Improvement of synthesis process of mirabegron

HAN Chengqun; ZOU Qiaogen; SUN Qian; XIA Yunyan

doi:10.11665/j.issn.1000-5048.20200409

Journal of China Pharmaceutical University > 2020 > 51(4): 449-453. > DOI: 10.11665/j.issn.1000-5048.20200409

HAN Chengqun, ZOU Qiaogen, SUN Qian, XIA Yunyan. Improvement of synthesis process of mirabegron[J]. Journal of China Pharmaceutical University, 2020, 51(4): 449-453. DOI: 10.11665/j.issn.1000-5048.20200409

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Improvement of synthesis process of mirabegron

School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, China

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Received Date: May 07, 2020

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Mirabegron is an agonist of human β-3 adrenergic receptor used to treat symptoms of overactive bladder. In this study, the synthesis process of mirabegron was improved based on literatures. Using p-nitrophenethylamine hydrochloride, (R)-mandelicacid and 2-aminothiazole-4-acetic acid as starting materials, the target product with high purity was obtained through four steps of amide condensation, carbonyl reduction, nitro reduction and amide condensation, and one-step purification, with a total yield of 39%. In this study, the hydrogen source of nitro reduction in step 3 was changed from hydrogen to ammonium formate, which increased the feasibility of industrialization, and mirabegron was refined to improve the purity of the product. The improved process has the advantages of simplified operation and mild reaction conditions, which provides a new method for the preparation and purification of mirabegron.
- mirabegron,
- overactive bladder,
- nitro reduction,
- process improvement,
- synthesis

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[1]	Zhou X, Cui SY, Run HL, et al. Meta-analysis of mirabegron in the treatment of overactive bladder [J]. J Mod Urol(现代泌尿外科杂志), 2015, 20(7):498-504.
[2]	Tang QD, Gong P. Mirabegron [J]. Chin J Med Chem (中国药物化学杂志), 2012, 22(6):544.
[3]	Fan M. Mirabegron, a treatment for overactive bladder [J]. Prog Pharm Sci(药学进展), 2012, 36(3):133-135.
[4]	Andersson KE, Martin N, Nitti V. Selective β3-adrenoceptor agonists for the treatment of overactive bladder[J]. J Urol, 2013, 190(4):1173-1180.
[5]	Deng XL, Chen WH, Guan ZC. Research progress of β-3 adrenergic receptor agonist in the treatment of overactive bladder [J]. Tianjin Med J(天津医药), 2014, 42(3):285-287.
[6]	Li HY, Zhou FH, Ma YL, et al. Mirabegron, a new treatment for overactive bladder [J]. Chin J New Drug(中国新药杂志), 2014, 23(19):2215-2218.
[7]	Michel MC, Ochodnicky P, Homma Y, et al. β-Adrenoceptor agonist effects in experimental models of bladder dysfunction[J]. Pharmacology & Therapeutics, 2011, 131(1):40-49.
[8]	Zhang H, Li Y, Cheng SJ, et al. Synthetic method of mirabegron(米拉贝隆的合成方法): 103896872A[P]. 2014-07-02.
[9]	Maruyama T, Suzuki T, Onda K, et al. Amide derivatives or salts thereof: 09920607[P]. 1994-04-29.
[10]	Maruyama T, Suzuki T, Onda K, et al. Amide derivatives or salts thereof: 6346532[P]. 2002-02-12.
[11]	Hu F, Wang SY, Wang XJ, et al.(R)- 4-(2-(2-hydroxy-2-phenylethylamine) ethyl) tert-butylanilinate(()-4-(2-(2-羟基-2-苯乙胺)乙基)苯胺基甲酸叔丁酯): 103232352[P]. 2013-08-07.
[12]	Mao LF, Yuan LS, Yan MY, et al. Study on the synthesis of mirabegron [J]. Chem Res Appl(化学研究与应用), 2016, 28(4):521-524.
[13]	Kawazoe S, Sakamoto K, Awamura Y, et al. Alpha-form or beta-form crystal of acetanilide derivative: 1440969[P]. 2004-07-28.
[14]	Mathad VT, Deshmukh DG, Varpe SP, et al. A process for preparation of mirabegron and alpha crystalline form thereof: 2015044965[P]. 2015-04-02.
[15]	Takasu T, Sato S, Ukai M, et al. Therapeutic agent for hyperactive hyperactivity of bladder containing acetate phthalanilide as active ingredient(含乙酸酰基苯胺衍生物作为活性成分的膀胱活动过度的治疗药物): 1711085A[P]. 2005-12-21.
[16]	Takasu T, Sato S, Ukai M, et al. Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient: 2004041276 [P]. 2004-05-21.
[17]	Zhou JC. Applications of ammonium formate and other derivatives of formic acid in the drug synthesis [J]. J China Pharm Univ(中国药科大学学报), 1989(5):313-320.
[18]	Pharmaceuticals and Medical Devices Agency. Selective β3 adrenergic receptor agonist Mirabegron tablets(Betanis^? Tablets 25 mg 50 mg)[EB/OL].(2019-07-01)[2020-04-30].https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/2590014.

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