Idoxifene, SB-223030, CB-7432, -Drug Synthesis Database

【结构式】

【药物名称】Idoxifene, SB-223030, CB-7432

【化学名称】(E)-1-(4-Iodophenyl)-2-phenyl-1-[4-(2-pyrrolidinoethoxy)phenyl]-1-butene
　　　　　　(E)-1-[2-[4-[1-(4-Iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl]pyrrolidine

【CA登记号】116057-75-1

【分子式】C₂₈H₃₀INO

【分子量】523.4618

【开发单位】BTG (Technology Transfer), Cancer Research UK (Originator), GlaxoSmithKline (Licensee)

【药理作用】Breast Cancer Therapy, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Oncolytic Drugs, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM)

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

A synthesis of iodine radiolabeled idoxifene has been published: The reaction of the tributylstannyl precursor (I) with 125INa and chloramine T in dichloromethane.

参考文献中间体

【1】 Hammersley, P.; Trivedi, M.; Young, H.; Carnochan, P.; Potter, G.; Ott, R.; Jarman, M.; NCA radioiodination of idoxifene. J Label Compd Radiopharm 1995, 36, 10, 921.

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)	12847	1-[2-(4-[(E)-2-Phenyl-1-[4-(tributylstannyl)phenyl]-1-butenyl]phenoxy)ethyl]pyrrolidine; 4-[(E)-2-Phenyl-1-[4-(tributylstannyl)phenyl]-1-butenyl]phenyl 2-(1-pyrrolidinyl)ethyl ether		C₄₀H₅₇NOSn	详情	详情

合成路线3

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

【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

Extended Information