Method for preparing silodosin chiral intermediate

Abstract

The present invention provides a method for synthesizing a silodosin intermediate with a high enantiomeric purity. The method comprises the steps of using 1-[3-(benzyloxy)propyl]-5-bromoindoline as the raw material, performing a bromine lithium exchange reaction with an organolithium reagent to obtain 1-[3-(benzyloxy)propyl]-5-lithiumindoline, performing a Weinreb amidization reaction with (R)-N-(alkoxycarbonyl)alanine to obtain the silodosin intermediate with a good yield and enantioselectivity. The method has the advantages of simple operation, cheap and easily-available raw materials, highenantiomeric purity of the product and no resolution step, and has extremely high application value for industrial preparation of silodosin.

Description

technical field

[0001] The present invention relates to a 1A - A new method for preparing a chiral intermediate of the adrenergic receptor antagonist silodosin, which belongs to the field of drug synthesis. 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 a novel highly selective α 1A - Adrenergic receptor antagonists, which have a good therapeutic effect on dysuria caused by benign prostatic hyperplasia in men.

[0003]

[0004] At present, most of the production of silodosin firstly prepares compound A, and then prepares silodosin through several subsequent steps. There are many reports about the synthetic method of compound A, mainly containing the following:

[0005]

[0006] Japanese patent JP200119956 discloses a method for preparing compound A by asymmetric reductive amination of 3-(1-(3-(benzyloxy)propyl)-7-...

Examples

Embodiment 1

[0025]

[0026] Take a three-necked reaction flask to vacuum and then fill it with nitrogen, repeat three times, add 34.6g (100mmol) of 1-[3-(benzyloxy)propyl]-5-bromoindoline and 200mL tetrahydrofuran. At -78°C, 50 mL (2.4 M, 120 mmol) of a n-butyllithium solution in n-hexane was slowly added dropwise, and stirring was continued for 15 minutes after the addition was complete. Take 31.9 g (120 mmol) of (R)-N-benzyloxycarbonyl-alanine Weinreb amide, dissolve it in 200 mL of tetrahydrofuran, and slowly add it dropwise to the above reaction solution at -78°C. Slowly warm to room temperature and stir overnight. Slowly add 400 mL of saturated ammonium chloride solution under ice bath, stir for 30 minutes, and transfer to a separatory funnel. Extracted with ethyl acetate (300 mL×3), the combined organic layer was washed twice with 400 mL saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by...

Embodiment 2

[0028] Using the same procedure as in Example 1, 92.3 mL of sec-butyl lithium (120 mmol, 1.3 M cyclohexane solution) was used instead of n-butyl lithium to obtain 30.0 g of the product with a yield of 63.6% and an ee value of 99.9%.

Embodiment 3

[0030] Using the same procedure as in Example 1, 92.3mL of tert-butyllithium (120mmol, 1.3M pentane solution) was used instead of n-butyllithium to obtain 26.6g of the product with a yield of 56.3% and an ee value of 99.9%.

technical field

[0001] The present invention relates to a 1A - A new method for preparing a chiral intermediate of the adrenergic receptor antagonist silodosin, which belongs to the field of drug synthesis. 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 a novel highly selective α 1A - Adrenergic receptor antagonists, which have a good therapeutic effect on dysuria caused by benign prostatic hyperplasia in men.

[0003]

[0004] At present, most of the production of silodosin firstly prepares compound A, and then prepares silodosin through several subsequent steps. There are many reports about the synthetic method of compound A, mainly containing the following:

[0005]

[0006] Japanese patent JP200119956 discloses a method for preparing compound A by asymmetric reductive amination of 3-(1-(3-(benzyloxy)propyl)-7-...

Examples

Embodiment 1

[0025]

[0026] Take a three-necked reaction flask to vacuum and then fill it with nitrogen, repeat three times, add 34.6g (100mmol) of 1-[3-(benzyloxy)propyl]-5-bromoindoline and 200mL tetrahydrofuran. At -78°C, 50 mL (2.4 M, 120 mmol) of a n-butyllithium solution in n-hexane was slowly added dropwise, and stirring was continued for 15 minutes after the addition was complete. Take 31.9 g (120 mmol) of (R)-N-benzyloxycarbonyl-alanine Weinreb amide, dissolve it in 200 mL of tetrahydrofuran, and slowly add it dropwise to the above reaction solution at -78°C. Slowly warm to room temperature and stir overnight. Slowly add 400 mL of saturated ammonium chloride solution under ice bath, stir for 30 minutes, and transfer to a separatory funnel. Extracted with ethyl acetate (300 mL×3), the combined organic layer was washed twice with 400 mL saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by...

Embodiment 2

[0028] Using the same procedure as in Example 1, 92.3 mL of sec-butyl lithium (120 mmol, 1.3 M cyclohexane solution) was used instead of n-butyl lithium to obtain 30.0 g of the product with a yield of 63.6% and an ee value of 99.9%.

Embodiment 3

[0030] Using the same procedure as in Example 1, 92.3mL of tert-butyllithium (120mmol, 1.3M pentane solution) was used instead of n-butyllithium to obtain 26.6g of the product with a yield of 56.3% and an ee value of 99.9%.

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