- Concise Synthesis of Key Intermediate of Mirabegron via a Mixed Anhydride Method
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An efficiently scalable synthesis of key intermediate toward mirabegron has been developed via a mixed anhydride method, employing PivCl instead of EDCI and HOBt. The developed process produced (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (10) in 91.5-92.3% yield and >99.0% HPLC purity under mild conditions. During this process, a side reaction induced by triethylamine hydrochloride was discovered and investigated, which was ultimately avoided by executing the reaction in a biphasic solvent system.
- Zhang, Qi-Long,Zhuang, Zhi-Yuan,Liu, Qing-Dong,Zhang, Zhan-Ming,Zhan, Fu-Xu,Zheng, Geng-Xiu
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- Systematic Investigation into the Formation of Significant Amounts of Unknown Impurity during Scale-up of NaBH4-I2 Mediated Reduction of Nitro-Amide Intermediate of Mirabegron No.
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After successful development of a manufacturing process for the Mirabegron (1) at the laboratory scale, a muddled situation was aroused during the scale-up batches, wherein sodium borohydride-iodine (NaBH4-I2) mediated reduction of nitro-amide 4 ended up with substantial amounts (~10%) of unspecified impurity in the nitro-amine intermediate 5. On the basis of the structure elucidation and meticulous investigation, a reaction path for its genesis during the process was identified and an efficient mechanism proposed to arrest its formation. In-situ generated nickel boride (Ni2B) due to reaction of NiI2 (corrosion product) with NaBH4 followed by electrophilic attack of THF (solvent) was found to be the reason for the formation of impurity (8a). Execution of subsequent batches with proper controls arrested this impurity and successfully provided the Mirabegron with the desired quality.
- Bangal, Mukund N.,Deshmukh, Dattatray G.,Kalawade, Kaustubh A.,Mathad, Vijayavitthal T.
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p. 286 - 293
(2020/03/10)
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- A METHOD FOR PREPARING MANDELIC ACID 4-NITROPHENYL ETHYLAMIDE FROM 4-NITROBENZYL CYANIDE
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Preparation of a salt of 4-nitrophenyl ethylamine with (R)-mandelic acid and its use for the synthesis of mirabegron is disclosed. 4-Nitrophenyl ethylamine (1) is prepared by reduction of 4-nitrobenzyl cyanide (7) in a solvent with the use of a borane generated in-situ in the reaction mixture from NaBH4 and BF3.Et2O, 4-nitrophenyl ethylamine (1) being isolated from the solution as the mandelate 3.
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Page/Page column 11-13
(2019/05/15)
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- A method for preparing milamila beilong
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The invention discloses a method for preparing milamila beilong, relates to the technical field of pharmaceutical, comprising the following steps: R - mandelic acid and P ethylamine under high-temperature to amide condensation reaction, to obtain the intermediate (R)- 2 - hydroxy - N - (4 - nitrophenyl ethyl) - 2 - phenyl acetamide; then diisobutyl hydrogenated aluminum reducing amide carbonyl, to obtain the intermediate (R)- 2 - ((4 - nitrophenyl ethyl) amino) - 1 - phenyl ethanol hydrochloride; ammonium formate - Pd/C by nitro reduction system, to obtain the intermediate (R)- 2 - ((4 - amino ethyl) amino) - 1 - phenyl ethanol; finally with the amino thiazole acetic acid to generate a condensation reaction, to obtain milamila beilong. The invention prepared milamila beilong purity is good, high yield, synthetic line few steps, conditions is mild and controllable, the operation is simple, low cost, and is suitable for industrial production, and with extensive prospect and industrial application value.
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Paragraph 0043; 0052; 0059-0061
(2019/03/28)
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- Aryl or heteroaryl substituted pyrrolidine amide derivatives and application thereof
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The invention discloses aryl or heteroaryl substituted pyrrolidine amide derivatives and an application thereof, in particular to a novel aryl or heteroaryl substituted pyrrolidine amide derivative and a pharmaceutical composition containing the same, which can be used for activating beta3-adrenergic receptor. The invention also relates to a method for preparing the compounds and pharmaceutical compositions, as well as an application thereof in preparing drugs for treating diseases or symptoms mediated by beta3-adrenergic receptor, and especially for treating the overactive bladder.
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Paragraph 0220-0222
(2019/05/22)
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- Amide substituted pyrrolidine amide derivatives and use thereof (by machine translation)
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The invention discloses amide substituted pyrrolidine amide derivatives and their use, in particular, the invention relates to a novel class of amide substituted pyrrolidine amide derivatives containing such compounds and pharmaceutical composition, can be used to activate β 3 - adrenergic receptor. The invention also relates to processes for preparing such compounds and pharmaceutical compositions, and in the preparation of the treatment by the β 3 - adrenergic receptor activation mediated diseases or conditions, in particular the overactive bladder of the use of the medicament. (by machine translation)
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Paragraph 0233; 0235; 0236
(2019/06/07)
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- Acyl-substituted pyrrolidine amide derivative and application thereof
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The invention discloses an acyl-substituted pyrrolidine amide derivative and application thereof. Specifically, the invention relates to a novel acyl-substituted pyrrolidine amide derivative and a pharmaceutical composition containing the compound, which can be used for activation of beta3-adrenoceptor. The invention also relates to a method for preparing the compound and the pharmaceutical composition and their application in the preparation of beta3-adrenoceptor activation-mediated diseases or symptoms, especially overactive bladder.
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Paragraph 0234; 0235; 0236; 0237; 0238
(2019/06/12)
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- Nitrogen heterocyclic ring group substituted amide derivative and application thereof
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The invention discloses a nitrogen heterocyclic ring group substituted amide derivative and application thereof, particularly relates to a novel nitrogen heterocyclic ring group substituted amide derivative and a drug composition comprising the compound, and further relates to methods for preparing the compound and the drug composition, and application of the compound and the drug composition to preparation of drugs for treating diseases or symptoms, particularly overactive bladder, excited and mediated by beta 3-adrenergic receptors. The compound and the drug composition can be used for activating the beta 3-adrenergic receptors.
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Paragraph 0213; 0221-0223
(2019/06/05)
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- Synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide
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The invention discloses synthesis of mirabegron intermediate (R)-2-hydroxy-N-(4-nitrophenyl ethyl)-2-phenylacetamide. The synthesis method comprises the following steps: performing esterification reaction on R-mandelic acid and triphosgene in a solvent under the existence of alkali to generate a lactide intermediate I; and performing acylation reaction on the intermediate I and 4-nitrophenylethylamine in a solvent to obtain a target product. The synthesis method avoids use of EDCI and HOBt with high price, has the advantages of easily available raw materials, low cost, simplicity in operationand few impurities, and is suitable for industrialized production.
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Paragraph 0028; 0029; 0031; 0034
(2018/11/22)
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- Investigation of mechanistic pathway for trimethyl borate mediated amidation of (R)-mandelic acid for the synthesisof mirabegron, an antimuscarinic agent
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The present work describes investigation of mechanistic pathway for trimethyl borate mediated amidation of (R)-mandelic acid (3) with 4-nitophenylethylamine (2) to provide (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (4) during mirabegron synthesis. Plausible reaction mechanism is proposed by isolating and elucidating the active a-hydroxy ester intermediate 16 from the reaction mass. Trimethyl borate mediated approach proved to be selective in providing 4 without disturbing a-hydroxyl group and stereochemistry of the chiral center, and is also a greener, more economic and production friendly over the reported methods. The developed approach is rapid and efficient for the preparation of 4 with an overall yield of 85-87% and around 99.0% purity by HPLC at scale.
- Deshmukh, Dattatray G.,Bangal, Mukund N.,Patekar, Mukunda R.,Medhane, Vijay J.,Mathad, Vijayavitthal Thippannachar
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p. 239 - 245
(2018/03/29)
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- The Synthesis of Chiral α-Aryl α-Hydroxy Carboxylic Acids via RuPHOX-Ru Catalyzed Asymmetric Hydrogenation
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A ruthenocenyl phosphino-oxazoline-ruthenium complex (RuPHOX?Ru) catalyzed asymmetric hydrogenation of α-aryl keto acids has been successfully developed, affording the corresponding chiral α-aryl α-hydroxy carboxylic acids in high yields and with up to 97% ee. The reaction could be performed on a gram scale with a relatively low catalyst loading (up to 5000 S/C) and the resulting products can be transformed to several chiral building blocks, biologically active compounds and chiral drugs. (Figure presented.).
- Guo, Huan,Li, Jing,Liu, Delong,Zhang, Wanbin
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p. 3665 - 3673
(2017/09/11)
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- A method for synthesizing intermediate [...]
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The invention provides a method for synthesizing a mirabegron intermediate, wherein the method comprises the following specific steps: 1) a hydrolysis reaction: with a compound (R)-2-((4-nitrophenethyl)amino)-2-oxo-1-phenethyl ester as a starting material, hydrolyzing to obtain an intermediate product (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenyl acetamide; and 2) a reduction reaction: reducing the intermediate product to obtain the mirabegron intermediate (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol salt. The method for synthesizing the mirabegron intermediate has the advantages of being low in cost, high in product yield, and suitable for large-scale industrialized production.
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Paragraph 0028; 0029; 0043; 0044
(2017/07/04)
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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 30-31
(2016/02/29)
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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 0017; 0018; 0019
(2016/10/10)
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- Synthetic method of mirabegron intermediate
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The invention discloses a synthetic method of a mirabegron intermediate (R)-2-(4-nitrobenzene ethyl amino)-1-phenyl ethanol hydrochloride (M-02) and belongs to the field of drug synthesis. The method comprises steps as follows: (1) R-mandelic acid and pivaloyl chloride produce a mixed anhydride intermediate (I); (2) the mixed anhydride intermediate (I) and 4-nitrobenzene ethylamine are subjected to an acrylation reaction to produce an intermediate (II); (3) a mirabegron intermediate (M-01) is obtained through hydrolysis of the intermediate (II); (4) an amido bond of the intermediate (M-01) is reduced and the mirabegron intermediate (M-02) is obtained. The reaction condition is mild, the yield is high, few impurities exist, the production cost is low, and the method is suitable for mass industrial production.
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Paragraph 0016; 0018
(2017/04/03)
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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 32
(2015/04/15)
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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 17-18
(2014/09/16)
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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 5-6
(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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