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【结 构 式】 
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【分子编号】21385 【品名】7-methoxy-3,4-dihydro-1(2H)-naphthalenone 【CA登记号】6836-19-7 |
【 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 7-methoxy-3,4-dihydro-1(2H)-naphthalenone (I) with tetramethylene dibromide (A) by means of NaH in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone (II), b.p.(0.05) = 120-3 C, which is treated with acetonitrile and butyllithium in THF yielding 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthaleneacetonitrile (III), m.p. 140-2 C. This compound is reduced with LiAlH4 in THF to afford hydro-2,2-tetramethylene-1-naphthol (IV), m.p 178-80 C, and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene (V), m.p. 187 C. This amine is cyclized by reaction with bromine in CHCl3 giving 3-methoxy-9a-bromonrhasybanan hydrobromide (VI), m.p. 207.0-8.5 C (decomp.), and isomerized with dehydrobromination by treatment with NaHCO3 in DMF affording 3-methoxy-DELTA(8,14)-morphinan (VII), m.p. 180-4 C. The acetylation of (VII) with trifluoroacetic anhydride (B) yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan (VIII), m.p. 94-6 C, which is epoxidized with m-chloroperbenzoic acid in methylene chloride giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphinan (IX), m.p. 102-5 C. The deacetylation of (IX) with NaSH4 in ethanol gives 8,14-epoxy-3-methoxymorphinan (X), oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan (XI) (HCl salt, m.p. 243-4 C (decomp.)). The condensation of (Xl) with cyclobutylcarbonyl chloride (C) by means of pyridine in CH2Cl2 affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan (XII), m.p. 183-5 C, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (XIII) (HCl salt, mp. 248-50 C (decomp.)). Finally, (XIII) is demethylated by treatment with refluxing 48% HBr.
| 【1】 Conway, T.T.; Monkovic, I.; J Am Chem Soc 1973, 95, 23, 7910-12. |
| 【2】 Pachter, I.; et al.; 14-Hydroxymorphinan derivatives. DE 2243961; FR 2154481; GB 1412129; GB 1412130; US 3819635 . |
| 【3】 Monkovic, I.; Conway, T.T.; Process for the preparation of 14-hydroxymorphinan derivatives. JP 49061169; NL 7306344; US 3775414 . |
| 【4】 Paton, D.M.; Castaner, J.; Butorphanol. Drugs Fut 1977, 2, 4, 231. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (B) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 33856 | C15H18O2 | 详情 | 详情 | ||
| (III) | 33857 | RCL R15,507-1 | C17H21NO2 | 详情 | 详情 | |
| (IV) | 33858 | C17H25NO2 | 详情 | 详情 | ||
| (V) | 33859 | 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]ethylamine; 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]-1-ethanamine | C17H23NO | 详情 | 详情 | |
| (VI) | 33860 | C17H22BrNO | 详情 | 详情 | ||
| (VII) | 33861 | (1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraene; (1S,9R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-4-yl methyl ether | C17H21NO | 详情 | 详情 | |
| (VIII) | 33863 | 2,2,2-trifluoro-1-[(1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-17-yl]-1-ethanone | C19H20F3NO2 | 详情 | 详情 | |
| (IX) | 33864 | 2,2,2-trifluoro-1-[(1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-18-yl]-1-ethanone | C19H20F3NO3 | 详情 | 详情 | |
| (X) | 33865 | (1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-triene; methyl (1S,9R,10S,12S)-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-4-yl ether | C17H21NO2 | 详情 | 详情 | |
| (XI) | 33866 | (1S,9R,10S)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol | C17H23NO2 | 详情 | 详情 | |
| (XII) | 33867 | cyclobutyl[(1S,9R,10S)-10-hydroxy-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-17-yl]methanone | C22H29NO3 | 详情 | 详情 | |
| (XIII) | 33868 | (1S,9R,10S)-17-(cyclobutylmethyl)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol | C22H31NO2 | 详情 | 详情 | |
| (C) | 18589 | cyclobutanecarbonyl chloride | 5006-22-4 | C5H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The methylation of 7-methoxy-1-tetralone (I) with methyl iodide and potassium tert-butoxide in THF gives the 2,2-dimethyl derivative (II), which is reduced with NaBH4 and acetylated with acetyl chloride yielding the acetate (III). The reduction of (III) with diethylborohydride in TFA affords 7-methoxy-2,2-dimethyltetraline (IV), which is submitted to a Birch reduction with Li/NH3 in THF affording 2,2-dimethyl-7-methoxy-1,2,3,4,5,8-hexahydronaphthalene (V). The condensation of (V) with homofarnesyl iodide (VI) by means of BuLi in THF gives intermediate (VII), which is treated with 2-sulfanylethanol and TFA yielding the ketone (VIII). The reaction of (VIII) with KHMDS and Tf2N-Ph in THF affords the enol triflate (IX), which is selectively brominated with N-bromosuccinimide (NBS) in THF giving the bromohydrine (X). The epoxidation of (X) with K2CO3 in methanol, followed by methylation with Me2CuLi in THF yields the epoxide (XI), which is treated with SiF4 and TFA to afford the fluoroketone (XII). The stereocontroled reduction of the ketone group of (XII) with a chiral oxaazaborolidine (OABL) gives the chiral alcohol (XIII), which is epoxidized by means of sodium isopropoxide in isopropanol yielding the chiral epoxide (XIV).
| 【1】 Corey, E.J.; Lee, J.; Enantioselective total synthesis of oleanolic acid, erythrodiol, beta-amyrin, and other pentacyclic triterpenes from a common intermediate. J Am Chem Soc 1993, 115, 8873. |
| 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) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 35723 | 7-methoxy-2,2-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (III) | 35724 | 7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydro-1-naphthalenyl acetate | C15H20O3 | 详情 | 详情 | |
| (IV) | 35725 | 7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene; 7,7-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl methyl ether | C13H18O | 详情 | 详情 | |
| (V) | 35726 | 7,7-dimethyl-1,4,5,6,7,8-hexahydro-2-naphthalenyl methyl ether; 7-methoxy-2,2-dimethyl-1,2,3,4,5,8-hexahydronaphthalene | C13H20O | 详情 | 详情 | |
| (VI) | 35727 | (6E,10E)-13-iodo-2,6,10-trimethyl-2,6,10-tridecatriene | C16H27I | 详情 | 详情 | |
| (VII) | 35728 | 7-methoxy-2,2-dimethyl-8-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-1,2,3,4,5,8-hexahydronaphthalene; 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-1,4,5,6,7,8-hexahydro-2-naphthalenyl methyl ether | C29H46O | 详情 | 详情 | |
| (VIII) | 35729 | 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-3,4,5,6,7,8-hexahydro-2(1H)-naphthalenone | C28H44O | 详情 | 详情 | |
| (IX) | 35730 | 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-3,4,5,6,7,8-hexahydro-2-naphthalenyl trifluoromethanesulfonate | C29H43F3O3S | 详情 | 详情 | |
| (X) | 35731 | 1-[(3E,7E)-11-bromo-12-hydroxy-4,8,12-trimethyl-3,7-tridecadienyl]-7,7-dimethyl-3,4,5,6,7,8-hexahydro-2-naphthalenyl trifluoromethanesulfonate | C29H44BrF3O4S | 详情 | 详情 | |
| (XI) | 35732 | 3-[(3E,7E)-3,7-dimethyl-10-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-3,7-decadienyl]-2,2-dimethyloxirane | C29H46O | 详情 | 详情 | |
| (XII) | 35733 | (6E,10E)-2-fluoro-2,6,10-trimethyl-13-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-6,10-tridecadien-3-one | C29H45FO | 详情 | 详情 | |
| (XIII) | 35734 | (3S,6E,10E)-2-fluoro-2,6,10-trimethyl-13-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-6,10-tridecadien-3-ol | C29H47FO | 详情 | 详情 | |
| (XIV) | 35735 | (3S)-3-[(3E,7E)-3,7-dimethyl-10-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-3,7-decadienyl]-2,2-dimethyloxirane | C29H46O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)2) The reaction of 7-methoxy-1-tetralone (VII) with isopentyl nitrite and potassium tert-butoxide in ethanol - ether gives 7-methoxy-2-oxyimino-1-tetralone (VIII), which by reduction with H2 over Pd/C in THF and acylation with propanoyl chloride is converted to 7-methoxy-2-propionamido-1-tetralone (IX). The reduction of (IX) with NaBH4 in ethanol yields the alcohol (X), which by further reduction with LiAlH4 in THF affords trans-7-methoxy-2-(proylamino)-1,2,3,4-tetrahydronaphthalen-1-ol (XI). The cyclization of (XI) with chloroacetyl chloride by means of NaH in THF - acetonitrile gives trans-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazin-3-one (XII), which is reduced with LiAlH4 in THF to compound (VI), already obtained.
| 【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 . |
| 【2】 Williams, M.; Jones, J.H.; Randall, W.C.; Clineschmidt, B.V.; Martin, G.E.; Lumma, P.K.; Hirshfield, J.M.; Anderson, P.S.; McClure, D.E.; Lundell, G.F.; Baldwin, J.J.; Smith, G.; Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists. J Med Chem 1984, 27, 12, 1607. |
| 【3】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (A) | 21382 | 1-nitropentane | 1002-16-0 | C5H11NO2 | 详情 | 详情 |
| (VI) | 21381 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C16H23NO2 | 详情 | 详情 | |
| (VII) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (VIII) | 21386 | 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime | C11H11NO3 | 详情 | 详情 | |
| (IX) | 21387 | N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide | C14H17NO3 | 详情 | 详情 | |
| (X) | 21388 | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO3 | 详情 | 详情 | |
| (XI) | 21389 | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | C14H21NO2 | 详情 | 详情 | |
| (XII) | 21390 | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | C16H21NO3 | 详情 | 详情 | |
| (C) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2OCHCl3) under Schotten-Baumann conditions.
| 【1】 Silvestre, J.S.; Bayes, M.; Chilman-Blair, K.; Castaner, J.; Agomelatine. Drugs Fut 2003, 28, 1, 7. |
| 【2】 Andrieux, J.; Houssin, R.; Said, Y.; Guardiola-Lemaitre, B.; Lesieur, D. (ADIR et Cie.); Novel derivs. with a naphthalenic structure, their process of preparation and pharmaceutical compsns. containing them. EP 0447285; FR 2658819; JP 1995048331; US 5318994 . |
| 【3】 Guardiola-Lemaitre, B.; Renard, P.; Pfeiffer, B.; Caignard, D.-H.; Andrieux, J.; Howell, H.-E.; Morgan, P.; Yous, S.; Lesieur, D.; Adam, G.; Novel naphthalenic ligands for the melatonin receptor. J Pharm Belg 1992, 47, 4, 374. |
| 【4】 Morgan, P.J.; Howell, H.E.; Lesieur, D.; Guardiola-Lemaitre, B.; Pfeiffer, B.; Andrieux, J.; Renard, P.; Yous, S.; Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 1992, 35, 8, 1484. |
| 【5】 Depreux, P.; Lesieur, D.; Mansour, H.A.; et al.; Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J Med Chem 1994, 37, 20, 3231. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 58079 | ethyl 2-[7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]acetate | C15H18O3 | 详情 | 详情 | |
| (III) | 58080 | ethyl 2-(7-methoxy-1-naphthyl)acetate | C15H16O3 | 详情 | 详情 | |
| (IV) | 58081 | 2-(7-methoxy-1-naphthyl)acetic acid | C13H12O3 | 详情 | 详情 | |
| (V) | 58082 | 2-(7-methoxy-1-naphthyl)acetamide | C13H13NO2 | 详情 | 详情 | |
| (VI) | 58083 | 2-(7-methoxy-1-naphthyl)-1-ethanamine; 2-(7-methoxy-1-naphthyl)ethylamine | C13H15NO | 详情 | 详情 | |
| (VII) | 36604 | 2-(7-methoxy-1-naphthyl)acetonitrile | C13H11NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Nitrosation of 7-methoxy-2-tetralone (I) using isoamyl nitrite and potassium tert-butoxide provided the oximino ketone (II). Catalytic hydrogenation of the oxime function of (II) in the presence of propionic anhydride gave rise to the propionamide (III). Ketone reduction by means of NaBH4 produced a mixture of cis- and trans-hydroxy amides from which the pure trans-isomer (IV) was isolated after two recrystallizations from EtOAc. The amide function of (IV) was subsequently reduced with LiAlH-4 to the N-propyl amine (V). Acylation of amino alcohol (V) with chloroacetyl chloride (VI) afforded the corresponding chloroacetamido alcohol (VII), which was further cyclized to compound (VIII) upon treatment with NaH. The lactam carbonyl group of (VIII) was then reduced with borane-dimethyl sulfide complex to the cyclic amine (IX). Methyl ether cleavage in (IX) to produce phenol (X) was then achieved by heating with pyridine hydrochloride (1). Phenol (X) was converted to the aryl triflate (XI) by treatment with trifluoromethanesulfonic anhydride. Displacement of the triflate group of (XI) with zinc cyanide in the presence of Pd catalyst furnished nitrile (XII). Partial hydrolysis of the nitrile (XII) under basic conditions produced the corresponding racemic amide. The title dextro-enantiomer was then isolated by preparative chiral HPLC.
| 【2】 Millan, M.; Lejeune, F.; Peglion, J.-L.; Harmange, J.-C. (ADIR et Cie.); Disubstd. trans-3,4,4a,5,6,10b-hexahydro-2H-napht(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical compsns. containing them. CA 2246482; EP 0899267; FR 2767825; JP 1999130759; US 6025356 . |
| 【1】 Peglion, J.-L.; et al.; Discovery of S32504. A preferential agonist at dopamine D3 vs. D2 receptors possessing antiparkinsonian and antidepressant properties. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 208. |
| 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) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 21386 | 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime | C11H11NO3 | 详情 | 详情 | |
| (III) | 21387 | N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide | C14H17NO3 | 详情 | 详情 | |
| (IV) | 21388 | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | C14H19NO3 | 详情 | 详情 | |
| (V) | 21389 | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | C14H21NO2 | 详情 | 详情 | |
| (VI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VII) | 21403 | 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylacetamide | C16H22ClNO3 | 详情 | 详情 | |
| (VIII) | 21390 | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | C16H21NO3 | 详情 | 详情 | |
| (IX) | 21381 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether | C16H23NO2 | 详情 | 详情 | |
| (X) | 51579 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol | C15H21NO2 | 详情 | 详情 | |
| (XI) | 51580 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl trifluoromethanesulfonate | C16H20F3NO4S | 详情 | 详情 | |
| (XII) | 51581 | (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-carbonitrile | C16H20N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of 7-methoxytetralone (I) with diethyl carbonate in the presence of NaH afforded ketoester (II), which was alkylated with ethyl 4-bromobutyrate (III) to give (IV). Hydrolysis and decarboxylation of (IV) using KOH in boiling MeOH provided ketoacid (V). Subsequent addition of thiophenol to (V) with concomitant esterification in the presence of ethanolic HCl, followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave rise to the (phenylthio)naphthalene (VI). Addition of methylmagnesium bromide to the ester function of (VI) yielded carbinol (VII), which was cyclized to the tetrahydroanthracene (VIII) employing ethereal H2SO4. After reductive removal of the phenylthio group of (VIII) by means of Raney Ni yielding (IX), its methyl ether group was cleaved with BBr3, providing phenol (X). Treatment with trifluoromethanesulfonic anhydride gave triflate (XI).
| 【1】 Ericsson, A.; Marinier, A.; Lapointe, P.; et al.; Synthesis and SAR of novel dihydroanthracene derivatives as retinoid analogs. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 43. |
| 【2】 Starrett, J.E. Jr.; Tramposch, K.M.; Martel, A.; Nair, X.; Zusi, F.C.; Reczek, P.R.; Marinier, A.; Ericsson, A. (Bristol-Myers Squibb Co.); Retinoid-like cpds.. WO 9849136 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 | |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 32514 | ethyl 7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C14H16O4 | 详情 | 详情 | |
| (III) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (IV) | 32515 | ethyl 2-(4-ethoxy-4-oxobutyl)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C20H26O6 | 详情 | 详情 | |
| (V) | 32516 | 4-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)butyric acid | C15H18O4 | 详情 | 详情 | |
| (VI) | 32517 | ethyl 4-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]butanoate | C23H24O3S | 详情 | 详情 | |
| (VII) | 32518 | 5-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]-2-methyl-2-pentanol | C23H26O2S | 详情 | 详情 | |
| (VIII) | 32519 | 5,5-dimethyl-9-(phenylsulfanyl)-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-10-(phenylsulfanyl)-1,2,3,4-tetrahydroanthracene | C23H24OS | 详情 | 详情 | |
| (IX) | 32520 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydroanthracene | C17H20O | 详情 | 详情 | |
| (X) | 32521 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenol | C16H18O | 详情 | 详情 | |
| (XI) | 32522 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl trifluoromethanesulfonate | C17H17F3O3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Condensation of 7-methoxytetralone (I) with diethyl carbonate in the presence of NaH afforded ketoester (II), which was alkylated with ethyl 4-bromobutyrate (III) to give (IV). Hydrolysis and decarboxylation of (IV) using KOH in boiling MeOH provided ketoacid (V). Subsequent addition of thiophenol to (V) with concomitant esterification in the presence of ethanolic HCl, followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave rise to the (phenylthio)naphthalene (VI). Addition of methylmagnesium bromide to the ester function of (VI) yielded carbinol (VII), which was cyclized to the tetrahydroanthracene (VIII) employing ethereal H2SO4. After reductive removal of the phenylthio group of (VIII) by means of Raney-Ni yielding (IX), its methyl ether group was cleaved with BBr3, providing phenol (X). Treatment with trifluoromethanesulfonic anhydride gave triflate (XI).
| 【1】 Ericsson, A.; Marinier, A.; Lapointe, P.; et al.; Synthesis and SAR of novel dihydroanthracene derivatives as retinoid analogs. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 43. |
| 【2】 Starrett, J.E. Jr.; Tramposch, K.M.; Martel, A.; Nair, X.; Zusi, F.C.; Reczek, P.R.; Marinier, A.; Ericsson, A. (Bristol-Myers Squibb Co.); Retinoid-like cpds.. WO 9849136 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 | |
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 32514 | ethyl 7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C14H16O4 | 详情 | 详情 | |
| (III) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (IV) | 32515 | ethyl 2-(4-ethoxy-4-oxobutyl)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate | C20H26O6 | 详情 | 详情 | |
| (V) | 32516 | 4-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)butyric acid | C15H18O4 | 详情 | 详情 | |
| (VI) | 32517 | ethyl 4-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]butanoate | C23H24O3S | 详情 | 详情 | |
| (VII) | 32518 | 5-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]-2-methyl-2-pentanol | C23H26O2S | 详情 | 详情 | |
| (VIII) | 32519 | 5,5-dimethyl-9-(phenylsulfanyl)-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-10-(phenylsulfanyl)-1,2,3,4-tetrahydroanthracene | C23H24OS | 详情 | 详情 | |
| (IX) | 32520 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydroanthracene | C17H20O | 详情 | 详情 | |
| (X) | 32521 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenol | C16H18O | 详情 | 详情 | |
| (XI) | 32522 | 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl trifluoromethanesulfonate | C17H17F3O3S | 详情 | 详情 |