|
【结 构 式】 
|
【药物名称】Lasofoxifene tartrate, CP-336156 【化学名称】(-)-(5R,6S)-6-Phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (-)-D-tartrate salt 【CA登记号】190791-29-8, 180916-16-9 (free base), 180915-85-9 (HCl) 【 分 子 式 】C32H37NO8 【 分 子 量 】563.65359 |
【开发单位】Pfizer (Originator), Ligand (Codevelopment) 【药理作用】Bone Diseases, Treatment of, Breast Cancer Therapy, METABOLIC DRUGS, Oncolytic Drugs, Prevention of Osteoporosis, Treatment of Osteoporosis, Selective Estrogen Receptor Modulators (SERM) |
合成路线1
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 |
合成路线2
The acetylation of racemic cis-lasofoxifene (CP-319609) (I) by conventional methods gives the corresponding acetate (II), which is submitted to an enzymatic hydrolysis with cholesterol lipase (porcine pancreas) in a pH 7 phosphate buffer to yield pure lasofoxifene with an e.e. of 96% at 35% conversion. This optical purity can be improved up to 99% e.e. by crystallization in 95:5 ethanol/water.
| 【1】 Rosati, R.L.; Liu, K.K.-C.; Yang, X.; Reinhold, A.R.; Enzyme-catalyzed asymmetric deacylation for the preparation of lasofoxifene (CP-336156), a selective estrogen receptor modulator. Org Lett 2000, 2, 25, 4025. |