1-nitro-3-(trifluoromethyl)benzene -Drug Synthesis Database

【结构式】

【分子编号】26346

【品名】1-nitro-3-(trifluoromethyl)benzene

【CA登记号】98-46-4

【分子式】C₇H₄F₃NO₂

【分子量】191.1095096

【元素组成】C 43.99% H 2.11% F 29.82% N 7.33% O 16.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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)

Iodination of 3-(trifluoromethyl)nitrobenzene (I) was accomplished by using N-iodosuccinimide in concentrated sulfuric acid to provide (II), which was then reduced to aniline (III) with SnCl2 in refluxing EtOH. Treatment of aniline (III) with sulfuryl chloride, followed by addition of ethyl (methylthio)acetate and Et3N gave rise to a mixture of regioisomeric 3-(methylthio)oxindoles (IV) and (V). Oxidation of this mixture with CuCl2/CuO generated the respective isatins (VI) and (VII) (1). After N-alkylation with 2-(diethylamino)ethyl chloride and NaH, the desired regioisomer (VIII) could be separated by column chromatography. Addition to (VIII) of the Grignard reagent (IX) provided the racemic 3-aryl-3-hydroxy oxindole (X). The enantiomers of (X) were separated using chiral, preparative HPLC, and the desired (S)-enantiomer (XI) was then converted to nitrile (XII) by iodide displacement with zinc cyanide in the presence of palladium catalyst. Finally, partial hydrolysis of nitrile (XII) with KOH in tert-butanol furnished the title amide

参考文献中间体

合成目标

【1】 Tokunaga, T.; Hume, W.E.; Umezome, T.; Okazaki, K.; Yasuyuki, U.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R.; Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem 2001, 44, 26, 4641.
【2】 Okazaki, K.; Kumagai, K.; Tokunaga, T.; Ueki, Y.; Nagata, R.; Umezome, T.; Hume, W.E. (Sumitomo Pharmaceuticals Co., Ltd.); Oxindole derivs. as growth hormone releasers. EP 1105376; JP 2002523400; WO 0010975 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	16194	2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine	100-35-6	C₆H₁₄ClN	详情	详情
(A)	48543	Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate	4455-13-4	C₅H₁₀O₂S	详情	详情
(I)	26346	1-nitro-3-(trifluoromethyl)benzene	98-46-4	C₇H₄F₃NO₂	详情	详情
(II)	60054	1-iodo-3-nitro-5-(trifluoromethyl)benzene		C₇H₃F₃INO₂	详情	详情
(III)	60055	3-iodo-5-(trifluoromethyl)phenylamine; 3-iodo-5-(trifluoromethyl)aniline		C₇H₅F₃IN	详情	详情
(IV)	60057	4-iodo-3-(methylsulfanyl)-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₀H₇F₃INOS	详情	详情
(V)	60056	6-iodo-3-(methylsulfanyl)-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₀H₇F₃INOS	详情	详情
(VI)	60059	4-iodo-6-(trifluoromethyl)-1H-indole-2,3-dione		C₉H₃F₃INO₂	详情	详情
(VII)	60058	6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione		C₉H₃F₃INO₂	详情	详情
(VIII)	60060	1-[2-(diethylamino)ethyl]-6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione		C₁₅H₁₆F₃IN₂O₂	详情	详情
(IX)	60061	(2-chlorophenyl)(iodo)magnesium		C₆H₄ClIMg	详情	详情
(X)	60062	3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₂₁H₂₁ClF₃IN₂O₂	详情	详情
(XI)	60063	(3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₂₁H₂₁ClF₃IN₂O₂	详情	详情
(XII)	60064	(3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indole-6-carbonitrile		C₂₂H₂₁ClF₃N₃O₂	详情	详情

Extended Information