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【结 构 式】

【分子编号】29563

【品名】2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine

【CA登记号】

【 分 子 式 】C8H8F3NO

【 分 子 量 】191.1528696

【元素组成】C 50.27% H 4.22% F 29.82% N 7.33% O 8.37%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).

1 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 19106 2-nitrophenol 88-75-5 C6H5NO3 详情 详情
(II) 29561 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 433-06-7 C9H9F3O3S 详情 详情
(III) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(IV) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(V) 21583 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine 821-48-7 C4H9Cl2N 详情 详情
(VI) 29564 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether C12H15F3N2O 详情 详情
(VII) 29565 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C15H17ClN2O2 详情 详情
(VIII) 29566 1-benzyl-5-methyl-3-(3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl)-2,4(1H,3H)-pyrimidinedione C27H31F3N4O3 详情 详情
(IX) 12204 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine 65-71-4 C5H6N2O2 详情 详情
(X) 29567 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione C12H12N2O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) in the presence of NaOEt to provide diethyl 2-(ethoxyethyl)malonate (III). Treatment of 2-chloronitrobenzene (IV) with 2,2,2-trifluoroethanol (V) afforded the trifluoroethyl ether (VI). Subsequent reduction of the nitro group of (VI) by means of iron in acetic acid gave aniline (VII), which was condensed with malonate (III) in refluxing diphenyl ether, yielding furoquinoline (VIII). Further reaction of (VIII) with o-toluidine (IX) in boiling diethylene glycol produced the tetrahydropyrroloquinoline (X). Aromatization of the pyrrole ring of (X) to give (XI) was achieved by dehydrogenation in diphenyl ether in the presence of Pd/C. Chloroquinoline (XII) was then obtained by chlorination of (XI) with POCl3. Finally, displacement of the chlorine atom of (XII) by means of ethanolamine at 180 C furnished the title compound.

1 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(I) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 34659 2-bromoethyl ethyl ether; 1-bromo-2-ethoxyethane 592-55-2 C4H9BrO 详情 详情
(III) 34660 diethyl 2-(2-ethoxyethyl)malonate C11H20O5 详情 详情
(IV) 15248 1-chloro-2-nitrobenzene 88-73-3 C6H4ClNO2 详情 详情
(V) 19483 2,2,2-trifluoro-1-ethanol 75-89-8 C2H3F3O 详情 详情
(VI) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(VII) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(VIII) 34661 6-(2,2,2-trifluoroethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one C13H10F3NO3 详情 详情
(IX) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline;2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(X) 34662 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one C20H17F3N2O2 详情 详情
(XI) 34663 1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one C20H15F3N2O2 详情 详情
(XII) 34664 4-chloro-1-(2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[3,2-c]quinoline; 4-chloro-1-(2-methylphenyl)-1H-pyrrolo[3,2-c]quinolin-6-yl 2,2,2-trifluoroethyl ether C20H14ClF3N2O 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IV)

Reaction of 2-chloronitrobenzene (I) with the sodium alkoxide of 2,2,2-trifluoroethanol (II) in cold THF afforded trifluoroethyl ether (III). The nitro group of (III) was then reduced by means of iron and AcOH to produce 2-(trifluoroethoxy)aniline (IV). Condensation of (IV) with diethyl (2-ethoxyethyl)malonate (V) in boiling diphenyl ether led to the furoquinolinone system (VI), and subsequent reaction of (VI) with 2-methyl-4-methoxyaniline (VII) in refluxing diethylene glycol generated the pyrroloquinolinone (VIII). Chlorination of (VIII) with POCl3 gave chloropyrroloquinoline (IX). Finally, displacement of the chlorine of (IX) by ethanolamine at 180 C yielded the title compound.

1 Kim, H.-J.; Kim, S.-S.; Yoo, Y.-K.; Kang, S.-K.; Cheon, H.-G.; Choi, J.-K.; Yum, E.-K. (Korea Research Institute of Chemical Technology); Pyrrolo[3,2-c]quinoline derivs. containing haloalkoxy group and pharmaceutically acceptable salts thereof. CA 2268166; EP 0966466; JP 2000504352; US 6011044; WO 9909029 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(I) 15248 1-chloro-2-nitrobenzene 88-73-3 C6H4ClNO2 详情 详情
(II) 19483 2,2,2-trifluoro-1-ethanol 75-89-8 C2H3F3O 详情 详情
(III) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(IV) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(V) 34660 diethyl 2-(2-ethoxyethyl)malonate C11H20O5 详情 详情
(VI) 34661 6-(2,2,2-trifluoroethoxy)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one C13H10F3NO3 详情 详情
(VII) 40006 4-methoxy-2-methylphenylamine; 4-methoxy-2-methylaniline 102-50-1 C8H11NO 详情 详情
(VIII) 40007 1-(4-methoxy-2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]quinolin-4-one C21H19F3N2O3 详情 详情
(IX) 40008 4-chloro-1-(4-methoxy-2-methylphenyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-6-yl 2,2,2-trifluoroethyl ether; 4-chloro-1-(4-methoxy-2-methylphenyl)-6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline C21H18ClF3N2O2 详情 详情
Extended Information