A kind of synthetic method of silodosin

Abstract

The invention discloses a method for synthesizing silodosin. The method comprises the following steps: by taking 7-cyanoindoline as an initial raw material, synthesizing a 1-(benzoyloxypropyl)-7-cyanoindoline compound (I); reacting with a compound (II) to synthesize a key chiral intermediate 5-[(2R)-2-(benzylamino)-1-acetone]-1-{3-(benzoyloxy)propyl]-7-cyanoindoline compound (III), and reducing through triethyl silicane to obtain a compound (IV); performing catalytic hydrogenation to obtain a compound (V), carrying out a condensation reaction with a compound (VI) under alkaline conditions to obtain a compound (VII), and finally, hydrolyzing under alkaline and H2O2 conditions to obtain silodosin. The compound (I) and the compound (II) are subjected to chiral synthesis to obtain the key chiral compound (III), resolution is avoided, and the optical purity is controllable, so that the reaction yield is greatly improved, the reaction conditions are mild, generation of byproducts in a conventional process is avoided, the production cost is reduced, and the purity is high. The labor intensity is alleviated, the method is environment-friendly and easy for industrial production, and the total yield is high and is improved from 20 percent in a literature report to be about 43 percent.

Description

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method for synthesizing silodosin, a drug for treating benign prostatic hyperplasia. Background technique

[0002] Silodosin (Silodosin) is a selective α1A-adrenergic blocker. Preclinical studies have shown that its selective effect on the urethra is 12 and 7.5 higher than that of Prazosin (Prazosin) and Tamsulosin (Tamsulosin). times. Silodosin can significantly inhibit norepinephrine-induced human prostate contraction; it has a dose-dependent inhibitory effect on bladder hyperactivity in rat benign prostatic hypertrophy model, and can increase the pressure threshold of bladder contraction. These data suggest that, in addition to improving bladder function, silodosin is also effective in relieving symptoms associated with benign prostatic hypertrophy.

[0003] Benign prostatic hyperplasia (BPH) is a common disease in elderly men, characterized by non-malignant ...

Examples

Embodiment 1

[0043] Example 1, a synthetic method of silodosin, the steps are as follows: 7-cyanoindoline is used as the starting material, and a benzoyloxypropyl group is introduced into the 1 position of indoline to synthesize 1-(benzoyloxypropyl)-7-cyanoindoline compound (I), and then with 2R-2-[(phenylmethyl)amino]-propionyl chloride compound (II) by Friedel-Crafts Synthesis of key chiral intermediate 5-[(2R)-2-(benzylamino)-1-propanone]-1-[3-(benzoyloxy)propyl]-7-cyano through acylation reaction The indoline compound (III) was reduced by triethylsilane to obtain 5-[(2R)-2-(benzylamino)propyl]-1-[3-(benzoyloxy)propyl]- 7-cyanoindoline compound (IV), and then through catalytic hydrogenation to obtain (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)7- A cyano]indoline compound (V) undergoes a condensation reaction with a 2-(2,2,2,-trifluoroethoxy) phenoxyethyl methanesulfonate compound (VI) under basic conditions to obtain 1 -(3-(4-fluorobenzoyl)hydroxypropyl)-5-((2R)-2-(2-(2-(2,2,2-tri...

Embodiment 2

[0044] Example 2, in the method described in Example 1: 7-cyanoindoline is used as raw material and 3-chloropropyl benzoate to react to obtain the compound of formula (I), and the specific steps are as follows: 1.0 parts by weight 3-chloropropyl benzoate and 1.6 parts by weight of 7-cyanoindoline were reacted in 5-10 times the amount of polar solvent at 80-100°C for 10-15 hours, and finally hydrochloric acid was added to form a salt to obtain Compound (I) hydrochloride; the polar solvent is selected from DMF or DMSO, and an acid reducing agent is added to DMF or DMSO.

Embodiment 3

[0045] Embodiment 3, in the method described in embodiment 2: the acid reducing agent that adds in the DMF or DMSO is the triethylamine or pyridine of 0.84 weight part.

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method for synthesizing silodosin, a drug for treating benign prostatic hyperplasia. Background technique

[0002] Silodosin (Silodosin) is a selective α1A-adrenergic blocker. Preclinical studies have shown that its selective effect on the urethra is 12 and 7.5 higher than that of Prazosin (Prazosin) and Tamsulosin (Tamsulosin). times. Silodosin can significantly inhibit norepinephrine-induced human prostate contraction; it has a dose-dependent inhibitory effect on bladder hyperactivity in rat benign prostatic hypertrophy model, and can increase the pressure threshold of bladder contraction. These data suggest that, in addition to improving bladder function, silodosin is also effective in relieving symptoms associated with benign prostatic hypertrophy.

[0003] Benign prostatic hyperplasia (BPH) is a common disease in elderly men, characterized by non-malignant ...

Examples

Embodiment 1

[0043] Example 1, a synthetic method of silodosin, the steps are as follows: 7-cyanoindoline is used as the starting material, and a benzoyloxypropyl group is introduced into the 1 position of indoline to synthesize 1-(benzoyloxypropyl)-7-cyanoindoline compound (I), and then with 2R-2-[(phenylmethyl)amino]-propionyl chloride compound (II) by Friedel-Crafts Synthesis of key chiral intermediate 5-[(2R)-2-(benzylamino)-1-propanone]-1-[3-(benzoyloxy)propyl]-7-cyano through acylation reaction The indoline compound (III) was reduced by triethylsilane to obtain 5-[(2R)-2-(benzylamino)propyl]-1-[3-(benzoyloxy)propyl]- 7-cyanoindoline compound (IV), and then through catalytic hydrogenation to obtain (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)7- A cyano]indoline compound (V) undergoes a condensation reaction with a 2-(2,2,2,-trifluoroethoxy) phenoxyethyl methanesulfonate compound (VI) under basic conditions to obtain 1 -(3-(4-fluorobenzoyl)hydroxypropyl)-5-((2R)-2-(2-(2-(2,2,2-tri...

Embodiment 2

[0044] Example 2, in the method described in Example 1: 7-cyanoindoline is used as raw material and 3-chloropropyl benzoate to react to obtain the compound of formula (I), and the specific steps are as follows: 1.0 parts by weight 3-chloropropyl benzoate and 1.6 parts by weight of 7-cyanoindoline were reacted in 5-10 times the amount of polar solvent at 80-100°C for 10-15 hours, and finally hydrochloric acid was added to form a salt to obtain Compound (I) hydrochloride; the polar solvent is selected from DMF or DMSO, and an acid reducing agent is added to DMF or DMSO.

Embodiment 3

[0045] Embodiment 3, in the method described in embodiment 2: the acid reducing agent that adds in the DMF or DMSO is the triethylamine or pyridine of 0.84 weight part.

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