. After solid-liquid separation, a solution of compound XL-6 was obtained. The XL-6 compound solution was mixed with a palladium-on-carbon catalyst and hydrogen was introduced to carry out a third reduction reaction to obtain the silodosine intermediate. ; Where X is a halogen and R is an acetyl or benzoyl group.

[0012] Preferably, the molar ratio of compound SM-1, compound SM-2, and Lewis acid is 1:1~3:2~5; The Friedel-Crafts reaction is carried out at a temperature of 0-60°C for a duration of 1-8 hours.

[0013] Preferably, the molar ratio of compound XL-1 to the esterifying agent is 1:0.8~2.5; The esterification reaction is carried out at a temperature of 50~120℃ for 1~10h.

[0014] Preferably, the alkaline conditions are provided by an alkaline reagent; The molar ratio of compound XL-2 to the basic reagent is 1:0.5~2.5; The hydrolysis reaction is carried out at a temperature of 30~100℃ for 1~10h.

[0015] Preferably, the molar ratio of compound XL-3 to triethylsilane is 1:0.5~3.5; The temperature of the first reduction reaction is 0~50℃, and the time is 3~24h.

[0016] Preferably, the oxidant includes manganese dioxide and / or potassium permanganate; The molar ratio of the compound XL-4 to the oxidant is 1:0.5~5; The oxidation reaction is carried out at a temperature of 20~100℃ for a time of 12~48h.

[0017] Preferably, the molar ratio of compound XL-4 and (R)-(+)-α-methylbenzylamine is 1:0.8~3; The imine reaction is carried out at a temperature of 10~140℃ for a time of 2~24h.

[0018] Preferably, the mass ratio of compound XL-4 to Raney nickel is 1:0.01~0.5; The temperature of the second reduction reaction is 10~40℃, and the time is 12~48h.

[0019] Preferably, the mass ratio of compound XL-4 to palladium on carbon catalyst is 1:0.04~0.4; The temperature of the third reduction reaction is 20~90℃, and the time is 12~48h.

[0020] Preferably, the first organic solvent comprises a haloalkane; The second organic solvent includes dimethylformamide and / or dimethyl sulfoxide; The third organic solvent includes one or more of trifluoroacetic acid, acetic acid, dichloromethane, chloroform, and 1,2-dichloroethane; The fourth organic solvent preferably includes one or more of 1,4-dioxane, tetrahydrofuran, and dimethyl sulfoxide; The fifth organic solvent includes one or more of toluene, xylene, methyl tert-butyl ether, n-hexane, and n-heptane; The sixth organic solvent includes lower alcohols.

[0021] This invention uses compounds SM-1 and SM-2 as starting materials to prepare silodocine intermediates via Friedel-Crafts reaction, esterification (using potassium acetate and / or sodium acetate as esterification reagents), hydrolysis, reduction, oxidation, imine-reduction (condensation reduction), and further reduction. The preparation method provided by this invention avoids the use of highly hazardous and explosive nitrobenzene or sodium azide, improving the safety of the silodocine intermediate production process. Furthermore, this invention employs chiral excipients to construct chiral centers, significantly improving the utilization rate of raw materials and excipients. The overall yield and purity of the silodocine intermediate are high, reducing waste emissions, increasing production efficiency, making it suitable for industrial production, and resulting in low production costs. Attached Figure Description

[0022] Figure 1 The hydrogen spectrum of the silodosine intermediate prepared in Example 1; Figure 2 The HPLC purity chromatogram of the silodoxine intermediate prepared in Example 1 is shown.

[0023] Figure 3 The chiral HPLC purity chromatogram of the silodoxine intermediate prepared in Example 1 is shown. Detailed Implementation

[0024] This invention provides a method for preparing a silodosine intermediate, comprising the following steps: Compound SM-1, compound SM-2, Lewis acid and first organic solvent were mixed and subjected to a Friedel-Crafts reaction to obtain compound XL-1; The compound XL-1, the esterifying agent, and the second organic solvent are mixed and subjected to an esterification reaction to obtain compound XL-2; the esterifying agent includes acetate or benzoate, the acetate includes potassium acetate and / or sodium acetate, and the benzoate includes sodium benzoate and / or potassium benzoate. The compound XL-2 was hydrolyzed under alkaline conditions to obtain compound XL-3; The compound XL-3, triethylsilane, and a third organic solvent were mixed and subjected to a first reduction reaction to obtain compound XL-4. The compound XL-4, the oxidant, and the fourth organic solvent were mixed and subjected to an oxidation reaction to obtain compound XL-5. The compound XL-5, (R)-(+)-α-methylbenzylamine and the fifth organic solvent were mixed to carry out an imine reaction. The resulting imine reaction product, Raney nickel and the sixth organic solvent were mixed and hydrogen gas was introduced to carry out a second reduction reaction. After solid-liquid separation, a solution of compound XL-6 was obtained. The XL-6 compound solution was mixed with a palladium-on-carbon catalyst and hydrogen was introduced to carry out a third reduction reaction to obtain the silodosine intermediate. ; Where X is a halogen and R is an acetyl or benzoyl group.

[0025] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0026] In this invention, compound SM-1, compound SM-2, a Lewis acid, and a first organic solvent are mixed and subjected to a Friedel-Crafts reaction to obtain compound XL-1.

[0027] In this invention, X in compound SM-2 is a halogen, preferably including fluorine, chlorine, bromine, or iodine, more preferably chlorine or bromine. In this invention, the Lewis acid preferably includes aluminum trichloride and / or ferric trichloride. In this invention, the molar ratio of compound SM-1, compound SM-2, and the Lewis acid is preferably 1:1~3:2~5, more preferably 1:1.5~2.5:2.5~4.5, and even more preferably 1:1.5~2:3~3.5.

[0028] In this invention, the first organic solvent preferably comprises a haloalkane, more preferably one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane. In this invention, the solid-liquid ratio of the compound SM-1 to the first organic solvent is preferably 1 kg: 1~5 L, more preferably 1 kg: 1.5~2.5 L.

[0029] In this invention, the mixing temperature is preferably <20°C; the mixing is preferably: mixing compound SM-2 and a first organic solvent, cooling to 0~5°C in an ice-water bath, adding Lewis acid and stirring, and then adding compound SM-1 and mixing; the stirring temperature is preferably <20°C, and the stirring time is preferably 10~60 min, more preferably 20~30 min.

[0030] In this invention, the temperature of the Friedel-Crafts reaction is preferably 0~60℃, more preferably 20~50℃, and even more preferably 20~25℃; the time of the Friedel-Crafts reaction is preferably 1~8h, more preferably 1~5h, and even more preferably 1.5~2h.

[0031] Following the Friedel-Crafts reaction, the present invention preferably includes a post-treatment process, which preferably includes: mixing the reaction solution after the Friedel-Crafts reaction with ice water, separating the liquid phase to obtain an organic phase and an aqueous phase, extracting the aqueous phase with a haloalkane to obtain an extracted organic phase, and combining the organic phase and the extracted organic phase and concentrating to dryness. In the present invention, the mass ratio of compound SM-1 to ice water is preferably 1:1~5, more preferably 1:2~3. In the present invention, the mixing time is preferably 5~60 min, more preferably 10~30 min. In the present invention, the solid-liquid ratio of compound SM-1 to the haloalkane is preferably 1:1~5, more preferably 1:1.5~2.5. In the present invention, the haloalkane preferably includes one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane. In the present invention, the mass ratio of compound SM-1 to the haloalkane is preferably 1:1~5, more preferably 1:1.5~2.5. The present invention does not have any special limitation on the concentration method, and any concentration method known to those skilled in the art can be used, such as vacuum concentration.

[0032] After obtaining compound XL-1, the present invention mixes compound XL-1, an esterifying agent, and a second organic solvent to carry out an esterification reaction to obtain compound XL-2; the esterifying agent includes acetate or benzoate, the acetate includes potassium acetate and / or sodium acetate, and the benzoate includes sodium benzoate and / or potassium benzoate.

[0033] In this invention, the molar ratio of compound XL-1 to the esterifying agent is preferably 1:0.8 to 2.5, more preferably 1:1 to 2, and even more preferably 1:1 to 1.5.

[0034] In this invention, the second organic solvent preferably comprises dimethylformamide and / or dimethyl sulfoxide. In this invention, the solid-liquid ratio of compound XL-1 and the second organic solvent is preferably 1 kg: 0.5-5 L, more preferably 1 kg: 1-2 L.

[0035] In this invention, the temperature of the esterification reaction is preferably 50~120℃, more preferably 60~100℃, and even more preferably 70~80℃; the time of the esterification reaction is preferably 1~10h, more preferably 2~8h, and even more preferably 3~6h.

[0036] Following the esterification reaction, the present invention preferably includes post-treatment, which preferably includes: cooling the reaction solution after the esterification reaction to room temperature and then stirring and mixing it with ice water, performing solid-liquid separation, and drying the resulting solid product to obtain compound XL-2. In the present invention, the mass ratio of compound XL-1 to ice water is preferably 1:1~10, more preferably 1:5~7. In the present invention, the stirring and mixing time is preferably 5~60 min, more preferably 10~30 min. The present invention does not have a special limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In the present invention, the drying temperature is preferably 20~70℃, more preferably 40~55℃, and the present invention does not have a special limitation on the drying time; drying to constant weight is sufficient.

[0037] After obtaining compound XL-2, the present invention hydrolyzes compound XL-2 under alkaline conditions to obtain compound XL-3.

[0038] In this invention, the alkaline conditions are provided by an alkaline reagent, which preferably includes alkali metal hydroxides, more preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, and lithium hydroxide hydrate. In this invention, the molar ratio of compound XL-2 to the alkaline reagent is preferably 1:0.5 to 2.5, more preferably 1:1 to 2, and even more preferably 1:1 to 1.5.

[0039] In this invention, the solvent used for the hydrolysis reaction preferably includes an alcohol solvent and water, wherein the alcohol solvent is preferably a lower alcohol, more preferably one or more selected from methanol, ethanol, isopropanol, and n-butanol. In this invention, the mass ratio of compound XL-2 to the solvent is preferably 1:1 to 5, more preferably 1:2 to 3. In this invention, the mass ratio of the alkaline reagent to water is preferably 0.05 to 0.5:1, more preferably 0.1 to 0.2:1.

[0040] In this invention, the temperature of the hydrolysis reaction is preferably 30~100℃, more preferably 40~80℃. In a specific embodiment of this invention, the hydrolysis reaction is preferably carried out under reflux conditions. The time of the hydrolysis reaction is preferably 1~10h, more preferably 1~5h, and even more preferably 1.5~2h.

[0041] Following the hydrolysis reaction, the present invention preferably further includes a post-treatment process, which preferably includes: concentrating the reaction solution after the hydrolysis reaction, then adding water and a haloalkane for extraction, and concentrating the resulting organic layer to dryness to obtain compound XL-3. The present invention does not have any particular limitation on the two concentration processes; any concentration method well known to those skilled in the art can be used, such as vacuum concentration. In the present invention, the haloalkane preferably includes one or more of dichloromethane, 1,2-dichloroethane, and trichloromethane. In the present invention, the mass ratio of compound XL-2, water, and haloalkane is preferably 1:1~3:0.5~2, more preferably 1:1.5~0.5:1~1.5, and even more preferably 1:1.7:1.1.

[0042] After obtaining compound XL-3, the present invention mixes compound XL-3, triethylsilane and a third organic solvent to carry out a first reduction reaction to obtain compound XL-4.

[0043] In this invention, the molar ratio of compound XL-3 to triethylsilane is preferably 1:0.5 to 3.5, more preferably 1:1 to 3, and even more preferably 1:2 to 3.

[0044] In this invention, the third organic solvent preferably includes one or more of trifluoroacetic acid, acetic acid, dichloromethane, chloroform, and 1,2-dichloroethane. In this invention, the molar ratio of compound XL-3 to the third organic solvent is preferably 1:1 to 15, more preferably 1:5 to 12, and even more preferably 1:8 to 10.

[0045] In this invention, the mixing is preferably performed by mixing the compound XL-3 with a third organic solvent, cooling the temperature of the resulting mixture to 0-5°C, and then adding triethylsilane dropwise. This invention does not have a specific limitation on the dropping rate; it can be added dropwise at a uniform rate.

[0046] In this invention, the temperature of the first reduction reaction is preferably 0~50℃, more preferably 10~40℃, and even more preferably 20~30℃; the time of the first reduction reaction is preferably 3~24h, more preferably 4~15h, and even more preferably 5~8h.

[0047] Following the first reduction reaction, the present invention preferably further includes concentrating the reaction solution after the first reduction reaction, adding dichloromethane and mixing, adding an alkaline solution to adjust the pH value to 6-10 (more preferably 7-8), separating the liquids, and concentrating the resulting organic layer to dryness to obtain compound XL-4. In the present invention, the mass ratio of compound XL-3 to dichloromethane is preferably 1:0.5-5, more preferably 1:1-2. In the present invention, the alkaline solution preferably includes one or more of the following: aqueous solution of bicarbonate, ammonia, aqueous solution of sodium carbonate, and aqueous solution of potassium carbonate, more preferably including aqueous solution of sodium bicarbonate and aqueous solution of sodium carbonate; the concentration of the alkaline solution is preferably 5-20 wt%, more preferably 10-15 wt%. The present invention does not have any particular limitation on the two concentrations; any concentration method well known to those skilled in the art can be used to completely remove the solvent, such as vacuum concentration.

[0048] After obtaining compound XL-4, the present invention mixes compound XL-4, an oxidant and a fourth organic solvent to carry out an oxidation reaction to obtain compound XL-5.

[0049] In this invention, the molar ratio of compound XL-4 to the oxidant is preferably 1:0.5~5, more preferably 1:1~3, and even more preferably 1:1~2. In this invention, the oxidant preferably comprises manganese dioxide and / or potassium permanganate, wherein the manganese dioxide is preferably active manganese dioxide.

[0050] In this invention, the fourth organic solvent preferably includes one or more of 1,4-dioxane, tetrahydrofuran, and dimethyl sulfoxide. In this invention, the mass ratio of compound XL-3 to the fourth organic solvent is preferably 1:1 to 5, more preferably 1:2 to 3.

[0051] In this invention, the temperature of the oxidation reaction is preferably 20~100℃, more preferably 40~80℃, and even more preferably 50~60℃; the time of the oxidation reaction is preferably 12~48h, more preferably 15~40h, and even more preferably 20~25h.

[0052] Following the oxidation reaction, the present invention preferably further includes: performing solid-liquid separation on the reaction solution after the oxidation reaction, and concentrating the obtained liquid product to dryness to obtain compound XL-5. The present invention does not have any particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. The present invention does not have any particular limitation on the two concentrations; any concentration method well known to those skilled in the art that can completely remove the solvent can be used, such as vacuum concentration.

[0053] After obtaining compound XL-5, this invention mixes compound XL-5, (R)-(+)-α-methylbenzylamine, and a fifth organic solvent to carry out an imine reaction. The resulting imine reaction product, Raney nickel, and a sixth organic solvent are mixed, and hydrogen gas is introduced to carry out a second reduction reaction, followed by solid-liquid separation to obtain a solution of compound XL-6. This invention does not have any particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation.

[0054] In this invention, the molar ratio of compound XL-4 (the amount of compound XL-5 is based on compound XL-4) and (R)-(+)-α-methylbenzylamine is preferably 1:0.8~3, more preferably 1:1~2, and even more preferably 1:1~1.5.

[0055] In this invention, the fifth organic solvent preferably includes one or more of toluene, xylene, methyl tert-butyl ether, n-hexane, and n-heptane. In this invention, the mass ratio of compound XL-4 to the fifth organic solvent is preferably 1:1 to 8, more preferably 1:2 to 3.

[0056] In this invention, the temperature of the imine reaction is preferably 10~140℃, more preferably 80~120℃; the time is preferably 2~24h, more preferably 2~10h. In a specific embodiment of this invention, the imine reaction is preferably carried out by heating and reflux to separate water, reacting until no water drips out, and then continuing to maintain the temperature for 2h.

[0057] Following the imine reaction, the present invention preferably further includes: removing the solvent from the reaction solution after the imine reaction to obtain the imine reaction product. In the present invention, the solvent removal is preferably carried out by vacuum distillation.

[0058] In this invention, the mass ratio of the compound XL-4 to Raney nickel is preferably 1:0.01~0.5, more preferably 0.1~0.45, and even more preferably 0.3~0.42.

[0059] In this invention, the sixth organic solvent preferably comprises a lower alcohol, more preferably one or more of methanol, ethanol, isopropanol, and n-butanol. In this invention, the mass ratio of compound XL-4 to the sixth organic solvent is preferably 1:1 to 5, more preferably 1:1.5 to 2.5.

[0060] In this invention, the temperature of the second reduction reaction is preferably 10~40℃, more preferably room temperature; the time of the second reduction reaction is preferably 12~48h, more preferably 15~24h; the pressure of the hydrogen gas is preferably atmospheric pressure; and the second reduction reaction is preferably carried out in a high-pressure reactor.

[0061] Following the second reduction reaction, the present invention preferably further includes solid-liquid separation of the reaction solution after the second reduction reaction to obtain a solution of compound XL-6. The present invention does not have any particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation.

[0062] After obtaining a solution of compound XL-6, the present invention mixes the solution of compound XL-6 with a palladium on carbon catalyst and introduces hydrogen gas to carry out a third reduction reaction to obtain silodosin intermediate.

[0063] In this invention, the palladium-on-carbon catalyst preferably comprises 5% palladium on carbon. In this invention, the mass ratio of compound XL-4 to the palladium-on-carbon catalyst is preferably 1:0.04~0.4, more preferably 1:0.05~0.3, and even more preferably 1:0.1~0.2.

[0064] In this invention, the temperature of the third reduction reaction is preferably 20~90℃, more preferably 40~80℃, and even more preferably 50~60℃; the time of the third reduction reaction is preferably 12~48h, more preferably 15~24h; and the pressure of the hydrogen gas is preferably atmospheric pressure.

[0065] Following the third reduction reaction, the present invention preferably includes post-treatment, which preferably includes: cooling the reaction solution after the third reduction reaction to room temperature, performing solid-liquid separation, concentrating the obtained liquid product to dryness, adding saturated alkanes and mixing, performing solid-liquid separation, and drying the obtained solid product to obtain the silodosin intermediate. The present invention does not have specific limitations on the two solid-liquid separations; any solid-liquid separation method well-known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. The present invention does not have specific limitations on the concentration; any concentration method well-known to those skilled in the art that can completely remove the solvent can be used, such as vacuum concentration. In the present invention, the saturated alkanes preferably include n-hexane and / or n-heptane; the mass ratio of the compound XL-4 to n-hexane is preferably 1:0.1~10, more preferably 1:0.5~1; the purpose of adding saturated alkanes in the present invention is to transfer the solid material out and simultaneously remove some impurities. In the present invention, the drying temperature is preferably 20~70℃, more preferably 45~60℃; the present invention does not have specific limitations on the drying time, drying to constant weight is sufficient.

[0066] To further illustrate the present invention, the silodosin intermediates are described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0067] In the following examples, the active manganese dioxide was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0068] Example 1 (1) Synthesis of compound XL-1 Compound SM-2 (2-bromopropionyl chloride, where X is bromine) was mixed with 1,2-dichloroethane and cooled to 0-5°C in an ice-water bath. Aluminum trichloride was added, and the mixture was stirred for 30 min while maintaining the temperature below 20°C. Then, compound SM-1 was added and the mixture was reacted at 20°C for 2 h. The reaction solution was poured into ice water and stirred for 30 min. The mixture was separated to obtain an organic phase and an aqueous phase. The aqueous phase was extracted with 1,2-dichloroethane to obtain an extracted organic phase. The organic phase and the extracted organic phase were combined and concentrated to dryness under reduced pressure to obtain compound XL-1 (a white solid with a yield of 95.3% and an HPLC purity greater than 99.8%). The mass ratio of compound SM-1, compound SM-2 and aluminum trichloride is 200:232.6:273.8; the mass ratio of compound SM-1 and 1,2-dichloroethane is 1:2.5; the mass ratio of compound SM-1 and ice water is 1:3; and the mass ratio of compound SM-1 and 1,2-dichloroethane for extraction is 1:2.5.

[0069] (2) Synthesis of compound XL-2 Compound XL-1, potassium acetate, and DMF were mixed and reacted at 75°C for 6 hours. The mixture was then cooled to room temperature, poured into ice water, and stirred for 30 minutes. The mixture was filtered, and the resulting solid product was dried at 55°C to constant weight to obtain compound XL-2 (a white solid with a yield of 98.0% and an HPLC purity greater than 99.8%). The mass ratio of compound XL-1 to potassium acetate was 200:55.3, the mass ratio of compound XL-1 to DMF was 1:2, and the mass ratio of compound XL-1 to ice water was 1:5.

[0070] (3) Synthesis of compound XL-3 Compound XL-2 (R=Ac), ethanol, sodium hydroxide, and water were mixed and refluxed for 2 hours. The solvent was removed under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated to dryness under reduced pressure to obtain compound XL-3 (an oily substance with a yield of 96.8% and an HPLC purity greater than 99.8%). The mass ratio of compound XL-2, sodium hydroxide, ethanol, and water (water for reaction) was 18:2.48:50:14, and the mass ratio of compound XL-2, water (water for post-treatment), and dichloromethane was 18:30:20.

[0071] (4) Synthesis of compound XL-4 Compound XL-3 and trifluoroacetic acid were mixed and cooled to 5°C in an ice-water bath, with the temperature controlled not to exceed 15°C. Triethylsilane was added dropwise, and the mixture was reacted at 28°C for 6 hours. The solvent was removed under reduced pressure, and dichloromethane was added. The pH was adjusted to 8 with a 15wt% sodium bicarbonate aqueous solution. The mixture was separated, and the organic layer was concentrated to dryness under reduced pressure to obtain compound XL-4 (an oily substance with a yield of 95.0% and an HPLC purity greater than 99.8%). The mass ratio of compound XL-3, trifluoroacetic acid, and triethylsilane was 150:450:105.4, and the mass ratio of compound XL-3 to dichloromethane was 1:2.

[0072] (5) Synthesis of compound XL-5 Compound XL-4, 1,4-dioxane, and activated manganese dioxide were mixed at room temperature, heated to 55°C, and reacted for 24 hours. The mixture was then filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound XL-5. The mass ratio of compound XL-4, activated manganese dioxide, and 1,4-dioxane was 100:37:300.

[0073] (6) Synthesis of compound XL-6 The compound XL-5 obtained in step (5), toluene, and (R)-(+)-α-methylbenzylamine were mixed, heated to reflux to remove water, and reacted until no water dripped out (8 h). The reaction was then continued at this temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was added to a high-pressure reactor. Methanol and Raney nickel were added, and the mixture was reacted at atmospheric pressure (hydrogen) at 25 °C for 24 h. The mixture was filtered, and the filtrate was a solution of compound XL-6, which was used directly in the next step of the reaction without purification. The mass ratio of compound XL-4, (R)-(+)-α-methylbenzylamine, and toluene was 100:300:41.5, and the mass ratio of compound XL-4, Raney nickel, and methanol was 1:0.05:2.5.

[0074] (7) Synthesis of Silodosin intermediate (XL-7) The XL-6 solution obtained in step (6) and 5% palladium on carbon were added to a high-pressure reactor. The reactor was heated to 60°C under normal hydrogen pressure and kept at that temperature for 24 hours. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Hexane was added and stirred until homogeneous. The mixture was then filtered again and the resulting solid product was dried to constant weight to obtain silodosin intermediate (white solid, total yield of steps (5) to (7) was 82.1%, HPLC purity > 99.8%). The mass ratio of XL-4 to 5% palladium on carbon was 1:01, and the mass ratio of XL-4 to hexane was 1:05.

[0075] The proton NMR spectrum of silodosine intermediate XL-7 is as follows: Figure 1 As shown, the HPLC purity test results for silodosin intermediate XL-7 are as follows: Figure 2 As shown in Table 1.

[0076] Table 1. HPLC purity peaks of silodosin intermediate XL-B The chiral HPLC purity determination chromatogram of silodosine intermediate XL-7 is shown below. Figure 3 As shown, by Figure 3 It can be seen that the main peak is 100%, indicating that the silodosine intermediate XL-7 prepared by this invention has no isomers, has a single configuration, and high purity.

[0077] Example 2 The silodosin intermediate was prepared according to the method of Example 1, with the only difference from Example 1 being: In step (1), X in compound SM-2 is chlorine, the mass ratio of compound SM-1 to compound SM-2 is 200:172.5, the yield of compound XL-1 is 93.0%, the HPLC purity is >99.8%, there are no isomers, the configuration is single, and the purity is high.

[0078] Example 3 The silodosin intermediate was prepared according to the method of Example 1, with the only difference from Example 1 being: In step (2), the esterification reagent is potassium benzoate, the mass ratio of compound XL-1 to potassium benzoate is 200:91, the mass ratio of compound XL-1 to DMF is 1:2.5, the mass ratio of compound XL-1 to ice water is 1:6.25, the yield of compound XL-2 is 96.1%, the HPLC purity is >99.8%, there are no isomers, the configuration is simple, and the purity is high.

[0079] The proton NMR spectral data of the silodosin intermediate XL-7 prepared in the above examples are as follows: 1 H-NMR 1 H-NMR (400MHz, DMSO- d 6) δ: 7.103(2H, d), 3.938(2H, s), 3.720(2H, m), 3.622(2H, m), 3.325(1H, m), 2.971(2H, m), 2.822(1H, m), 2.554(1H, m), 2.106(2H, m), 1.101(3H, d).

[0080] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of an intermediate of silodosin, characterized in that, Includes the following steps: Compound SM-1, compound SM-2, Lewis acid and first organic solvent were mixed and subjected to a Friedel-Crafts reaction to obtain compound XL-1; The compound XL-1, the esterifying agent, and the second organic solvent are mixed and subjected to an esterification reaction to obtain compound XL-2; the esterifying agent is selected from potassium acetate, sodium acetate, sodium benzoate, or potassium benzoate. The compound XL-2 was hydrolyzed under alkaline conditions to obtain compound XL-3; The compound XL-3, triethylsilane, and a third organic solvent were mixed and subjected to a first reduction reaction to obtain compound XL-4; the third organic solvent was selected from trifluoroacetic acid and / or acetic acid. The compound XL-4, the oxidant, and the fourth organic solvent were mixed and subjected to an oxidation reaction to obtain compound XL-5. The compound XL-5, (R)-(+)-α-methylbenzylamine and the fifth organic solvent were mixed to carry out an imine reaction. The resulting imine reaction product, Raney nickel and the sixth organic solvent were mixed and hydrogen gas was introduced to carry out a second reduction reaction. After solid-liquid separation, a solution of compound XL-6 was obtained. The XL-6 compound solution was mixed with a palladium-on-carbon catalyst and hydrogen was introduced to carry out a third reduction reaction to obtain the silodosine intermediate. ； Where X is a halogen and R is an acetyl or benzoyl group.

2. The production method according to claim 1, characterized by, The molar ratio of compound SM-1, compound SM-2, and Lewis acid is 1:1~3:2~5; The Friedel-Crafts reaction is carried out at a temperature of 0-60°C for a duration of 1-8 hours.

3. The preparation method according to claim 1, characterized in that, The molar ratio of compound XL-1 to the esterifying agent is 1:0.8~2.5; The esterification reaction is carried out at a temperature of 50~120℃ for 1~10h.

4. The method of claim 1, wherein, The alkaline conditions are provided by an alkaline reagent; The molar ratio of compound XL-2 to the basic reagent is 1:0.5~2.5; The hydrolysis reaction is carried out at a temperature of 30~100℃ for 1~10h.

5. The preparation method according to claim 1, characterized in that, The molar ratio of compound XL-3 to triethylsilane is 1:0.5~3.5; The temperature of the first reduction reaction is 0~50℃, and the time is 3~24h.

6. The preparation method according to claim 1, characterized in that, The oxidant is selected from manganese dioxide and / or potassium permanganate; The molar ratio of the compound XL-4 to the oxidant is 1:0.5~5; The oxidation reaction is carried out at a temperature of 20~100℃ for a time of 12~48h.

7. The preparation method according to any one of claims 1 or 6, characterized in that, The molar ratio of the compound XL-4 and (R)-(+)-α-methylbenzylamine is 1:0.8~3; The imine reaction is carried out at a temperature of 10~140℃ for a time of 2~24h.

8. The preparation method according to any one of claims 1 or 6, characterized in that, The mass ratio of compound XL-4 to Raney nickel is 1:0.01~0.5; The temperature of the second reduction reaction is 10~40℃, and the time is 12~48h.

9. The preparation method according to any one of claims 1 or 6, characterized in that, The mass ratio of compound XL-4 to palladium on carbon catalyst is 1:0.04~0.4; The temperature of the third reduction reaction is 20~90℃, and the time is 12~48h.

10. The preparation method according to claim 1, characterized in that, The first organic solvent is selected from haloalkanes; The second organic solvent is selected from dimethylformamide and / or dimethyl sulfoxide; The fourth organic solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, and dimethyl sulfoxide; The fifth organic solvent is selected from one or more of toluene, xylene, methyl tert-butyl ether, n-hexane, and n-heptane; The sixth organic solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol.

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