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【结 构 式】 
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【药物名称】Bazedoxifene acetate, WAY-140424, TSE-424 【化学名称】2-(4-Hydroxyphenyl)-3-methyl-1-[4-[2-(perhydroazepin-1-yl)ethoxy]benzyl]-1H-indol-5-ol acetate 【CA登记号】198481-33-3, 252555-09-2 (deleted CAS), 198481-32-2 (free base) 【 分 子 式 】C32H38N2O5 【 分 子 量 】530.67006 |
【开发单位】Wyeth Pharmaceuticals (Originator), Ligand (Codevelopment) 【药理作用】Bone Diseases, Treatment of, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , METABOLIC DRUGS, Prevention of Osteoporosis, Treatment of Osteoporosis, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM) |
合成路线1
Alkylation of 4-hydroxybenzaldehyde (I) with chloro derivative (II) by means of K2CO3 in DMF at reflux affords benzaldehyde derivative (III), which is reduced with NaBH4 in MeOH to provide the benzylic alcohol (IV) --alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (V) with chloro derivative (II) by means of NaOH and benzyltriethylammonium bromide in toluene--. Alcohol (V) is treated with HCl in THF and then chlorinated with SOCl2 to furnish hydrochloride salt (VI), which is condensed with the indole derivative (VII) – produced by condensation of the bromo ketone (VIII) and 4-benzyloxyaniline hydrochloride (IX) either refluxing by with DMF or with Et3N in refluxing DMF – by means of NaH in DMF to give the N-alkylated indole (X). Finally, the O-benzyl protecting groups of (X) are removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.
| 【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】 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 |
|---|---|---|---|---|---|---|
| (I) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 22918 | 1-(2-chloroethyl)azepane | C8H16ClN | 详情 | 详情 | |
| (III) | 60165 | 4-[2-(1-azepanyl)ethoxy]benzaldehyde | C15H21NO2 | 详情 | 详情 | |
| (IV) | 60166 | {4-[2-(1-azepanyl)ethoxy]phenyl}methanol | C15H23NO2 | 详情 | 详情 | |
| (V) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (VI) | 60167 | 1-{2-[4-(chloromethyl)phenoxy]ethyl}azepane; 2-(1-azepanyl)ethyl 4-(chloromethyl)phenyl ether | C15H22ClNO | 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) | 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 |
| (IX) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (X) | 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
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 |