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【结 构 式】 
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【药物名称】Lapatinib, 572016, GW-2016, GW-572016 【化学名称】N-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[2-(methylsulfonyl)ethylaminomethyl]furan-2-yl]quinazolin-4-amine 【CA登记号】231277-92-2, 388082-78-8 (4-methylbenzenesulfonate) 【 分 子 式 】C29H26ClFN4O4S 【 分 子 量 】581.07037 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Breast Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, EGFR (erbB1) Inhibitors, HER2 (erbB2) Inhibitors, Inhibitors of Signal Transduction Pathways, Tyrphostins |
合成路线1
Williamson's ether synthesis between 2-chloro-4-nitrophenol (I) and 3-fluorobenzyl bromide (II) afforded ether (III). The nitro group of (III) was then reduced to the aniline (IV) by means of catalytic hydrogenation over Pt/C. Condensation of aniline (IV) with 4-chloro-6-iodoquinazoline (V) furnished the diaryl amine (VI). Subsequent Stille coupling between iodide (VI) and 5-dioxolanyl-2-(tributylstannyl)furan (VII) gave rise to adduct (VIII), which was further subjected to acid hydrolysis of the cyclic ketal to yield aldehyde (IX). Finally, reductive amination of (IX) with 2-(methanesulfonyl)ethylamine (X) in the presence of sodium triacetoxyborohydride provided the title compound.
| 【1】 Guntrip, S.B.; Lackey, K.E.; Cockerill, G.S.; Carter, M.C.; Smith, K.J. (Glaxo Group Ltd.); Bicyclic heteroaromatic cpds. as protein tyrosine kinase inhibitors. EP 1047694; WO 9935146 . |
| 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) | 49872 | 1-Chloro-2-Hydroxy-5-Nitrobenzene; 2-Chloro-4-nitrophenol; 4-Nitro-2-chlorophenol; p-Nitro-o-chlorophenol | 619-08-9 | C6H4ClNO3 | 详情 | 详情 |
| (II) | 17221 | 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene | 456-41-7 | C7H6BrF | 详情 | 详情 |
| (III) | 49873 | 2-chloro-1-[(3-fluorobenzyl)oxy]-4-nitrobenzene; 2-chloro-4-nitrophenyl 3-fluorobenzyl ether | C13H9ClFNO3 | 详情 | 详情 | |
| (IV) | 49874 | 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine; 3-chloro-4-[(3-fluorobenzyl)oxy]aniline | C13H11ClFNO | 详情 | 详情 | |
| (V) | 49875 | 4-chloro-6-iodoquinazoline | 98556-31-1 | C8H4ClIN2 | 详情 | 详情 |
| (VI) | 49876 | N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-N-(6-iodo-4-quinazolinyl)amine; N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-iodo-4-quinazolinamine | C21H14ClFIN3O | 详情 | 详情 | |
| (VII) | 49877 | tributyl[5-(1,3-dioxolan-2-yl)-2-furyl]stannane | C19H34O3Sn | 详情 | 详情 | |
| (VIII) | 49878 | N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-[5-(1,3-dioxolan-2-yl)-2-furyl]-4-quinazolinamine; N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-N-[6-[5-(1,3-dioxolan-2-yl)-2-furyl]-4-quinazolinyl]amine | C28H21ClFN3O4 | 详情 | 详情 | |
| (IX) | 49879 | 5-(4-[3-chloro-4-[(3-fluorobenzyl)oxy]anilino]-6-quinazolinyl)-2-furaldehyde | C26H17ClFN3O3 | 详情 | 详情 | |
| (X) | 49880 | 2-(methylsulfonyl)-1-ethanamine; 2-(methylsulfonyl)ethylamine | C3H9NO2S | 详情 | 详情 |
合成路线2
| 【1】 Petrov KG, Zhang YM, Carter M, et al. 2006. Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series. Bioorganic & Medicinal Chemistry Letters, 16, 4686～4691. |
| 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) | 11240 | 2-(Methylsulfanyl)ethylamine; 2-(Methylthio)ethylamine; 2-(Methylsulfanyl)-1-ethanamine | 18542-42-2 | C3H9NS | 详情 | 详情 |
| (II) | 67211 | benzyl (2-(methylthio)ethyl)carbamate | C11H15NO2S | 详情 | 详情 | |
| (III) | 67212 | benzyl (2-(methylsulfonyl)ethyl)carbamate | C11H15NO4S | 详情 | 详情 | |
| (IV) | 49880 | 2-(methylsulfonyl)-1-ethanamine; 2-(methylsulfonyl)ethylamine | C3H9NO2S | 详情 | 详情 | |
| (VI) | 49872 | 1-Chloro-2-Hydroxy-5-Nitrobenzene; 2-Chloro-4-nitrophenol; 4-Nitro-2-chlorophenol; p-Nitro-o-chlorophenol | 619-08-9 | C6H4ClNO3 | 详情 | 详情 |
| (VII) | 17221 | 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene | 456-41-7 | C7H6BrF | 详情 | 详情 |
| (VIII) | 49873 | 2-chloro-1-[(3-fluorobenzyl)oxy]-4-nitrobenzene; 2-chloro-4-nitrophenyl 3-fluorobenzyl ether | C13H9ClFNO3 | 详情 | 详情 | |
| (IX) | 49874 | 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine; 3-chloro-4-[(3-fluorobenzyl)oxy]aniline | C13H11ClFNO | 详情 | 详情 | |
| (X) | 49875 | 4-chloro-6-iodoquinazoline | 98556-31-1 | C8H4ClIN2 | 详情 | 详情 |
| (XI) | 49876 | N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-N-(6-iodo-4-quinazolinyl)amine; N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-iodo-4-quinazolinamine | C21H14ClFIN3O | 详情 | 详情 | |
| (XII) | 67214 | (5-formylfuran-2-yl)boronic acid | 27329-70-0 | C5H5BO4 | 详情 | 详情 |
| (XIII) | 49879 | 5-(4-[3-chloro-4-[(3-fluorobenzyl)oxy]anilino]-6-quinazolinyl)-2-furaldehyde | C26H17ClFN3O3 | 详情 | 详情 |
合成路线3
| 【1】 Tung R. 2008. Preparation of 4-aminoquinazolines as EGFR and HER-2 inhibitors. PCT Int Appl WO 2008024439(Concert Pharmaceuticals Inc, USA). |
| 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) | 31326 | 5-bromo-2-furoic acid | 585-70-6 | C5H3BrO3 | 详情 | 详情 |
| (II) | 67215 | N,O-dimethylhydroxylamine hydrochloride | C2H8NO.HCl | 详情 | 详情 | |
| (III) | 67216 | 5-bromo-N-methoxy-N-methylfuran-2-carboxamide | C7H8BrNO3 | 详情 | 详情 | |
| (IV) | 52428 | Bis(tributyltin); Hexabutyldistannane; Bis(tri-n-butyltin); Hexa-n-butylditin; Hexa-n-butyldistannane | 813-19-4 | C24H54Sn2 | 详情 | 详情 |
| (V) | 67217 | N-methoxy-N-methyl-5-(tributylstannyl)furan-2-carboxamide | C19H35NO3Sn | 详情 | 详情 | |
| (VI) | 19964 | 5-Iodoanthranilic acid; 2-amino-5-iodobenzoic acid | 5326-47-6 | C7H6INO2 | 详情 | 详情 |
| (VII) | 16598 | Formamide | 75-12-7 | CH3NO | 详情 | 详情 |
| (VIII) | 67218 | 6-iodoquinazolin-4(1H)-one | 16064-08-7 | C8H5IN2O | 详情 | 详情 |
| (IX) | 49875 | 4-chloro-6-iodoquinazoline | 98556-31-1 | C8H4ClIN2 | 详情 | 详情 |
| (X) | 67219 | C10H9N.K | 详情 | 详情 | ||
| (XI) | 67220 | 2-(2-bromoethyl)isoindoline-1,3-dione | C12H4D4BrNO2 | 详情 | 详情 | |
| (XII) | 67221 | iodomethane | CD3I | 详情 | 详情 | |
| (XIII) | 67222 | 2-(2-(methylthio)ethyl)isoindoline-1,3-dione | C11H4D7NO2S | 详情 | 详情 | |
| (XIV) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (XV) | 67223 | tert-butyl (2-(methylsulfonyl)ethyl)carbamate | C8H10D7NO4S | 详情 | 详情 | |
| (XVI) | 67224 | 2-(methylsulfonyl)ethanamine hydrochloride | C3H2D7NO2S.HCl | 详情 | 详情 | |
| (XVII) | 49872 | 1-Chloro-2-Hydroxy-5-Nitrobenzene; 2-Chloro-4-nitrophenol; 4-Nitro-2-chlorophenol; p-Nitro-o-chlorophenol | 619-08-9 | C6H4ClNO3 | 详情 | 详情 |
| (XVIII) | 17221 | 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene | 456-41-7 | C7H6BrF | 详情 | 详情 |
| (XIX) | 49873 | 2-chloro-1-[(3-fluorobenzyl)oxy]-4-nitrobenzene; 2-chloro-4-nitrophenyl 3-fluorobenzyl ether | C13H9ClFNO3 | 详情 | 详情 | |
| (XX) | 49874 | 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine; 3-chloro-4-[(3-fluorobenzyl)oxy]aniline | C13H11ClFNO | 详情 | 详情 | |
| (XXI) | 49876 | N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-N-(6-iodo-4-quinazolinyl)amine; N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-iodo-4-quinazolinamine | C21H14ClFIN3O | 详情 | 详情 | |
| (XXII) | 67225 | 5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-N-methoxy-N-methyltetrahydrofuran-2-carboxamide | C28H26ClFN4O4 | 详情 | 详情 | |
| (XXIII) | 67226 | 5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)tetrahydrofuran-2-carbaldehyde | C26H20DClFN3O3 | 详情 | 详情 | |
| (XXIV) | 67227 | tert-butyl ((5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)tetrahydrofuran-2-yl)methyl)(2-(methylsulfonyl)ethyl)carbamate | C34H27D9ClFN4O6S | 详情 | 详情 | |
| (XXV) | 67228 | 4-methylbenzenesulfonic acid | 104-15-4 | C7H8O3S | 详情 | 详情 |
Extended Information