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【结 构 式】 
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【药物名称】Ly-134046 【化学名称】8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride 【CA登记号】69739-51-1, 71274-97-0 (free base) 【 分 子 式 】C10H12Cl3N 【 分 子 量 】252.57284 |
【开发单位】Lilly (Originator) 【药理作用】PHARMACOLOGICAL TOOLS, Phenylethanolamine N-Methyltransferase Inhibitors |
合成路线1
A new synthesis for LY-134046 has been described: The reaction of 6,7-dichloro-3-hydroxyphthalide (I) with diethyl cyanomethylphosphonate (II) by means of NaH in dimethoxyethane gives 2-carboxy-3,4-dichlorocinnamonitrile (III), which is reduced with NaBH4 in refluxing isopropanol to yield 3-(2-carboxy-3,4-dichlorophenyl)propionitrile (IV). The esterification of (IV) with methyl iodide and K2CO3 affords the cyano ester (V), which is reduced with BH3 in THF giving 6-(3-aminopropyl)-2,3-dichlorobenzoic acid methyl ester (VI). The cyclization of (VI) by means of sodium methoxide in methanol yields 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (VII), which is finally reduced with BH3 in refluxing THF.
| 【1】 Paradkar, V.M.; Grunewald, G.L.; A regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046), a potent phenylethanolamine N-methyltransferase inhibitor. Bioorg Med Chem Lett 1991, 1, 1, 59-60. |
| 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) | 10044 | 6,7-Dichloro-3-hydroxy-2-benzofuran-1(3H)-one | C8H4Cl2O3 | 详情 | 详情 | |
| (II) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (III) | 10046 | 2,3-Dichloro-6-[(E)-2-cyanoethenyl]benzoic acid | C10H5Cl2NO2 | 详情 | 详情 | |
| (IV) | 10047 | 2,3-Dichloro-6-(2-cyanoethyl)benzoic acid | C10H7Cl2NO2 | 详情 | 详情 | |
| (V) | 10048 | methyl 2,3-dichloro-6-(2-cyanoethyl)benzoate | C11H9Cl2NO2 | 详情 | 详情 | |
| (VI) | 10049 | methyl 6-(3-aminopropyl)-2,3-dichlorobenzoate | C11H13Cl2NO2 | 详情 | 详情 | |
| (VII) | 10050 | 8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one | C10H9Cl2NO | 详情 | 详情 |
合成路线2
The condensation of 2,3-dichlorobenzaldehyde (I) with 2,2-dimethoxyethylamine (II) in refluxing toluene gives the corresponding Schiff base (III), which is reduced with H2 over PtO2 in ethyl acetate and acetylated with acetic anhydride yielding N-(2,3-dichlororobenzyl)-N-(2,2-dimethoxyethyl)acetamide (IV). The cyclization of (IV) with AlCl3 in dichloroethane affords 7,8-dichloro-2-acetyl-1,2-dihydroisoquinoline (V), which is submitted to cyclopropanation with CHCl3, NaOH and benzyltriethylammonium chloride giving 1,1,4,5-tetrachloro-2-acetyl-1a,2,3,7b-tetrahydro-1H-cycloprop[c]isoquinoline (VI). Ring opening of (VI) by refluxing with tert-butyl alcohol yields 2-acetyl-3-(tert-butoxy)-4,8,9-trichloro-2,3-dihydro-1H-2-benzazepine (VII), which is reduced with H2 over PtO2 in methanol affording 2-acetyl-8,9-dichloro 2,3,4,5-tetrahydro-1H-2-benzazepine (VIII). Finally, this compound is desacetylated by means of refluxing aqueous HCl.
| 【1】 Perchonock, C.D.; Lantos, I.; Holden, K.G.; Finkelstei, J.A.; Facile synthesis of halo-substituted tetrahydroisoquinolines and tetrahydro-2-benzazepines via N-acetyl-1,2-dihydroisoquinolines. J Org Chem 1980, 45, 10, 1950-53. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 34159 | N-[(Z)-(2,3-dichlorophenyl)methylidene]-2,2-dimethoxy-1-ethanamine; N-[(Z)-(2,3-dichlorophenyl)methylidene]-N-(2,2-dimethoxyethyl)amine | C11H13Cl2NO2 | 详情 | 详情 | |
| (IV) | 34160 | N-(2,3-dichlorobenzyl)-N-(2,2-dimethoxyethyl)acetamide | C13H17Cl2NO3 | 详情 | 详情 | |
| (V) | 34161 | 1-[7,8-dichloro-2(1H)-isoquinolinyl]-1-ethanone | C11H9Cl2NO | 详情 | 详情 | |
| (VI) | 34162 | 1-(1,1,4,5-tetrachloro-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-1-ethanone | C12H9Cl4NO | 详情 | 详情 | |
| (VII) | 34163 | 1-[3-(tert-butoxy)-4,8,9-trichloro-1,3-dihydro-2H-2-benzazepin-2-yl]-1-ethanone | C16H18Cl3NO2 | 详情 | 详情 | |
| (VIII) | 34164 | 1-(8,9-dichloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-1-ethanone | C12H13Cl2NO | 详情 | 详情 |
合成路线3
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4
By a Friedel-Kraft's cyclization of N-(2,3-dichlorobenzyl)-3-bromopropylamine (XVII) by means of AlCl3 in decalin at 150 C.
| 【1】 Molloy, B.B.; Chlorinated tetrahydro-2-benzazepines, N-methyl transferase inhibitors. CA 1122528 . |
| 【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 |
|---|---|---|---|---|---|---|
| (XVII) | 34171 | 5-bromo-8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine | C10H10BrCl2N | 详情 | 详情 |