- Preparation method of mirabegron key intermediate
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The invention provides a preparation method of a mirabegron key intermediate, namely, a compound as shown in a formula (III). The method is simple, convenient and safe to operate, free of harsh reaction conditions, high in reaction purity and yield and low in process cost which is about 40% of that of a process using a metal catalyst such as palladium carbon, is suitable for large-scale production and conforms to the green chemistry principle. A finished product of mirabegron continues to be prepared by using the intermediate compound as shown in the formula (III) prepared by the method so as to meet the existing requirements.
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Paragraph 0049-0051
(2022/01/12)
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- A new process for the preparation of (R)-2-((4-Aminophenethyl)amino)-1-phenylethanol
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The present invention relates to a process for the preparation (R)-2 - ((4-aminophenethyl) amino) -1 - phenylethanol, which is an intermediate of mirabberone intermediate. A manufacturing method of a high purity and high yield amide derivative is provided to produce an amide derivative having high purity and high yield without using a specific purification process by using a zinc powder reduction catalyst.
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Paragraph 0070-0072
(2021/07/01)
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- Preparation method of mirabegron (by machine translation)
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The method is convenient to operate, controllable in reaction process, high in 2 - final product purity,4 - high in yield and suitable for industrial production, so that a more valuable synthesis route is provided for preparing mirabead, good social benefits and economic benefits can be brought, and the economic value potential is great. (by machine translation)
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- Mirabegron impurity compound, and preparation method and application thereof
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The invention discloses a mirabegron impurity compound, and a preparation method and application thereof. The mirabegron impurity compound disclosed by the invention is relatively high in purity and can be used as a reference substance for effectively identifying impurities generated in mirabegron synthesis, so that the drug quality of mirabegron is controlled.
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Paragraph 0143-0145
(2020/09/23)
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- Preparation method of mirabegron
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The invention discloses a preparation method of mirabegron, and the method comprises: S1, carrying out reduction reaction on p-nitrophenylacetonitrile to obtain p-nitrophenylacetaldehyde; S2, carryingout condensation reduction on the p-nitrophenylacetaldehyde and (R) 2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol; S3, carrying out reduction on the (R)2-amino-1-phenethyl alcohol to obtain (R) 2-(4-nitrophenethyl) amino)-1-phenyl ethyl alcohol to obtain an intermediate (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol; and S4, carrying outcondensation on the (R) 2-((4-aminophenyl ethyl) amino)-1-phenyl ethyl alcohol and aminothiazole acetic acid to obtain the mirabegron. According to the method, the starting raw materials are cheap and easy to obtain, the reaction conditions are controllable, the synthetic route steps are few, the yield is high, the cost is low, and the prepared mirabegron is high in purity.
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- Salts of amide derivatives and method for preparing the same
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In the present invention, a cyclised amino acid is disclosed as an aliphatic or aromatic disulfonate or lactam structure, which is a salt of an amide derivative represented by chemical formula 1. The salt of the amide derivative does not absorb moisture, and is stable and has excellent solubility in water. In chemical formula 1, the B ring is a substituted or unsubstituted heteroaryl group, X is a bond, hydroxy, lower alkylene, lower alkenylene, carbonyl or -NH-, and A is lower alkylene or -lower alkylene-O-.COPYRIGHT KIPO 2019
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- Method for preparing amide derivatives
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Disclosed in the present specification is a method for producing amide derivatives of chemical formula 1. The method comprises the steps of: conducting a reaction of chemical formula 2 and chemical formula 3; and reacting chemical formula 4 with a compound produced by the reaction. By using the method disclosed in the present specification, it is possible to exclude a hydrogenation reaction which is limited by high production cost and low production yield in on-site production.COPYRIGHT KIPO 2018
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- Synthetic method of the compound
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A synthesis method of a compound shown as a formula 1 is provided. The method includes (1) bringing a compound shown as a formula 2 into contact with compound shown as a formula 3 to produce a compound shown as a formula 4; (2) subjecting nitro of the compound shown as the formula 4 to a reduction reaction to produce a compound shown as a formula 5; and (3) bringing the compound shown as the formula 5 into contact with a compound shown as a formula 6 to produce the compound shown as the formula 1. The method is short in route. Initial raw materials are cheap and easily available. All the intermediates are easy to purify and simple in after-treatment. The product is high in purity and high in yield. The method benefits industrial production.
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Paragraph 0055; 0056; 0057; 0058; 0059; 0060; 0061-0066
(2017/06/02)
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- Study on a New Method for Synthesis of Mirabegron
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Mirabegron is a muscle relaxing drug for the treatment of overactive bladder. The existing synthetic methods for mirabegron produced intermediate product 4-(2-(phenethylamino)ethyl)aniline, which complicated the final product purification process. In this study, we designed a new synthetic route for mirabegron with low cost starting materials and a production of mirabegron at a 99.6% purity and a 61% overall yield. Particularly, this new synthetic route did not produce side product 4-(2-(phenethylamino)ethyl)aniline, which significantly simplified the product purification process.
- Xu, Guiqing,Mao, Shen,Mao, Longfei,Jiang, Yuqin,Zhou, Yong,Shen, Jiaxuan,Dong, Wenpei
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p. 2703 - 2707
(2017/09/26)
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- A phenyl acetyl amine compounds and in the application of the preparation [...] takanaka
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The invention discloses a new intermediate (R)-N-(4-amino phenethyl)-2-hydroxy-2-acetylaniline for preparing mirabegron, and a method for preparing the mirabegron through the intermediate. The method is simple and convenient to operate, has low cost, and is applicable to industrial production.
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Paragraph 0039; 0040-0043; 0052; 0051-0057; 0065; 0066-0070
(2017/07/01)
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- First Direct Isolation of Stable α-Form Crystals of Mirabegron, a Selective β3-Adrenoceptor Agonist
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An efficient and scalable method for the direct isolation of stable α-form crystals of Mirabegron (1) is developed. The developed method negates transformation of metastable β-form crystals into α-form crystals thereby overcoming the limitations of reported methods and avoids additional processing steps during its manufacture. The developed method directly provides stable α-form crystals of Mirabegron (1) with yield of around 84% and purity of >99.77% by HPLC in a single step.
- Deshmukh, Dattatray G.,Bangal, Mukund N.,Mali, Anil C.,Medhane, Vijay J.,Mathad, Vijayavitthal T.
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p. 461 - 466
(2017/06/23)
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- Preparation and application of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol
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The invention provides an intermediate, (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol, of mirabegron, and a synthetic method and application of the intermediate, and belongs to the technical field of pharmaceutical synthesis. The structural formula of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol is shown in the description. A synthetic step comprises: reducing (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethyl alcohol monohydrochloride (I) into (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol (II) in the presence of an alcohol solvent through taking Pd/C as a catalyst and using a phase-transfer reagent. The synthetic method is mild in reaction condition and simple to operate. What's more, an organic compound instead of hydrogen is taken as a hydrogen donor during reaction, thereby overcoming technique, equipment, and safety problems due to usage of hydrogen. The synthetic method is extremely beneficial for industrial production.
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Paragraph 0024; 0025; 0026
(2016/10/10)
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- SOLID FORMS OF MIRABEGRON
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Solid forms of Mirabegron, including forms APO-I, APO-II, and various salt forms, and processes for the preparation thereof, are provided.
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Page/Page column 27
(2016/04/26)
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- A PROCESS FOR THE PREPARATION OF MIRABEGRON AND ITS INTERMEDIATES
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The present invention relates to a novel process for preparation of Mirabegron of Formula (I) using intermediates of Formula (II), (IIIa), (Illb) and (IV).
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Page/Page column 33; 33-34
(2016/02/29)
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- PROCESS FOR PREPARATION OF POLYMORPHIC FORM OF MIRABEGRON
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The present invention is directed to process for preparation of α-form crystal of Mirabegron, (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) acetamide of formula (1).
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Page/Page column 8
(2016/09/22)
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- NOVEL PROCESS FOR PREPARATION OF MIRABEGRON AND IT'S INTERMEDIATE
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The present invention related to a novel process for preparation of Mirabegron of formula (I) and its intermediate. I
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- CRYSTALLINE FORMS OF AN ADRENERGIC AGONIST
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The present invention relates to the acetate salt of Mirabegron, in particular in two novel crystalline forms, a process for their preparation and the use of said salt and its crystalline forms in the synthesis of Mirabegron with high yields and chemical purity.
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Paragraph 0078-0079
(2015/04/28)
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- A PROCESS FOR PREPARATION OF MIRABEGRON AND ALPHA CRYSTALLINE FORM THEREOF
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An improved process for the preparation of Mirabegron of formula (I) where 4- nitrophenylethylamine of formula (III) or its acid addition salt of formula (IlIa) reacted with compound of formula (XII) in a solvent, optionally in presence of base and/or catalyst to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) followed by reducing (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula (XIII) in a solvent to obtain (R)-2-[2'-(4-nitrophenyl)ethyl]amino]-l-phenylethanol of formula (XIV), optionally converting it into its acid addition salt of formula (XlVa); reducing (R)-2-[2'-(4- nitrophenyl)ethyl]amino]-l -phenylethanol of formula (XIV) or its acid addition salt of formula (XlVa) further in solvent to obtain (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l -phenylethanol of formula (XV) or its acid addition salt of formula (XVa) respectively; and reacting compound (R)- 2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol of formula (XV) or its acid addition salt of compound of formula (XVa) with compound of formula (VII) in solvent, optionally in the presence of acid, and/or a catalyst to obtain Mirabegron of formula (I) which is further isolated as its a- crystalline form. The compound of formula (XIV) used in the foregoing process can also be prepared by reacting with a compound of formula (III) or acid addition salt of compound of formula (IlIa) in presence of a solvent, a catalyst and optionally in presence of a base to obtain compound of formula (XIV) optionally converting it into its acid addition salt of formula (XlVa); and the same is used in the above-referred process. The compound of formula (XV) used in the foregoing process can also be prepared by reacting a compound of formula (III) or its acid addition salt of formula (IlIa) with a compound of formula (XVI) in a solvent, optionally in presence of a base, optionally in presence of a catalyst to obtain compound of formula (XVII); and optionally isolate the compound of formula (XVII) followed by reducing the compound of formula (XVII) using reducing agent, in a solvent, optionally in presence of a base, optionally in presence of a catalyst to obtain compound of formula (XV) which is further used in the above- referred process for the preparation of Mirabegron of formula (I) and its a-crystalline form. Another additional single-pot process for preparation of Mirabegron of formula (I) is disclosed, wherein compound of formula (XV) or its acid addition salt of formula (XVa) reacted with compound of formula (XVIII) in presence of a solvent and oxidizing agent, optionally in presence of base, optionally in presence of a catalyst to obtain Mirabegron of formula (I).
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Page/Page column 34; 36
(2015/04/15)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF 2-(2-AMINOTHIAZOL-4-YL)-N-[4-(2-[[(2R)-2-HYDROXY-2- PHENYLETHYL]AMINO]-ETHYL)PHENYL]ACETAMIDE
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The present invention relates to an improved process for the preparation of pure 2-(2- amino-1,3-thiazol-4-yl)-N-[4-(2-[(2R)-2-hydroxy-2-phenylethyl]amino]ethylphenyl]- acetamide of formula (1) substantially free of impurities. The present invention relates to the novel process of preparing intermediate (R)-1- Phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol hydrochloride of formula (2) in high yield, which is useful in the preparation of mirabegron of formula (1). The process also relates to the preparation of pure α –form crystal of 2-(2-Amino- 1,3-thiazol-4-yl)-N-[4-(2-[(2R)-2-hydroxy-2-phenylethyl]amino]ethylphenyl]acetamide Mirabegron (1) without isolation of β-form.
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Page/Page column 20; 21
(2015/11/17)
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- PROCESS FOR THE PREPARATION OF 2-(2-AMINOTHIAZOL-4-YL)-N-[4-(2-{[(2R)-2-HYDROXY-2-PHENYL ETHYL]AMINO}ETHYL)PHENYL]ACETAMIDE MONOHYDROCHLORIDE, ITS INTERMEDIATES AND POLYMORPH THEREOF
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The present invention relates to a process for the preparation of 2-(2-aminothiazol-4-yl)- N-[4-(2- {[(2R)-2-hydroxy-2-phenylethyl]amino} ethyl)phenyl]acetamide monohydrochloride compound of formula- la, its intermediates and polymorph thereof. [Formula should be inserted here]
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Page/Page column 25
(2014/09/16)
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- BENZYLAMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AND USE THEREOF FOR MEDICAL PURPOSES
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The benzylamine derivative represented by the formula below and a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical containing the derivative or the pharmaceutically acceptable acid addition salt thereof, and a therapeutic or prophylactic agent for pollakiuria or urinary incontinence containing the derivative or the pharmaceutically acceptable acid addition salt thereof are provided. The benzylamine derivative of the present invention and the pharmaceutically acceptable acid addition salt thereof have less possibility of occurrence of side effects than known compounds, and show a better therapeutic effect against pollakiuria or urinary incontinence, so that they can be used as excellent therapeutic or prophylactic agents for pollakiuria or urinary incontinence.
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Page/Page column 12
(2009/12/05)
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- REMEDY FOR OVERACTIVE BLADDER COMPRISING ACETIC ACID ANILIDE DERIVATIVE AS THE ACTIVE INGREDIENT
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(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or its salt shows a potent bladder relaxation effect in "isolated rat bladder smooth muscle relaxation test", dose-dependently lowers the contraction frequency of rhythmic bladder contractions in "rat rhythmic bladder contraction measurement test" and, moreover, prolongs the urination intervals in "urination functions measurement test on cyclophosphamide-induced overactive bladder model rat". Owing to these effects, the above compound is useful as a remedy for ovaractive bladder.
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Page/Page column 6
(2008/06/13)
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- ALPHA-FORM OR BETA-FORM CRYSTAL OF ACETANILIDE DERIVATIVE
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To provide novel crystals useful as an ingredient for the production of a diabetes remedy. The invention is concerned with α-form crystal and β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. The α-form crystal does not exhibit hygroscopicity and has stability such that it can be used as a medicine, and is useful for mass synthesis in the industrial production. The β-form crystal does not relatively exhibit hygroscopicity and is also useful as a production intermediate of the α-form crystal.
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