cas 239463-72-0, 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-carbonitrile-1H-indole

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5-substituted indoline derivative or salt thereof, preparation method and application of 5-substituted indoline derivative or salt thereof, and preparation method of silodosin
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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(2022/04/06)

Preparation method of silodosin
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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(2020/10/21)

Improved Preparation of Silodosin
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Liu, Hui,Lv, Fei,Liu, Yuan
p. 287 - 293
(2019/05/17)

Preparation method of silodosin intermediate
The invention discloses a preparation method of a silodosin intermediate. The preparation method includes: allowing 5-bromoindoline solution and triethylamine to be in alkylation reaction to obtain asubstance A; allowing a solution of the substance A, ethyl acetoacetate, catalyst and acid-binding agent to be in substitution reaction to obtain a substance B; allowing a solution of the substance Band Lewis acid to be in decarboxylic reaction to obtain a substance C; allowing a solution of the substance C, R-tert butyl sulfonamide, catalyst and reducer to be in amination reaction to obtain a substance D; allowing a solution of the substance D and N-bromosuccinimide solution to be in bromination reaction to obtain a substance E; allowing a solution of the substance E and cuprous cyanide to be in cyanation reaction to obtain a substance F; allowing a solution of the substance F and acid to be in acidolysis reaction to obtain a substance G; preparing the substance G into tartrate to obtainthe silodosin intermediate. The preparation method is simple, high in yield, low in energy consumption and environment-friendly; the silodosin intermediate prepared by the method is high in quality and suitable for large-scale industrial production.
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Paragraph 0102; 0112; 0119; 0122; 0129; 0141; 0148

(2019/04/17)

Improved synthetic method of (R)-1-aryl-2-propylamine
The invention provides an improved synthetic method of (R)-1-aryl-2-propylamine. The improved synthetic method comprises the following steps of: adopting 1-arylacetone as a raw material, adding (R)-1-phenylethylamine, carrying out reductive amination reaction with hydrogen under a common action of a Lewis acid additive and a transitional metal hydrogenation catalyst; carrying out Pd/C catalytic hydrogenation on an obtained intermediate to remove phenethyl on nitrogen and thus obtaining (R)-1-aryl-2-propylamine. The improved synthetic method provided by the invention has the beneficial effectsthat the operation is simple, the adopted Lewis acid additive is low in cost and easy in obtaining, the yield and the enantioselectivity of a product are high, and the application value for industrialsynthesis of (R)-1-aryl-2-propylamine is very high.
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Paragraph 0026; 0028; 0030; 0032; 0034; 0039; 0040; 0041

(2018/07/30)

Preparation method of indoline derivative for synthesizing silodosin
The invention provides a preparation method of an indoline derivative for synthesizing silodosin. Indoline is taken as a starting raw material and reacts with benzoic acid and 1-chloro-3-bromopropane to prepare a compound (1); a reaction is carried out in a Vilsmeier agent, and a formyl group in introduced to the 5th position to prepare a compound (2); the compound (2) and nitroethane undergoes an asymmetric Henry reaction in the catalysis of quinidine-copper acetate to prepare a compound (3); the compound (3) is subjected to acetylation through acetic anhydride to prepare a compound (4); a cyano group is introduced to the 7th position to prepare a compound (6); and two functional groups are reduced through palladium-on-carbon hydrogenation in one step to obtain a high-chiral-purity target compound: (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)-7-cyano]indoline. In the early stage of the method, cheap quinidine is used to perform an asymmetric Henry reaction for introduction of chiral centers, thereby avoiding resolution in the latter stage. The method is reasonable in design, simple to operate, effectively improved in yield and reduced in cost, and therefore is suitable for massive production.
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(2017/03/08)

Preparation method of intermediate for synthesis of silodosin
The invention provides a preparation method of an intermediate for synthesis of silodosin. The preparation method comprises that indoline as a starting material, benzoic acid and 1-chloro-3-bromopropane undergo a reaction so that a benzoyloxypropyl group is introduced to the 1th site of indoline and a compound I is obtained, the compound I and L-lactic acid undergo a reaction to produce a compound II, the compound II undergoes a Friedel-Crafts acylation reaction so that a chiral center is introduced and a compound III is obtained, a compound V is prepared through carbonyl reduction and inversion of configuration, a cyano group is introduced into the 7th site of the compound V so that a compound VII is obtained, and the nitro group is reduced so that a desired compound with high chiral purity is obtained and is (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)-7-cyano]indoline. The preparation method introduces a chiral center through cheap lactic acid in the early stage of the route, prevents the later resolution, has a reasonable design, can be operated simply, effectively improves a yield, reduces a cost and is suitable for large-scale production.
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(2017/05/11)

A process for preparing the silodosin intermediates
The invention discloses a preparation method of a silodosin intermediate, wherein the structure of the silodosin intermediate is represented as the formula A. The preparation method, wherein indoline is employed as a start raw material, includes the reactions of Friedel-Crafts acylation, carbonyl reduction, Gabriel reaction and chiral resolution and the like. The preparation method is simple in operation, is low in cost, is high in yield, allows the product to purify easily and is stable in processes, and is suitable for industrial production. The invention also discloses a new intermediate compound which is related in the method.
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(2017/11/16)

Method for preparing silodosin
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 0044-0049; 0079-0084; 0114-0119; 0149-0154

(2017/09/01)

Synthesis of silodosin glucuronide and its deuterated counterpart: Solving a problematic O-glycosylation of a nitrogen-containing molecule
We report here the first chemical synthesis of silodosin glucuronide, a metabolite of the α1A-adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O-glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated d-glucuronosyl N-phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.
Zhou, Jun,Liu, Yunpeng,Zhu, Hailiang,Zhu, He,Wang, Peng George
p. 187 - 195
(2017/07/22)

THE PROCESS OF PREPARING INDOLINE COMPOUNDS AND A NOVEL INDOLINE SALT
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)

Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists
A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α1A-adrenergic receptor (α1A-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α1A-AR antagonists, compounds (R)-14r (IC50 = 2.7 nM, α1B/α1A = 640.1, α1D/α1A = 408.2) and (R)-23l (IC50 = 1.9 nM, α1B/α1A = 1506, α1D/α1A = 249.6), which exhibited similar activities and better selectivities in cell-based calcium assays as compared with the marketed drug silodosin (IC50 = 1.9 nM, α1B/α1A = 285.9, α1D/α1A = 14.4), were identified. In the functional assays with isolated rat tissues, compounds (R)-14r and (R)-23l also showed high potency and uroselectivity. Most importantly, (R)-14r and (R)-23l can significantly decrease the micturition frequency and increase the mean voided volume of the BPH rats in a dose-dependent manner, making them worthy of further investigation for the development of anti-BPH agents.
Zhao, Fei,Li, Jing,Chen, Ying,Tian, Yanxin,Wu, Chenglin,Xie, Yanan,Zhou, Yu,Wang, Jiang,Xie, Xin,Liu, Hong
p. 3826 - 3839
(2016/05/24)

Method for preparing silodosin midbody
The invention discloses a method for preparing a silodosin midbody. The silodosin midbody is the compound shown in the formula (1) and prepared with indoline derivative and R-alanine derivative which are easy to obtain as starting materials through Friedel-Crafts acylation reaction, reduction reaction, formylation reaction, oximation reaction, dehydration reaction, hydrolysis reaction and salt forming reaction. The compound is used for preparing silodosin. Silodosin is used for treating urination disorder related to benign prostatic hyperplasia. The method has the advantages that raw materials are cheap and easy to obtain, operation is easy, yield is high, production cost is reduced, and the method is suitable for large-scale industrial production.
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(2016/10/10)

A method for synthesizing silodosin
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 0036; 0060-0061

(2016/12/12)

INDOLINE DERIVATIVES AND METHOD OF PREPARING THE SAME
The present invention relates to a new indoline derivative usable as a synthetic intermediate of silodosin used in a medicine for dysuresia accompanied with prostatomegaly, and a preparing method thereof. The preparing method according to the present invention using chemical formula (I) and chemical formula (II) can optically synthesize a pure indoline derivative, which is the synthetic intermedia of the silodosin, under a warm reaction condition. R and P in the chemical formula (I) and chemical formula (II) are the same as defined in the detailed specification.COPYRIGHT KIPO 2015
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(2016/10/20)

N-HALOALKYLINDOLINE INTERMEDIATES, THEIR PROCESS AND USE IN PREPARATION OF SILODOSIN AND ITS DERIVATIVES
The present invention provides novel indoline compounds, derivatives of Formula 1 and salts thereof; which can be eftectively used for the preparation of a 1 -adrenoceptor antagonists, Silodosin and its pharmaceutically acceptable salts.
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(2014/10/29)

Enzymatic asymmetric synthesis of the silodosin amine intermediate
Various enantiocomplementary ω-transaminases (ωTAs) were investigated in kinetic resolution and asymmetric reductive amination reactions to prepare silodosin amine. Whilst the enzymatic kinetic resolution gave moderate to good results with respect to the yield and enantioselectivity, the asymmetric reductive amination proved to be superior. The best results were obtained with the ωTA originating from (R)-Arthrobacter sp. which afforded the desired bioactive (R)-enantiomer in enantiomerically pure form (ee >97%) at excellent conversion (conv. >97%) under mild and benign reaction conditions.
Simon, Robert C.,Sattler, Johann H.,Farnberger, Judith E.,Fuchs, Christine S.,Richter, Nina,Zepeck, Ferdinand,Kroutil, Wolfgang
p. 284 - 288
(2014/03/21)

METHOD FOR PREPARING SILODOSIN
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)

PROCESS FOR PREPARING AN INTERMEDIATE FOR SILODOSIN
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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(2011/10/31)

Indole derivatives and medicinal compositions containing the same
The present invention relates to indole derivatives represented by the general formula: (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group; and the carbon atom marked with (R) represents a carbon atom in (R) configuration) and pharmaceutically acceptable salts thereof, which have potent and prolonged reducing effects on intraocular pressure and are useful as agents for lowering intraocular pressure.
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(2008/06/13)