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【结 构 式】 
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【分子编号】28363 【品名】ethylene 【CA登记号】9002-88-4 |
【 分 子 式 】C2H4 【 分 子 量 】28.05376 【元素组成】C 85.63% H 14.37% |
合成路线1
该中间体在本合成路线中的序号：(C)The diazotation of 2,3-dichloroaniline (IX) with NaNO2 and HCl gives the corresponding diazonium chloride (X), which by a Sandmeyer reaction with CuCN yields 2,3-dichlorophenyl cyanide (XI). The Grignard reaction of (XI) with methylmagnesium bromide (A) in ether affords 2,3-dichloroacetophenone (XII), which by a Willgerodt reaction with S and morpholine is converted into 2,3-dichlorophenylacetic acid (XIII). The reaction of (XIII) with oxalyl chloride (B) in carbon tetrachloride affords the corresponding acyl chloride (XIV), which is cyclized with ethylene (C) by means of AlCl3 in methylene chloride yielding 7,8-dichloro-2-tetralone (XV). The reaction of (XV) with sodium azide in CHCl3 by means of H2SO4 gives 8,9-dichloro-2-benzazepin-3-one (XVI), which is finally reduced with diborane in THF.
| 【1】 Molloy, B.B.; Chlorinated tetrahydro-2-benzazepines, N-methyl transferase inhibitors. CA 1119592 . |
| 【2】 Serradell, M.N.; Castaner, J.; LY-134046. Drugs Fut 1984, 9, 4, 268. |
| 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) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (A) | 33623 | bromo(methyl)magnesium | 75-16-1 | CH3BrMg | 详情 | 详情 |
| (IX) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (X) | 34165 | 2,3-dichlorobenzenediazonium chloride | C6H3Cl3N2 | 详情 | 详情 | |
| (XI) | 30204 | 2,3-dichlorobenzonitrile | 6574-97-6 | C7H3Cl2N | 详情 | 详情 |
| (XII) | 34166 | 1-(2,3-dichlorophenyl)-1-ethanone | C8H6Cl2O | 详情 | 详情 | |
| (XIII) | 34167 | 2-(2,3-dichlorophenyl)acetic acid | C8H6Cl2O2 | 详情 | 详情 | |
| (XIV) | 34168 | 2-(2,3-dichlorophenyl)acetyl chloride | C8H5Cl3O | 详情 | 详情 | |
| (XV) | 34169 | 7,8-dichloro-3,4-dihydro-2(1H)-naphthalenone | C10H8Cl2O | 详情 | 详情 | |
| (XVI) | 34170 | 8,9-dichloro-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one | C10H9Cl2NO | 详情 | 详情 | |
| (C) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1,3-bis(trimethylsilyloxy)propane (II) by means of trimethylsilyl trifluoromethanesulfonate in THF gives the propylene ketal (III), which is treated with dimethyldisulfide and BuLi in THF yielding the methylsulfanyl derivative (IV). The hydrolysis of (IV) by means of HCl in THF affords 6-(methylsulfanyl)-1,2,3,4-tetrahydronaphthalen-2-one (V), which is condensed with 1(R)-phenyl ethylamine (VI) by means of p-toluenesulfonic acid in refluxing toluene giving the enamine (VII). The methylation of (VII) with lithium diisopropylamide and methyl iodide in THF yields the 1-methyldihydronaphthalene (VIII), which is cyclized with acryloyl anhydride (IX) in toluene affording the benzoquinoline derivative (X). The treatment of (X) with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar gives intermediate (XI), which is methylated with methyllithium in THF yielding the N-methylbenzoquinoline (XII). The oxidation of (XII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane affords the corresponding methylsulfinyl derivative (XIII), which by reaction with trifluoroacetic anhydride provides the trifluoroacetoxymethylsulfanyl derivative (XIV). Finally, this compound is condensed with 2-chloro-4-ethylbenzothiazole (XV) by means of tetrabutylammonium bisulfate (BNS) and NaBH4 in toluene/water.
| 【1】 Udodong, U.E.; Brennan, J.; Doecke, C.W.; Heath, P.C.; Patterson, L.E.; Weigel, L.O. (Eli Lilly and Company); Synthesis of benzo[f]quinolinones. WO 9818757 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 28593 | trimethyl[5-(trimethylsilyl)pentyl]silane | C11H28Si2 | 详情 | 详情 | |
| (III) | 28594 | 6'-Bromo-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C13H15BrO2 | 详情 | 详情 | |
| (IV) | 28595 | 6'-(Methylsulfanyl)-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C14H18O2S | 详情 | 详情 | |
| (V) | 28596 | 6-(methylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone | C11H12OS | 详情 | 详情 | |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VII) | 28598 | 6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C19H21NS | 详情 | 详情 | |
| (VIII) | 28599 | 1-methyl-6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C20H23NS | 详情 | 详情 | |
| (IX) | 28600 | acrylic anhydride | C6H6O3 | 详情 | 详情 | |
| (X) | 28601 | (10bR)-10b-methyl-8-(methylsulfanyl)-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C23H25NOS | 详情 | 详情 | |
| (XI) | 28602 | (4aR,10bR)-10b-methyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XII) | 28603 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NOS | 详情 | 详情 | |
| (XIII) | 28604 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfinyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NO2S | 详情 | 详情 | |
| (XIV) | 28605 | [[(4aR,10bR)-4,10b-dimethyl-3-oxo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-8-yl]sulfanyl]methyl 2,2,2-trifluoroacetate | C18H20F3NO3S | 详情 | 详情 | |
| (XV) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 | |
| (XVI) | 28597 | 2-[4-(methylsulfanyl)phenyl]acetic acid | C9H10O2S | 详情 | 详情 | |
| (XVII) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (XVIII) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
| (XIX) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of 3,5-difluorophenylacetic acid with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with ethylene (III) by means of AlCl3 in dichloromethane yielding the tetralone (IV). The stereoselective reduction of (IV) with LiAlH4 catalyzed by (1R,2S)-N-methylephedrine affords 5,7-difluoro-1,2,3,4-tetrahydro-2(R)-naphthol (V). The reaction of (V) with methanesulfonyl chloride and triethylamine gives the expected mesylate (VI), which is treated with LiN3 in DMF yielding the 2(S)-azide (VII). The reduction of (VII) with H2 over Pd/C in ethyl acetate affords the corresponding amine (VIII), which is treated with formaldehyde and KCN to give the 2-aminoacetonitrile (IX). The acylation of (IX) with butyl formate in refluxing acetonitrile yields the formamide (X), with is treated with ethyl formate and potassium tert-butoxide in THF to afford the hydroxyvinyl derivative (XI). The cyclization of (XI) with potassium thiocyanate in hot ethanol gives 1-(5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2(S)-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbonitrile (XII), which is finally reduced with LiAlH4 in THF.
| 【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 . |
| 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) | 28361 | 2-(3,5-difluorophenyl)acetic acid | 105184-38-1 | C8H6F2O2 | 详情 | 详情 |
| (II) | 28362 | 2-(3,5-difluorophenyl)acetyl chloride | C8H5ClF2O | 详情 | 详情 | |
| (III) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
| (IV) | 28364 | 5,7-difluoro-3,4-dihydro-2(1H)-naphthalenone | C10H8F2O | 详情 | 详情 | |
| (V) | 28365 | (2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenol | C10H10F2O | 详情 | 详情 | |
| (VI) | 28366 | (2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl methanesulfonate | C11H12F2O3S | 详情 | 详情 | |
| (VII) | 28367 | (2S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene | C10H9F2N3 | 详情 | 详情 | |
| (VIII) | 18416 | (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine | C10H11F2N | 详情 | 详情 | |
| (IX) | 28368 | 2-[[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]amino]acetonitrile | C12H12F2N2 | 详情 | 详情 | |
| (X) | 28369 | cyanomethyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide | C13H12F2N2O | 详情 | 详情 | |
| (XI) | 28370 | (Z)-1-cyano-2-hydroxyethenyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide | C14H12F2N2O2 | 详情 | 详情 | |
| (XII) | 28371 | 3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazole-4-carbonitrile | C14H11F2N3S | 详情 | 详情 |