1,4-dibromobenzene -Drug Synthesis Database

【结构式】

【分子编号】18983

【品名】1,4-dibromobenzene

【CA登记号】106-37-6

【分子式】C₆H₄Br₂

【分子量】235.90576

【元素组成】C 30.55% H 1.71% Br 67.74%

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：(IX)

The etherification of hydroquinone (I) with 2,2,2-trifluoroethyl trifluoromethanesulfonate (II) by means of K2CO3 in refluxing acetone gives the corresponding diether (III), which is submitted to a Friedel-Crafts condensation with Ac-Cl or Ac2O and AlCl3 in dichloromethane yielding the acetophenone (IV). The chlorination of (IV) with Cl2 in acetic acid at 55 C gives the alpha, alpha-dichloroacetophenone (V), which is further chlorinated with Cl2 and NaOAc in acetic acid at 100 C affording the corresponding trichloro derivative (VI). The reaction of (VI) with 2-(aminomethyl)pyridine (VII) in cyclohexane/toluene or isopropanol furnishes the benzamide (VIII), which is finally hydrogenated with H2 over Pt/C in isopropanol/acetic acid to give the target piperidine derivative.

参考文献中间体

合成目标

【1】 Leir, C.M. (3M Pharmaceuticals); Process for the preparation of derivs. of pyrrolidine and piperidine. US 4642384 .

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)	13163	p-Dihydrobenzene; Hydroquinone	123-31-9	C₆H₆O₂	详情	详情
(II)	40675	2,2,2-trifluoroethyl trifluoromethanesulfonate	6226-25-1	C₃H₂F₆O₃S	详情	详情
(III)	40737	1,4-bis(2,2,2-trifluoroethoxy)benzene; 4-(2,2,2-trifluoroethoxy)phenyl 2,2,2-trifluoroethyl ether	66300-61-6	C₁₀H₈F₆O₂	详情	详情
(IV)	40738	1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1-ethanone	76784-40-2	C₁₂H₁₀F₆O₃	详情	详情
(V)	40739	1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2-dichloro-1-ethanone		C₁₂H₈Cl₂F₆O₃	详情	详情
(VI)	40740	1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2,2-trichloro-1-ethanone	76784-42-4	C₁₂H₇Cl₃F₆O₃	详情	详情
(VII)	13582	2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine	3731-51-9	C₆H₈N₂	详情	详情
(VIII)	33970	N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide		C₁₇H₁₄F₆N₂O₃	详情	详情
(IX)	18983	1,4-dibromobenzene	106-37-6	C₆H₄Br₂	详情	详情
(X)	19483	2,2,2-trifluoro-1-ethanol	75-89-8	C₂H₃F₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Grignard reagent (II) prepared from 1,4-dibromobenzene (I) was condensed with biphenylaldehyde (III) to afford alcohol (IV), which was oxidized to ketone (V) under Swern conditions with oxalyl chloride and DMSO at low temperature. Then, allylic bromination with N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) gave (VI). Finally, N-allyl-N-methylamine (VII) was alkylated with bromide (VI) to provide the tertiary amine.

参考文献中间体

合成目标

【1】 Aebi, J.; Guerry, P.; Jolidon, S.; Morand, O. (F. Hoffmann-La Roche AG); Use of phenylalkylamines for producing cholesterol lowering agents. EP 0636367; JP 1995053479; US 5637771 .

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)	18984	bromo(4-bromophenyl)magnesium		C₆H₄Br₂Mg	详情	详情
(III)	18985	4'-methyl[1,1'-biphenyl]-4-carbaldehyde		C₁₄H₁₂O	详情	详情
(IV)	18986	(4-bromophenyl)(4'-methyl[1,1'-biphenyl]-4-yl)methanol		C₂₀H₁₇BrO	详情	详情
(V)	18987	(4-bromophenyl)(4'-methyl[1,1'-biphenyl]-4-yl)methanone		C₂₀H₁₅BrO	详情	详情
(VI)	18988	[4'-(bromomethyl)[1,1'-biphenyl]-4-yl](4-bromophenyl)methanone		C₂₀H₁₄Br₂O	详情	详情
(VII)	18989	N-allyl-N-methylamine; N-methyl-2-propen-1-amine	627-37-2	C₄H₉N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

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