2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid -Drug Synthesis Database

【结构式】

【分子编号】21130

【品名】2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid

【CA登记号】90-27-7

【分子式】C₁₀H₁₂O₂

【分子量】164.20408

【元素组成】C 73.15% H 7.37% O 19.49%

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：(A)

Initially, a small-scale synthetic route to idoxifene had been described involving Friedel-Crafts acylation of 2-chloroethoxybenzene by 2-phenylbutyric acid followed by reaction of the resulting ketone with 4-iodophenyllithium (prepared by monolithiation of 1,4-diiodobenzene) . A mixture of E and Z isomers of the triphenylbutene was then produced by dehydration of the intermediate tertiary alcohol from which the desired E isomer (in which the unsubstituted phenyl and iodophenyl residues are in a trans relationship) was separated by crystallization. Idoxifene was then produced by final modification of the chloroethoxy side chain using pyrrolidine. Modification of the above scheme to provide an efficient, large-scale synthesis of idoxifene has now been described initially involving treatment of 2-phenoxyethanol with pyridine (in catalytic amounts) and thionyl chloride/heat to produce 2-chloroethoxybenzene.

参考文献中间体

合成目标

【1】 Kelland, L.R.; Jarman, M.; Idoxifene. Drugs Fut 1995, 20, 7, 666.
【2】 Potter, G.A.; Jarman, M.; McCague, R.; An efficient, large-scale synthesis of idoxifene ((E)-1-[4-[N-(pyrrolidino)ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene). Org Prep Proced Int 1994, 26, 343-6.
【3】 McCague, R. (National Research Development Corp.); Tamoxifen derivs. EP 0260066; GB 2196003; JP 1988077845 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	12844	(4-Iodophenyl)lithium		C₆H₄ILi	详情	详情
(A)	21130	2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid	90-27-7	C₁₀H₁₂O₂	详情	详情
(I)	12841	2-Phenoxyethanol; 2-Phenoxy-1-ethanol	122-99-6	C₈H₁₀O₂	详情	详情
(II)	12842	2-Chloroethyl phenyl ether; b-Chlorophenetole; 1-(2-Chloroethoxy)benzene	622-86-6	C₈H₉ClO	详情	详情
(III)	12843	1-[4-(2-Chloroethoxy)phenyl]-2-phenyl-1-butanone		C₁₈H₁₉ClO₂	详情	详情
(IV)	12845	2-Chloroethyl 4-[(E)-1-(4-iodophenyl)-2-phenyl-1-butenyl]phenyl ether; 1-[(E)-1-[4-(2-Chloroethoxy)phenyl]-2-phenyl-1-butenyl]-4-iodobenzene		C₂₄H₂₂ClIO	详情	详情
(V)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 2-phenylbutyric acid (I) with LDA gives the enolate (II), which is condensed with ethyl 4-iodobenzoate (III) to yield the not isolated intermediate (IV), which decarboxylates to afford 1-(4-iodophenyl)-2-phenyl-1-butanone (V). The Grignard reaction of the ketone (V) with 4-[2-(1-pyrroliidnyl)ethyl]phenylmagnesium bromide (VI) (obtained from the corresponding bromobenzene (VII) and Mg in THF) affords the tertiary alcohol (VIII), which is esterified with pivaloyl chloride (IX) and KHMDS to provide the pivalate (X). Finally, this compound is treated with hexamethyldisylazane at 165 C to provide the target ethylene.

参考文献中间体

合成目标

【1】 Ace, K.W.; et al.; Development of an efficient and stereoselective manufacturing route to idoxifene. Org Process Res Dev 2001, 5, 5, 479.

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)	21130	2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid	90-27-7	C₁₀H₁₂O₂	详情	详情
(II)	51918			C₁₀H₁₀Li₂O₂	详情	详情
(III)	23796	ethyl 4-iodobenzoate	51934-41-9	C₉H₉IO₂	详情	详情
(IV)	51919	lithium 2-(4-iodobenzoyl)-2-phenylbutanoate		C₁₇H₁₄ILiO₃	详情	详情
(V)	51920	1-(4-iodophenyl)-2-phenyl-1-butanone		C₁₆H₁₅IO	详情	详情
(VI)	51921	bromo[4-[2-(1-pyrrolidinyl)ethyl]phenyl]magnesium		C₁₂H₁₆BrMgN	详情	详情
(VII)	51922	1-(4-bromophenethyl)pyrrolidine		C₁₂H₁₆BrN	详情	详情
(VIII)	51923	(1R,2R)-1-(4-iodophenyl)-2-phenyl-1-[4-[2-(1-pyrrolidinyl)ethyl]phenyl]-1-butanol		C₂₈H₃₂INO	详情	详情
(IX)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(X)	51924	1-(tert-butyl)vinyl (1R,2R)-1-(4-iodophenyl)-2-phenyl-1-[4-[2-(1-pyrrolidinyl)ethyl]phenyl]butyl ether; 1-[4-[(1R,2R)-1-[[1-(tert-butyl)vinyl]oxy]-1-(4-iodophenyl)-2-phenylbutyl]phenethyl]pyrrolidine		C₃₄H₄₂INO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

1) Racemic igmesine has been synthesized as follows: Alkylation of 2-phenylbutyric acid (I) with cinnamyl bromide (II) by means of butyllithium in THF gives 2-ethyl-2,5-diphenyl-4-pentenoic acid (III), which is treated with sodium azide and phenyl dichlorophosphate in dichloromethane, yielding the corresponding azide (IV). The Curtius rearrangement of (IV) in refluxing toluene affords the isocyanate (V), which is reduced with LiAlH4/AlCl3 in THF to give N-(1-ethyl-1,4-diphenyl-3-butenyl)-N-metylamine (VI). The acylation of (VI) with cyclopropanecarbonyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding amide (VIII), which is finally reduced with LiAlH4/AlCl3 in THF/ethyl ether.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Igmesine Hydrochloride . Drugs Fut 1999, 24, 2, 133.
【2】 Aubard, G.; Calvet, A.; Gouret, C.; Grouhel, A.; Jacobelli, H.; Junien, J.-L. (Jouveinal SA); Disubstituted benzylamines, process for their preparation, their use as medicament and their synthesis intermediates. EP 0361990; EP 0362001; FR 2636625; US 5034419; US 5089639 .

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)	21130	2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid	90-27-7	C₁₀H₁₂O₂	详情	详情
(II)	21131	1-[(E)-3-bromo-1-propenyl]benzene	4392-24-9	C₉H₉Br	详情	详情
(III)	21132	(E)-2-ethyl-2,5-diphenyl-4-pentenoic acid		C₁₉H₂₀O₂	详情	详情
(IV)	21133	(E)-2-ethyl-2,5-diphenyl-4-pentenoyl azide		C₁₉H₁₉N₃O	详情	详情
(V)	21134	1-[(E)-1-ethyl-1-isocyanato-4-phenyl-3-butenyl]benzene; (E)-1-ethyl-1,4-diphenyl-3-butenyl isocyanate		C₁₉H₁₉NO	详情	详情
(VI)	21135	(rac)-[(E)-N-methyl-3,6-diphenyl-5-hexen-3-amine]; (rac)-[N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylamine]		C₁₉H₂₃N	详情	详情
(VII)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(VIII)	21137	(rac)-[N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylcyclopropanecarboxamide]		C₂₃H₂₇NO	详情	详情

Extended Information