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Preparation method of R-5-(2-amino propyl)-1-(3-hydroxy propyl)-7-nitrile indole

A technology of cyanoindoline and hydroxypropyl, which is applied in the field of medicinal chemistry, can solve the problems of high toxicity of reagent nitroethane, lengthy synthesis process steps, unreasonable design, etc., and achieve low cost, short synthesis route, Simple operation effect

Active Publication Date: 2018-05-18
CHANGZHOU RUIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The reaction route of this method is long, the design is not very reasonable, and the total yield is low
[0010] In summary, the existing synthetic process steps are tedious, the total yield is low, the toxicity of reagents such as nitroethane is relatively large, and there is a dangerous reaction that will explode when heated for a long time, so it is necessary to improve the silodosin intermediate Synthetic process of R-5-(2-aminopropyl)-1-(3-hydroxypropyl)-7-cyanoindoline, improving yield, reducing production cost and safety risk

Method used

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  • Preparation method of R-5-(2-amino propyl)-1-(3-hydroxy propyl)-7-nitrile indole
  • Preparation method of R-5-(2-amino propyl)-1-(3-hydroxy propyl)-7-nitrile indole
  • Preparation method of R-5-(2-amino propyl)-1-(3-hydroxy propyl)-7-nitrile indole

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Effect test

Embodiment 1

[0039] Embodiment 1: Step 1: Preparation of Compound 2

[0040] At room temperature, add 200ml of dichloroethane and 200ml of sodium hydroxide aqueous solution to the reaction vessel, then add 50g of indoline, cool down to 0°C, add dropwise 45g of acetic anhydride, react at 20°C for 12 hours and then separate into layers. The layers were washed with water, the organic layer was collected and dried, and the filtrate was concentrated to dryness under reduced pressure to obtain Compound 2 as a gray solid.

Embodiment 2

[0041] Embodiment 2: Step 2: Preparation of Compound 3

[0042] Add 102.9g of anhydrous aluminum trichloride to the reaction vessel, cool down to 0°C, add 2-chloropropionyl chloride dropwise, and control the temperature not to exceed 10°C; dissolve the compound 2 obtained in step 1 in 300ml of dichloromethane, and batch Added, and reacted at room temperature for 6h after the addition. Pour the reaction into crushed ice, stir to dissolve, and separate layers. The organic layer was washed with water, saturated sodium bicarbonate and saturated brine. The organic layer was collected and dried, and the filtrate was concentrated under reduced pressure to dryness to obtain a solid, which was recrystallized from toluene to obtain compound 3 as an off-white solid. The total yield of step 1 plus step 2 is 72.9%.

Embodiment 3

[0043] Embodiment 3: Step 3: Preparation of Compound 4

[0044] Add 20.0 g of compound 3, 220 ml of absolute ethanol, and 30 ml of hydrochloric acid into the reaction vessel. The temperature was raised to 76°C and the reaction was refluxed for 7 hours, the temperature was lowered, and the solvent was distilled off under reduced pressure. Add 500ml of water to dissolve, and slowly add potassium carbonate solution until the pH is about 11. Stir for 1h, filter and wash with water. A gray solid compound 4 was obtained in a yield of 85.2%.

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Abstract

The invention relates to a preparation method of R-5-(2-amino propyl)-1-(3-hydroxy propyl)-7-nitrile indole. The preparation method includes that the formula is as shown in specification; the raw materials in use are market product, the price and cost are low; the method simplifies a synthesis step, and is short in synthesis route, high in reaction yield of every step, and high in total yield; theindustrial production cost is reduced; the reagent in use is free from toxic or risk; every step is simple in operation and convenient to achieve industrialization.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of R-5-(2-aminopropyl)-1-(3-hydroxypropyl)-7-cyanoindoline. Background technique [0002] Silodosin (Silodosin), the 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 is an adrenergic receptor antagonist developed by Japan Kissei Company and is clinically used for the treatment of benign prostatic hyperplasia. This product was approved for marketing in Japan for the first time in February 2006, and the US FDA accepted the new drug application in February 2008. [0003] According to literature reports, the preparation process of silodosin intermediate R-5-(2-aminopropyl)-1-(3-hydroxypropyl)-7-cyanoindoline has the following two kinds. [0004] The first is the method disclosed in WO2012131710, [0005] [0006] This method has many reaction steps, and the Vilsmeie...

Claims

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Application Information

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IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 史卫明王小亮周禾
Owner CHANGZHOU RUIMING PHARMA