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【结 构 式】 
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【药物名称】FILGOTINIB 【化学名称】N-[5-[4-(1,1-Dioxidothiomorpholin-4-ylmethyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide 【CA登记号】1206161-97-8 【 分 子 式 】C21H23N5O3S 【 分 子 量 】425.504 |
【开发单位】Originated by Galapagos, NV (BE); licensed to AbbVie, Inc. (US). 【药理作用】Tyrosine-protein kinase JAK1 inhibitor;Treatment of rheumatoid arthritis;Treatment of Crohn’s disease |
合成路线1
Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl) thiourea (III), which by cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia, results in the carboxamide (VII) . Suzuki coupling of compound (VII) with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3, affords the benzyl bromide intermediate (IX), which is finally condensed with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH .
Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) by means of DIEA in CH2Cl2/MeOH gives intermediate (XII), which finally undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C .
| 【1】 Menet, C.J.M., Smits, K.K. (Galapagos NV). 5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl carboxamides as JAK inhibitors. CN 102482273, EP 2445911, JP 2012530766, KR 2012107919, US 201331319, US 8088764, WO 2010149769. |
| 【2】 Menet, C.J.M., Smits, K.K. (Galapagos NV). Novel compound useful for the treatment of degenerative and inflammatory diseases. US 2012142678, US 8563545. |
| 【3】 Van ‘t Klooster, G.A.E., Brys, R.C.X., Van Rompaey, L.J.C., Namour, F.S. (Galapagos NV). Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical composition thereof. US 2013345209, WO 2013189771. |
| 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) | 41341 | 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine | 19798-81-3 | C5H5BrN2 | 详情 | 详情 |
| (II) | 25964 | 1-[(isothiocyanatocarbonyl)oxy]ethane | 16182-04-0 | C4H5NO2S | 详情 | 详情 |
| (III) | 67818 | 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea | C9H10BrN3O2S | 详情 | 详情 | |
| (IV) | 65957 | Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride | 5470-11-1 | H3NO.HCl | 详情 | 详情 |
| (V) | 67819 | 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine | C6H5BrN4 | 详情 | 详情 | |
| (VI) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (VII) | 67820 | N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide | C10H9BrN4O | 详情 | 详情 | |
| (VIII) | 67821 | 4-(hydroxymethyl)phenylboronic acid | 59016-93-2 | C7H9BO3 | 详情 | 详情 |
| (IX) | 67822 | N-(5-(4-(bromomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide | C17H15BrN4O | 详情 | 详情 | |
| (X) | 67823 | thiomorpholine-1,1-dioxide | 39093-93-1 | C4H9NO2S | 详情 | 详情 |
| (XI) | 67824 | (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane | 138500-85-3 | C13H18BBrO2 | 详情 | 详情 |
| (XII) | 67825 | 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide | C17H26BNO4S | 详情 | 详情 |