4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene -Drug Synthesis Database

【结构式】

【分子编号】52131

【品名】4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene

【CA登记号】402-44-8

【分子式】C₇H₄F₄

【分子量】164.1023728

【元素组成】C 51.23% H 2.46% F 46.31%

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：(VI)

A new enantioselective synthesis of (S)-fluoxetine has been reported: Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III), which were used in the next step without previous separation. The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (S)-1,1'-binaphthol and titanium isopropoxide furnished the target (S)-2-(3-furyl)-1-phenylethanol (V). Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII). Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4. Coupling of acid (VIII) with methylamine gave amide (IX). Finally, amide reduction employing borane in THF yielded the title compound.

参考文献中间体

合成目标

【1】 Miles, W.H.; et al.; Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride. Tetrahedron 2001, 57, 50, 9925.

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)	47247	3-Furaldehyde	498-60-2	C₅H₄O₂	详情	详情
(II)	55641	3-methylene-2,3-dihydrofuran		C₅H₆O	详情	详情
(III)	55642	3-Methylfuran	930-27-8	C₅H₆O	详情	详情
(IV)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(V)	55651	(1S)-2-(3-furyl)-1-phenyl-1-ethanol		C₁₂H₁₂O₂	详情	详情
(VI)	52131	4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene	402-44-8	C₇H₄F₄	详情	详情
(VII)	55652	(1S)-2-(3-furyl)-1-phenylethyl 4-(trifluoromethyl)phenyl ether; 3-{(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl}furan		C₁₉H₁₅F₃O₂	详情	详情
(VIII)	55653	(3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanoic acid		C₁₆H₁₃F₃O₃	详情	详情
(IX)	55654	(3S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanamide		C₁₇H₁₆F₃NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III), which were used in the next step without previous separation. The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (R)-1,1'-binaphthol and titanium isopropoxide furnished the target (R)-2-(3-furyl)-1-phenylethanol (V). Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII). Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4. Coupling of acid (VIII) with methylamine gave amide (IX). Finally, amide reduction employing borane in THF yielded the title compound.

参考文献中间体

合成目标

【1】 Miles, W.H.; et al.; Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride. Tetrahedron 2001, 57, 50, 9925.

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)	47247	3-Furaldehyde	498-60-2	C₅H₄O₂	详情	详情
(II)	55641	3-methylene-2,3-dihydrofuran		C₅H₆O	详情	详情
(III)	55642	3-Methylfuran	930-27-8	C₅H₆O	详情	详情
(IV)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(V)	55643	(1R)-2-(3-furyl)-1-phenyl-1-ethanol		C₁₂H₁₂O₂	详情	详情
(VI)	52131	4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene	402-44-8	C₇H₄F₄	详情	详情
(VII)	55644	(1R)-2-(3-furyl)-1-phenylethyl 4-(trifluoromethyl)phenyl ether; 3-{(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl}furan		C₁₉H₁₅F₃O₂	详情	详情
(VIII)	55645	(3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanoic acid		C₁₆H₁₃F₃O₃	详情	详情
(IX)	55646	(3R)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanamide		C₁₇H₁₆F₃NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Coupling between N-Boc-4-piperidinol (I) and 4-fluorobenzotrifluoride (II) in the presence of cesium carbonate afforded ether (III). Subsequent acidic cleavage of the Boc protecting group of (III) furnished piperidine (IV) (1). Acylation of piperidine (IV) with 3,4-dimethoxybenzenesulfonyl chloride (V) yielded the corresponding sulfonamide (VI). Regioselective metalation of (VI) by means of tert-butyllithium, followed by quenching with dry carbon dioxide gave rise to the carboxylic acid (VII). This was converted to the corresponding acid chloride (VIII) employing oxalyl chloride, and then condensed with O-tetrahydropyranylhydroxylamine (IX). The resultant tetrahydropyranyl-protected hydroxamate (X) was finally deprotected by treatment with an in situ generated solution of methanolic HCl.

参考文献中间体

合成目标

【1】 Barta, T.E.; et al.; Selective, orally active MMP inhibitor with an aryl backbone. Bioorg Med Chem Lett 2001, 11, 18, 2481.
【2】 Villamil, C.I.; Becker, D.P.; Bedell, L.J.; Freskos, J.N.; Rao, S.N.; Getman, D.P.; Decrescenzo, G.A.; Mischke, B.V.; Barta, T.E.; McDonald, J.J. (Pharmacia Corp.); Hydroxamic acid derivs. as matrix metalloprotease inhibitors. EP 1177173; WO 0069819 .

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)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(II)	52131	4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene	402-44-8	C₇H₄F₄	详情	详情
(III)	52132	tert-butyl 4-[4-(trifluoromethyl)phenoxy]-1-piperidinecarboxylate		C₁₇H₂₂F₃NO₃	详情	详情
(IV)	52133	4-[4-(trifluoromethyl)phenoxy]piperidine; 4-piperidinyl 4-(trifluoromethyl)phenyl ether		C₁₂H₁₄F₃NO	详情	详情
(V)	47469	3,4-dimethoxybenzenesulfonyl chloride	23095-31-0	C₈H₉ClO₄S	详情	详情
(VI)	52134	1-[(3,4-dimethoxyphenyl)sulfonyl]-4-piperidinyl 4-(trifluoromethyl)phenyl ether; 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-[4-(trifluoromethyl)phenoxy]piperidine		C₂₀H₂₂F₃NO₅S	详情	详情
(VII)	52135	2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoic acid		C₂₁H₂₂F₃NO₇S	详情	详情
(VIII)	52136	2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoyl chloride		C₂₁H₂₁ClF₃NO₆S	详情	详情
(IX)	52106	2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine		C₅H₁₁NO₂	详情	详情
(X)	52137	2,3-dimethoxy-N-(tetrahydro-2H-pyran-2-yloxy)-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzamide		C₂₆H₃₁F₃N₂O₈S	详情	详情

Extended Information