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【结 构 式】 
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【分子编号】17594 【品名】6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone 【CA登记号】1078-19-9 |
【 分 子 式 】C11H12O2 【 分 子 量 】176.21508 【元素组成】C 74.98% H 6.86% O 18.16% |
合成路线1
该中间体在本合成路线中的序号：(I)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
该中间体在本合成路线中的序号：(I)Imine (III) was prepared by condensation of 6-methoxy-1-tetralone (I) with p-aminophenol (II) at 180 C. After silylation of the hydroxyl group of (III) with tert-butyldimethylsilyl chloride to give (IV), acylation of the enamine function with 2-bromo-5-methoxybenzoyl chloride (V) yielded enamide (VI). Halogenation of (VI) with N-bromosuccinimide gave the beta-bromo enamide (VII). Photocyclization of (VII) produced the benzophenanthridine (VIII), which was further dehydrogenated with DDQ providing (IX). Desilylation of (IX) to afford phenol (X) was achieved by treatment with hydrogen fluoride-pyridine.
| 【1】 Grese, T.A.; et al.; Photochemical synthesis of N-arylbenzophenanthridine selective estrogen receptor modulators (SERMs). J Med Chem 2001, 44, 17, 2857. |
| 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) | 15715 | 4-Aminophenol | 123-30-8 | C6H7NO | 详情 | 详情 |
| (III) | 50224 | 4-[[6-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]amino]phenol | C17H17NO2 | 详情 | 详情 | |
| (IV) | 50225 | N-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-N-[6-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]amine; 4-[[tert-butyl(dimethyl)silyl]oxy]-N-[6-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]aniline | C23H31NO2Si | 详情 | 详情 | |
| (V) | 50226 | 2-Bromo-5-methoxybenzoyl chloride | 56658-04-9 | C8H6BrClO2 | 详情 | 详情 |
| (VI) | 50227 | 2-bromo-N-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-5-methoxy-N-(6-methoxy-3,4-dihydro-1-naphthalenyl)benzamide | C31H36BrNO4Si | 详情 | 详情 | |
| (VII) | 50228 | 2-bromo-N-(2-bromo-6-methoxy-3,4-dihydro-1-naphthalenyl)-N-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-5-methoxybenzamide | C31H35Br2NO4Si | 详情 | 详情 | |
| (VIII) | 50229 | 5-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-2,8-dimethoxy-11,12-dihydrobenzo[c]phenanthridin-6(5H)-one | C31H35NO4Si | 详情 | 详情 | |
| (IX) | 50230 | 5-(4-[[tert-butyl(dimethyl)silyl]oxy]phenyl)-2,8-dimethoxybenzo[c]phenanthridin-6(5H)-one | C31H33NO4Si | 详情 | 详情 | |
| (X) | 50231 | 5-(4-hydroxyphenyl)-2,8-dimethoxybenzo[c]phenanthridin-6(5H)-one | C25H19NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)6-Methoxy-alpha-tetralone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine in the presence of sodium acetate. Subsequent Beckmann rearrangement of (II) employing polyphosphoric acid produced a mixture of two regioisomeric lactams from which the required 1-benzazepine (III) was isolated by flash chromatography. Iodination of (III) to give (IV) was carried out following a previously described metodolgy. Displacement of the iodolactam (IV) with ammonia in aqueous ethanol furnished the racemic primary amine, which was resolved by means of L-pyroglutamic acid. The desired (S)-amine (V) was protected as the benzyl carbamate (VII) by treatment with N-(benzyloxycarbonyloxy)succinimide (VI). Then, selective alkylation of the lactam ring nitrogen of (VII) with tert-butyl bromoacetate in the presence of lithium hexamethyldisilazide provided ester (VIII). After hydrogenolysis of the carbobenzoy moiety of (VIII), the resulting amino lactam (IX) was condensed with benzylsulfonyl chloride (X) to give sulfonamide (XI). Deprotection of the tert-butyl ester of (XI) with trifluoroacetic acid afforded carboxylic acid (XII), which was coupled with nitroargininal ethyl aminal (XIII), yielding amide (XIV).
| 【1】 Tamura, S.Y.; Goldman, E.A.; Semple, J.E.; Bergum, P.W.; Novel benzo-fused lactam scaffolds as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 17, 2573. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (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) | 38125 | 6-methoxy-3,4-dihydro-1(2H)-naphthalenone oxime | C11H13NO2 | 详情 | 详情 | |
| (III) | 38126 | 7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H13NO2 | 详情 | 详情 | |
| (IV) | 38127 | 3-iodo-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H12INO2 | 详情 | 详情 | |
| (V) | 38128 | (3S)-3-amino-7-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C11H14N2O2 | 详情 | 详情 | |
| (VI) | 30663 | N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione | 13139-17-8 | C12H11NO5 | 详情 | 详情 |
| (VII) | 38129 | benzyl (3S)-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate | C19H20N2O4 | 详情 | 详情 | |
| (VIII) | 38130 | tert-butyl 2-((3S)-3-[[(benzyloxy)carbonyl]amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C25H30N2O6 | 详情 | 详情 | |
| (IX) | 38131 | tert-butyl 2-[(3S)-3-amino-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XI) | 38132 | tert-butyl 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C24H30N2O6S | 详情 | 详情 | |
| (XII) | 38133 | 2-[(3S)-3-[(benzylsulfonyl)amino]-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C20H22N2O6S | 详情 | 详情 | |
| (XIII) | 38136 | C8H17N5O3 | 详情 | 详情 | ||
| (XIV) | 38134 | C28H37N7O8S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Conjugate addition of methyl acrylate (II) to 3-methoxybenzaldehyde (I) under reversion of reactivity conditions in the presence of KCN produced the keto ester (III). The Wolff-Kishner reduction of the keto group caused simultaneous ester hydrolysis, yielding acid (IV), which was further cyclized to the tetralone (V) employing hot polyphosphoric acid. Mannich reaction of ketone (V) with N-benzyl methylamine and paraformaldehyde furnished amino ketone (VI). To this was added phenylmagnesium bromide (VII), yielding amino alcohol (VIII), which was subsequently dehydrated to (IX) by means of trifluoroacetic acid. Catalytic hydrogenation of the olefin double bond of (IX) with simultaneous N-benzyl group hydrogenolysis gave the secondary amine (X). This was then alkylated with ethyl bromoacetate, producing the substituted glycine ester (XI), which was finally hydrolyzed by means of LiOH.
| 【1】 Jaap, D.R.; Gilfillan, R.; Gibson, S.G.; Thorn, S.N. (Akzo Nobel N.V.); Aminomethylcarboxylic acid derivs.. EP 1100769; WO 0007978 . |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (III) | 51352 | methyl 4-(3-methoxyphenyl)-4-oxobutanoate | C12H14O4 | 详情 | 详情 | |
| (IV) | 51353 | 4-(3-methoxyphenyl)butyric acid | C11H14O3 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 51354 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone | C20H23NO2 | 详情 | 详情 | |
| (VII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VIII) | 51355 | 2-[[benzyl(methyl)amino]methyl]-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-1-naphthalenol | C26H29NO2 | 详情 | 详情 | |
| (IX) | 51356 | N-benzyl(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)-N-methylmethanamine; N-benzyl-N-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-N-methylamine | C26H27NO | 详情 | 详情 | |
| (X) | 51357 | [(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylmethanamine; N-[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-N-methylamine | C19H23NO | 详情 | 详情 | |
| (XI) | 51358 | ethyl 2-[[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl](methyl)amino]acetate | C23H29NO3 | 详情 | 详情 |