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【结 构 式】

【分子编号】26348

【品名】1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride

【CA登记号】401-78-5

【 分 子 式 】C7H4BrF3

【 分 子 量 】225.0079696

【元素组成】C 37.37% H 1.79% Br 35.51% F 25.33%

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:(VI)

A synthesis of [14C]-labeled SR-57746A has been described: The iodination of [14C6]-benzene (I) with nitric acid/I2 gives iodobenzene (II), which is treated with sodium trifluoroacetate and CuI yielding trifluoromethylbenzene (III). The nitration of (III) with sodium nitrate affords 3-(trifluoromethyl)nitrobenzene (IV), which is reduced with Fe/HCl to the corresponding aniline (V). The reaction of (V) with tert-butyl nitrite and CuBr2 provides 3-(trifluoromethyl)bromobenzene (VI), which is treated with Mg in THF affording the corresponding Grignard reagent (VII). The condensation of (VII) with piperidone (VIII) gives the piperidol (IX), which is finally dehydrated in acidic medium. In order to aviod radioactive contamination during the purification of compounds iodobenzene (II) and trifluoromethylbenzene (III) by liquid chromatography, a safer route using less volatile compounds has been developed: The nitration of [14C6]-benzene (I) with nitric acid gives nitrobenzene (X), which is iodinated with IPy2BF4/CF3SO3H yielding 3-iodonitrobenzene (XI). Finally, this compound is trifluoromethylated with CF3SiMe3, CuI and KF to provide 3-(trifluoromethyl)nitrobenzene (IV) already reported.

1 Robic, N.; Noel, J.P.; Synthesis of [trifluoromethyl-[C-14(6)]-phenyl] SR 57746A. J Label Compd Radiopharm 1999, 42, 2, 109.
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) 13364 Benzene 71-43-2 C6H6 详情 详情
(I) 45201 benzene C6H6 详情 详情
(II) 26344 1-Iodobenzene 591-50-4 C6H5I 详情 详情
(II) 45202 1-iodobenzene C6H5I 详情 详情
(III) 26345 1-(Trifluoromethyl)benzene 98-08-8 C7H5F3 详情 详情
(III) 45203 1-(trifluoromethyl)benzene C7H5F3 详情 详情
(IV) 26346 1-nitro-3-(trifluoromethyl)benzene 98-46-4 C7H4F3NO2 详情 详情
(IV) 45204 1-nitro-3-(trifluoromethyl)benzene C7H4F3NO2 详情 详情
(V) 26347 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride 98-16-8 C7H6F3N 详情 详情
(V) 45205 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline C7H6F3N 详情 详情
(VI) 26348 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride 401-78-5 C7H4BrF3 详情 详情
(VI) 45206 1-bromo-3-(trifluoromethyl)benzene C7H4BrF3 详情 详情
(VII) 12028 Bromo[3-(trifluoromethyl)phenyl]magnesium 402-26-6 C7H4BrF3Mg 详情 详情
(VII) 45207 bromo[3-(trifluoromethyl)phenyl]magnesium C7H4BrF3Mg 详情 详情
(VIII) 26349 1-[2-(2-naphthyl)ethyl]-4-piperidinone C17H19NO 详情 详情
(IX) 26350 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol C24H24F3NO 详情 详情
(IX) 45208 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol C24H24F3NO 详情 详情
(X) 22523 1-nitrobenzene 28250-14-8 C6H5NO2 详情 详情
(X) 45209 1-nitrobenzene C6H5NO2 详情 详情
(XI) 26352 3-Iodonitrobenzene; 1-iodo-3-nitrobenzene 645-00-1 C6H4INO2 详情 详情
(XI) 45210 1-iodo-3-nitrobenzene C6H4INO2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

3-Bromobenzotrifluoride (I) is converted into the corresponding Grignard reagent (II), which is then condensed with 1,2-dibromo-1-methoxyethane (III) producing the phenethyl bromide (IV). Reaction of bromide (IV) with (S)-alpha-methylbenzylamine (V) yields amine (VI) as a diastereomeric mixture. Recrystallization of (VI) from isopropanol leads to a pure diastereoisomer, which is subsequently treated with ethyl bromoacetate to furnish amino ester (VII). Reduction of (VII) using LiAlH4 provides alcohol (VIII), and further chlorination with SOCl2 leads to chloro amine (IX). Acid (X) is then alkylated with chloride (IX) producing ester (XI). The chiral auxiliary alpha-methylbenzyl group is finally removed by hydrogenolysis to afford the title compound.

1 Wierzbicki, M.; Hugon, P.; Duhault, J.; Lacour, F.; Boulanger, M. (ADIR et Cie.); Ethanolaminebenzoate deriv., process for their preparation and pharmaceutical compsns. containing them. EP 0518769; FR 2677647; JP 1993238997; US 5266718 .
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) 26348 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride 401-78-5 C7H4BrF3 详情 详情
(II) 12028 Bromo[3-(trifluoromethyl)phenyl]magnesium 402-26-6 C7H4BrF3Mg 详情 详情
(III) 58091 1,2-dibromo-1-methoxyethane; 1,2-dibromoethyl methyl ether C3H6Br2O 详情 详情
(IV) 58092 1-(2-bromo-1-methoxyethyl)-3-(trifluoromethyl)benzene; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethyl methyl ether C10H10BrF3O 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 58093 2-methoxy-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine; N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1S)-1-phenylethyl]amine C18H20F3NO 详情 详情
(VII) 58094 ethyl 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}acetate C22H26F3NO3 详情 详情
(VIII) 58095 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}-1-ethanol C20H24F3NO2 详情 详情
(IX) 58096 N-(2-chloroethyl)-N-{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}-N-[(1R)-1-phenylethyl]amine; N-(2-chloroethyl)-2-methoxy-N-[(1R)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-1-ethanamine C20H23ClF3NO 详情 详情
(X) 58097 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoic acid C24H21NO3 详情 详情
(XI) 58098 2-{{2-methoxy-2-[3-(trifluoromethyl)phenyl]ethyl}[(1R)-1-phenylethyl]amino}ethyl 4-(2-{[2-(9H-fluoren-9-yl)acetyl]amino}ethyl)benzoate C44H43F3N2O4 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 Lifshitz Liron R. Eisenstadt A, et aL 2006. Process for preparing cinacalcet from 3-(3-trifluoromethylphenyl) propanol. W0 2006125026
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 66204 3-(3-(trifluoromethyl)phenyl)propan-1-ol   C10H11F3O 详情 详情
(I) 26348 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride 401-78-5 C7H4BrF3 详情 详情
(II) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(III) 42936 ethyl (E)-3-[3-(trifluoromethyl)phenyl]-2-propenoate 113048-68-3 C12H11F3O2 详情 详情
(IV) 42937 (E)-3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol C10H9F3O 详情 详情
(VI) 66205 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate   C11H13F3O3S 详情 详情
(VII) 17443 (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine 3886-70-2 C12H13N 详情 详情
Extended Information