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Synthesizing method of silodosin and intermediate thereof

A synthesis method and technology for silodosin, which are applied in the field of synthesis of silodosin and its intermediates, can solve the problems of many protection and deprotection steps, unsuitable control of process conditions, lengthy route steps and the like, and reduce industrial production costs. and risk, improve yield, the effect of high reaction yield

Active Publication Date: 2017-08-18
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In summary, the existing synthesis process has lengthy steps, many protection and deprotection steps, low overall yield, dangerous reactions such as nitrification, azidation, and cyanation, and unsuitable control of process conditions. It is necessary to improve the synthesis process of silodosin and its intermediates, increase the yield, reduce production costs and safety risks

Method used

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  • Synthesizing method of silodosin and intermediate thereof
  • Synthesizing method of silodosin and intermediate thereof
  • Synthesizing method of silodosin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation of embodiment 1 compound 3

[0042]

[0043] At room temperature, drop 251g compound 2, 1500mL 30% hydrochloric acid, 1000mL acetic acid into the reaction vessel, optionally, the feed ratio (mass) of compound 2, hydrochloric acid and acetic acid is 1:5~10:5~10; then Slowly raise the temperature to 80-90°C for reaction, monitor by liquid chromatography until the reaction is complete (4-10 hours), concentrate the reaction solution to dryness under reduced pressure, add 1500mL dichloromethane and 2000mL cold saturated sodium carbonate aqueous solution, and stir for 1 hour The layers were separated, the organic layer was washed with saturated brine, the collected organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 203 g of compound 3 as a yellow solid, yield: 97%. Melting point: 91-93°C; HRMS m / z (ESI): C 11 h 13 C1NO[M+H + ]Theoretical calculation value: 210.068...

Embodiment 2

[0044] Embodiment 2: the preparation of compound 4

[0045]

[0046] At room temperature, in an organic solvent, put 209g of compound 3, 194g of potassium phthalimide, 1000mL of acetonitrile, and 151g of potassium carbonate into the reaction vessel. Optionally, the organic solvent can be selected from acetonitrile, toluene, tetrahydrofuran Among others, acetonitrile is preferred. Wherein the molar ratio of compound 3, potassium phthalimide and potassium carbonate can be 1:1.0-2.0:1.0-2.0; preferably 1:1.1:1.05.

[0047] Then slowly warming up to 80-90 ℃ of reaction, liquid chromatographic monitoring until the reaction is complete (4-10 hours), the reaction solution was concentrated to dryness under reduced pressure, added in 1500mL dichloromethane and 2000mL cold saturated sodium carbonate aqueous solution, stirred for 1 After hours, the layers were separated, the organic layer was washed with saturated brine, the collected organic layer was dried over anhydrous sodium sul...

Embodiment 3

[0048] Embodiment 3: the preparation of compound 5

[0049]

[0050] At room temperature, in an organic solvent, put 48g of compound 4, 32g of 3-chloropropyl benzoate, 26g of potassium iodide, 33g of potassium carbonate, 2.2g of tetrabutylammonium bromide, 600mL of DMF into the reaction flask, optional Yes, the organic solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, nitrogen methylpyrrolidone, preferably dimethylformamide. Wherein the molar ratio of compound 4 to 3-chloropropyl benzoate, potassium carbonate, potassium iodide, and phase transfer catalyst tetrabutylammonium bromide can be selected as 1: 1.0~2.0: 1.0~2.0: 2.0~4.0: 0.05~0.1 , preferably 1: 1.6: 2.4: 1.6: 0.07; wherein the phase transfer catalyst can also be selected from tetrabutylammonium chloride, tetrabutylammonium iodide, benzyl trimethyl ammonium chloride or benzyl triethyl chloride ammonium chloride.

[0051] Then slowly raise the temperature to 90-100°C for reaction, ...

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Abstract

The invention relates to the field of medicine chemistry, aims to solve the problems that the prior art is complex in reaction steps, high in production risk, low in yield, and the like, and provides a synthesizing method of silodosin and an intermediate thereof. The synthesizing method includes: using hydrochloric acid / acetic acid to perform deacetylation on chloride 2 to obtain indoline 3, performing SN2 substitution reaction to obtain imide 4, performing N alkylation reaction to obtain benzoate 5, reducing carbonyl to obtain indoline 6, performing Vilsmeier reaction to obtain aldehyde 7, performing oximation dewatering to obtain nitrile 8, performing hydrazine hydrate reaction to obtain amine 9, performing L-tartaric acid separation on the amine 9 to obtain the silodosin key intermediate 10, performing condensation under an alkaline condition to obtain a compound 11, allowing the compound 11 to have salt formation crystallization with L-malic acid to form salt 12, and performing alkaline hydrogen peroxide hydrolysis on the salt 12 to obtain the silodosin 1. The synthesizing method has the advantages that the L-malic acid is used to perform the salt formation crystallization, impurities such as bipolymer which are hard to remove are removed effectively, high reaction conversion rate is achieved, industrial production cost is lowered effectively, and synthesizing safety is increased by avoiding the use of dangerous reagents.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing silodosin and its intermediates. Background technique [0002] Silodosin is an α-adrenergic receptor antagonist invented by Kissei Pharmaceutical Company of Japan, which is clinically used for urinary disorders related to benign prostatic hyperplasia. The chemical name of silodosin is: 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro Ethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide, its chemical structure is shown in formula one. [0003] [0004] Patent US5387603 discloses silodosin compound and its basic synthesis route (Formula 2). After indoline is protected by acetyl group, it undergoes Friedel-Crafts acylation reaction with propionyl chloride and then halogenated with concentrated sulfuric acid / hydrobromic acid to obtain Halogenated ketones, halogenated ketones reduce the carbonyl group by triethylsilane / trifluoroace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08C07B2200/07C07B2200/13C07C59/255
Inventor 朱国荣王臻杨会林黄荣明屠勇军
Owner ZHEJIANG TIANYU PHARMA
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