4-Bromostyrene; p-Bromostyrene -Drug Synthesis Database

【结构式】

【分子编号】49237

【品名】4-Bromostyrene; p-Bromostyrene

【CA登记号】2039-82-9

【分子式】C₈H₇Br

【分子量】183.04758

【元素组成】C 52.49% H 3.85% Br 43.65%

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：(I)

Polymerization of p-bromostyrene (I) in refluxing benzene in the presence of benzoyl peroxide affords poly(p-bromostyrene) (II) (1), which undergoes metalation to the polystyryl lithium (III) by treatment with butyl lithium in THF or benzene (1, 2). Exposure of (III) to sulfur dioxide atmosphere generates an intermediate polysulfinic acid (IV), which spontaneously oxidizes to the sulfonic acid tolevamer (3). Tolevamer is reported to dissolve in basic solutions to form the corresponding salts (3). Scheme 1.

参考文献中间体

合成目标

【1】 Trefouel, M.J. Sur une préparation de polyparabutylstyrène. Compt Rend 1959, 248: 800-2.
【2】 Trefouel, M.J. Sur la conversion partielle du polyparabromostyrène en acide polystyrèneparacarboxylique. Compt Rend 1960, 250: 2209-10.
【3】 Trefouel, M.J. Sur une préparation d’acide polystyrèneparasulfonique. Compt Rend 1960, 250: 3839-40.

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)	49237	4-Bromostyrene; p-Bromostyrene	2039-82-9	C₈H₇Br	详情	详情
(II)	65361	Poly(p-bromostyrene)		(C₆H₇Br)n	详情	详情
(III)	65362	Polystyryl lithium		(C₆H₇Li)n	详情	详情
(IV)	65363			(C₆H₇LiO₂S)n	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The reaction of cyclohexanone (I) with acrylonitrile (II) by means of pyrrolidine gives 3-(2-oxocyclohexyl)propionitrile (III), which is condensed with methoxymethyltriphenylphosphonium chloride (IV) in THF to yield the methoxymethylene derivative (V). The condensation of propionitrile (V) with 4-bromostyrene (VI) by means of n-BuLi ethyl ether affords the styryl ketone (VII), which is cyclized by means of triphenyl phosphite and O3 (or air, methylene blue and light) to provide trioxane (VIII) as a diastereomeric mixture that is separated by column chromatography. Finally, the vinyl group of the desired diastereomer (VIII) is oxidized with KMnO4 in acetone to afford the target compound.

参考文献中间体

合成目标

【1】 Parker, M.H.; Krasavin, M.; Posner, G.H.; Paik, I.-H.; Jeon, H.B.; Shapiro, T.A.; Antimalarial simplified 3-aryltrioxanes: Synthesis and preclinical efficacy/toxicity testing in rodents. J Med Chem 2001, 44, 19, 3054.
【2】 Posner, G.H.; Shapiro, T.A.; Parker, M.H.; Krasavin, M. (Johns Hopkins University); Water-soluble trioxanes as potent and safe antimalarial agents. US 6136847; WO 0059501 .

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)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(II)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(III)	49235	2-(beta-Cyanoethyl)cyclohexanone		C₉H₁₃NO	详情	详情
(IV)	39163	(methoxymethyl)(triphenyl)phosphonium chloride	4009-98-7	C₂₀H₂₀ClOP	详情	详情
(V)	49236	3-[2-[(Z)-methoxymethylidene]cyclohexyl]propanenitrile		C₁₁H₁₇NO	详情	详情
(VI)	49237	4-Bromostyrene; p-Bromostyrene	2039-82-9	C₈H₇Br	详情	详情
(VII)	49238	3-[2-[(Z)-methoxymethylidene]cyclohexyl]-1-(4-vinylphenyl)-1-propanone		C₁₉H₂₄O₂	详情	详情
(VIII)	49239	(1S,6R,9S,12R)-12-methoxy-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridecane; methyl (1S,6R,9S,12R)-6-methyl-9-(4-vinylphenyl)-10,11,13-trioxatricyclo[7.2.2.0(1,6)]tridec-12-yl ether		C₂₀H₂₆O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Michael addition of acrylonitrile to the enamine resultant from cyclohexanone (I) and pyrrolidine, followed by alkylation with ethyl bromoacetate, leads to the cyano ester (II). Subsequent Wittig reaction of (II) with methoxymethylene triphenylphosphorane affords the enol ether (III). The ester group of (III) is then reduced to alcohol (IV) using L-selectride. Further intramolecular cyclization of (IV) under acidic conditions gives rise to the bicyclic compound (V). Lithiation of p-bromostyrene (VI) with tert-butyllithium, followed by addition to nitrile (V) produces the ketone adduct (VII). Photooxygenation of (VII), followed by cyclization in the presence of trimethylsilyl triflate, furnishes the fused trioxane derivative (VIII). Finally, oxidative cleavage of the vinyl group of (VIII) with potassium permanganate yields the target carboxylic acid.

参考文献中间体

合成目标

【1】 Paik, I.-H.; Posner, G.H.; Jeon, H.B.; Shapiro, T.A.; Xie, S.; Borstnik, K.; Ploypradith, P.; Orally active, water-soluble antimalarial 3-aryltrioxanes: Short synthesis and preclinical efficacy testing in rodents. J Med Chem 2002, 45, 18, 3824.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	57612	ethyl 2-{3-(2-cyanoethyl)-2-[(Z)-methoxymethylidene]cyclohexyl}acetate		C₁₅H₂₃NO₃	详情	详情
(IIIb)	57613	ethyl 2-{3-(2-cyanoethyl)-2-[(E)-methoxymethylidene]cyclohexyl}acetate		C₁₅H₂₃NO₃	详情	详情
(IVa)	57614	3-{(1R,3S)-3-(2-hydroxyethyl)-2-[(Z)-methoxymethylidene]cyclohexyl}propanenitrile		C₁₃H₂₁NO₂	详情	详情
(IVb)	57615	3-{(1R,3S)-3-(2-hydroxyethyl)-2-[(E)-methoxymethylidene]cyclohexyl}propanenitrile		C₁₃H₂₁NO₂	详情	详情
(I)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(II)	57611	ethyl 2-[3-(2-cyanoethyl)-2-oxocyclohexyl]acetate		C₁₃H₁₉NO₃	详情	详情
(V)	57616	3-[(4aS,8R)-4,4a,5,6,7,8-hexahydro-3H-isochromen-8-yl]propanenitrile		C₁₂H₁₇NO	详情	详情
(VI)	49237	4-Bromostyrene; p-Bromostyrene	2039-82-9	C₈H₇Br	详情	详情
(VII)	57617	3-[(4aS,8R)-4,4a,5,6,7,8-hexahydro-3H-isochromen-8-yl]-1-(4-vinylphenyl)-1-propanone		C₂₀H₂₄O₂	详情	详情
(VIII)	57618	(1S,4R,8S,12R,13R)-1-(4-vinylphenyl)-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecane		C₂₀H₂₄O₄	详情	详情

Extended Information