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【结 构 式】 
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【分子编号】17507 【品名】4-[2-[methyl(2-pyridinyl)amino]ethoxy]benzaldehyde 【CA登记号】 |
【 分 子 式 】C15H16N2O2 【 分 子 量 】256.30432 【元素组成】C 70.29% H 6.29% N 10.93% O 12.48% |
与该中间体有关的原料药合成路线共 4 条
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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2
该中间体在本合成路线中的序号：(I)
| 【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） |
合成路线3
该中间体在本合成路线中的序号：(III)
| 【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4
该中间体在本合成路线中的序号：(V)
| 【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 |
Extended Information