Synthetic method of silodosin

A technology of silodosin and compounds, applied in the field of pharmaceutical chemical synthesis, can solve problems such as spraying materials, violent reactions, unfavorable process control, etc.

Inactive Publication Date: 2014-12-24
KUNMING JIDA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since hydrogen peroxide is used in the reaction, it is an exothermic reaction, the reacti

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  • Synthetic method of silodosin
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  • Synthetic method of silodosin

Examples

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Embodiment 1

[0034]To a mixture of ethyl acetate (500 mL) and aqueous potassium carbonate (133 g) (500 mL) was added 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzyl] Acyloxy)propyl]-1H-indole-7-carbonitrile-mono-tartrate (100g), stirred at room temperature for 1 hour, separated the ethyl acetate layer, the aqueous layer was extracted once with 500mL of ethyl acetate, combined with ethyl acetate The ester layer was washed once with 300 mL of saturated potassium carbonate solution and once with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried. Add 451g polyphosphoric acid and 44g benzoic acid to the concentrate, heat up to 85°C, stir for about 5h, cool to room temperature, add 500mL ice water and 400mL ethyl acetate, carefully add 470g anhydrous sodium carbonate in stages, separate out organic phase, the aqueous phase was extracted once with ethyl acetate (300 mL), the organic phases were combined, back-extracted with 1 mol / L hydrochloric acid (100 mL x...

Embodiment 2

[0038] To a mixture of ethyl acetate (50 mL) and potassium carbonate (7.6 g) aqueous solution (50 mL) was added 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzene Formyloxy)propyl]-1H-indole-7-carbonitrile-mono-tartrate (2.8g), stirred at room temperature for 30min, separated the ethyl acetate layer, the aqueous layer was extracted once with 50mL of ethyl acetate, combined with acetic acid The ethyl ester layer was washed once with 50 mL of saturated potassium carbonate solution and once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried. 6 mL of methanesulfonic acid was added to the concentrate, the temperature was raised to 93 °C, stirred for about 4 h, cooled to room temperature, added with 50 mL of ice water, adjusted to pH=3 with sodium carbonate, the aqueous layer was extracted with ethyl acetate (20 mLⅹ3), the organic phase was Discarded, the aqueous layer was adjusted to pH=9 with sodium carbonate solution, extracted with dichloro...

Embodiment 3

[0042] Add 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole- 1.2 g of 7-carboxamide, 1.22 g of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide, 367 mg of sodium carbonate, 10 mL of tert-butanol, react at 90°C for about 24 hours, The reaction solution was concentrated to dryness under reduced pressure, 15 mL of dichloromethane was added, stirred and filtered, the filter cake was washed twice with 5 mL of dichloromethane, the filtrate was washed with 0.05N aqueous phosphoric acid (15 mLⅹ3), the organic phase was discarded, and the dichloromethane used for the aqueous phase was Extraction (15mL), the organic phase was discarded, the aqueous layer was adjusted to pH=9 with sodium carbonate, extracted with butyl acetate (20mLⅹ2); the organic phases were combined, washed with 0.25N aqueous ammonium dihydrogen phosphate (20mLⅹ2), saturated brine Washed (15 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 3-(7-carboxamide-5-((2R)-2-(2...

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Abstract

The invention provides a synthetic method of silodosin, which is high in yield, simple to operate and safe. The method comprises the following steps: (1) performing acidolysis on a compound shown in a structural formula 4 to obtain a compound shown in a structural formula 2 under the condition that acid used in acidolysis reaction is methylsulfonic acid, trifluoroacetic acid/sulfuric acid, acetic acid/sulfuric acid, polyphosphoric acid or orthophosphoric acid; (2) reacting the compound shown in the structural formula 2 with a compound shown in a structural formula 5 to obtain a compound shown in a structural formula 3; and (3) hydrolyzing the compound shown in the structural formula 3 or salts of the compound to obtain silodosin shown in the structural formula 1, wherein R1 in the structural formulas 2, 3 and 4 is ester groups such as butyryl, valeryl, isobutyryl, benzoyl, p-fluoro benzoyl, p-methyl benzoyl and m-methyl benzoyl; and R2 in the structural formula 5 is good leaving groups such as halogen or sulphonate such as bromine, chlorine, methanesulfonate, benzenesulfonate, p-methyl benzenesulfonate and the like. The method provided by the invention has the advantages that the method is easily-available in raw material and stable and safe in reaction, is convenient to operate, can avoid the reaction conditions which can cause material spraying, and is easy in process control and industrial amplification production.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of a medicinal compound silodosin and an intermediate thereof. Background technique [0002] Silodosin is an alpha 1A - Adrenoceptor antagonists with the chemical name 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-(2,2,2-tri Fluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide, its structural formula is shown in formula 1: [0003] [0004] 1 [0005] Silodosin has a selective inhibitory effect on the contraction of urethral smooth muscle and is clinically used in the treatment of benign prostatic hyperplasia. Silodosin is well absorbed orally, with linear pharmacokinetics within the therapeutic dose range, t max About 2.6-3.5 hours, the absolute bioavailability is about 32%, the apparent volume of distribution is 49.5 L, and the plasma protein binding rate is 97%. A diet with moderate amounts of fat and calories can affec...

Claims

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Application Information

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IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 李德耀王春水郭雷雷
Owner KUNMING JIDA PHARMA
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