4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde -Drug Synthesis Database

【结构式】

【分子编号】13380

【品名】4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde

【CA登记号】455-19-6

【分子式】C₈H₅F₃O

【分子量】174.1223096

【元素组成】C 55.18% H 2.89% F 32.73% O 9.19%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The Grignard reaction of 4-(trifluoromethyl)benzaldehyde (I) with ethylmagnesium bromide in ethyl ether gives 1-[4-(trifluoromethyl)phenyl]-1-propanol (II), which is oxidized with CrO3/H2SO4 yielding 4-(trifluoromethyl)propiophenone (III). The condensation of (III) with pyrrolidine (IV) and paraformaldehyde by means of HCl in refluxing isopropanol affords racemic 2-methyl-3-(1-pyrrolidinyl)propiophenone (V), which is finally submitted to optical resolution with N-acetyl-L-phenylglycine (VI) or D-malic acid (VII) and treated with dry HCl gas.

参考文献中间体

合成目标

【1】 Kurashige, S.; Izumi, G.; Shiozawa, A.; Narita, K.; Sakitama, K.; Ishikawa, M.; Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants. Eur J Med Chem 1995, 30, 1, 85-94.
【2】 Wroblewskki, T.; Castaner, J.; Leeson, P.; Lanperisone Hydrochloride. Drugs Fut 1998, 23, 5, 485.
【3】 Shiozawa, A.; Ishikawa, M.; Sugimura, H.; Yamamoto, H.; Sakasai, T.; Ohtsuki, K.; Kurashige, S. (Nippon Kayaku Co., Ltd.); An optically active propanone deriv. and process for producing the same and use thereof. EP 0266577; JP 1989131171 .

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)	13380	4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde	455-19-6	C₈H₅F₃O	详情	详情
(II)	13381	1-[4-(Trifluoromethyl)phenyl]-1-propanol		C₁₀H₁₁F₃O	详情	详情
(III)	13382	1-[4-(Trifluoromethyl)phenyl]-1-propanone; 4-(Trifluoromethyl)propiophenone	711-33-1	C₁₀H₉F₃O	详情	详情
(IV)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(V)	13384	2-Methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone		C₁₅H₁₈F₃NO	详情	详情
(VI)	13385	(2S)-2-(Acetamido)-2-phenylethanoic acid		C₁₀H₁₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

In a different approach, addition of isopropylmagnesium bromide to 4-(trifluoromethyl)benzaldehyde (V) afforded alcohol (VI), which was further oxidized to the corresponding ketone (VII) by treatment with pyridinium chlorochromate. Bromination of 4'-(trifluoromethyl)isobutyrophenone (VII) in HOAc provided bromo ketone (VIII). Sulfide (IV) was then obtained by displacement of the bromide group of (VIII) with sodium methanethiolate.

参考文献中间体

合成目标

【1】 Tokizawa, M.; Kanamaru, Y.; Matsumoto, M.; Asaoka, T.; Matsuda, H.; Kuraishi, T.; Maebashi, K.; Taido, N.; Kawahara, R. (SSP Co., Ltd.); Triazole derivs.. EP 0435081; JP 1991223266; US 5147886 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	56166	2-methyl-2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone		C₁₂H₁₃F₃OS	详情	详情
(V)	13380	4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde	455-19-6	C₈H₅F₃O	详情	详情
(VI)	56167	2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanol		C₁₁H₁₃F₃O	详情	详情
(VII)	56168	2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanone		C₁₁H₁₁F₃O	详情	详情
(VIII)	56169	2-bromo-2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanone		C₁₁H₁₀BrF₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

1,1-Dibromo-3,3,3-trifluoroacetone (I) is treated with a hot aqueous solution of sodium acetate, and subsequently condensed with 4-(trifluoromethyl)benzaldehyde (II) in the presence of ammonium hydroxide to furnish the trifluoromethyl imidazole (III). The imidazole trifluoromethyl group of (III) is then selectively converted to nitrile (IV) upon heating with a methanolic solution of ammonium hydroxide. Reduction of the cyano group of (IV) employing DIBAL in cold THF leads to aldehyde (V). This is finally converted to the target nitrone by condensation with N-tert-butyl hydroxylamine.

参考文献中间体

合成目标

【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165.
【2】 Dhainaut, A.; Lestage, P.; Lockhart, B.; Tizot, A.; Goldstein, S. (ADIR et Cie.); Nitrone derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2274621; EP 0967207; FR 2780404; JP 2000026428; US 6034250 .

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)	35450	3,3-dibromo-1,1,1-trifluoroacetone	431-67-4	C₃HBr₂F₃O	详情	详情
(II)	13380	4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde	455-19-6	C₈H₅F₃O	详情	详情
(III)	57671	4-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-1H-imidazole		C₁₁H₆F₆N₂	详情	详情
(IV)	57672	2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carbonitrile		C₁₁H₆F₃N₃	详情	详情
(V)	57673	2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carbaldehyde		C₁₁H₇F₃N₂O	详情	详情

Extended Information