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Preparation method of indoline compound, indoline compound and use

A technology of indoline compounds and compounds, applied in the field of indoline compounds, can solve problems affecting the purity of silodosin, toxic and side effects, etc.

Active Publication Date: 2021-11-02
北京华氏康源医药科技有限公司
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Problems solved by technology

[0002] The chemical name of silodosin is: 1-(3-hydroxypropyl)-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)phenoxy]ethyl Base}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide, which is a kind of indoline compound, there is a chiral carbon in silodosin, and in silodosin The enantiomers of silodosin inevitably exist in silodosin, and the enantiomers of silodosin exist in silodosin as impurities, which will not only affect the purity of silodosin, but may also affect the purity of silodosin. Bring non-therapeutic toxic and side effects, but there are no reports related to the preparation method of silodosin enantiomers and the enantiomers of silodosin intermediates, so it is determined that a The preparation method of the indoline compound related to the doxin enantiomer is of great significance for the effective control of the quality of silodosin

Method used

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  • Preparation method of indoline compound, indoline compound and use
  • Preparation method of indoline compound, indoline compound and use
  • Preparation method of indoline compound, indoline compound and use

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preparation example Construction

[0068] The preparation method of the silodosin enantiomer comprises:

[0069] Step S10: Resolution, 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano- 1H-indole is resolved by D-tartaric acid to obtain 5-[(2S)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2 represented by structural formula (2) ,3-Dihydro-7-cyano-1H-indole tartrate;

[0070]

[0071] Step S20: Reaction, the compound represented by structural formula (2) is reacted with phenoxyethane compound, and utilizes oxalic acid to form a salt to obtain 1-[3-(benzoyloxy) represented by structural formula (3) )propyl]-2,3-dihydro-5-[(2S)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino] Propyl]-1H-indole-7-carbonitrile oxalate;

[0072]

[0073] Step S30: first hydrolysis, the compound represented by structural formula (3) is hydrolyzed to generate 1-propanol-2,3-dihydro-5-[(2S)-2-[[2- [2-(2,2,2-Trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile;

[0074]

[0075] Step 40: Second h...

Embodiment 1

[0139] Preparation of 5-[(2S)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole tartrate :

[0140] 5.00g 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole (13.76mmol), Add 150mL tetrahydrofuran, 10mL purified water and 2.27g D-tartaric acid (15.12mmol) into a 250mL three-necked flask, control the resolution temperature at 60°C, stir for 1h, cool down to 10°C, stir and crystallize for 2h, and filter the precipitated solid. The cake was recrystallized twice with 50 mL of a mixed solvent of tetrahydrofuran and water (9:1), and the filter cake was vacuum-dried at 50°C to 60°C for 8 hours to obtain 2.12g of off-white solid with a yield of 30.03%.

[0141] Identification of the off-white solid product:

[0142] H NMR spectrum, the spectrum is as follows figure 1 shown.

[0143] 1H-NMR (400MHz, DMSO+D 2O): 8.000-7.984(d, 2H), 7.675-7.645(m, 1H), 7.530-7.499(m, 2H), 7.095(s, 1H), 7.033(s, 1H), 4.398-4.374(m, 2H), 3.945(s, 2H), 3.722-3....

Embodiment 2

[0152] Preparation of 5-[(2S)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole tartrate :

[0153] 5.01g 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole (13.78mmol), Add 150mL of tetrahydrofuran, 10mL of purified water and 2.28g of D-tartaric acid (15.19mmol) into a 250mL three-neck flask, control the resolution temperature at 20°C, stir for 1h, cool down to 10°C, stir and crystallize for 2h, and filter the precipitated solid. The cake was recrystallized twice with 50 mL of a mixed solvent of tetrahydrofuran and water (9:1), and the filter cake was vacuum-dried at 50°C to 60°C for 8 hours to obtain 1.08g of off-white solid with a yield of 15.25%.

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Abstract

The invention belongs to the field of medicines, and in particular relates to a preparation method of an indoline compound, an indoline compound and applications thereof. The indoline compound includes silodosin enantiomers. The preparation method of the indoline compound provided by the invention is of great significance for effectively controlling the quality of silodosin.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a preparation method of an indoline compound, an indoline compound and uses thereof. Background technique [0002] The chemical name of silodosin is: 1-(3-hydroxypropyl)-5-[(2R)-2-({2-(2,2,2-trifluoroethoxy)phenoxy]ethyl Base}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide, which is a kind of indoline compound, there is a chiral carbon in silodosin, and in silodosin The enantiomers of silodosin inevitably exist in silodosin, and the enantiomers of silodosin exist in silodosin as impurities, which will not only affect the purity of silodosin, but may also affect the purity of silodosin. Bring non-therapeutic toxic and side effects, but there are no reports related to the preparation method of silodosin enantiomers and the enantiomers of silodosin intermediates, so it is determined that a The preparation method of the indoline compound related to the doxin enantiomer is of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08C07C59/255C07C51/41G01N30/06
CPCC07B2200/07C07C51/412C07C59/255C07D209/08G01N30/06
Inventor 柴国举李静武艳朋张鼎葛志敏戴信敏
Owner 北京华氏康源医药科技有限公司
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