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【结 构 式】

【分子编号】38492

【品名】ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate

【CA登记号】

【 分 子 式 】C40H37NO5

【 分 子 量 】611.73752

【元素组成】C 78.54% H 6.1% N 2.29% O 13.08%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

The reaction of 4-hydroxybenzyl alcohol (V) with ethyl 2-bromoacetate (XI) by means of K2CO3 gives the phenoxyacetate (XII), which is then treated with SOCl2 in THF to obtain the benzyl chloride (XIII). Reaction of (XIII) with the indole derivative (VII) by means of NaH in DMF yields the adduct (XIV), whose ester group is reduced with LiAlH4 in THF to afford the 2-hydroxyethoxy compound (XV). Treatment of (XV) with CBr4 and PPh3 in THF provides the 2-bromoethoxy compound (XVI), which is converted into compound (XVIIII) by reaction with hexamethyleneimine (homopiperidine) (XVII) in THF. Finally, compound (XVIII) is debenzylated by hydrogenation with either H2 over Pd/C in ethanol/THF or with cyclohexadiene and Pd/C in THF/EtOH.

1 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.
2 Harris, H.A.; Miller, C.P.; Komm, B.S.; Bazedoxifene Acetate. Drugs Fut 2002, 27, 2, 117.
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
(V) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 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
(XI) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XII) 51988 ethyl 2-[4-(hydroxymethyl)phenoxy]acetate C11H14O4 详情 详情
(XIII) 38491 ethyl 2-[4-(chloromethyl)phenoxy]acetate C11H13ClO3 详情 详情
(XIV) 38492 ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate C40H37NO5 详情 详情
(XV) 38493 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]-1-ethanol C38H35NO4 详情 详情
(XVI) 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
(XVII) 18672 azepane 111-49-9 C6H13N 详情 详情
(XVIII) 38495 1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; 4-[1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl benzyl ether C44H46N2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

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.

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