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【结 构 式】 
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【药物名称】SK&F-86466 【化学名称】6-Chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 【CA登记号】73943-10-9 【 分 子 式 】C11H14ClN 【 分 子 量 】195.69393 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, alpha2-Adrenoceptor Antagonists |
合成路线1
A new synthesis of 13C- or 14C-labeled SKF-86466 has been described: The Friedel Craft's condensation of labeled benzene (I) with oxalyl chloride by means of AlCl3 in CS2 yields benzoic acid (II), which is chlorinated by means of cupric chloride and thallium (III) trifluoroacetate in trifluoroacetic acid to give 2-chlorobenzoic acid (III). The reduction of (III) by means of borane/THF complex in THF affords 2-chlorobenzyl alcohol (IV), which is treated with hot concentrated HCl to afford 2-chlorobenzyl chloride (V). The Grignard condensation of (V) with N-methyloxazolidine (VI) by means of Mg in ether gives N-[2-(2-chlorophenyl)ethyl]-N-methyl-2-hydroxyethylamine (VII), which is finally cyclized by treatment with PCl5 in hot trichlorobenzene followed by addition of AlCl3 and heating at 215-25 C.
| 【1】 Etzkorn, F.; Villani, A.J.; Rotert, G.A.; Heys, J.R.; Synthesis of 13C, 14C and 2H13C labeled adrenoceptor antagonists: 6-c hloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride and its N-desmethyl analog. J Label Compd Radiopharm 1988, 25, 12, 1339. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 44622 | C6H6 | 详情 | 详情 | ||
| (II) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (II) | 44623 | C7H6O2 | 详情 | 详情 | ||
| (III) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (III) | 44624 | C7H5ClO2 | 详情 | 详情 | ||
| (IV) | 10204 | 2-Chlorobenzyl alcohol; (2-Chlorophenyl)methanol | 17849-38-6 | C7H7ClO | 详情 | 详情 |
| (IV) | 44625 | C7H7ClO | 详情 | 详情 | ||
| (V) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (V) | 44626 | C7H6Cl2 | 详情 | 详情 | ||
| (VI) | 10206 | 3-Methyl-1,3-oxazolane | C4H9NO | 详情 | 详情 | |
| (VII) | 10207 | 2-[(2-Chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (VII) | 44627 | C11H16ClNO | 详情 | 详情 |
合成路线2
The reaction of o-chlorophenylacetic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with 2-(methylamino) ethanol (III) yielding o-chloro-N-methyl-N-(2-hydroxyethyl)phenylacetamide (IV). The reduction of (IV) with diborane in THF affords N-methyl-N-(2-hydroxyethyl)-2-(2-chlorophenyl)ethylamine (V), which by reaction with PCl5 in CHCl3 is con-verted into N-methyl-N-(2-chloroethyl)-2-(2-chlorophenyl)ethylamine (VI). Finally, this compound is cyclized by means of anhydrous AlCl3-NH4Cl at 175 C.
| 【1】 Holden K.G.; Kaiser, C. (SmithKline Beecham Corp.); 2,3,4,5-Tetrahydro-1H-3-Benzazepines, process for their production and pharmaceutical compositions having dopamine receptor blocking activity. EP 0007070; EP 0080012; ES 482276; ES 482281; JP 8011584; US 4265890 . |
| 【2】 Castaner, J.; Serradell, M.N.; Badia, A.; SKF-86466. Drugs Fut 1984, 9, 2, 119. |
| 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) | 29994 | 2-(2-chlorophenyl)acetic acid | 2444-36-2 | C8H7ClO2 | 详情 | 详情 |
| (II) | 29995 | 2-(2-chlorophenyl)acetyl chloride | C8H6Cl2O | 详情 | 详情 | |
| (III) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (IV) | 29996 | 2-(2-chlorophenyl)-N-(2-hydroxyethyl)-N-methylacetamide | C11H14ClNO2 | 详情 | 详情 | |
| (V) | 10207 | 2-[(2-Chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (VI) | 29997 | N-(2-chloroethyl)-N-(2-chlorophenethyl)-N-methylamine; 2-chloro-N-(2-chlorophenethyl)-N-methyl-1-ethanamine | C11H15Cl2N | 详情 | 详情 |
合成路线3
The condensation of labeled 2-(3-chlorphenyl)acetic acid (I) with N-methylethanolamine (II) by means of SOCl2 gives the corresponding amide (III), which is reduced with BH3, yielding the tertiary amine (IV). The reaction of (IV) with PCl3 affords the chloroethylamine (V), which is finally cyclized by means of AlCl3 to provide the target benzazepine.
| 【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645. |
| 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) | 39705 | 2-(3-chlorophenyl)acetic acid; 3-chlorophenylacetic acid | 1878-65-5 | C8H7ClO2 | 详情 | 详情 |
| (I) | 44628 | 2-(3-chlorophenyl)acetic acid | C8H7ClO2 | 详情 | 详情 | |
| (II) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (III) | 44044 | 2-(3-chlorophenyl)-N-(2-hydroxyethyl)-N-methylacetamide | C11H14ClNO2 | 详情 | 详情 | |
| (III) | 44629 | 2-(3-chlorophenyl)-N-(2-hydroxyethyl)-N-methylacetamide | C11H14ClNO2 | 详情 | 详情 | |
| (IV) | 44045 | 2-[(3-chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (IV) | 44630 | 2-[(3-chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (V) | 44046 | 2-chloro-N-(3-chlorophenethyl)-N-methyl-1-ethanamine; N-(2-chloroethyl)-N-(3-chlorophenethyl)-N-methylamine | C11H15Cl2N | 详情 | 详情 | |
| (V) | 44631 | 2-chloro-N-(3-chlorophenethyl)-N-methyl-1-ethanamine; N-(2-chloroethyl)-N-(3-chlorophenethyl)-N-methylamine | C11H15Cl2N | 详情 | 详情 |