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【结 构 式】

【药物名称】Rosiglitazone maleate, SB-206846((-)-enantiomer, free base), SB-210232((+)-enantiomer, free base), BRL-49653C, Venvia, Nyracta, Avandia

【化学名称】(±)-5-[4-[2-[N-Methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate

【CA登记号】155141-29-0, 122320-73-4 (free base)

【 分 子 式 】C22H23N3O7S

【 分 子 量 】473.50851

【开发单位】GlaxoSmithKline (Originator), Bristol-Myers Squibb (Licensee), Asahi Kasei (Distributor)

【药理作用】Alzheimer's Dementia, Treatment of , Antidiabetic Drugs, Antipsoriatics, Cognition Disorders, Treatment of, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, NEUROLOGIC DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARgamma Agonists, Thiazolidinediones (Glitazones)
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8

合成路线1

　

参考文献 中间体
【1】 Duran Lopez E. Tojo Suarez G. 2005. Process for the perparation of rosiglitazone using 1,4-dihydropyridines, especially Hantzsch esters, as reductants. WO 2005108394(本专利属于Medichem S A, Spain)
【2】 Fu Y, Wang SJ, Zhang WG, et al. 2001. An improved procedure for the synthesis of rosiglitazone maleate. 沈阳药科大学学报，18: 18～19（本论文作者来自于Department of Pharmaceutical, Shenyang Pharmacentical University, Shengyang, Peop Rep China）
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17507 4-[2-[methyl(2-pyridinyl)amino]ethoxy]benzaldehyde C15H16N2O2 详情 详情
(II) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情

合成路线2

　

参考文献 中间体
【1】 Kankan RN, Rao DR 2005. Prooess for the preparation of rosiglitazone from 4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzaldehyde metabisulfite complex. GB 2413795(本专利属于Cipla Limited, India)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(II) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(III) 17507 4-[2-[methyl(2-pyridinyl)amino]ethoxy]benzaldehyde C15H16N2O2 详情 详情
(IV) 66654 hydroxy(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)methanesulfonic acid 　 C15H18N2O5S 详情 详情
(V) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情

合成路线3

　

参考文献 中间体
【1】 Li JM，Li F，Cha DJ．2001．Synthesis of antihyperglycemic agent rosiglitazone. 中国药物化学杂志．11 : 291～292(本论文作者来自于Dpartment of Pharmaceutical Chemistry，Anhui College of TCM．Hefei, Peop Rep China)
【2】 Nambiar S. Pise AC. 2005. Process for preparing thiazolidinediones such as pioglitazone via reduction of exocyclic double bonds at the 5-position of thiazolidinediones using dithionite. W0 2005049610(本专利属于Sandoz A-G．Switz)
【3】 Vyas SK. 2002. Process for the preparation of rosiglitazone maleate. W0 2002051823
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17503 2-chloropyridine 109-09-1 C5H4ClN 详情 详情
(II) 13324 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol 109-83-1 C3H9NO 详情 详情
(III) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(IV) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(V) 17507 4-[2-[methyl(2-pyridinyl)amino]ethoxy]benzaldehyde C15H16N2O2 详情 详情
(VI) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情

合成路线4

　

参考文献 中间体
【1】 Giles RG. Lewis NJ, Quick JK, et aL. 2000. Regiospecific reduction of 5-benzylidene-2,4-thiuolidoines and 4-oxo-2-thiazolidinethiones using lithium borohydride in pyridine and tetrahydrofuran. Tetnhedron, 56: 4531～4537(本论文作者来自于SmithKline Beecham Pharmaceuticals．Old Powder Mills, Kent, UK)
【2】 Li X, Abell C, Warrington BH．et aL. 2003. Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia). Org Biomol Chem. 1: 4392～4395(本论文作者来自于Department of Chemistry, University Chemical Laboratories, Cambridge,UK)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 66657 (4-(2-(methylamino)ethoxy)phenyl)methanol 　 C10H15NO2 详情 详情
(I) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(II) 66655 ethyl 2-iodoacetate 623-48-3 C4H7IO2 详情 详情
(III) 51988 ethyl 2-[4-(hydroxymethyl)phenoxy]acetate C11H14O4 详情 详情
(IV) 66656 2-(4-(hydroxymethyl)phenoxy)-N-methylacetamide 　 C10H13NO3 详情 详情
(VI) 34512 2-fluoropyridine 372-48-5 C5H4FN 详情 详情
(VII) 66658 (4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)methanol 　 C15H18N2O2 详情 详情
(VIII) 60164 4-{2-[methyl(2-pyridinyl)amino]ethoxy}benzaldehyde C15H16N2O2 详情 详情
(IX) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(X) 59997 　 C18H17N3O3S 详情 详情

合成路线5

　

参考文献 中间体
【1】 Lu XZ, Zhang SW, Zhao YL. 200l. Preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino]ethoxybenzyl]thiazolidine-2,4-dione and its salts. 发明专利申请公开说明书，CN 1301700(本专利属于China Medicine Research and Development Centre, Peop Rep China)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(II) 13909 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene 100-00-5 C6H4ClNO2 详情 详情
(III) 66659 N-methyl-N-(2-(4-nitrophenoxy)ethyl)pyridin-2-amine 329249-47-0 C14H15N3O3 详情 详情
(IV) 66660 N-(2-(4-aminophenoxy)ethyl)-N-methylpyridin-2-amine 　 C14H17N3O 详情 详情
(V) 66661 methyl 2-chloro-3-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)propanoate 　 C18H21ClN2O3 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线6

The reaction of 2-chloropyridine (I) with 2-(methyl-amino)ethanol (II) by heating at 150 C gives 2-[N-methyl-N-(2-pyridyl)amino]ethanol (III), which is condensed with 4-fluorobenzaldehyde (IV) by means of NaH in DMF, yielding 4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzaldehyde (V) (1-3). The reaction of (V) with thiazolidine-2,4-dione (VI) by means of piperidinium acetate in refluxing toluene affords 5-[4-[2-[N-methyl-N-(2-pyridyl)- amino]ethoxy]benzylidene]thiazolidine-2,4-dione (VII). Finally, this compound is reduced with H2 over Pd/C (1), Mg in methanol (2,3) or biocatalytically by incubation with whole cells of the yeast Rhodotorula rubra CBS 6469 at pH 7.5-8.0 (4-6). Under acidic conditions, pH 3.0-5.0, this microbial biotransformation is enantioselective, giving the (+)-(R)-enantiomer of rosiglitazone.

参考文献 中间体
【1】 Jones, J.J.; Verrall, M.S.; Heath, C.M.; Imrie, R.C.; Rees, M.J.; Robins, K.G.; Whole cell biotransformation of 5-(4-(2-(2-pyridyl)methylamino)ethoxy)benzylidenethiazolidine-2,4-dione to its benzyl derivative using a yeast reductase. J Chem Tech Biotech 1997, 68, 324-30.
【2】 Cantello, B.C.C.; Haigh, D.; Eggleston, D.S.; Jennings, K.R.; Heath, C.M.; Sime, J.T.; Haltiwanger, R.C.; Woroniecki, S.R.; Hindley, R.M.; Facile biocatalytic reduction of the carbon-carbon double bond of 5-benzylidenethiazolidine-2,4-diones. Synthesis of (?-5-(4-(2-[methyl(2-pyridyl)amino]ethoxy)benzyl)-thiazolidine-2,4-dione (BRL 49653), its (R)-(?-enantiomer and analogues. J Chem Soc - Perkins Trans I 1994, 22, 22, 3319-24.
【3】 Thurlby, P.L.; Lister, C.A.; Duff, P.T.; Hindley, R.M.; Cottam, G.P.; Haigh, D.; Smith, S.A.; Cantello, BB.C.C.; Cawthorne, M.A.; [[*-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J Med Chem 1994, 37, 23, 3977-85.
【4】 Sorbera, L.A.; Rabasseda, X.; Leeson,P.A.; Rosiglitazone Maleate. Drugs Fut 1998, 23, 9, 977.
【5】 Hindley, R.M. (SmithKline Beecham plc); Substd. Thiazolidine-dione derivs. AU 8821738; EP 0306228; EP 0842925; JP 1989131169; JP 1997183726; JP 1997183771; JP 1997183772; JP 1998194970; JP 1998194971; US 5002953; US 5194443; US 5232925; US 5646169 .
【6】 Hindley, R.M.; Woroniecki, S.R. (SmithKline Beecham plc); Process for the preparation of pharmaceutically active thiazolidine or oxazolidine cpds. by a yeast reductase. WO 9310254 .
【7】 Vyas, S.K. (Torrent Pharmaceuticals Ltd.); Process for the preparation of rosiglitazone maleate. US 2002115866; US 6515132; WO 0251823 .
【8】 Smith, S.A.; Thurlby, P.L.; Cantello, B.C.C.; Haigh, D.; Cawthorne, M.A.; Hindley, R.M.; The synthesis of BRL 49653 - A novel and potent antihyperglycaemic agent. Bioorg Med Chem Lett 1994, 4, 10, 1181-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17503 2-chloropyridine 109-09-1 C5H4ClN 详情 详情
(II) 13324 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol 109-83-1 C3H9NO 详情 详情
(III) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(IV) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(V) 17507 4-[2-[methyl(2-pyridinyl)amino]ethoxy]benzaldehyde C15H16N2O2 详情 详情
(VI) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(VII) 17509 5-[(E)-(4-[2-[methyl(2-pyridinyl)amino]ethoxy]phenyl)methylidene]-1,3-thiazolidine-2,4-dione 122320-74-5 C18H17N3O3S 详情 详情

合成路线7

The bromination of rosiglitazone (I) with NBS in hot acetic acid gives the dibromo compound (II), which is the hydrogenated with tritium over Pd/BaSO4 in DMF/TEA to yield the target labeled compound.

参考文献 中间体
【1】 Kirefu, T.; Landwater, S.W.; Latter, A.J.; Lawrie, K.W.M.; Morecombe, D.J.; Willcocks, K.; Rosiglitazone maleate (BRL 49653-C); the preparation of [14C] and [3H] isotopomers. J Label Compd Radiopharm 2001, 44, 5, 329.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 59994 　 C18H19N3O3S 详情 详情
(II) 59995 　 C18H17Br2N3O3S 详情 详情

合成路线8

The reaction of 4-fluoroiodobenzene (I) with 14C-KCN and CuI in refluxing DMF gives 4-fluorobenzonitrile (II), which is reduced with HCO2H and RaNi in DMF to yield 4-fluorobenzaldehyde (III). The condensation of (III) with the substituted ethanolamine (IV) by means of tBu-OK in DMF affords 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (V), which is condensed with thiazolidine-2,4-dione (VI) by means of piperidine acetate in refluxing toluene to provide the benzylidene-thiazolidinedione (VII). Finally this compound is hydrogenated with H2 over Pd/C in DMF to furnish the target labeled compound.

参考文献 中间体
【1】 Kirefu, T.; Landwater, S.W.; Latter, A.J.; Lawrie, K.W.M.; Morecombe, D.J.; Willcocks, K.; Rosiglitazone maleate (BRL 49653-C); the preparation of [14C] and [3H] isotopomers. J Label Compd Radiopharm 2001, 44, 5, 329.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54686 1-Fluoro-4-iodobenzene; 4-Fluoroiodobenzene; 4-Iodofluorobenzene; p-Fluoroiodobenzene 352-34-1 C6H4FI 详情 详情
(II) 60162 4-fluorobenzonitrile C7H4FN 详情 详情
(III) 60163 4-fluorobenzaldehyde C7H5FO 详情 详情
(IV) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(V) 60164 4-{2-[methyl(2-pyridinyl)amino]ethoxy}benzaldehyde C15H16N2O2 详情 详情
(VI) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(VII) 59997 　 C18H17N3O3S 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)