- 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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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.
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- Preparation method of silodosin
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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.
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Paragraph 0053; 0059; 0077; 0081
(2020/10/21)
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- Preparation method of silodosin intermediate
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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.
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Paragraph 0030-0054
(2020/06/17)
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- NOVEL SULFONAMIDE INTERMEDIATE AND METHOD FOR PRODUCING SILODOSIN BY USING THE SAME
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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
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- METHOD FOR PRODUCING INDOLINE COMPOUND
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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.
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Paragraph 0107; 0108; 0109; 0110; 0111-0115; 0118-0120
(2017/01/31)
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- THE PROCESS OF PREPARING INDOLINE COMPOUNDS AND A NOVEL INDOLINE SALT
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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.
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Page/Page column 12; 13; 14
(2017/04/11)
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- Method for preparing silodosin
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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.
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Paragraph 0053-0063; 0088-0098; 0123-0133; 0158-0168
(2017/09/01)
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- Process for preparing silodosin
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The present invention provides a method for producing silodosin through a novel synthesis pathway, wherein the silodosin is a therapeutic agent of urinary disturbances by benign prostatic hyperplasia. In addition, the present invention provides a method for producing a beta crystal form and/or a gamma crystal form of the silodosin using a crystallization solvent with excellent stability.COPYRIGHT KIPO 2016
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Paragraph 0058; 0059
(2017/03/22)
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- Process for preparing an intermediate useful for the synthesis of silodosin
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The present invention provides an improved producing method of 3-{7-cyano-5[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aminopropyl)-2,3-dihydro-1H-indole-1-yl}propylene benzoate, as an essential intermediate product used in synthesizing silodosin which is a therapeutic agent of urinary disturbances by benign prostatic hyperplasia. In addition, the present invention provides: a novel acid addition salt of the essential intermediate product; and a producing method of silodosin using the improved producing method.COPYRIGHT KIPO 2016
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Paragraph 0064-0070
(2017/04/25)
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- Process for preparing intermediate of silodosin
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The present invention relates to a novel intermediate material of silodosin, and to a method for producing the same. More specifically, the present invention relates to 2,3-dihydro-1-(3- hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl] amino]propyl]-1H-indole-7-carbonitrile malate of chemical formula 1 useful as an intermediate material for producing silodosin which is an agent for treating dysuria accompanied by prostatomegaly, and to a method for producing the same.COPYRIGHT KIPO 2016
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Paragraph 0026; 0037-0038
(2018/03/06)
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- A method for synthesizing silodosin
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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.
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Paragraph 0038; 0062-0063
(2016/12/12)
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- 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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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
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Paragraph 0064
(2016/10/10)
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- METHOD FOR PREPARING SILODOSIN
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The present invention relates to a process for preparing silodosin with high optical purity up to 99.9% enantiomeric excess (e.e.) or above. The process makes use of a method step, in which the enantiomers contained in a racemic mixture of a compound represented by the general formula V: wherein * denotes the asymmetric center, R1 is a protecting group, and R2 is cyano or carbamoyl, are separated.
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Page/Page column 20
(2013/05/09)
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- NOVEL PROCESS FOR THE SYNTHESIS OF INDOLINE DERIVATIVES
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The present invention provides an improved process for the synthesis of indoline intermidiate and its pharmaceutically acceptable derivatives, salts or solvates thereof, useful in the synthesis of α-1 adrenoceptor blockers such as silodosin.
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Page/Page column 33
(2012/10/18)
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- PROCESS FOR THE PREPARATION OF INDOLINE DERIVATIVES AND THEIR INTERMEDIATES THEREOF
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Processes for the preparation of Silodosin and its intermediates comprising reductive amination of compound of Formula (VIII) with a compound of Formula (VII) or a compound of Formula (XV) in a suitable solvent using a reducing agent.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SILODOSIN
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The present invention provides a process for the preparation of Silodosin of Formula (I). More particularly, the present invention provides the process for preparation of tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2, 3-dihydro-1H-indol-1 -yl }propyl benzoate of Formula (IV), which is a precursor in the preparation of Silodosin.
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Page/Page column 14
(2012/11/13)
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- PROCESS FOR PREPARING AN INTERMEDIATE FOR SILODOSIN
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The present invention provides a process for preparing a compound of formula (I), wherein R1 is a hydroxyl-protecting group and R2 is a cyano group or a carbamoyl group, wherein the process comprises the direct hydrogenation of the corresponding achiral nitro compound and the resolution of the racemic amino compound. The compound of formula (I) can easily be further transferred to silodosin.
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- PROCESS FOR THE PREPARATION OF INDOLINE DERIVATIVES AND THEIR INTERMEDIATES THEREOF
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Processes for the preparation of Silodosin and its intermediates comprising reductive amination of compound of Formula (VIII) with a compound of Formula (VII) or a compound of Formula (XV) in a suitable solvent using a reducing agent.
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- INDOLINE COMPOUND AND PROCESS FOR PRODUCING THE SAME
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The present invention provides an industrial method production of silodosin, which is useful for a therapeutic agent for dysuria associated with benign prostatic hyperplasia. The production of silodosine is characterized by mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate and oxalic acid to yield the oxalate, subsequently hydrolyzing the oxalate salt to yield 1-(3-hydroxypropyl)-5-[(2R)-2-((2-[2-(2,2,2-trifluoro-ethoxy)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile and hydrolyzing the same, and manufacturing intermediates used therefore.
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- INDOLINE COMPOUND AND PROCESS FOR PRODUCING THE SAME
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A process for industrially producing silodosin, which is a therapeutic agent for urination disorders accompanying prostatic hypertrophy. The process for silodosin production is characterized by mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate with oxalic acid to yield an oxalate, subsequently hydrolyzing the oxalate to yield 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro-ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile, and hydrolyzing it. Also provided is an intermediate for use in the production.
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Page/Page column 10-11
(2010/11/08)
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