A kind of preparation method of silodosin

Abstract

The invention discloses a preparation method of silodosin, and belongs to the technical field of organic synthesis. The invention uses 2,3-dihydroindoline as a raw material, reacts with boron trichloride and methyl thiocyanate to obtain compound 2, then bromines with NBS to obtain compound 3, then N-alkylates indoline with 3-bromoacetate to obtain compound 4, then reacts with (R)-propylene oxide under the action of a nucleophilic reagent and a boron trifluoride ether complex to obtain compound 5, then replaces the hydroxyl group with methanesulfonyl chloride to obtain compound 6, then replaces the amination reaction with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine to obtain compound 7, then hydrolyzes with an oxidant, and performs post-treatment deacetylation protection to obtain compound 8. The synthetic route is simple, the total yield is high, the operation is relatively coherent, and the high enantiopure compound is obtained without splitting, the atomic utilization rate is improved, and the use of Pd / C catalytic hydrogenation is avoided to reduce heavy metal residues.

Description

Technical Field

[0001] The invention relates to a preparation method of silodosin, and belongs to the technical field of organic synthesis. Background Art

[0002] Silodosin, CAS 160970-54-7, trade name Urief(R), Chinese name 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide, English name 1-(3-Hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-dihydro-1H-indole-7-carboxamide.

[0003] Silodosin is an enantiopure active pharmaceutical ingredient (API) developed by Kissei Pharmaceuticals of Japan. In 2006, the first marketing authorization for silodosin was obtained, and two years later it was authorized by the FDA. Silodosin is a selective α1A adrenergic receptor antagonist currently used to treat benign prostatic hyperplasia (BPH) associated with lower urinary tract symptoms and dysuria. BPH, a male disease, affects up to 90% of men over the age of 85. With the development of an aging society, it has a serious impact on men's health. In a sense, the demand for silodosin will increase, and the market has broad prospects.

[0004] The literature [European Journal of Organic Chemistry, 2015, vol. 2015, #27, 6011-6016] reported that indoline was used as the raw material, and cyano group was introduced by boron trichloride and trichloroacetonitrile Houben–Hoesch, NBS bromination, benzoylation, ketone catalysis and acetylacetone substitution, (R)-α-phenylethylamine reduction amination, Pd / C catalytic hydrogenation debenzylation, OMs and primary amine substitution, amino Boc protection, debenzoylation, indoline N alkylation, cyano group hydrolysis, Pd / C catalytic hydrogenation debenzylation, after 12 steps, 4 steps of purification, the total yield was 10%, purity> 99.0% ee> 99.0%. This route has long steps, low total yield, and relatively high cost. Its reaction equation is as follows:

[0005]

[0006] From the current literature and patents, the difficulty of silodosin synthesis is basically the introduction of cyano group at position 7 and the introduction of enantiomerically pure chirality. The present invention makes the introduction of the above group simpler and more economical through a new synthesis method, thereby shortening the reaction steps, saving synthesis time, and having high product quality, which is suitable for large-scale production to meet the growing market demand. Summary of the invention

[0007] In order to overcome the above technical defects, the present invention provides a preparation method of silodosin. 2,3-dihydroindoline is used as a raw material, reacted with boron trichloride and methyl thiocyanate to obtain compound 2, then brominated with NBS to obtain compound 3, then N-alkylated indoline with 3-bromoacetate to obtain compound 4, then reacted with (R)-propylene oxide under the action of a nucleophile and a boron trifluoride ether complex to obtain compound 5, then substituted the hydroxyl group with methanesulfonyl chloride to obtain compound 6, then substituted with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine to obtain compound 7, then hydrolyzed with an oxidant, and post-treated with deacetylation protection to obtain compound 8. The synthetic route is simple, the total yield is high, the operation is relatively coherent, and the problem of obtaining high ee enantiopure compounds without splitting is solved, the atomic utilization rate is improved, and the use of Pd / C catalytic hydrogenation is avoided to reduce heavy metal residues.

[0008] The preparation method of silodosin of the present invention comprises the following steps:

[0009]

[0010] Step 1 (Compound 1-Compound 4): 2,3-dihydroindoline is mixed with an organic solvent, boron trichloride is introduced, reflux reaction is carried out, methyl thiocyanate is added to react to obtain 7-cyanoindoline, which is then reacted with NBS in acetonitrile to obtain 5-bromo-7-cyanoindoline, which is then mixed with 3-bromoacetate and tetrahydrofuran, and then reacted under the action of a Lewis base to obtain 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline;

[0011] Step 2 (Compound 4-Compound 5): 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, (R)-propylene oxide, boron trifluoride ether complex and tetrahydrofuran are mixed, and a nucleophilic reagent is added dropwise at ultra-low temperature to obtain 1-[3-(acetoxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline;

[0012] Step 3 (Compound 5-Compound 6): 1-[3-(acetoxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline, methanesulfonyl chloride and dichloromethane are mixed, an acid binding agent is added, and then recrystallization is performed to obtain 1-[3-(acetoxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline;

[0013] Step 4 (Compound 6-Compound 8): 1-[3-(Acetoxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine, potassium carbonate, potassium iodide and acetonitrile are mixed to obtain 2,3-dihydro-1-(3-acetoxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile, which is then mixed with an inorganic base and DMSO, an oxidant is added, and the mixture is post-treated by acidification and deacetylation protection, followed by recrystallization to obtain 2,3-dihydro-1-(3-hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide.

[0014] Furthermore, in the above technical solution, in the first step, the organic solvent is selected from ethylene dichloride or toluene, and the Lewis base is selected from sodium hydride or potassium tert-butoxide.

[0015] Furthermore, in the above technical scheme, in the first step, the molar ratio of the 2,3-dihydroindoline, boron trichloride, methyl thiocyanate, NBS (N-bromosuccinimide), 3-bromoacetate, and Lewis base is 1:1.50-1.60:1.10-1.20:0.98-0.95:0.95-0.93:1.10-1.20.

[0016] Furthermore, in the above technical solution, in the second step, the nucleophilic reagent is selected from 2.5M / L n-butyllithium n-hexane solution or 2.2M / L n-hexyllithium n-hexane solution.

[0017] Furthermore, in the above technical scheme, in the second step, the molar ratio of the 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, (R)-propylene oxide, boron trifluoride ether complex and nucleophilic reagent is 1:1.10-1.15:1.10-1.15:1.20-1.25.

[0018] Furthermore, in the above technical solution, in the third step, the acid binding agent is selected from triethylamine or N,N-diisopropylethylamine.

[0019] Furthermore, in the above technical solution, in the third step, the molar ratio of the 1-[3-(acetoxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline, methanesulfonyl chloride and acid binding agent is 1:1.10-1.20:1.50-1.80.

[0020] Furthermore, in the above technical solution, in the third step, the recrystallization solvent is selected from a mixed solvent of dichloromethane and n-heptane, and the volume ratio is 1:3.

[0021] Furthermore, in the above technical solution, in the fourth step, the inorganic base is selected from cesium carbonate or sodium hydroxide, and the oxidant is selected from hydrogen peroxide or urea hydrogen peroxide complex.

[0022] Furthermore, in the above technical scheme, in the fourth step, the molar ratio of the 1-[3-(acetyloxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine, potassium carbonate, potassium iodide, inorganic base and oxidant is 1:1.0-1.01:5.00-6.00:0.01-0.012:2.00-2.50:2.50-4.00.

[0023] Furthermore, in the above technical solution, in the fourth step, the recrystallization condition is a mixed solvent of isopropanol and n-heptane in a volume ratio of 1:3.5.

[0024] Advantageous Effects of the Invention

[0025] 1. The introduction of a cyano group by reacting the ortho-position of N- with methyl thiocyanate through boron trichloride is simpler, faster and safer than first introducing an aldehyde group through a Vilsmeier reaction and then condensing and dehydrating with a hydroxylamine salt.

[0026] 2. The chiral hydroxyl alcohol is introduced by (R)-propylene oxide, which is simple to operate and has a high optical purity. The amino group can be better introduced by reacting the chiral hydroxyl alcohol with MsCl.

[0027] 3. By purifying compound 6, the subsequent purification steps are easier and some unnecessary impurities or tar residues are avoided. Specific embodiments

[0028] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0029] Synthesis of Silodosin

[0030] Example 1

[0031]

[0032] Into the reaction bottle, add 59.6g (0.5mol, 1eq) of 2,3-dihydroindoline and mix with 600mL of toluene, pass 87.9g (0.75mol, 1.5eq) of boron trichloride at room temperature, heat to 80°C for 4 hours, cool to room temperature, add 40.2g (0.55mol, 1.1eq) of methyl thiocyanate, stir at room temperature overnight, add 50% sodium hydroxide aqueous solution to adjust to pH = 10.5-11.0, and heat to 80°C for 4 hours. The mixture was heated to 60°C for 6 hours, at which the pH was maintained at 10.5-11.0, and then cooled to 10°C, and hydrochloric acid was added to adjust the pH to 1.5-2.0. The layers were separated, and the toluene layer was separated. The aqueous phase was adjusted to pH 11 with NaOH, and extracted with MTBE for 3 times. The organic phases were combined and concentrated under reduced pressure until no liquid was obtained to obtain a crude 7-cyanoindoline product; then the mixture was mixed with 700 mL of acetonitrile, cooled to 10-15°C, and NBS 87.2 g (0.49 mol, 0.98 eq) was added. The mixture was added in 10 portions, reacted at room temperature for 8 hours, and concentrated under reduced pressure until no liquid flowed. 800 mL of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dissolved with 800 mL of ethyl acetate, and washed once with sodium bicarbonate aqueous solution. The organic phase was concentrated under reduced pressure until no liquid flowed to obtain a crude product of 5-bromo-7-cyanoindolinol. Then, 13.2 g (0.55 mol, 1.1 eq) of sodium hydride was added to 500 mL of tetrahydrofuran at 0-10°C, and 84 g (0.55 mol, 1.1 eq) of 3-bromoacetate was added dropwise at this temperature. .2g (0.465mol, 0.93eq) was reacted for 3 hours, cooled to -10°C, quenched with dilute hydrochloric acid, and adjusted to pH = 8.5-9.0, and methyl tert-butyl ether was added. The layers were separated and the organic phase was retained. The organic phase was washed with saturated aqueous sodium chloride solution, and the organic phase was concentrated under reduced pressure until there was no liquid. Methyl tert-butyl ether and n-heptane were added for crystallization to obtain 127.5g of 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, with a yield of 78.9% and HPLC 98.9%. 1 HNMR(400MHz, CDCl3):7.43(s,1H),7.32(s,1H),4.14-4.10(m,2H),3.66-3.56(m,4H),2.95-2.91(m,2H),2.06(s,3H),1.98-1.93(m,2H).

[0033] Example 2

[0034]

[0035] Add 59.6 g (0.5 mol, 1 eq) of 2,3-dihydroindoline and 800 mL of 1,2-dichloroethane to the reaction bottle, add 87.9 g (0.75 mol, 1.5 eq) of boron trichloride at 0-10°C, heat and reflux for 2 hours, cool to room temperature, add 40.2 g (0.55 mol, 1.1 eq) of methyl thiocyanate, stir at room temperature overnight, add 50% aqueous sodium hydroxide solution to adjust to pH = 10.5-11.0, and heat to 400 °C. The mixture was heated to 60°C for 6 hours, at which the pH was maintained at 10.5-11.0, and then cooled to 10°C, and hydrochloric acid was added to adjust the pH to 1.5-2.0. The layers were separated, and the toluene layer was separated. The aqueous phase was adjusted to pH 11 with NaOH, and extracted with MTBE for 3 times. The organic phases were combined and concentrated under reduced pressure until no liquid was obtained to obtain a crude 7-cyanoindoline product; then the mixture was mixed with 700 mL of acetonitrile, and the temperature was lowered to 10-15°C. NBS 87.2 g (0.49 mol, 0.98 eq) was divided into 10 portions. Add, react at room temperature for 8 hours, concentrate under reduced pressure until liquid does not flow, add 800 mL of water, a large amount of solid precipitates, filter, dissolve the filter cake with 800 mL of ethyl acetate, add sodium bicarbonate aqueous solution to wash once, and concentrate the organic phase under reduced pressure until liquid does not flow to obtain crude 5-bromo-7-cyanoindolin; then mix with 86.0 g (0.475 mol, 0.95 eq) of 3-bromoacetate and 450 mL of tetrahydrofuran, control the temperature at 0-5 ° C, and add 20% potassium tert-butoxide dissolved in tetrahydrofuran dropwise; 322.6g (0.575mol, 1.15eq) of liquid was added, reacted at this temperature for 3 hours, quenched by adding acetic acid aqueous solution, and the pH was adjusted to 7.1-7.5, methyl tert-butyl ether was added, layers were separated, and the organic phase was retained. The organic phase was washed with saturated sodium chloride aqueous solution, and the organic phase was concentrated under reduced pressure until no liquid flowed. Methyl tert-butyl ether and n-heptane were added for recrystallization to obtain 119.9g of 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, with a yield of 74.2% and an HPLC yield of 99.4%.

[0036] Example 3

[0037]

[0038] Under nitrogen protection, 64.6 g (0.2 mol, 1 eq) of 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, 12.8 g (0.22 mol, 1.1 eq) of (R)-propylene oxide and 600 mL of tetrahydrofuran were added to the reaction bottle, the temperature was cooled to -85°C, 96 mL (0.24 mol, 1.2 eq) of 2.5 M n-butyl lithium hexane solution was added dropwise, the reaction was carried out at this temperature for 1 hour, and the temperature was raised to -70 to -65°C. 31.2 g (0.22 mol, 1.1 eq) of boron trifluoride ether complex was added dropwise, and the reaction was carried out in this temperature range for 2 hours. The temperature was slowly raised to -10°C, quenched with saturated aqueous ammonium chloride solution, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated aqueous sodium chloride solution, the organic phase was concentrated until liquid did not flow, and ethanol and a small amount of water were added for recrystallization to obtain 45.7 g of 1-[3-(acetyloxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline, HPLC 98.8%, 99.7% ee, yield 75.6%. 1 HNMR(400MHz, CDCl3):7.45(s,1H),7.25(s,1H),5.15(s,1H),4.16-4.11(m,2H),4.08-4.05(m ,1H),3.70-3.60(m,4H),2.98-2.61(m,4H),2.04(s,3H),1.85-1.81(m,2H),1.18-1.15(m,3H).

[0039] Example 4

[0040]

[0041] Under nitrogen protection, 64.6 g (0.2 mol, 1 eq) of 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, 13.4 g (0.23 mol, 1.15 eq) of (R)-propylene oxide and 600 mL of tetrahydrofuran were added to the reaction bottle, the temperature was cooled to -85 °C, 113.6 mL (0.25 mol, 1.25 eq) of 2.2 M n-hexyllithium n-hexane solution was added dropwise, the reaction was carried out at this temperature for 1 hour, and the temperature was raised to -70 to -65 °C. ℃, 32.6g (0.23mol, 1.15eq) of boron trifluoride ether complex was added dropwise, the reaction was carried out in this temperature range for 2 hours, the temperature was slowly raised to -10℃, quenched with saturated aqueous ammonium chloride solution, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, the organic phase was concentrated until liquid did not flow, ethanol and a small amount of water were added for recrystallization to obtain 49.1g of 1-[3-(acetyloxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline, HPLC 99.3%, 99.6%ee, yield 81.2%.

[0042] Example 5

[0043]

[0044] Under nitrogen protection, 45.4 g (0.15 mol, 1 eq) of 1-[3-(acetyloxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline and 500 mL of dichloromethane were added to the reaction bottle, the mixture was cooled to 0°C, 22.8 g (0.225 mol, 1.5 eq) of triethylamine was added, and a solution of 18.9 g (0.165 mol, 1.1 eq) of methanesulfonyl chloride diluted with dichloromethane was added dropwise. Then the temperature was slowly raised to room temperature to react for 2 hours, diluted hydrochloric acid was added to quench, the layers were separated, the organic phase was washed once with saturated potassium bicarbonate and water respectively, the organic phase was concentrated until no liquid flowed, a small amount of dichloromethane was added, the temperature was raised to 40°C, and n-heptane was added dropwise for recrystallization to obtain 1-[3-(acetyloxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline 53 g, HPLC 99.6%, 99.7% ee, yield 92.9%. 1 HNMR(400MHz,CD Cl3):7.45(s,1H),7.27(s,1H),5.31-5.27(m,1H),4.16-4.11(m,2H),3.81-3.72(m,4H),3.18(s,3H),3. 02-2.98(m,2H),2.72-2.69(m,1H),2.54-2.51(m,1H),2.04(s,3H),1.85-1.81(m,2H),1.42-1.39(m,3H).

[0045] Example 6

[0046]

[0047] Under nitrogen protection, 45.4 g (0.15 mol, 1 eq) of 1-[3-(acetyloxy)propyl]-5-[(2R)-2-hydroxypropyl]-indoline and 500 mL of dichloromethane were added to the reaction bottle, the mixture was cooled to 0°C, 34.9 g (0.27 mol, 1.8 eq) of N,N-diisopropylethylamine was added, and a solution of 19.8 g (0.1725 mol, 1.15 eq) of methanesulfonyl chloride diluted with dichloromethane was added dropwise, and the temperature was then slowly raised to room temperature for 2 hours. Dilute hydrochloric acid was added to quench, the layers were separated, and the organic phase was washed once with saturated potassium bicarbonate and water respectively. The organic phase was concentrated until no liquid flowed, a small amount of dichloromethane was added, the temperature was raised to 40°C, and n-heptane was added dropwise for recrystallization to obtain 51.2 g of 1-[3-(acetyloxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline. HPLC 99.7%, 99.6%ee, yield 89.7%.

[0048] Example 7

[0049]

[0050] Add 1-[3-(acetyloxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline 38g (0.1mol, 1eq), 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine 23.5g (0.1mol, 1eq), potassium carbonate 82.9g (0.6mol, 6eq), potassium iodide 0.25g (0.0015mol, 0.015eq) and acetonitrile 400mL into the reaction bottle, mix, heat to 65-70℃, react for 5 hours, cool to room temperature, and add The mixture was stirred with 300 mL of water to dissolve the solution, and the layers were separated. The upper acetonitrile solution was retained and concentrated under reduced pressure until no liquid flowed out. Toluene was added and the solution was concentrated under reduced pressure until the water content was less than 0.5%. The solution was filtered to obtain a clear toluene solution. The solution was concentrated under reduced pressure until 3 volumes of water remained. N-heptane was added and the wet product of 2,3-dihydro-1-(3-acetoxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile was obtained. The wet product was then mixed with 81.5 g (0.25 mol, 2.5 eq) of cesium carbonate and 300 mL of DMSO. The temperature was lowered to 10°C and UHP23.5 was added in batches. g (0.25 mol, 2.5 eq) (add another portion after bubbles appear and the temperature stabilizes), slowly heat to room temperature and react for 5 hours, add the reaction solution into water, a large amount of white solid precipitates, filter, rinse with water, add the obtained filter cake into acetone, add dilute hydrochloric acid and reflux, after the acetyl protection is removed, add 2N / L NaOH aqueous solution to adjust pH=8.5-9.5, filter, rinse the filter cake with water to obtain crude silodosin, then heat and dissolve the crude silodosin with isopropyl acetate and filter the insoluble matter, concentrate the filtrate under reduced pressure until it does not flow, and recrystallize from isopropanol and n-heptane to obtain 40.4 g of 2,3-dihydro-1-(3-hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide, yield 81.5%, HPLC 99.9%, 99.4% ee. 1 HNMR(400MHz, CDCl3):7.45(s,1H),7.27(s,1H),5.31-5.27(m,1H),4.16-4.11(m,2H),3.81-3.72(m,4H),3.18(s ,3H),3.02-2.98(m,2H),2.72-2.69(m,1H),2.54-2.51(m,1H),2.04(s,3H),1.85-1.81(m,2H),1.42-1.39(m,3H).

[0051] Example 8

[0052]

[0053] Add 1-[3-(acetyloxy)propyl]-5-[(2R)-2-[(methylsulfonyl)oxy]propyl]-indoline (0.1 mol, 1 eq), 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine (0.1 mol, 1 eq), potassium carbonate (0.6 mol, 6 eq), potassium iodide (0.0015 mol, 0.015 eq) and acetonitrile 500 mL to the reaction bottle, mix, heat to 65-70 ° C, react for 5 hours, cool to room temperature, add 300 mL of water and stir to dissolve. The mixture was separated into layers, the upper acetonitrile solution was retained and concentrated under reduced pressure until no liquid flowed out, toluene was added, and the solution was concentrated under reduced pressure until the water content was less than 0.5%. The solution was filtered to obtain a clear toluene solution, which was concentrated under reduced pressure until 3 volumes of water remained. N-heptane was added and filtered to obtain a wet product of 2,3-dihydro-1-(3-acetoxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile, which was then mixed with 8 g (0.2 mol, 2.0 eq) of sodium hydroxide and 300 g of DMSO. mL mixed, cooled to 10 ° C, 50% hydrogen peroxide 22.7g (0.4mol, 4.0eq) was added dropwise, the temperature was slowly raised to room temperature for reaction for 5 hours, the reaction solution was added to water, a large amount of white solid precipitated, filtered, rinsed with water, the filter cake obtained was added to acetone, added with dilute hydrochloric acid and refluxed, the acetyl protection was removed, and 2M NaOH aqueous solution was added to adjust the pH to 8.5-9.5, filtered, and the filter cake was rinsed with water to obtain crude silodosin. Subsequently, the crude silodosin was dissolved in isopropyl acetate by heating and the insoluble matter was filtered, and the filtrate was concentrated under reduced pressure until no liquid flowed, and recrystallized from isopropanol and n-heptane to obtain 2,3-dihydro-1-(3-hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide 38g, yield 76.7%, HPLC 99.9%, 99.6% ee. H NMR (400MHz, CDCl3): 1.07 (3H, d, J = 6.0Hz), 1.79 (2H, t, J = 5.8Hz), 1.98 (2H, brs), 2 .52(1H,dd,J=6.8Hz,J=13.6Hz),2.70(1H,dd,J=6.8Hz,J=13.6Hz),2.98-3.10(5H, m),3.17(2H,t,J=6.8Hz),3.40(2H,t,J=8.8Hz),3.74(2H,t,J=5.6Hz),4.02-4.18( 2H,m),4.30(2H,m),6.09(1H,brs),6.72(1H,brs),6.75-7.08(5H,m),7.15(1H,s).

[0054] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing silodosin, characterized in that: The steps include: The first step: 2,3-dihydroindoline is mixed with an organic solvent, boron trichloride is introduced, reflux reaction is carried out, methyl thiocyanate is added to react to obtain 7-cyanoindoline, and then reacted with NBS in acetonitrile to obtain 5-bromo-7-cyanoindoline, and then mixed with 3-bromoacetate and tetrahydrofuran, and then reacted under the action of a Lewis base to obtain 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, wherein the organic solvent is selected from dichloroethane or toluene, and the Lewis base is selected from sodium hydride or potassium tert-butoxide; Step 2: 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, (R)-propylene oxide, boron trifluoride ether complex and tetrahydrofuran are mixed, and a nucleophilic reagent is added dropwise at ultra-low temperature to obtain compound 5, wherein the nucleophilic reagent is selected from 2.5M n-butyllithium hexane solution or 2.2M n-hexyllithium hexane solution; Step 3: Compound 5, methanesulfonyl chloride and dichloromethane are mixed, an acid binding agent is added, and then recrystallization is performed to obtain compound 6; Step 4: Compound 6, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine, potassium carbonate, potassium iodide and acetonitrile are mixed to obtain 2,3-dihydro-1-(3-acetoxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile, which is then mixed with an inorganic base and DMSO, an oxidant is added, and the compound 8 is post-treated by acidification and deacetylation, followed by recrystallization. The inorganic base is selected from cesium carbonate, and the oxidant is selected from urea hydrogen peroxide complex.

2. A method for preparing silodosin according to claim 1, characterized in that: In the first step, the molar ratio of the 2,3-dihydroindoline, boron trichloride, methyl thiocyanate, NBS, 3-bromoacetate and Lewis base is 1:1.50-1.60:1.10-1.20:0.98-0.95:0.95-0.93:1.10-1.

20.

3. A method for preparing silodosin according to claim 1, characterized in that: In the second step, the molar ratio of the 5-bromo-7-cyano-1-(3-acetoxypropyl)indoline, (R)-propylene oxide, boron trifluoride ether complex and nucleophilic reagent is 1:1.10-1.15:1.10-1.15:1.20-1.

25.

4. A method for preparing silodosin according to claim 1, characterized in that: In the third step, the acid binding agent is selected from triethylamine or N,N-diisopropylethylamine.

5. A method for preparing silodosin according to claim 1, characterized in that: In the third step, the molar ratio of compound 5, methanesulfonyl chloride and acid binding agent is 1:1.10-1.20:1.50-1.

80.

6. A method for preparing silodosin according to claim 1, characterized in that: In the fourth step, the molar ratio of compound 6, 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamine, potassium carbonate, potassium iodide, inorganic base and oxidant is 1:1.0-1.01:5.00-6.00:0.01-0.012:2.00-2.50:2.50-4.00.

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