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Method for preparing silodosin midbody

A technology of intermediates and compounds, applied in the preparation of carboxylate, bulk chemical production, organic chemistry, etc., can solve problems such as high cost, complicated preparation process, and complicated introduction of chiral centers

Active Publication Date: 2016-01-20
黄欢
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In summary, when preparing silodosin in the prior art, due to the intermediate, i.e. (R)-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl) -7-cyano]indoline tartrate has a complex chiral center introduction method and expensive chiral reagents, complicated preparation process and high cost

Method used

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  • Method for preparing silodosin midbody
  • Method for preparing silodosin midbody
  • Method for preparing silodosin midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1: the preparation of compound (4-1)

[0077]

[0078] Add 300 milliliters of anhydrous dichloromethane into the reactor, add 60.0 grams of anhydrous aluminum trichloride under stirring, after adding, cool to room temperature in a water bath, add 47.6 grams of 1-(3-benzoyloxypropyl)ind Indoline hydrochloride, stirred for 10 minutes, nitrogen protection. 52.4 g of (R)-2-acetamidopropionyl chloride was dissolved in dichloromethane solution and added dropwise to the above mixed solution. After dropping, raise the temperature to reflux to continue the reaction. After the reaction of the raw materials is complete, the reaction solution is lowered to room temperature, added to 3000 ml of ice-water mixture, stirred, added with sodium bicarbonate to adjust the pH to 7, allowed to stand for stratification, and dichloromethane layer, the upper aqueous layer was extracted twice with 250 ml of dichloromethane, the combined dichloromethane layers were washed with satu...

Embodiment 2

[0079] Embodiment 2: the preparation of compound (5-1)

[0080]

[0081] Add 39.4 grams of (4-1), 5.8 grams of trifluoroacetic acid and 150 milliliters of toluene into the reaction vessel, stir and add 25.5 grams of triethylsilane, nitrogen protection, react at 45 ° C for 22 hours, the raw materials basically react completely, and the reaction solution Cool down to room temperature, add the reaction solution to 300 ml of ice-water mixture, stir for half an hour, let stand to separate layers, extract the water layer twice with 100 ml of toluene, combine the organic layers, wash with saturated sodium bicarbonate solution, and wash with saturated brine, After drying, the desiccant was filtered out, and the filtrate was evaporated to dryness under reduced pressure to obtain a dark reddish-brown oil, which was obtained by column chromatography, which was compound (5-1).

Embodiment 3

[0082] Embodiment 3: the preparation of compound (6-1)

[0083]

[0084] Under ice-water cooling, 30.7 grams of phosphorus oxychloride was slowly added dropwise to 40.8 grams of DMF. After the drop, the ice-water bath continued to stir for half an hour. Under nitrogen protection, 38.0 grams of compound (5-1) was dissolved in Add 40ml of dichloromethane dropwise to the reaction solution, control the reaction temperature at 45-50°C, stir at 50°C for three hours after the drop is complete, and slowly add dropwise into 350ml of ice-water mixture after the reaction solution is cooled to room temperature , stirred for half an hour, extracted three times with 300 ml of dichloromethane, combined the organic layers, washed with saturated sodium bicarbonate solution, washed with saturated saline, dried, filtered out the desiccant, and the filtrate was evaporated to dryness under reduced pressure to obtain a reddish-brown oily substance, namely Compound (6-1).

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Abstract

The invention discloses a method for preparing a silodosin midbody. The silodosin midbody is the compound shown in the formula (1) and prepared with indoline derivative and R-alanine derivative which are easy to obtain as starting materials through Friedel-Crafts acylation reaction, reduction reaction, formylation reaction, oximation reaction, dehydration reaction, hydrolysis reaction and salt forming reaction. The compound is used for preparing silodosin. Silodosin is used for treating urination disorder related to benign prostatic hyperplasia. The method has the advantages that raw materials are cheap and easy to obtain, operation is easy, yield is high, production cost is reduced, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of silodosin intermediate. Background technique [0002] Benign prostatic hyperplasia (BPH) is a common and frequently-occurring disease in middle-aged and elderly men. Currently, there are two main types of drugs used clinically for the treatment of BPH: α1-adrenoceptor (α-AR) antagonists and 5α-reductase inhibitors. Among them, the α-AR antagonist has the characteristics of rapidity, safety and high efficiency. Silodosin (Silodosin) is an α-AR antagonist developed by Japanese Kissei Pharmaceutical Company for the treatment of BPH, and is used for the treatment of dysuria caused by benign prostatic hyperplasia. Silodosin has a selective inhibitory effect on the contraction of urethral smooth muscle, and reduces urethral pressure, but has no great effect on blood pressure, and has few side effects, so it can be used to treat benign prostatic hyperplasia. Optically active R-compounds such a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08C07C59/255C07C51/41
CPCC07C51/41C07C59/255C07D209/08Y02P20/55
Inventor 黄欢
Owner 黄欢
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