3-(trifluoromethyl)benzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】35964

【品名】3-(trifluoromethyl)benzaldehyde

【CA登记号】454-89-7

【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 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：(I)

The reaction of 3-trifluoromethylbenzaldehyde (I) with morpholine (II) and potassium cyanide by means of p-toluenesulfonic acid in refluxing THF gives alpha-(3-trifluoromethylphenyl)-4-morpholineacetonitrile (III), which is condensed with ethyl acrylate (IV) by means of KOH in THF yielding gamma-cyano-gamma-(3-trifluoromethylphenyl)-4-morpholinebutyric acid ethyl ester (V). The cyclization of (V) with hydrazine in refluxing ethanol affords 4,5-dihydro-6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VI), which is dehydrogenated by treatment with Br2 in hot acetic acid to give 6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VII). The reaction of (VII) with POCl3 at 100 C affords 3-chloro-6-(3-trifluoromethylphenyl)pyridazine (VIII), which is finally cyclized with acetylhydrazine (IX) in refluxing n-butanol.

参考文献中间体

合成目标

【1】 Allen, G.R. Jr.; Hanifin, J.W. Jr.; Moran, D.B.; Albright, J.D.; 6-Phenyl-1,2,4-triazolo{8 4,3-b{9 pyridazine hypotensive agents. US 4112095 .
【2】 Albright, J.D.; et al.; Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines. J Med Chem 1981, 24, 5, 592-600.
【3】 Owen, R.T.; Serradell, M.N.; Blancafort, P.; Castaner, J.; CL-218,872. Drugs Fut 1983, 8, 3, 191.

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)	35964	3-(trifluoromethyl)benzaldehyde	454-89-7	C₈H₅F₃O	详情	详情
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(III)	35965	2-(4-morpholinyl)-2-[3-(trifluoromethyl)phenyl]acetonitrile		C₁₃H₁₃F₃N₂O	详情	详情
(IV)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(V)	35966	ethyl 4-cyano-4-(4-morpholinyl)-4-[3-(trifluoromethyl)phenyl]butanoate		C₁₈H₂₁F₃N₂O₃	详情	详情
(VI)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(VII)	35968	6-[3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone		C₁₁H₇F₃N₂O	详情	详情
(VIII)	35969	3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine		C₁₁H₆ClF₃N₂	详情	详情
(IX)	29262	acetohydrazide	1068-57-1	C₂H₆N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of 3-(trifluoromethyl)benzaldehyde (I) with phosphonate (II) by means of NaH in THF gives the unsaturated ester (III), which is reduced with DIBAL in ethyl ether / hexane, yielding 3-[3-(trifluoromethyl)phenyl]allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) affords the epoxyalcohol (V), which is oxidized with pyridine·SO3 to the corresponding aldehyde and condensed with phosphorane (A) to provide the unsaturated epoxyaldehyde (VI). The condensation of aldehyde (VI) with the pentylphosphonium derivative (VII) by means of NaNH2 in THF gives the corresponding adduct (VIII). The addition of 4-oxo-7-sulfanyl-4H-1-benzopyran-2-carboxylic acid methyl ester (IX) to the epoxide group of (VIII) by means of Et3N in methanol yields the expected alpha-hydroxy thioether (X), which is finally hydrolyzed with NaOH in THF/water to afford the target sodium salt. The intermediate pentylphosphonium derivative (VII) has been obtained by selective alkylation of 2,4-dihydroxy-3-propylacetophenone (XI) with 1,5-dibromopentane (XII) followed by reaction of the resulting ether with triphenylphosphine in refluxing toluene.

参考文献中间体

合成目标

【1】 Von Sprecher, A.; Beck, A.; Sallmann, A.; Breitenstein, W.; Wiestner, H.; Kimmel, S.; Anderson, G.P.; Subramanian, N.; Bray, M.A.; Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A. Drugs Fut 1991, 16, 9, 827.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	20110	2-(triphenylphosphoranyl)acetaldehyde		C₂₀H₁₉OP	详情	详情
(I)	35964	3-(trifluoromethyl)benzaldehyde	454-89-7	C₈H₅F₃O	详情	详情
(II)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	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
(V)	42938	[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]methanol		C₁₀H₉F₃O₂	详情	详情
(VI)	42939	(E)-3-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-2-propenal		C₁₂H₉F₃O₂	详情	详情
(VII)	42940	[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl](triphenyl)phosphonium bromide		C₃₄H₃₈BrO₃P	详情	详情
(VIII)	42941	1-[2-hydroxy-3-propyl-4-[((5Z,7E)-8-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-5,7-octadienyl)oxy]phenyl]-1-ethanone		C₂₈H₃₁F₃O₄	详情	详情
(IX)	42942	methyl 4-oxo-7-sulfanyl-4H-chromene-2-carboxylate		C₁₁H₈O₄S	详情	详情
(X)	42943	methyl 7-[((1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(R)-hydroxy[3-(trifluoromethyl)phenyl]methyl]-2,4-nonadienyl)sulfanyl]-4-oxo-4H-chromene-2-carboxylate		C₃₉H₃₉F₃O₈S	详情	详情
(XI)	13137	2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone	40786-69-4	C₁₁H₁₄O₃	详情	详情
(XII)	30560	1,5-dibromopentane	111-24-0	C₅H₁₀Br₂	详情	详情

Extended Information