Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline

Abstract

The invention provides a preparation method for synthesizing 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline which is a key intermediate of silodosin. The method comprises the following steps: 1-acetylindoline is adopted to serve as the material, and 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline can be obtained through the such 7 steps as friedel-crafts acylation reaction, phthalimide amination, alkylsilane reduction, nitrification, reduction, heavy nitrogen cyaniding and deprotection. According to the method, the materials in the whole synthesizing line are cost-saving and easy to obtain, the operation is simple and the operation cost is low. Moreover, the yield rate of each step of reaction is higher than that in the prior art. Therefore, the method provided by the invention is very suitable for industrial production and has larger industrial application value.

Description

technical field

[0001] The present invention relates to a preparation method of 1-acetyl-7-cyano-5-(2-aminopropyl)indoline, wherein, 1-acetyl-7-cyano-5-(2-amino Propyl)indoline is a key intermediate used in the synthesis of silodosin, a drug for benign prostatic hyperplasia. Background technique

[0002] Silodosin (silodosin) is an a1 adrenergic receptor antagonist, which has selective inhibitory effect on urethral smooth muscle contraction, and can reduce urethral pressure without significant effect on blood pressure. It is used for the treatment of benign prostatic hyperplasia.

[0003] 1-Acetyl-7-cyano-5-(2-aminopropyl)indoline (ie compound (1)), is a key intermediate for the synthesis of silodosin. According to literature reports, in the prior art, there are two main synthetic routes for preparing 1-acetyl-7-cyano-5-(2-aminopropyl)indoline (1):

[0004] The first synthetic route is described in European Patent Application Publication No. EP0600675A1:

[0005] [00...

Examples

example 1

[0032] Example 1: Put 32.2g of 1-acetylindoline (that is, compound (2)), 94.5g of anhydrous aluminum trichloride and 160ml of dichloroethane into a flask, stir at room temperature, and add 33g of 2-chloropropionyl chloride dropwise .

[0033] After the dropwise addition was completed, the reaction was incubated for 8 hours, and then the reaction mixture was poured into ice water and stirred for 30 minutes.

[0034] The aqueous layer was extracted with dichloroethane, and the organic phases were combined, washed with water, then with saturated brine, and dried over sodium sulfate.

[0035] The solvent was distilled off under reduced pressure, ethanol was added to the residue, and 40.3 g of compound (3) was obtained by recrystallization with a yield of 80%.

example 2

[0036] Example 2: Put 32.2g of 1-acetylindoline (ie compound (2)), 100g of anhydrous zinc chloride and 160ml of dichloromethane into a flask, stir at room temperature, and add 33g of 2-chloropropionyl chloride dropwise.

[0037] After the dropwise addition was completed, the reaction was carried out at 50° C. for 10 hours, and then the reaction mixture was poured into ice water and stirred for 30 minutes.

[0038] The aqueous layer was extracted with dichloromethane, and the organic phases were combined, washed with water, then with saturated brine, and dried over sodium sulfate.

[0039] The solvent was distilled off under reduced pressure, ethanol was added to the residue, and 38 g of compound (3) was obtained by recrystallization with a yield of 78%.

[0040] b: Preparation of 1-acetyl-5-(2-phthalimidopropionyl), compound (4):

[0041] 50 g of compound (3), 48 g of phthalimide potassium salt, and 400 ml of DMF were put into a flask, stirred and heated to 80-100° C., and re...

technical field

[0001] The present invention relates to a preparation method of 1-acetyl-7-cyano-5-(2-aminopropyl)indoline, wherein, 1-acetyl-7-cyano-5-(2-amino Propyl)indoline is a key intermediate used in the synthesis of silodosin, a drug for benign prostatic hyperplasia. Background technique

[0002] Silodosin (silodosin) is an a1 adrenergic receptor antagonist, which has selective inhibitory effect on urethral smooth muscle contraction, and can reduce urethral pressure without significant effect on blood pressure. It is used for the treatment of benign prostatic hyperplasia.

[0003] 1-Acetyl-7-cyano-5-(2-aminopropyl)indoline (ie compound (1)), is a key intermediate for the synthesis of silodosin. According to literature reports, in the prior art, there are two main synthetic routes for preparing 1-acetyl-7-cyano-5-(2-aminopropyl)indoline (1):

[0004] The first synthetic route is described in European Patent Application Publication No. EP0600675A1:

[0005] [00...

Examples

example 1

[0032] Example 1: Put 32.2g of 1-acetylindoline (that is, compound (2)), 94.5g of anhydrous aluminum trichloride and 160ml of dichloroethane into a flask, stir at room temperature, and add 33g of 2-chloropropionyl chloride dropwise .

[0033] After the dropwise addition was completed, the reaction was incubated for 8 hours, and then the reaction mixture was poured into ice water and stirred for 30 minutes.

[0034] The aqueous layer was extracted with dichloroethane, and the organic phases were combined, washed with water, then with saturated brine, and dried over sodium sulfate.

[0035] The solvent was distilled off under reduced pressure, ethanol was added to the residue, and 40.3 g of compound (3) was obtained by recrystallization with a yield of 80%.

example 2

[0036] Example 2: Put 32.2g of 1-acetylindoline (ie compound (2)), 100g of anhydrous zinc chloride and 160ml of dichloromethane into a flask, stir at room temperature, and add 33g of 2-chloropropionyl chloride dropwise.

[0037] After the dropwise addition was completed, the reaction was carried out at 50° C. for 10 hours, and then the reaction mixture was poured into ice water and stirred for 30 minutes.

[0038] The aqueous layer was extracted with dichloromethane, and the organic phases were combined, washed with water, then with saturated brine, and dried over sodium sulfate.

[0039] The solvent was distilled off under reduced pressure, ethanol was added to the residue, and 38 g of compound (3) was obtained by recrystallization with a yield of 78%.

[0040] b: Preparation of 1-acetyl-5-(2-phthalimidopropionyl), compound (4):

[0041] 50 g of compound (3), 48 g of phthalimide potassium salt, and 400 ml of DMF were put into a flask, stirred and heated to 80-100° C., and re...

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