3,4-dimethylpyridine -Drug Synthesis Database

【结构式】

【分子编号】39869

【品名】3,4-dimethylpyridine

【CA登记号】583-58-4

【分子式】C₇H₉N

【分子量】107.1552

【元素组成】C 78.46% H 8.47% N 13.07%

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：(XV)

The condensation of 3,4-dimethylpyridine (XV) with 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-chlorobutane (XVI) gives the corresponding pyridinium salt (XVII), which by reaction with p-methoxybenzylmagnesium chloride (I) in ether yields the dihydropyridine (XVIII). The reduction of (XVIII) with NaBH4 in methanol affords the tetrahydropyridine (XIX), which is finally cyclized by refluxing with AlBr3 in CS2; this reaction can also be performed by heating (XIX) with 48% aqueous HBr at 130 C.

参考文献中间体

合成目标

【1】 Atsumi, T.; et al. (Sumitomo Chemical Co., Ltd.); Preparation of 2-benzoylalkylbenzomorphan. DE 2128525; FR 2100743; GB 1329504; US 3953441 .
【2】 Castaner, J.; Paton, D.M.; ID-1229. Drugs Fut 1978, 3, 4, 298.

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)	39855	chloro(4-methoxybenzyl)magnesium		C₈H₉ClMgO	详情	详情
(XV)	39869	3,4-dimethylpyridine	583-58-4	C₇H₉N	详情	详情
(XVI)	28203	2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane	3308-94-9	C₁₂H₁₄ClFO₂	详情	详情
(XVII)	39870	1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3,4-dimethylpyridinium chloride		C₁₉H₂₃ClFNO₂	详情	详情
(XVIII)	39871	1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-2-(4-methoxybenzyl)-3,4-dimethyl-1,2-dihydropyridine; 4-[(1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3,4-dimethyl-1,2-dihydro-2-pyridinyl)methyl]phenyl methyl ether		C₂₇H₃₂FNO₃	详情	详情
(XIX)	39872	1-(4-fluorophenyl)-4-[6-(4-methoxybenzyl)-4,5-dimethyl-3,6-dihydro-1(2H)-pyridinyl]-1-butanone		C₂₅H₃₀FNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Metallation of 1,4-dibromobenzene (I) followed by addition to hexafluoroacetone afforded the bis(trifluoromethyl)carbinol (II), which was subsequently protected as the trimethylsilylethoxymethyl ether (III). 3,4-Dihydroxybenzaldehyde (IV) was alkylated with either chlorodifluoromethane or methyl chlorodifluoroacetate to give the bis(difluoromethyl)ether (V). Addition of either the organolithium or Grignard reagent prepared from aryl bromide (III) to aldehyde (V) furnished the diaryl carbinol (VI), which was converted to chloride (VII) by treatment with SOCl2 and diisopropyl ethylamine. Selective carbomethoxylation of 3,4-dimethylpyridine (VIII) using dimethyl carbonate and LDA afforded (IX). Condensation of chloride (VII) with the lithium anion of (IX) yielded the triarylpropionate derivative (X). Ester group hydrolysis with LiOH, followed by acidification with NH4Cl, provided the decarboxylated compound (XI). After SEM group cleavage by treatment with tetrabutylammonium fluoride, the pyridine ring of the resulting (XII) was finally oxidized to the target N-oxide.

参考文献中间体

合成目标

【2】 Guay, D.; Ducharme, Y.; Blouin, M.; Hamel, P.; Girard, M. (Merck Frosst Canada Inc.); Tri-aryl ethane derivs. as PDE IV inhibitors. EP 0873311; JP 2000501742; US 5710170; WO 9722586 .
【1】 Brideau, C.; Ducharme, Y.; Blouin, M.; et al.; Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-12.

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)	18983	1,4-dibromobenzene	106-37-6	C₆H₄Br₂	详情	详情
(II)	45834	2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol		C₉H₅BrF₆O	详情	详情
(III)	45835	[1-(4-bromophenyl)-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether; (2-[[1-(4-bromophenyl)-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methoxy]ethyl)(trimethyl)silane		C₁₅H₁₉BrF₆O₂Si	详情	详情
(IV)	39749	3,4-dihydroxybenzaldehyde	139-85-5	C₇H₆O₃	详情	详情
(V)	45836	3,4-bis(difluoromethoxy)benzaldehyde		C₉H₆F₄O₃	详情	详情
(VI)	45837	[3,4-bis(difluoromethoxy)phenyl][4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]methanol	597-43-3	C₂₄H₂₆F₁₀O₅Si	详情	详情
(VII)	45838	[1-[4-[[3,4-bis(difluoromethoxy)phenyl](chloro)methyl]phenyl]-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether; (2-[[1-[4-[[3,4-bis(difluoromethoxy)phenyl](chloro)methyl]phenyl]-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methoxy]ethyl)(trimethyl)silane		C₂₄H₂₅ClF₁₀O₄Si	详情	详情
(VIII)	39869	3,4-dimethylpyridine	583-58-4	C₇H₉N	详情	详情
(IX)	45839	methyl 2-(3-methyl-4-pyridinyl)acetate		C₉H₁₁NO₂	详情	详情
(X)	45840	methyl 3-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)-3-[4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]propanoate		C₃₃H₃₅F₁₀NO₆Si	详情	详情
(XI)	45841	4-[2-[3,4-bis(difluoromethoxy)phenyl]-2-[4-(2,2,2-trifluoro-1-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methoxy]ethyl)phenyl]ethyl]-3-methylpyridine; [1-[4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)ethyl]phenyl]-2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether		C₃₁H₃₃F₁₀NO₄Si	详情	详情
(XII)	45842	2-[4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-4-pyridinyl)ethyl]phenyl]-1,1,1,3,3,3-hexafluoro-2-propanol		C₂₅H₁₉F₁₀NO₃	详情	详情

Extended Information