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Preparation method of silodosin intermediate

A technology for silodosin and intermediates, which is applied in the field of medicinal chemistry, can solve the problems of many synthesis steps, low total yield, and large environmental impact, and achieve the effects of simple post-processing, good product quality, and easy industrialization

Active Publication Date: 2018-05-15
CHANGZHOU RUIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route has many synthetic steps, and the total yield is low. The Vilsmeier formylation method is used in the two-step reaction, which has a large environmental impact and a lot of waste water. The resolution reagents used are not easy to obtain, and are not suitable for large-scale production.
[0010] In summary, the existing synthetic process steps are tedious, the total yield is low, and the toxicity of reagents such as nitroethane is relatively large, so it is necessary to improve the silodosin intermediate 1-(3-hydroxypropyl)-5 -[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-cyano-1H-indoline Synthetic process, increase yield, reduce production cost and safety risk

Method used

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  • Preparation method of silodosin intermediate
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  • Preparation method of silodosin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1: the preparation of compound 3

[0039] Add 460ml of dichloroethane and 36.8g of anhydrous aluminum trichloride into the flask, cool to 0-5°C, and stir for 1h; then add 37.2g of 7-cyanoindoline, and stir for 10min; 30.5g of S-3 Dissolve -chloropropionyl chloride in 150ml of dichloroethane, slowly drop it into the flask from the dropping funnel, keep at 0-5°C, stir for 5h, then react overnight at 20°C; slowly pour the reactant into crushed ice , stirred for 2h; separated the organic layer, washed with water, washed with saturated sodium bicarbonate, and then washed with water until nearly neutral; concentrated under reduced pressure to obtain a light brown solid; added 50ml of ethyl acetate to reflux and stirred, cooled to 20°C, and suction filtered to obtain off-white Solid 48.3g, yield 87.5%.

Embodiment 2

[0040] Embodiment 2: the preparation of compound 4

[0041] Dissolve 41.4g of compound 3 in 270ml of trifluoroacetic acid, cool down to 5°C in an ice bath, slowly add 25.94g of triethylsilane dropwise, keep at 5-10°C, drop it for about 0.5h; keep stirring for 3h, evaporate under reduced pressure solvent, washed off the supernatant with n-hexane; the residue was dissolved in 200ml of dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and distilled off the dichloromethane to obtain 36.4g of dark brown liquid, yield 92.7%.

Embodiment 3

[0042] Embodiment 3: the preparation of compound 5

[0043] 260ml of acetonitrile, 39.4g of compound 4, 19.3g of benzylamine and 18.2g of triethylamine were added into the flask, and the temperature was raised to 50°C to react overnight. Evaporate the solvent under reduced pressure, add 220ml of dichloromethane and 350ml of water, stir for 1h; separate the organic layer, concentrate under reduced pressure to an oily substance; add 300ml of hydrochloric acid (1:1) and stir for 1h, and suction filter to obtain a brown solid; Stir in 500ml of water, slowly add sodium carbonate solution until neutral, stir for 1h, then add sodium carbonate solution until neutral, stir for another 2h; filter with suction, recrystallize the solid with ethanol; get 40.6g of brown solid, yield 81.3 %.

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Abstract

The invention relates to a preparation method of a silodosin intermediate. The preparation method is characterized in that: the intermediate is 1-(3- hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxyl] phenoxyl] ethylamino] propyl]-7-nitrile-1H-indoline. The preparation method is shown in the description. The raw materials used in the method are sold on the market, are cheap, and are low in cost. The yield in various step is relatively high, and the post-processing is simple. The preparation method does not use poisonous or hazardous agent, and is convenient for industrialization. The product quality is high, and the optical purity is high.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a silodosin intermediate. Background technique [0002] Silodosin (Silodosin), the chemical name is 1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)benzene Oxy]ethylamino]propyl]-1H-indoline-7-carboxamide is an adrenergic receptor antagonist developed by Japan Kissei Company and is clinically used to treat benign prostatic hyperplasia. Silodosin was approved for marketing in Japan for the first time in February 2006, and the US FDA received a new drug application in February 2008. [0003] In the synthesis process, 1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino] Propyl]-7-cyano-1H-indoline is the intermediate of silodosin in the previous step. According to literature reports, its preparation process has the following two types. [0004] The first is the method disclosed in JP2001199956, the synthesis route is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 史卫明王小亮周禾
Owner CHANGZHOU RUIMING PHARMA
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