Silodosin intermediate and preparation method thereof

Abstract

The invention provides a silodosin intermediate and a preparation method thereof, and relates to the technical field of medicine preparation. Comprising the following steps: S1, 3-(indoline-1-yl) propyl benzoate is used as a raw material and is subjected to a substitution reaction with a bromination reagent, and 3-(5.7-dibromo-indoline-1-yl) propyl benzoate is obtained; s2, carrying out a substitution reaction on the 3-(5.7-dibromo-indoline-1-yl) propyl benzoate to obtain 3-(7-cyano-5-bromo-indoline-1-yl) propyl benzoate, and carrying out a substitution reaction on the 3-(5.7-dibromo-indoline-1-yl) propyl benzoate to obtain 3-(7-cyano-5-bromo-indoline-1-yl) propyl benzoate; s3, carrying out nucleophilic addition on the 3-(7-cyano-5-bromo-indoline-1-yl) propyl benzoate and epoxypropane, and carrying out ring opening on the 3-(7-cyano-5-(2-hydroxy-propyl) indoline-1-yl) propyl benzoate, so as to obtain 3-(7-cyano-5-(2-hydroxy-propyl) indoline-1-yl) propyl benzoate; s4, the 3-(7-cyano-5-(2-hydroxy-propyl) indoline-1-yl) propyl benzoate is subjected to oxidation, and the 3-(7-cyano-5-(2-oxopropyl) indoline-1-yl) propyl benzoate is generated. According to the synthesis method disclosed by the invention, all raw materials are easy to obtain, high-risk and high-pollution reagents are not used, the synthesis method is safe and environment-friendly, and the prepared silodosin intermediate is good in purity and high in yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically relates to a silodosin intermediate and a preparation method thereof. Background Art

[0002] Prostatic hyperplasia (BPH) or hypertrophy is one of the common diseases in elderly men, characterized by non-malignant enlargement of the prostate. More than 50% of the elderly aged 60 or above suffer from this disease. The cause of the disease has not yet been clarified, but it is generally believed to be related to the secretion and metabolic disorders of sex hormones and cholesterol. Some people believe that the elderly have testicular degeneration, decreased sexual function, lower testosterone levels, and increased connective tissue in the prostate, which causes glandular epithelial changes and prostate enlargement. The enlargement of the prostate will compress the urethra, resulting in poor bladder urine flow and even blockage of the bladder outlet. There are a1A-adrenaline receptors in the human prostate, and the activation of this receptor will aggravate the symptoms of urethral obstruction and dysuria. In clinical practice, 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 a1-receptor antagonist invented by Kissei Pharmaceuticals of Japan. Kissei applied for it in cooperation with Daiichi Sankyo and obtained marketing approval in Japan in May 2006 under the trade name Urief(R). Kissei also licensed silodosin to Watson Pharmaceuticals of the United States, which recently obtained FDA approval for marketing in August 2008.

[0004] At present, there are many literature reports using 3-(7-cyano-5-(2-oxopropyl)indolin-1-yl)benzoic acid propyl ester as a reaction intermediate to prepare silodosin through multi-step reactions, as shown in Reaction Formula 1:

[0005]

[0006] At present, there are many synthetic routes for 3-(7-cyano-5-(2-oxopropyl)indolin-1-yl)propyl benzoate, and the relevant literature and patents mainly include the following items. First, Japanese patent JP2001199956 reports a synthetic route using indolin, benzoyl chloride, etc. as starting materials, as shown in synthetic route 1, the synthetic route of the reaction is long, the yield is relatively low, POCl3 is used, phosphorus-containing wastewater is easily generated, and it is not friendly to the environment. In addition, nitroethane is used as an explosive reagent, which is not suitable for industrial production.

[0007] Synthetic route 1:

[0008]

[0009] Secondly, patent CN102675182 also uses indoline as the starting material, undergoes nitrogen alkylation, uses phosphorus oxychloride and DMF to make Vilsmeier reagent, performs an aldehyde reaction, and then performs a halogenation reaction to synthesize compound 4, which is then reduced to obtain compound 5, and finally cyanided to obtain compound IV, i.e., compound 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester. This route is relatively complicated, and in addition, nitroethane hazardous reagent is used. The use of cyanide will produce a highly toxic substance, hydrocyanic acid, which is not suitable for industrial production.

[0010] Third, patent CN115838349B reports 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 the formaldehyde reaction. The post-treatment is relatively dangerous and produces 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 processes, which increases the cost of industrial production.

[0011] Synthetic route 2:

[0012]

[0013] In summary, the existing synthetic route of silodosin intermediates is long, and phosphorus oxychloride is used, which is easy to produce phosphorus-containing wastewater, which is not conducive to environmental protection. The use of nitroethane as a riot-proof reagent increases the danger of actual operation, and the use of precious metal palladium reagent increases the economic cost. Based on the above reasons, it is urgent to develop a green, economical, environmentally friendly and safe synthetic route of silodosin intermediates, which has broad application prospects. Summary of the invention

[0014] 1. Technical issues to be resolved

[0015] In view of the deficiencies in the prior art, the present invention provides a silodosin intermediate and a preparation method thereof, which solves the technical problem that the prior preparation method uses highly dangerous and highly polluting reagents, which is not conducive to safety and environmental protection.

[0016] (II) Technical solution

[0017] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0018] A method for preparing a silodosin intermediate 3-(7-cyano-5-(2-oxopropyl)indolin-1-yl)propyl benzoate, the synthetic route of which is as follows:

[0019]

[0020] The following steps are involved:

[0021] S1. Under nitrogen protection, 3-(indolin-1-yl) propyl benzoate and solvent were mixed evenly, and a bromination reagent was added in batches at low temperature to cause a substitution reaction, and then stirring was continued at room temperature to obtain 3-(5.7-dibromo-indolin-1-yl) propyl benzoate.

[0022] S2, under nitrogen protection, take 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate, cuprous cyanide and reaction solvent and mix them evenly, start heating reaction, and obtain 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate;

[0023] S3. Under nitrogen protection, 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate, a reaction solvent, and a catalyst are added to the container in sequence, and the temperature is lowered to -80-25°C, and propylene oxide is added to obtain compound III, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl) propyl benzoate;

[0024] S4, under nitrogen protection, the compound of formula III, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester, acyl chloride, and reaction solvent are subjected to oxidation reaction under low temperature conditions, and the reaction is monitored until the raw material point disappears to obtain the compound of formula IV, 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester;

[0025] Furthermore, the S1 specifically includes the following steps:

[0026] Under nitrogen protection, 3-(indolyl-1-yl) propyl benzoate and solvent were mixed evenly, and bromination reagent was added in batches at low temperature to cause substitution reaction to obtain 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate.

[0027] The reaction equation is as follows:

[0028]

[0029] Furthermore, in step S1, the molar ratio of 3-(indolyl-1-yl)benzoic acid propyl ester to the bromination reagent is 1:2-3.5; the solvent is dichloromethane or ethyl acetate, and the mass ratio of 3-(indolyl-1-yl)benzoic acid propyl ester to the solvent volume is 1g:10-30ml;

[0030] Furthermore, the bromination reagent is selected from any one of Br2, PBr3, and NBS, preferably NBS, and the substitution reaction temperature is 0-50°C, preferably, the reaction temperature is 0-25°C; the reaction time is 1-8h, preferably, the reaction time is 3-5h.

[0031] Furthermore, after step S1, post-treatment of the reaction solution is also included, which specifically includes the following steps: after the reaction is completed, adding water to wash the organic layer, separating the organic layer, extracting the water layer, combining the organic layers, and concentrating to dryness to obtain the product.

[0032] Furthermore, the S2 specifically includes the following steps:

[0033] Take 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate and a cyaniding agent, add them to a reaction solvent and mix them evenly, then start heating the reaction to obtain 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate of structural formula II.

[0034] The reaction equation is as follows:

[0035]

[0036] Further, the reaction solvent in step S2 is DMF (N, N-dimethylformamide), NMP (N-methylpyrrolidone) or DMAc (N, N-dimethylacetamide), preferably DMF;

[0037] Further, the molar ratio of the 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate to the cyaniding agent is 1:1.1-2.0;

[0038] Further, the cyaniding agent is selected from any one of zinc cyanide, cuprous cyanide, and potassium ferrocyanide, preferably cuprous cyanide;

[0039] Furthermore, the reaction temperature is 100-180°C, preferably 110-130°C; the reaction time is 1-24h, preferably 12-17h.

[0040] Furthermore, after step S2, the post-treatment of 3-(7-cyano-5-bromo-indolyl-1-yl)benzoic acid propyl ester is also included, which specifically includes the following steps: adding water, cooling to room temperature, filtering, extracting the aqueous layer with dichloromethane, combining the organic layers, and concentrating to dryness to obtain the product.

[0041] Furthermore, the S3 specifically includes the following steps:

[0042] Add 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate, solvent and catalyst to the container in sequence, pass nitrogen protection, cool to -80-25°C, add propylene oxide at one time, react at room temperature after addition, quench with saturated ammonium chloride solution, adjust pH, and obtain 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl) propyl benzoate. The reaction equation is as follows:

[0043]

[0044] Furthermore, the reaction solvent in step S3 is methyl pyrrolidone;

[0045] Further, the molar ratio of the 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate to propylene oxide is 1:1-5.0;

[0046] Further, the catalyst is a mixture of nickel iodide hexahydrate, bipyridine, pyridine, potassium iodide, and zinc powder;

[0047] Further, the molar ratio of the 3-(7-cyano-5-bromo-indolyl-1-yl)benzoic acid propyl ester 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: 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;

[0048] Further, the feeding temperature is -80°C to 10°C, preferably -80°C to 0°C; the reaction temperature is 0-25°C;

[0049] Furthermore, after step S3, the method further includes post-treatment of 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoic acid propyl ester, which specifically includes the following steps: after the reaction is completed, saturated ammonium chloride solution is added to quench, dichloromethane is added to extract, the organic layers are combined, the organic layers are washed with water, and concentrated to obtain the product.

[0050] Furthermore, the S4 specifically includes the following steps:

[0051] 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester, acyl chloride, and reaction solvent are subjected to oxidation reaction under low temperature conditions, and the reaction is monitored until the raw material point disappears to obtain the compound of formula IV, 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester;

[0052] The reaction equation is as follows:

[0053]

[0054] Further, the reaction solvent in step S4 is dichloromethane;

[0055] Further, the acyl chloride is any one of oxalyl chloride, phosphorus oxychloride, and thionyl chloride, preferably oxalyl chloride;

[0056] Furthermore, the molar ratio of 3-(7-cyano-5-(2-hydroxy-propyl)indoline-1-yl)benzoic acid propyl ester to the acyl chloride is 1:1-2.5; the reaction temperature is -20-30°C, preferably -20-10°C; and the reaction time is 12-48h, preferably 24-30h.

[0057] Furthermore, after step S4, the method further includes post-treatment of the compound of formula IV, 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester, which specifically includes the following steps: concentrating the solvent under reduced pressure, adding dichloromethane and stirring to dissolve, washing the organic layer with water, concentrating part of the solvent, cooling, crystallizing, filtering, and drying to obtain 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester.

[0058] (III) Beneficial effects

[0059] The present invention provides a silodosin intermediate and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:

[0060] The invention provides a preparation method of a silodosin intermediate. The method comprises the following steps: taking 3-(indolyl-1-yl) propyl benzoate as a raw material, substituting the 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate with a bromination reagent, and then subjecting the 3-(5-bromo-7-cyano-indolyl-1-yl) propyl benzoate to a substitution reaction to obtain 3-(5-bromo-7-cyano-indolyl-1-yl) propyl benzoate. The 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl) propyl benzoate is subjected to a substitution reaction with propylene oxide, and then subjecting the propylene oxide to a ring opening to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl) propyl benzoate. Propyl (2-hydroxy-propyl) indoline-1-yl) benzoate is oxidized to generate a key intermediate 3-(7-cyano-5-(2-oxopropyl) indoline-1-yl) benzoate. The synthesis route of the invention is novel, all raw materials and reagents used are easy to obtain or prepare, and no highly dangerous and highly polluting reagents are used. The invention is safe and environmentally friendly, the reaction conditions are mild, the operation is convenient and controllable, the prepared silodosin intermediate has good purity and high yield, and the cost advantage is obvious, which is suitable for industrial production and also provides a new idea for the preparation of silodosin. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0062] The embodiment of the present application provides a method for preparing a silodosin intermediate, thereby solving the technical problem that the existing preparation method uses highly dangerous and highly polluting reagents and is unsafe and environmentally unfriendly.

[0063] The technical solution in the embodiment of the present application is to solve the above technical problems, and the overall idea is as follows:

[0064] A method for preparing a silodosin intermediate 3-(7-cyano-5-(2-oxopropyl)indolin-1-yl)propyl benzoate comprises the following steps:

[0065]

[0066] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0067] Example 1

[0068] This embodiment provides a method for preparing a silodosin intermediate, which specifically comprises the following steps:

[0069] S1. Synthesis of 3-(5,7-dibromo-indolyl-1-yl)benzoic acid propyl ester (Formula I).

[0070] The reaction equation is as follows:

[0071]

[0072] Under nitrogen protection, 3-(indolin-1-yl) propyl benzoate (2.81 g, 10 mmol) and dichloromethane (28 ml) were added to a four-necked flask in sequence. Bromine (3.20 g, 20 mmol) was added in batches at low temperature. After the addition, the temperature was controlled at 25°C. The reaction was continued for 3 h. The mixture was washed with water, and the organic layer was separated. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phases were combined and concentrated to dryness to give off-white 3-(5.7-dibromo-indolin-1-yl) propyl benzoate (3.95 g, yield 90%, purity 98%), which was directly used in the next step.

[0073] 1H NMR (400MHz, CDCl3) δ = 8.54 (s, 1H), 8.17 (m, 1H), 7.65–7.57 (m, 1H), 7.46 (t, J = 7.7Hz, 2H), 7.12 (m, 2H), 4.34(t,J=6.5Hz,2H), 3.42(t,J=8.4Hz,2H), 3.25(t,J=7.2Hz,2H), 2.97(t,J=8.4Hz,2H), 2.15(m,2H). 13 C NMR (150MHz, 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.

[0074] S2. Synthesis of 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (Formula II)

[0075] The reaction equation is as follows:

[0076]

[0077] Into a four-necked flask, 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate (4.36 g, 10 mmol), cuprous cyanide (1.34 g, 15 mmol), and DMF (15 mL) were added in sequence, stirred at room temperature for 20 min, heated to 110 ° C, and reacted for 15 h. After the reaction was complete, 50 mL of water was added, cooled to room temperature, and the solid waste was filtered out. The aqueous layer was extracted with dichloromethane 50 mL x 3, the organic layers were combined, and concentrated to dryness to obtain a light yellow solid 3-(5-bromo-7-cyano-indolyl-1-yl) propyl benzoate (3.35 g, yield 87%, purity 97.5%), which was directly used in the next step.

[0078] 1 H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 8.14 (m, 1H), 7.62–7.45 (m, 1H), 7.46 (t, J = 7.6Hz, 2H), 7.10 (m, 2H), 4.32(t,J=6.5Hz,2H), 3.45(t,J=8.3Hz,2H), 3.17(t,J=7.2Hz,2H), 2.99(t,J=8.3Hz,2H), 2.15(m,2H).

[0079] 13C NMR (150MHz, 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.

[0080] S3. Synthesis of 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester (Formula III)

[0081] The reaction equation is as follows:

[0082]

[0083] In a round-bottom flask, 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (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), zinc powder (1.3 g, 20 mmol) were added in sequence. Under nitrogen protection, the temperature was lowered to -70°C, and propylene oxide (1.16 g, 20 mmol) was added at one time. After the addition was completed, the temperature was controlled to 25°C for reaction. The reaction of the raw materials was monitored by plate counting. The reaction was complete, and the reaction was quenched with 20 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 30 mL*3 of dichloromethane. The organic layers were combined, washed with water, and concentrated to obtain 3.10 g of 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoic acid propyl ester. The yield was 85%.

[0084] 1 H NMR (400MHz, CDCl3) δ = 8.45 (m, 1H), 8.00 (m, 1H), 7.65–7.52 (m, 1H), 7.29 (t, J = 7.6Hz, 2H), 7.13 (m, 2H), 6.12 (s, 1H) ,4.43(m,1H),4.37(t,J=6.5Hz,2H),3.42(t,J=8.2Hz,2H),3.14(t,J=7.2Hz,2H),2.95(td,J=8.7,1.1Hz,2H),2.55

[0085] (t,J=8.2Hz,2H),2.05(m,2H),1.63(m,3H).

[0086] 13C NMR (150MHz, 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.

[0087] S4. Synthesis of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester (Formula IV)

[0088] The reaction equation is as follows:

[0089]

[0090] Into a four-necked round-bottom flask, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)propyl 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 in sequence. The temperature was controlled at 10°C and the reaction was carried out for 24 h. The reaction of the raw materials was completed by monitoring the plate (PE:EA=1:1). The solvent was concentrated under reduced pressure, 30 mL of dichloromethane was added, stirred to dissolve, 50 mL of water was added to wash the organic layer, the organic layer was separated, part of the solvent was concentrated, the temperature was lowered to -5°C, crystallized, filtered, and dried to obtain 3.15 g of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)propyl benzoate, with a yield of 87% and a purity of 99%.

[0091] 1 H NMR (400MHz, CDCl3) δ=8.67(m,1H),8.05(m,1H),7.62–7.55(m,1H),7.26(t,J=7.6Hz,2H),7.10(m,2H),4.32(t,J=6.5Hz,2H ), 3.45 (t, J = 8.4Hz, 2H), 3.17 (t, J = 7.2Hz, 2H), 2.97 (td, J = 8.8, 1.2Hz, 2H), 2.85 (t, J = 8.4Hz, 2H), 2.15 (m, 2H), 1.75 (s, 3H).

[0092] 13 C NMR(150MHz, 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.

[0093] Example 2

[0094] This embodiment provides a method for preparing a silodosin intermediate, which specifically comprises the following steps:

[0095] S1. Synthesis of 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate (Formula I)

[0096] The reaction equation is as follows:

[0097]

[0098] Under nitrogen protection, 3-(indolin-1-yl) propyl benzoate (2.81 g, 10 mmol) and ethyl acetate (84 ml) were added to a four-necked flask in sequence. The temperature was controlled at 0°C, and NBS (6.23 g, 35 mmol) was added in batches. After the addition, the mixture was reacted at 0°C for 5 h, 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 give off-white 3-(5.7-dibromo-indolin-1-yl) propyl benzoate. Off-white 3-(5.7-dibromo-indolin-1-yl) propyl benzoate (3.82 g, yield 87%, purity 98%) was obtained, which was directly used in the next step.

[0099] S2. Synthesis of 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (Formula II)

[0100] The reaction equation is as follows:

[0101]

[0102] Into a four-necked flask, 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate (4.36 g, 10 mmol), zinc cyanide (1.34 g, 15 mmol), and DMAC (15 mL) were added in sequence, and 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, cooled to room temperature, and the solid waste was filtered out. The aqueous layer was extracted with dichloromethane 100 mL x 3, and the organic layers were combined and concentrated to dryness to obtain a light yellow solid 3-(5-bromo-7-cyano-indolyl-1-yl) propyl benzoate (3.31 g, yield 86%, purity 97%), which was directly used in the next step.

[0103] S3. Synthesis of 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester (Formula III)

[0104] The reaction equation is as follows:

[0105]

[0106] In a round-bottom flask, 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (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 in sequence. The mixture was protected by nitrogen and cooled to -80°C. Propylene oxide (2.9 g, 50 mmol) was added at one time. After the addition was completed, the temperature was controlled to 0°C for reaction. The reaction of the raw materials was monitored by plate counting. The reaction was complete. The mixture was quenched with 40 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 60 mL*3 of dichloromethane. The organic layers were combined, washed with water, and concentrated to obtain 3.02 g of 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoic acid propyl ester. The yield was 83%.

[0107] S4. Synthesis of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester (Formula IV)

[0108] The reaction equation is as follows:

[0109]

[0110] Into a four-necked round-bottom flask, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)propyl 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 in sequence. The temperature was controlled at -20 ° C. The reaction was carried out for 30 h. The reaction of the raw materials was completed by monitoring the plate (PE:EA=1:1). The solvent was concentrated under reduced pressure, 30 mL of dichloromethane was added, stirred to dissolve, 50 mL of water was added to wash the organic layer, the organic layer was separated, part of the solvent was concentrated, the temperature was lowered to -5 ° C, crystallized, filtered, and dried to obtain 3.09 g of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)propyl benzoate, with a yield of 85% and a purity of 98%.

[0111] Example 3

[0112] This embodiment provides a method for preparing a silodosin intermediate, which specifically comprises the following steps:

[0113] S1. Synthesis of 3-(5,7-dibromo-indolyl-1-yl)benzoic acid propyl ester (Formula I).

[0114] Under nitrogen protection, 3-(indolyl-1-yl)benzoic acid propyl ester (2.81 g, 10 mmol) and dichloromethane (56 ml) were added to a four-necked flask in sequence. Phosphorus tribromide (6.77 g, 25 mmol) was added in batches at low temperature. After the addition, the temperature was controlled at 10°C. The reaction was continued 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 3-(5.7-dibromo-indolyl-1-yl)benzoic acid propyl ester (3.82 g, yield 87%, purity 98%), which was directly used in the next step.

[0115] S2. Synthesis of 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (Formula II)

[0116] Into a four-necked flask, 3-(5.7-dibromo-indolyl-1-yl) propyl benzoate (4.36 g, 10 mmol), potassium ferrocyanide (5.53 g, 15 mmol), and NMP (10 mL) were added in sequence, stirred at room temperature for 20 min, heated to 120 ° C, and reacted for 14 h. After the reaction was complete, 100 mL of water was added, and the temperature was cooled to room temperature. The solid waste was filtered out, and the aqueous layer was extracted with dichloromethane 50 mL x 3. The organic layers were combined and concentrated to dryness to obtain a light yellow solid 3-(5-bromo-7-cyano-indolyl-1-yl) propyl benzoate (3.23 g, yield 84%, purity 97%), which was directly used in the next step.

[0117] S3. Synthesis of 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester (Formula III)

[0118] In a round-bottom flask, 3-(5-bromo-7-cyano-indolyl-1-yl)benzoic acid propyl ester (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), zinc powder (1.63 g, 25 mmol) were added in sequence. l), nitrogen protection, cooling to 0°C, adding propylene oxide (1.76 g, 30 mmol) at one time, after the addition, controlling the temperature to 10°C for reaction, spot plate monitoring the complete reaction of the raw materials, quenching with 40 mL of saturated ammonium chloride solution, extracting the aqueous layer with 40 mL*3 of dichloromethane, combining the organic layers, washing the organic layers with water, and concentrating to obtain 2.95 g of 3-(7-cyano-5-(2-hydroxy-propyl)indolin-1-yl)benzoic acid propyl ester, with a yield of 81%.

[0119] S4. Synthesis of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester (Formula IV)

[0120] Into a four-necked round-bottom flask, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)propyl 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 in sequence. The temperature was controlled at 0°C and the reaction was carried out for 30 h. The reaction of the raw materials was completed by monitoring the plate (PE:EA=1:1). The solvent was concentrated under reduced pressure, 40 mL of dichloromethane was added, stirred to dissolve, 50 mL of water was added to wash the organic layer, the organic layer was separated, part of the solvent was concentrated, the temperature was lowered to -5°C, crystallized, filtered, and dried to obtain 3.08 g of 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)propyl benzoate, with a yield of 85% and a purity of 99%.

[0121] In summary, compared with the prior art, the present invention has the following beneficial effects:

[0122] The invention provides a method for preparing a silodosin intermediate. The method has readily available raw materials, is environmentally friendly, has a novel route, and a short synthesis route. The prepared silodosin intermediate has good purity, high yield, and low cost.

[0123] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0124] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a silodosin intermediate, characterized in that: The synthetic route is as follows: Wherein, the preparation method of the compound of formula IV, 3-(7-cyano-5-(2-oxopropyl)indolin-1-yl)propyl benzoate, comprises the following steps: S1, 3-(indolyl-1-yl) propyl benzoate as raw material, and a bromination reagent are used for substitution reaction to obtain 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate; S2, 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate is subjected to substitution reaction to obtain 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate; S3, 3-(7-cyano-5-bromo-indolyl-1-yl)benzoic acid propyl ester and propylene oxide undergo nucleophilic addition ring opening to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester; S4, 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester is oxidized to generate the compound of formula IV, 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester.

2. The method for preparing a silodosin intermediate according to claim 1, wherein The S1 specifically includes the following steps: Under nitrogen protection, 3-(indolyl-1-yl)benzoic acid propyl ester and solvent were mixed evenly, and bromination reagent was added in batches at low temperature to cause substitution reaction to obtain 3-(5,7-dibromo-indolyl-1-yl)benzoic acid propyl ester.

3. The method for preparing a silodosin intermediate according to claim 1, wherein S1 satisfies at least one of the following conditions: The molar ratio of 3-(indolin-1-yl)benzoic acid propyl ester to the bromination reagent is 1:2-3.5; The solvent is selected from dichloromethane or ethyl acetate; The mass ratio of 3-(indolin-1-yl)propyl benzoate to the volume of the solvent is 1g:10-30ml.

4. The method for preparing a silodosin intermediate according to claim 1, wherein The S2 specifically includes the following steps: Under nitrogen protection, 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate, a cyaniding agent and a reaction solvent were mixed evenly, and the temperature was raised to react to obtain 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate.

5. The method for preparing a silodosin intermediate according to claim 1, wherein S2 satisfies at least one of the following conditions: The reaction solvent is selected from DMF, NMP or DMAc; The molar ratio of 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate to the cyaniding agent is 1:1.1-2.0; The cyaniding agent is selected from any one of zinc cyanide, cuprous cyanide, and potassium ferrocyanide; The reaction temperature is 100-180°C; The reaction time is 1-24h.

6. The method for preparing a silodosin intermediate according to claim 1, characterized in that: The S3 specifically includes the following steps: Under nitrogen protection, 3-(7-cyano-5-bromo-indolyl-1-yl) propyl benzoate, solvent and catalyst were added to the container in sequence, and nitrogen was passed through the container to cool to -80-25°C. Propylene oxide was added and reacted at room temperature after the addition to obtain 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl) propyl benzoate.

7. The method for preparing a silodosin intermediate according to claim 1, characterized in that: S3 satisfies at least one of the following conditions: The reaction solvent is methyl pyrrolidone; The molar ratio of 3-(7-cyano-5-bromo-indolyl-1-yl)benzoic acid propyl ester to propylene oxide is 1:1-5.

0.

8. The method for preparing a silodosin intermediate according to claim 1, characterized in that: The S4 specifically comprises the following steps: Under nitrogen protection, compound III 3-(7-cyano-5-(2-hydroxy-propyl)indolyl-1-yl)benzoic acid propyl ester, acyl chloride and reaction solvent are subjected to oxidation reaction at low temperature to obtain compound IV 3-(7-cyano-5-(2-oxopropyl)indolyl-1-yl)benzoic acid propyl ester.

9. A silodosin intermediate, characterized in that: 3-(5,7-dibromo-indolyl-1-yl) propyl benzoate (Formula I) prepared by the preparation method according to any one of claims 1 to 8 has the structural formula as shown below:

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