Pipendoxifene, ERA-923, -Drug Synthesis Database

【结构式】

【药物名称】Pipendoxifene, ERA-923

【化学名称】2-(4-Hydroxyphenyl)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-5-ol

【CA登记号】198480-55-6, 352233-89-7 (deleted CAS), 389125-71-7 (hydrochloride hydrate), 245124-69-0 (monohydrochloride)

【分子式】C₂₉H₃₂N₂O₃

【分子量】456.58999

【开发单位】Wyeth Pharmaceuticals (Originator), Ligand (Codevelopment)

【药理作用】Breast Cancer Therapy, Oncolytic Drugs, 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

Alkylation of p-hydroxybenzaldehyde (I) with 1-(2-chloroethyl)piperidine (II) afforded 4-(2-piperidinylethoxy)benzaldehyde (III). Aldehyde function reduction using NaBH4 provided the benzylic alcohol (IV). Alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (A) with 1-(2-chloroethyl)piperidine hydrochloride (II) by means of NaOH and benzyl triethylammonium bromide in toluene.The hydrochloride salt of (IV) was then treated with SOCl2 to furnish chloride (V).

参考文献中间体

【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942.
【2】 Vid, G.; Potoski, J.R.; Raveendranath, P.; Zeldis, J.; Ren, J. (American Home Products Corp.); Novel aryloxy-alkyl-dialkylamines. EP 1025077; WO 9919293 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	29474	4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol	623-05-2	C₇H₈O₂	详情	详情
(I)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(II)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(III)	35795	4-[2-(1-piperidinyl)ethoxy]benzaldehyde	26815-04-3	C₁₄H₁₉NO₂	详情	详情
(IV)	35796	[4-[2-(1-piperidinyl)ethoxy]phenyl]methanol		C₁₄H₂₁NO₂	详情	详情
(V)	46522	1-[2-[4-(chloromethyl)phenoxy]ethyl]piperidine; 4-(chloromethyl)phenyl 2-(1-piperidinyl)ethyl ether		C₁₄H₂₀ClNO	详情	详情

合成路线2

Condensation between p-benzyloxyaniline (VI) and bromo ketone (VII) in refluxing DMF produced the indole derivative (VIII). Alkylation of (VIII) with chloride (V) in the presence of NaH gave the N-alkylated indole (IX). The O-benzyl protecting groups of (IX) were then removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.

参考文献中间体

【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942.
【2】 Vid, G.; Potoski, J.R.; Raveendranath, P.; Zeldis, J.; Ren, J. (American Home Products Corp.); Novel aryloxy-alkyl-dialkylamines. EP 1025077; WO 9919293 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	46522	1-[2-[4-(chloromethyl)phenoxy]ethyl]piperidine; 4-(chloromethyl)phenyl 2-(1-piperidinyl)ethyl ether		C₁₄H₂₀ClNO	详情	详情
(VI)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(VII)	38489	4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone	54081-45-9	C₁₆H₁₅BrO₂	详情	详情
(VIII)	38490	5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether		C₂₉H₂₅NO₂	详情	详情
(IX)	46523	5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indole; benzyl 4-(5-(benzyloxy)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-2-yl)phenyl ether		C₄₃H₄₄N₂O₃	详情	详情

合成路线3

The intermediate 2-[4-(chloromethyl)phenoxy]acetic acid ethyl ester (IV) has been obtained as follows: The reaction of 4-hydroxybenzyl alcohol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 gives the phenoxyacetate (III), which is then treated with SOCl2 in THF to obtain the desired intermediate (IV). The cyclization of 4-(benzyloxy)aniline (V) with 2-bromo-1-[4-(benzyloxy)phenyl]-1-propanone (VI) by means of TEA in DMF gives 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole (VII), which is alkylated with the intermediate (IV) by means of NaH in DMF to yield the adduct (VIII). The reduction of the ester group of (VIII) with LiAlH4 in THF affords the 2-hydroxyethoxy compound (IX), which is treated with CBr4 and PPh3 in THF to provide the 2-bromoethoxy compound (X). The reaction of (X) with piperidine in THF gives the piperidinoethoxy compound (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol/THF to afford the target indole derivative.

参考文献中间体

【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942.
【2】 Miller, C.P.; Collini, M.D.; Tran, B.D.; et al.; Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001, 44, 11, 1654.
【3】 Miller, C.P.; Tran, B.D.; Collini, M.D. (American Home Products Corp.); Estrogenic agents. EP 0802183; JP 1998036346; US 5998402 .

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)	29474	4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol	623-05-2	C₇H₈O₂	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	51988	ethyl 2-[4-(hydroxymethyl)phenoxy]acetate		C₁₁H₁₄O₄	详情	详情
(IV)	38491	ethyl 2-[4-(chloromethyl)phenoxy]acetate		C₁₁H₁₃ClO₃	详情	详情
(V)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(VI)	38489	4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone	54081-45-9	C₁₆H₁₅BrO₂	详情	详情
(VII)	38490	5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether		C₂₉H₂₅NO₂	详情	详情
(VIII)	38492	ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate		C₄₀H₃₇NO₅	详情	详情
(IX)	38493	2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]-1-ethanol		C₃₈H₃₅NO₄	详情	详情
(X)	38494	benzyl 4-[5-(benzyloxy)-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indol-2-yl]phenyl ether; 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indole		C₃₈H₃₄BrNO₃	详情	详情
(XI)	46523	5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indole; benzyl 4-(5-(benzyloxy)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-2-yl)phenyl ether		C₄₃H₄₄N₂O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)