4-Bromochlorobenzene; 1-bromo-4-chlorobenzene -Drug Synthesis Database

【结构式】

【分子编号】14733

【品名】4-Bromochlorobenzene; 1-bromo-4-chlorobenzene

【CA登记号】106-39-8

【分子式】C₆H₄BrCl

【分子量】191.45446

【元素组成】C 37.64% H 2.11% Br 41.74% Cl 18.52%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The metalation of 4-chlorobromobenzene (I) with lithium gives 4-chlorophenyllithium (II), which is condensed with dimethyl squarate (III) in THF at -78 C giving 4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-2-cyclobuten-1-one (IV). The isomerization of (IV) in refluxing xylene (38 C) affords naphthohydroquinone (VI) through the intermediate ketene (V). Finally, compound (VI) is acetylated with acetic anhydride in pyridine - dimethylaminopyridine.

参考文献中间体

合成目标

【1】 Perri, S.T.; Moore, H.W.; Synthesis of lonapalene. Tetrahedron Lett 1987, 28, 39, 4507-10.

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)	14733	4-Bromochlorobenzene; 1-bromo-4-chlorobenzene	106-39-8	C₆H₄BrCl	详情	详情
(II)	19396	(4-chlorophenyl)lithium		C₆H₄ClLi	详情	详情
(III)	19999	3,4-dimethoxy-3-cyclobutene-1,2-dione	5222-73-1	C₆H₆O₄	详情	详情
(IV)	20000	4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-2-cyclobuten-1-one		C₁₂H₁₁ClO₄	详情	详情
(V)	20001	(3Z)-4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-1,3-butadien-1-one		C₁₂H₁₁ClO₄	详情	详情
(VI)	20002	6-chloro-2,3-dimethoxy-1,4-naphthalenediol		C₁₂H₁₁ClO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The reaction of 3-chloro-4-nitrobenzoic acid (I) with methylamine gives 3-(methylamino)-4-nitrobenzoic acid (II), which is hydrogenated in the presence of Raney Nickel to yield 4-amino-3-(methylamino)benzoic acid (III). Treatment of compound (III) with sodium nitrite affords 1-methyl-1H-benzotriazole-6-carboxylic acid (IV), which is reduced with lithium aluminum hydride in THF to give 6-(hydroxymethyl)-1-methyl-1H-benzotriazole (V). Oxidation of (V) with potassium permanganate in dichloroethane yields 1-methyl-1H-benzotriazole-6-carboxaldehyde (VI), which on treatment with the Grignard reagent derived from 1-bromo-4-chlorobenzene (VII) gives 6-(4-chloro-alpha-hydroxybenzyl)-1-methyl-1H-benzotriazole (VIII). Treatment of compound (VIII) with thionyl chloride in THF yields 6-(alpha,4-dichlorobenzyl)-1-methyl-1H-benzotriazole (IX), which is finally condensed with 1,2,4-triazole (X) and sodium hydride in DMF.

参考文献中间体

合成目标

【1】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Van Gelder, J.L.H.; Vener, M.G. (Janssen Pharmaceutica NV); (1H-Arol-1-ylmethyl)substd. Benzotriazole derivatives. AU 8816537; EP 0293978; JP 1988316775 .
【2】 Graul, A.; Prous, J.; Castaner, J.; Vorozole. Drugs Fut 1994, 19, 5, 457.

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)	14727	3-chloro-4-nitrobenzoic acid		C₇H₄ClNO₄	详情	详情
(II)	14728	3-(methylamino)-4-nitrobenzoic acid		C₈H₈N₂O₄	详情	详情
(III)	14729	4-amino-3-(methylamino)benzoic acid		C₈H₁₀N₂O₂	详情	详情
(IV)	14730	1-methyl-1H-1,2,3-benzotriazole-6-carboxylic acid		C₈H₇N₃O₂	详情	详情
(V)	14731	(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol		C₈H₉N₃O	详情	详情
(VI)	14732	1-methyl-1H-1,2,3-benzotriazole-6-carbaldehyde		C₈H₇N₃O	详情	详情
(VII)	14733	4-Bromochlorobenzene; 1-bromo-4-chlorobenzene	106-39-8	C₆H₄BrCl	详情	详情
(VIII)	14734	(4-chlorophenyl)(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol		C₁₄H₁₂ClN₃O	详情	详情
(IX)	14735	6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-1,2,3-benzotriazole		C₁₄H₁₁Cl₂N₃	详情	详情
(X)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Grignard reagent (II), prepared from 4-chlorobromobenzene (I) and Mg in refluxing THF, was coupled with 1,10-dibromodecane (III) in the presence of Li2CuCl4 as the catalyst to afford the bromodecyl compound (IV). Then, the dianion of dichloroacetic acid (V), generated in the presence of two equivalents of LDA in cold THF, was alkylated with bromide (IV) to provide the title compound.

参考文献中间体

合成目标

【1】 Meyer, K.; et al.; omega-Substituted alkyl carboxylic acids as antidiabetic and lipid-lowering agents. Eur J Med Chem 1998, 33, 10, 775.

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)	14733	4-Bromochlorobenzene; 1-bromo-4-chlorobenzene	106-39-8	C₆H₄BrCl	详情	详情
(II)	25127	bromo(4-chlorophenyl)magnesium	873-77-8	C₆H₄BrClMg	详情	详情
(III)	18615	1,10-dibromodecane	4101-68-2	C₁₀H₂₀Br₂	详情	详情
(IV)	25128	1-(10-bromodecyl)-4-chlorobenzene		C₁₆H₂₄BrCl	详情	详情
(V)	25129	2,2-dichloroacetic acid	79-43-6	C₂H₂Cl₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

Darzen’s condensation of 4,4'-dichlorobenzophenone (I) with ethyl chloroacetate (II) produced the glycidic ester (III), which was subsequently converted to aldehyde (IV) upon treatment with KOH. Diol (V) was then obtained by Tollens’ reaction of aldehyde (IV) with formaldehyde. Ethyl 4-chlorophenylglyoxylate (VII) was prepared by addition of the Grignard reagent prepared from 1-bromo-4-chlorobenzene (VI) to diethyl oxalate. The condensation between diol (V) and keto ester (VII) in the presence of boron trifluoride furnished the cyclic ketal (VIII). Finally, saponification of the ethyl ester group gave rise to the target carboxylic acid.

参考文献中间体

合成目标

【1】 Al Hazaa, A.; et al.; ZD1839 (Iressa(TM)), an EGFR-TKI, and cisplatin have an additive effect on programmed cell death in human head and neck squamous carcinoma cells in vitro. Clin Cancer Res 2000, 6, Suppl., Poster Nº 308.
【2】 Zeiller, J.-J.; Raspé, E.; Guerrier, D.; Berthelon, J.-J. (Merck Patent GmbH); Cyclic cpds. useful in the treatment of dyslipidaemia, atherosclerosis and diabetes, pharmaceutical compsns. and preparation process. EP 1098893; FR 2781222; WO 0004011 .

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)	47449	bis(4-chlorophenyl)methanone	90-98-2	C₁₃H₈Cl₂O	详情	详情
(II)	16601	ethyl chloroacetate; ethyl 2-chloroacetate	105-39-5	C₄H₇ClO₂	详情	详情
(III)	47450	ethyl 3,3-bis(4-chlorophenyl)-2-oxiranecarboxylate		C₁₇H₁₄Cl₂O₃	详情	详情
(IV)	47451	2,2-bis(4-chlorophenyl)acetaldehyde		C₁₄H₁₀Cl₂O	详情	详情
(V)	47452	2,2-bis(4-chlorophenyl)-1,3-propanediol		C₁₅H₁₄Cl₂O₂	详情	详情
(VI)	14733	4-Bromochlorobenzene; 1-bromo-4-chlorobenzene	106-39-8	C₆H₄BrCl	详情	详情
(VII)	47453	ethyl 2-(4-chlorophenyl)-2-oxoacetate		C₁₀H₉ClO₃	详情	详情
(VIII)	47454	ethyl 2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylate		C₂₅H₂₁Cl₃O₄	详情	详情

Extended Information