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【结 构 式】

【分子编号】17599

【品名】1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydro-1-naphthalenyl)phenoxy]ethyl]pyrrolidine; 4-(6-methoxy-2-phenyl-3,4-dihydro-1-naphthalenyl)phenyl 2-(1-pyrrolidinyl)ethyl ether

【CA登记号】

【 分 子 式 】C29H31NO2

【 分 子 量 】425.57068

【元素组成】C 81.85% H 7.34% N 3.29% O 7.52%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VI)

The condensation of 6-methoxy-1-tetralone (I) with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (II) by means of CeCl3 and butyllithium in THF gives 1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (III), which is brominated with pyridinium bromide perbromide in THF yielding the bromo derivative (IV). The condensation of (IV) with phenylboronic acid (V) by means of tetrakis(triphenylphosphonium) palladium/Na2CO3 in THF affords 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (nafoxidene) (VI). Nadoxifene is reduced with H2 over Pd/C in ethanol/methanol giving (±)-cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl]-pyrrolidine (VII). The demethylation of (VII) with boron tribromide in dichloromethane or 48% HBr in hot acetic acid yields (±)-cis-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (VIII), which is submitted to optical resolution by chromatography over a Chiralcell OD column in 99.95% (ethanol/heptane 5:95)/0.05% diethylamine, by crystallization with (­)-(R)-1,1'- binaphthyl-2,2'-diyl hydrogenphosphate (R-binaph) or by crystallization with D-tartaric acid.

1 Rosati, R.L.; Da Silva Jardine, P.; Cameron, K.O.; et al.; Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem 1998, 41, 16, 2928-31.
2 Leeson, P.A.; Castañer, J.; Sorbera, L.A.; CP-336156. Drugs Fut 1998, 23, 10, 1066-1070.
3 Cameron, K.O.; Jardine, P.A. (Pfizer Inc.); Estrogen agonists/antagonists.. EP 0802910; JP 1998503215; US 5552412; WO 9621656 .
4 Chiu, C.K.; Meltz, M. (Pfizer Inc.); (­)-cis-6(S)-Phenyl-5(R)-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol D-tartrate.. EP 0876359; JP 1999502866; WO 9716434 .
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) 17594 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone 1078-19-9 C11H12O2 详情 详情
(II) 17595 4-[2-N,N-Pyrrolidinoethoxy]phenyl bromide; 1-[2-(4-bromophenoxy)ethyl]pyrrolidine; 1-(2-(4-bromophenoxy)ethyl)pyrrolidine; 4-bromophenyl 2-(1-pyrrolidinyl)ethyl ether 1081-73-8 C12H16BrNO 详情 详情
(III) 17596 1-[2-[4-(6-methoxy-3,4-dihydro-1-naphthalenyl)phenoxy]ethyl]pyrrolidine; 4-(6-methoxy-3,4-dihydro-1-naphthalenyl)phenyl 2-(1-pyrrolidinyl)ethyl ether C23H27NO2 详情 详情
(IV) 17597 4-(2-bromo-6-methoxy-3,4-dihydro-1-naphthalenyl)phenyl 2-(1-pyrrolidinyl)ethyl ether; 1-[2-[4-(2-bromo-6-methoxy-3,4-dihydro-1-naphthalenyl)phenoxy]ethyl]pyrrolidine C23H26BrNO2 详情 详情
(V) 16593 Phenylboronic acid;Benzeneboronic acid;Phenylboron dihydroxide 98-80-6 C6H7BO2 详情 详情
(VI) 17599 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydro-1-naphthalenyl)phenoxy]ethyl]pyrrolidine; 4-(6-methoxy-2-phenyl-3,4-dihydro-1-naphthalenyl)phenyl 2-(1-pyrrolidinyl)ethyl ether C29H31NO2 详情 详情
(VII) 17600 1-(2-[4-[(1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydro-1-naphthalenyl]phenoxy]ethyl)pyrrolidine; 4-[(1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydro-1-naphthalenyl]phenyl 2-(1-pyrrolidinyl)ethyl ether C29H33NO2 详情 详情
(VIII) 17601 (5R,6S)-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-5,6,7,8-tetrahydro-2-naphthalenol C28H31NO2 详情 详情
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