- 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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- THE MANUFACTURING METHOD OF INTERMEDIATE FOR SYNTHESIS OF SILODOSIN AND THE MANUFACTURING METHOD OF SILODOSIN
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The present invention relates to a method for producing an intermediate for the synthesis, of a cilodosin, and a method for producing, a cilodosin using the, same, which can be used in a method for producing a cilodosin, which can increase the price competitiveness and can reduce. risk factors in the production process, facilitate mass production, and obtain a high purity of xylodosin. (by machine translation)
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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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- MALEIC ACID SALT OF A SILODOSIN INTERMEDIATE
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The present invention relates to a salt of formula (I), the preparation method for preparing same, and the use thereof in the preparation of silodosin.
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Paragraph 0086-0087
(2018/11/02)
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- PROCESS FOR THE PREPARATION OF INDOLINE COMPOUND
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The present invention relates to an improved process for the preparation of Silodosin (I) which is useful in the treatment of Benign Prostate Hyperplasia (BPH) and related disorders. The present invention also relates to the purification process resulting in substantially pure Silodosin.
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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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- 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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- A silodosin intermediate and its preparation method, and the intermediate for method of preparation of the silodosin
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The invention relates to the field of compound synthesis and especially relates to a silodosin intermediate, a preparation method of the silodosin intermediate, and a method for preparing silodosin from the silodosin intermediate. The method for preparing silodosin from the silodosin intermediate has the characteristics of economy, safety, high purity and high yield and is suitable for large-scale industrial production.
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- New preparation method of silodosin compound
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The invention belongs to the technical field of medical chemistry, and concretely relates to a new preparation method of silodosin. A compound III reacts with a compound II to generate an imine intermediate IV, and the imine intermediate IV is reduced to obtain silodosin, so impurity P1 is effectively removed, the content of the impurity P1 is reduced, and the product quality is improved. The preparation method has the advantages of simplicity in operation, mild reaction conditions, good safety and controllability, good product purity, and suitableness for industrial production.
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Paragraph 0017-0029
(2017/10/14)
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- Process for preparing crystalline forms of silodosin
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Provided is a method for producing high-purity crystalline silodosin beta and gamma which are treatment agents for urination disorder accompanying prostatic hypertrophy, by using a specific crystalline solvent.COPYRIGHT KIPO 2016
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Paragraph 0069; 0070
(2017/04/26)
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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 0077; 0078
(2017/03/22)
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- A method for preparing intermediate silodosin into salt
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The invention relates to a method of maleate formation of a silodosin intermediate indoline compound 1 - (3 - (4 - fluoro benzoyl) hydroxypropyl) -5 - ((2R) -2 - (2 - (2 - (2,2,2 - trifluoroethoxyl) phenoxy) ethylamine) propyl) indoline -7 - cyano (compound (1)), i.e., a crude product of the compound (1) forms a salt with maleic acid in a mixed solvent of a good solvent and a poor solvent. The maleate of the compound can be stably obtained by the method, and the method has the advantages of good impurity removal effect, stable process, high yield, simpleness in operation and the like.
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Paragraph 0032; 0033
(2017/03/21)
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- A method for preparing raw match Luo river multi-Xin thereof, pharmaceutical compositions
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The invention discloses a beta crystal form silodosin bulk drug as well as a preparation method and a medicine composition thereof. A residual solvent of the bulk drug does not contain normal hexane; calculated by an internal standard method according to a peak area, the content of ethyl acetate in the residual solvent does not exceed 0.5%; calculated by the internal standard method according to the peak area, the content of beta crystal form silodosin in the bulk drug is 98.0%-102.0%; and calculated by a principal component external standard method according to the peak area, the content of total impurities in related substances does not exceed 0.5%. The beta crystal form silodosin bulk drug prepared by the method has low residual quantity of solvents and stable quality, especially does not contain normal hexane and is suitable for industrialized large-scale production.
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Paragraph 0106-0109
(2017/02/09)
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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; 0041-0043
(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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- METHOD FOR PRODUCING SILODOSIN AND INTERMEDIATE
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PROBLEM TO BE SOLVED: To provide methods for producing silodosin and intermediates thereof. SOLUTION: The present invention provides a method for synthesis via a compound 2 as a novel intermediate by using a compound of chemical formula 5. The present invention also provides a production method that makes it possible to produce high-yield and high-purity silodosin by a simple production process and is very suitable for industrial use. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0044
(2016/11/21)
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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 0076
(2016/10/10)
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- A NOVEL PROCESS FOR THE PREPARATION OF CONSIDERABLY PURE SILODOSIN
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The present invention relates to a novel, improved, commercially viable and industrially advantageous process for the preparation of Silodosin of Formula (I), its pharmaceutically acceptable salts or solvates thereof. The invention relates to the preparation of considerably pure Silodosin with high yield.
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Page/Page column 15
(2016/04/10)
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- METHOD FOR PRODUCING (-)-1-(3-HYDROXYPROPYL)-5-[[(2R)-2-({2-[2-(2,2,2-TRIFLUORO ETHOXY)PHENOXY]ETHYL}AMINO)PROPYL]-2,3-DIHYDRO-1H-INDOLE-7-CARBOXAMIDE])
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PROBLEM TO BE SOLVED: To provide a method for efficiently producing a high purity (-)-1-(3-hydroxypropyl)-5-[[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide]) in which the amount of a certain impurity is reduced. SOLUTION: The method includes hydrolyzing 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile in water-soluble organic solvent, water, or a mixture of water-soluble organic solvent and water, under the presence of alkali, using an oxidizer, at reaction temperature of 15°C or less. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0044
(2017/03/24)
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- Synthesis of Silodosin by Copper-Catalysed C-C Arylation
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The synthesis of silodosin, an antidysuria drug, has been accomplished starting from commercially available indoline. The synthetic strategy is based on CuI-catalysed C-C arylation, regioselective cyanation, and diastereoselective reductive amination. The enantiopure compound was obtained by selective crystallisation of a diasteroisomeric mixture.
- Calogero, Francesco,Allegrini, Pietro,Attolino, Emanuele,Passarella, Daniele
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p. 6011 - 6016
(2015/09/22)
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- NOVEL INTERMEDIATE USED FOR THE PREPARATION OF SILODOSIN, METHOD FOR PREPARING SAME, AND METHOD FOR PREPARING SILODOSIN USING SAME
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The present invention relates to a 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoro-ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate 2-oxoglutaric acid salt of chemical formula 5b as a novel intermediate used in preparation of silodosin, a method for preparing the same, and a method for preparing silodosin using the same. The intermediate has excellent filterability of crystals. A process for preparing silodosin uses the intermediate, so that the reaction time is short, and the amount of an unreacted starting material and a dialkylated byproduct is low. Therefore, the novel intermediate according to the present invention can be useful for preparing of silodosin which is a treating agent for prostatism.COPYRIGHT KIPO 2015
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- METHOD OF PREPARING ADRENERGIC ANTAGONIST
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PROBLEM TO BE SOLVED: To provide a method of preparing a selective adrenergic antagonist for an α-1A-adrenergic receptor and a useful intermediate thereof. SOLUTION: This invention provides an advantageous production method of a novel intermediate particularly fitted for production on an industrial scale, regarding the production of a pharmaceutical compound represented by formula (I), silodosin: 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino) propyl]indoline-7-carboxamide, or salt thereof. COPYRIGHT: (C)2015,JPOandINPIT
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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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- First asymmetric synthesis of Silodosin through catalytic hydrogenation by using Ir-SIPHOX catalysts
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An asymmetric synthesis of Silodosin was accomplished in high yield via catalytic hydrogenation of α,β-unsaturated carboxylic acid derivatives by using chiral catalyst Ir-SIPHOX, followed by Curtius rearrangement. Copyright
- Yan, Pu-Cha,Zhang, Xian-Yi,Hu, Xiao-Wei,Zhang, Bin,Zhang, Xiang-Dong,Zhao, Michael,Che, Da-Qing,Li, Yuan-Qiang,Zhou, Qi-Lin
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p. 1449 - 1451
(2013/04/10)
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- PROCESS FOR THE PREPARATION OF SILODOSIN
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The invention relates to a process for preparing silodosin. The invention relates to the preparation of substantially pure silodosin. The invention also relates to silodosin solid particles, wherein 90 volume-percent of the particles (D90) are less than 10 microns and a process for achieving the particle size (D90) less than 10 microns. The invention also relates to pharmaceutical compositions of silodosin comprising 90 volume-percent of the particles (D90) less than 10 microns.
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Page/Page column 11; 12
(2013/06/05)
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- Enantioselective synthesis of (-)-(R) Silodosin by ultrasound-assisted diastereomeric crystallization
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Enantioselective synthesis of clinically approved drug - Silodosin for the treatment of benign prostatic hyperplasia from the commercially available compounds 1-acetyl-5-(2-aminopropyl) indoline-7-carbonitrile A and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate C is explored. Key step in the synthesis is chiral resolution of intermediate 1, which was achieved by a simple diastereomeric crystallization using (S)-(+)-mandelic acid assisted by ultrasonication. The present synthetic strategy has lesser number of steps and is vastly improved the overall yield in this short route towards target compound - Silodosin.
- Barve, Indrajeet J.,Chen, Li-Hsun,Wei, Patrick C.P.,Hung, Jui-Te,Sun, Chung-Ming
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p. 2834 - 2843
(2013/04/10)
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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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- 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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- A METHOD OF MANUFACTURING (-)-L-(3-HYDROXYPROPYL)-5-[(2R)-2-({2,2,2-TRIFLUOROETHOXY)- PHENOXYETHYL}AMINO)PROPYL]-2,3-DIHYDRO-LH-INDOLE-7-CARBOXAMIDE
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A method of manufacturing optically pure or optically enriched silodosin of formula I and of its pharmaceutically acceptable salts, in which a secondary amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, (a) is N-alkylated with an alkylating agent of general formula III, wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS020 or an arene SLilfonyloxyl group ArS020, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group; (b) the obtained tertiary amine of general formula IV, wherein Bn is as defined above, is hydrogenolyzed with hydrogen on a metal catalyst; (c) and the resulting nitrile of formula V, wherein Bn is as defined above, is hydrolyzed by treatment with alkaline agents; and optionally, (d) additional O-debenzylation of the amide-ether of general formula VI, wherein Bn is as defined above, with dealkylating agents is carried out; and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.
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- PROCESS FOR THE PREPARATION OF SILODOSIN AND ITS NOVEL INTERMEDIATES
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The present invention relates to novel intermediates of silodosin and a process for their preparation. The present invention further relates to a process for the preparation of silodosin using the novel intermediates.
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Page/Page column 58
(2012/02/13)
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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 13
(2010/11/08)
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