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【结 构 式】

【分子编号】17221

【品名】3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene

【CA登记号】456-41-7

【 分 子 式 】C7H6BrF

【 分 子 量 】189.0270432

【元素组成】C 44.48% H 3.2% Br 42.27% F 10.05%

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:(II)

The condensation of cyclohexanecarbonyl chloride (I) with 3-fluorobenzyl bromide (II) by means of tetrakis(triphenylphosphine)palladium and Zn in dimethoxyethane gives the ethanone (III), which is treated with lead tetraacetate in acetic acid, yielding the alpha-acetoxyethanone (IV). The cyclization of (IV) with ammonium acetate in refluxing acetic acid affords the oxazole derivative (V), which is treated with chlorosulfonic acid at 100 C, yielding the 4-chlorosulfonyl derivative (VI). Finally, this compound is amidated with ammonia in THF/water.

1 Hashimoto, H.; et al.; 4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522. J Med Chem 2002, 45, 7, 1511.
2 Silvestre, J.S.; Leeson, P.A.; Castañer, J.; JTE-522. Drugs Fut 1998, 23, 6, 598.
3 Haruta, J.; Hashimoto, H.; Matsushita, M. (Japan Tobacco Inc.); Heteroaromatic oxazole cpds. and use thereof. EP 0745596; EP 0826676; JP 1996325249; JP 1997052882; US 5994381; WO 9619462; WO 9619463 .
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) 17220 cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride 2719-27-9 C7H11ClO 详情 详情
(II) 17221 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene 456-41-7 C7H6BrF 详情 详情
(III) 17222 1-cyclohexyl-2-(3-fluorophenyl)-1-ethanone C14H17FO 详情 详情
(IV) 17223 2-cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate C16H19FO3 详情 详情
(V) 17224 5-(3-fluorophenyl)-2-methyl-4-phenyl-1,3-oxazole C16H12FNO 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

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3

该中间体在本合成路线中的序号:(VII)

 

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4

该中间体在本合成路线中的序号:(XVIII)

 

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