160970-54-7

Basic information

• Product Name: Silodosin
• Synonyms: Silodosin-d4;Silodoxin;1H-Indole-7-carboxaMide,2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]aMino]propyl]-;1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aMino)propyl]indoline-7-carboxaMide;(–)-1-(3-Hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-di-hydro-1H-indole-7-carboxamide;Silodosin;KAD 3213;KMD 3213
• CAS NO: 160970-54-7
• Molecular Formula: C₂₅H₃₂F₃N₃O₄
• Molecular Weight: 495.53
• EINECS: 1308068-626-2
• Product Categories: KAD 3213, KMD 3213;Other APIs;Amines;Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 160970-54-7.mol

Chemical Properties

• Boiling Point: 601.4 °C at 760 mmHg
• Flash Point: 317.5 °C
• Appearance: /
• Density: 1.249 g/cm³
• Vapor Pressure: 2.58E-15mmHg at 25°C
• Refractive Index: 1.552
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: Aqueous Base (Slightly, Heated Sonicated), DMSO (Slightly, Sonicated), Methanol
• PKA: 14.85±0.10(Predicted)
• CAS DataBase Reference: Silodosin(CAS DataBase Reference)
• NIST Chemistry Reference: Silodosin(160970-54-7)
• EPA Substance Registry System: Silodosin(160970-54-7)

Safety Data

• Hazardous Substances Data: 160970-54-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Silodosin is used as a treatment for benign prostatic hyperplasia (BPH) due to its selective action on α1A adrenoceptors, which are primarily located in the prostate and bladder neck. This selective action leads to improved urinary flow rates and reduced symptoms associated with BPH.
Silodosin is used as an α1A-adrenoceptor antagonist for the treatment of benign prostatic hypertrophy, as it helps in the relaxation of smooth muscle in the bladder neck and prostate, improving symptoms and urinary flow rates.
Silodosin is used as a highly selective inhibitor of the α1A adrenergic receptor, which results in minimal orthostatic hypotension compared to other α1 blockers. This selective inhibition is beneficial for patients with BPH, as it reduces the risk of blood pressure-related side effects.

Treatment of prostatic hyperplasia

Silodosin is a kind of α-adrenergic receptor antagonists developed by Japanese Kissei pharmaceutical company. It has a very good therapeutic efficacy on treating the dysuria related to benign prostatic hyperplasia. The selective effect on urethra of Silodosin is 12 times and 7.4 times as high as that of prazosin and tamsulosin, respectively, which can significantly inhibit norepinephrine-induced contraction of the prostate; it has dose-dependent inhibition bladder activity excitation in the benign prostatic hypertrophy models of rats, and can also improve the pressure threshold of bladder contraction. These data have suggested that, in addition to helping improve bladder function, silodosin is also effective in alleviating the related symptoms associated with benign prostatic hypertrophy. Compared with similar drugs such as prazosin and tamsulosin, silodosin has a high selectivity onn theα1A-receptors located in the prostate and bladder neck, while having a low affinity to theα1B-and α1D-receptor. It can block theα1A-receptors in these sites, and relax the smooth muscle, and thus leading to the improvement of urinary flow rate and the alleviation of BPH symptoms. The selective binding to the α1A-receptor by silodosin has a higher selectivity compared to the binding to the cardiovascular associated receptors α1B, thus maximizing the activity of the target organ as well as minimizing the potential effect on blood pressure.The above information is edited by the lookchem of Dai Xiongfeng.

Benign prostatic hyperplasia

Benign prostatic hyperplasia (referred as BPH) is one of the most common diseases in older male with the non-malignant prostate being the character. It can cause the obstructive urination symptoms and other irritation symptoms which have brought significant negative impact on the life of older people. In recent years, with the increasing level of industrialization of China, the annual intake of animal protein intake gradually increased and life expectancy increases, the incidence of benign prostatic hyperplasia also has increased year by year. Over 50 percent in elderly people at age 60 or above has got this disease. This ratio increases to over 90% for elderly people over 85 years-old. Its triggering factor has not been totally elucidated. It is generally believed that this is related to the secretion of sex hormones and cholesterol as well as other kinds of metabolic disorders. Some people think that, for elder people, their weakened pituitary-gonadotropin-pathway or endogenous change cause degeneration of testicles decreased sexual function, reduced testosterone value, as well as the change of glandular epithelium and enlarged prostate caused by the increased connected tissue of prostate. The enlargement of prostate will compress the urethra, resulting in poor urine flow of bladder and even blocked bladder outlet. There is α1A-adrenergic receptor located in the human prostate. The activation of the receptor will deteriorate the symptoms of dysuria and urethral obstruction. Therefore, by blocking the binding α1A-adrenergic receptor, we can relax the obstructed prostate smooth muscle relaxation, and thereby alleviating the symptoms. In recent years, people has achieved excellent efficacy by clinically applying 5α-reductase inhibitors and α1-adrenergic receptors (α1-AR) blocker (silodosin). This is considered as a major breakthrough in drug treatment of benign prostatic hyperplasia.

Synthesis

The synthesis of silodosin has been disclosed in several patents. The latest synthetic route disclosed in the 2006 patent is highlighted in the scheme. The synthesis started with Grignard generation from readily available bromoindoline 65 by treating it with Mg in the presence of a catalytic dibromoethane in THF. After initiation of the reaction with some heat and refluxing at a steady rate, CBZ protected oxazolidinone 66 [39b] was added over 1 h, refluxed for 4 h and then stirred at room temperature for 2 days. The reaction was quenched with 6 M aqueous HCl and stirred for 12 h after which time the reaction was worked up to provide product 67 in 53% yield. Ketone 67 was then treated with triethylsilane in TFA at 0oC and stirred at room temperature for 10 h to provide amine 68 in 61% yield. Bromination of the indoline 68 with bromine in warm acetic acid furnished bromide 69 in 53% yield which was reacted with copper cyanide in DMF at 130oC to give the cyano indoline 70 in 82% yield. Selective deprotection of the benzyloxycarbonyl over the benzyl group was accomplished by reacting indoline 70 with 1 atm hydrogen in the presence of 5% Pd/C in ethanol at room temperature. The resulting free amine 71 was then reacted with mesylate 72 in t-butanol with sodium carbonate as base at 80-90oC for 46 h to provide 73 in 67% yield. Removal of the benzyl ether was accomplished by reacting 73 with 1 atm hydrogen in the presence of 10%Pd/C to give alcohol 74, which upon hydrolysis provided the desired silodosin (X). No yield for the final reaction was given.

InChI:InChI=1/C25H32F3N3O4/c1-17(30-8-12-34-21-5-2-3-6-22(21)35-16-25(26,27)28)13-18-14-19-7-10-31(9-4-11-32)23(19)20(15-18)24(29)33/h2-3,5-6,14-15,17,30,32H,4,7-13,16H2,1H3,(H2,29,33)/t17-/m1/s1

Upstream product

• 120-80-9 benzene-1,2-diol 
• 239463-72-0 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile 
• 1269801-73-1 [2-(2,2,2-trifluoroethoxy)phenoxy]acetaldehyde 
• 106854-74-4 2-methoxy-1-(2,2,2-trifluoroethoxy)benzene 
• 160968-99-0 2-O-(2,2,2-trifluoroethyl)catechol 
• 160969-02-8 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol 
• 1269801-74-2 2-[2-(2,2,2-trifluoroethoxy)phenoxy-ethyl]-[1,3]dioxalane 
• 175837-01-1 1-acetyl-5-(2-aminopropyl)-2,3-dihydro-1H-indole-7-carbonitrile 
• 175837-07-7 1-acetyl-5-(2-((2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile 
• 161024-53-9 (R)-(-)-1-acetyl-5-(2-((2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile 
• 160969-20-0 tert-butyl [(2R)-1-(7-cyanoindolin-5-yl)propan-2-yl]-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate 
• 160969-12-0 (R)-tert-butyl(1-(1-acetyl-7-cyanoindolin-5-yl)propan-2-yl)(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate 
• 900518-67-4 C₂₉H₃₃BrN₂O₃ 
• 1394258-01-5 C₂₂H₂₆BrNO₃ 

Downstream Products

• 160970-07-0 (R)-tert-butyl 1-(7-carbamoyl-1-(3-hydroxypropyl)indolin-5-yl)propan-2-yl(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate 

Relevant articles and documents

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.

THE MANUFACTURING METHOD OF INTERMEDIATE FOR SYNTHESIS OF SILODOSIN AND THE MANUFACTURING METHOD OF SILODOSIN

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)

NOVEL SULFONAMIDE INTERMEDIATE AND METHOD FOR PRODUCING SILODOSIN BY USING THE SAME

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

MALEIC ACID SALT OF A SILODOSIN INTERMEDIATE

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.

PROCESS FOR THE PREPARATION OF INDOLINE COMPOUND

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.

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.

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.

A silodosin intermediate and its preparation method, and the intermediate for method of preparation of the silodosin

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.

A method for preparing intermediate silodosin into salt

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.