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【结 构 式】 
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【分子编号】17505 【品名】2-[methyl(2-pyridinyl)amino]-1-ethanol 【CA登记号】 |
【 分 子 式 】C8H12N2O 【 分 子 量 】152.19616 【元素组成】C 63.13% H 7.95% N 18.41% O 10.51% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(IV)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.
| 【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 |
合成路线3
该中间体在本合成路线中的序号：(I)
| 【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：(III)
| 【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5
该中间体在本合成路线中的序号：(I)
| 【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 |