885340-11-4Relevant academic research and scientific papers
5-substituted indoline derivative or salt thereof, preparation method and application of 5-substituted indoline derivative or salt thereof, and preparation method of silodosin
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, (2022/04/06)
The invention relates to the technical field of medicines, in particular to a 5-substituted indoline derivative or a salt thereof, a preparation method and application of the 5-substituted indoline derivative or the salt thereof, and a preparation method of silodosin. Silodosin can be prepared by taking the 5-substituted indoline derivative provided by the invention as an intermediate through first N-alkylation, bromination, cyano substitution, deprotection, second N-alkylation and hydrolysis. The reaction route is short, and the total yield of the silodosin is high. The 5-substituted indoline derivative salt provided by the invention has good stability. According to the method, phthalic anhydride or substituted phthalic anhydride and D-alanine are taken as starting materials, the 5-substituted indoline derivative can be obtained through condensation, acylating chlorination, Friedel-Crafts reaction, reduction and hydrolysis, the reaction route is short, chiral construction does not need resolution, the atom utilization rate is high, the total yield is larger than 57.5%, and the yield is high; and the raw materials are cheap and easily available, and the production cost is low.
Preparation method of silodosin
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Paragraph 0053; 0059; 0077; 0081, (2020/10/21)
The invention discloses a preparation method of silodosin. The preparation method comprises the following steps: S1, carrying out an asymmetric Henry condensation reaction on a substance 1 and nitroethane under the action of a copper salt and a chiral catalyst 2 to obtain a substance 3; S2, carrying out a reduction reaction on the substance 3 and hydrogen under the action of a catalyst 4 to obtaina substance 5; and S3, enabling the substance 5 to react with 2-(2-trifluoroethoxyphenoxy)ethyl methanesulfonate and an alkali to obtain a substance 6, and hydrolyzing the substance 6 to obtain silodosin. The method is novel in route, short in synthetic route, mild in reaction condition and convenient and controllable to operate, the chiral center is directly synthesized by the chiral catalyst without chiral resolution, and the prepared silodosin is good in chiral purity, high in yield, obvious in cost advantage and suitable for industrial production.
Preparation method of silodosin intermediate
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Paragraph 0030-0054, (2020/06/17)
The present invention relates to a method for preparing a silodosin intermediate represented by a formula III. The method comprises: reacting a compound represented by a formula I or a salt thereof with a compound represented by a formula II to generate a compound represented by a formula III, wherein X is a leaving group, PG is a protecting group of hydroxyl, and the reaction system used in the reaction comprises alkali metal phosphate and/or alkali metal halide.
NOVEL SULFONAMIDE INTERMEDIATE AND METHOD FOR PRODUCING SILODOSIN BY USING THE SAME
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, (2019/04/26)
PROBLEM TO BE SOLVED: To provide a method for producing silodosin by using a novel sulfonamide intermediate. SOLUTION: The method for producing silodosin or a pharmaceutically acceptable salt thereof includes reacting a compound of the formula as given below and a thiol group-containing Meisenheimer complex forming agent in the presence of an alkali metal carbonate or an alkali metal alkoxide. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
THE PROCESS OF PREPARING INDOLINE COMPOUNDS AND A NOVEL INDOLINE SALT
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Page/Page column 12; 13; 14, (2017/04/11)
The present invention provides an industrial method for production of silodosin, which is useful for a therapeutic agent for dysuria associated with benign prostatic hyperplasia. The production of silodosin is characterized by mixing (R)-l-(3-hydroxypropyl)-5-(2-(2- (2-(2, 2, 2-trifluoroethoxy) phenoxy) ethyl amino) propyl) indoline-7-carbonitrile (V) and N-acetyl-L-glutamic acid to yield the N-acetyl-L-glutamate salt, subsequently neutralising the N-acetyl-L-glutamate salt and hydrolyzing the same, and manufacturing intermediates used therefore. The invention also provides an industrial production method of silodosin alpha, beta and gamma crystalline forms.
Method for preparing silodosin
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Paragraph 0053-0063; 0088-0098; 0123-0133; 0158-0168, (2017/09/01)
The invention relates to a method for preparing silodosin, especially to an industrial preparation method of a silodosin compound, and belongs to the field of pharmaceutical chemical synthesis. The method includes: carrying out salt hydrolysis on 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-nitrile tartrate to obtain 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-nitrile, preparing benzoic acid-R-3-[7-cyano-5-(2-{2-[2-(2,2,2-trifluoro-ethoxy)-phenoxyl]-ethylamino}-propyl)-2,3-dihydro-indole-1-yl]-propylester which is an intermediate, and finally performing a hydrolysis reaction to produce silodosin. According to the provided industrial production method of silodosin, the yield is high, purification becomes easy and the impurity content is low.
METHOD FOR PRODUCING INDOLINE COMPOUND
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Paragraph 0107; 0108; 0109; 0110; 0111-0115; 0118-0120, (2017/01/31)
Provided is a method for producing a compound represented by a formula (6), the method comprising: a step of mixing a compound represented by a formula (4) and a compound represented by a formula (5) to form a salt consisting of the compound represented by the formula (4) and the compound represented by the formula (5); and a step of removing a protecting group P1 of the salt. In the following formulae, P1 is a protecting group and P2 is a protecting group.
A method for synthesizing silodosin
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Paragraph 0038; 0062-0063, (2016/12/12)
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.
METHOD FOR PRODUCING 1-(3-BENZOYLOXY PROPYL)-7-CYANO-5-[(2R)-2-({2-[2-(2,2,2-TRIFLUORO ETHOXY)PHENOXY]ETHYL}AMINO)PROPYL]INDOLINE OR ITS SALT
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Paragraph 0064, (2016/10/10)
PROBLEM TO BE SOLVED: To provide a method for producing efficiently high-purity 1-(3-benzoyloxy propyl)-7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]indoline in which the amount of a specific impurity is reduced. SOLUTION: A nucleophilic substitution reaction at an amino group in 5-(2-aminopropyl)-1-(3-benzoyloxy propyl)-7-cyano indoline is performed by using a mixture of a low polar organic solvent and water as a reaction solvent. COPYRIGHT: (C)2016,JPOandINPIT
