Indoline derivative as well as preparation method and application thereof

A technology of indoline and compounds, applied in the field of medicinal chemistry, to achieve the effects of easy purification, reduction of reaction steps, and cost reduction

Active Publication Date: 2011-03-30
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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The column chromatography yiel

Method used

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  • Indoline derivative as well as preparation method and application thereof
  • Indoline derivative as well as preparation method and application thereof
  • Indoline derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of compound (Ia)

[0030] With reference to reaction formula (1), 20 grams of tartrate salt of compound II (R=4-fluorobenzoyl), 10 grams of potassium carbonate, 1 gram of tetrabutylammonium bromide, and 0.5 grams of potassium iodide are placed in a reaction flask, and 120ml of water was heated to 80°C, 14g of compound III (X=Br) was added dropwise, and the reaction was continued at 80°C for 6 hours. Extract with ethyl acetate, wash with sodium bicarbonate, wash with saturated brine, dry over magnesium sulfate, and concentrate. The oil was dissolved in isopropanol, 4.2 g of oxalic acid dihydrate was added, and a solid was precipitated to obtain 22 g of a white solid.

[0031] Mp 135-137°C

[0032] 1 NMR spectrum (DMSO-d6): δppm 1.1-1.2 (3H, d), 2.0-2.1 (2H, m), 2.5-2.6 (1H, dd), 2.8-2.9 (2H, t), 2.96-3.0 (1H , dd), 3.3-3.5 (3H, m), 3.5-3.7 (4H, m), 4.2-4.3 (2H, t), 4.3-4.4 (2H, t), 4.6-4.7 (2H, m), 4.8 -5.2 (1H, broad peak), 6.9-7.15 (6...

Embodiment 2

[0033] Embodiment 2: the preparation of silodosin

[0034] 8 g of compound (I a), dissolved in 100 ml of DMSO, added 12 ml of 5 mol / L NaOH, slowly added 30% H 2 o 2 7 g, and then at 30° C., the reaction was completed in 4 hours. Extract with ethyl acetate, combine the organic layers, wash the organic layer with 2N HCl, neutralize the obtained aqueous layer with sodium hydroxide, extract with ethyl acetate, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, and reduce pressure Concentrate, then dissolve with ethyl acetate, cool and crystallize, filter, and dry 5 g (87%), the purity is >99%.

[0035] Mp105~108℃

[0036] [α] 20 D =-16.2 C=1, MeOH

[0037] 1 NMR spectrum (DMSO-d6): δppm 0.9-1.0 (3H, d), 1.5-1.6 (1H, s), 1.6-1.7 (2H, m), 2.3-2.4 (1H, dd), 2.6-2.7 (1H ,dd), 2.8-3.0(5H,m), 3.1-3.2(2H,m), 3.3-3.4(2H,m), 3.4-3.5(2H,t), 4.0-4.1(2H,t), 4.2 -4.3(1H, s), 4.6-4.8(2H, t), 6.9-7.15(6H, m), 7.2-7.3(1H, s), 7.5-7.6(1H, s)

Embodiment 3

[0038] Embodiment 3: the preparation of compound (Ia)

[0039] With reference to reaction formula (1), 20 grams of tartrate salt of compound II (R=4-fluorobenzoyl), 10 grams of potassium carbonate, 1 gram of tetrabutylammonium bromide, and 0.5 grams of potassium iodide are placed in a reaction flask, and 120ml of water was heated to 80°C, 16g of compound III (X=OMs) was added dropwise, and the mixture was reacted at 80°C for another 6 hours after dropping. Extract with ethyl acetate, wash with sodium bicarbonate, wash with saturated brine, dry over magnesium sulfate, and concentrate. The oil was dissolved in isopropanol, 4.2 g of oxalic acid dihydrate was added, and a solid was precipitated to obtain 20 g of a white solid.

[0040] Mp 133-135°C

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Abstract

The invention provides a preparation method of 1-(3-protecting propyl)-5-((2R)-2-(2-(2-(2,2,2-trifluoroethyoxyl)phenoxy)ethylamine)propyl)indoline-7-cyan and 1-(3-(4-flurobenzoyl)hydroxyl propyl)-5-((2R)-2-(2-(2-(2,2,2-trifluoroethyoxyl)phenoxy)ethylamine)propyl)indoline-7-cyan shown as in a specific compound structure (Ia) in the specification. The method is characterized in that water is used as a solvent and the yield is high. The 1-(3-(4-flurobenzoyl)hydroxyl propyl)-5-((2R)-2-(2-(2-(2,2,2-trifluoroethyoxyl)phenoxy)ethylamine)propyl)indoline-7-cyan shown as in the specific compound structure (Ia) can be used as an intermediate to be applied to the preparation of an indoline derivative. The method of the invention is simple in operation and high in yield.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a compound 1-(3-(4-fluorobenzoyl)hydroxypropyl)-5-((2R)-2-(2-(2-(2,2, 2-trifluoroethoxy) phenoxy) ethylamino) propyl) indoline-7-cyano and its use in the synthesis of silodosin, and the present invention also relates to 1-(3-protecting groups Hydroxypropyl)-5-((2R)-2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-cyano method of base preparation. Background technique [0002] Optically active (R)-1-(3-protected hydroxypropyl)-7-cyano-5-((2-trifluoroethoxyphenoxyethylamino)propyl)indoline was prepared The key intermediate of the drug silodosin for the treatment of benign prostatic hyperplasia. [0003] WO2006046499 reports the preparation method of R-compound I b (R = benzoyl, see the figure below for the structure), which is through 2-trifluoroethoxyphenoxyethanol methanesulfonate and compound II b (R = benzoyl Acyl) was refluxed in tert-butanol i...

Claims

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Application Information

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IPC IPC(8): C07D209/08
Inventor 王小梅王哲烽隋强刘启皓时惠麟
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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