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【结 构 式】 
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【药物名称】Mianserin hydrochloride, Tetramide, Lantanon, Tolvin, Athymil, Tolvon, Lerivon, Bolvidon 【化学名称】2-Methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine hydrochloride 【CA登记号】21535-47-7, 24219-97-4 (free base) 【 分 子 式 】C18H21ClN2 【 分 子 量 】300.83447 |
【开发单位】Nippon Organon (Originator), Organon (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS |
合成路线1
The title compound has been synthesized by several procedures. Acylation of 2-benzylaniline (I) by chloroacetyl chloride (II) gave chloroacetamide (III). Subsequent cyclization of amide (III) under Vilsmeier conditions furnished the dibenzoazepine (IV). Nucleophilic substitution of the chlorine atom of (IV) by methylamine led to amine (V). The imine function of (V) was reduced with either LiAlH4 or NaBH4 to the diamine (VI), which was further converted into the fused diketopiperazine (VII) upon heating with diethyl oxalate. The amide groups of (VII) were then reduced by means of borane in THF, yielding the target tetracyclic diamine, which was finally isolated as the corresponding hydrochloride salt
| 【1】 van der Burg, W.J.; et al.; A novel type of substituted piperazine with high antiserotonin potency. J Med Chem 1970, 13, 1, 35. |
| 【2】 van der Burg, W.J.; Delobelle, J.; Polycyclic piperazines. US 3534041 . |
| 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) | 62393 | 2-benzylaniline; 2-benzylphenylamine | 28059-64-5 | C13H13N | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 62394 | N-(2-benzylphenyl)-2-chloroacetamide | C15H14ClNO | 详情 | 详情 | |
| (IV) | 62395 | 6-(chloromethyl)-11H-dibenzo[b,e]azepine | 21535-44-4 | C15H12ClN | 详情 | 详情 |
| (V) | 62396 | 11H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(11H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine | C16H16N2 | 详情 | 详情 | |
| (VI) | 62397 | 6,11-dihydro-5H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine | C16H18N2 | 详情 | 详情 | |
| (VII) | 62398 | 2-methyl-1,2,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepine-3,4-dione | C18H16N2O2 | 详情 | 详情 |
合成路线2
Treatment of alpha-chlorophenylacetyl chloride (VIII) with methylamine provided the corresponding chloro amide (IX), which was subsequently condensed with 2-aminobenzyl alcohol (X) to afford amino alcohol (XI). Cyclization of (XI) in the presence of AlCl3 led to the dibenzoazepine (XII). This was converted to the tetracyclic compound (XIV) by reaction with dibromoethane (XIII) in the presence of Na2CO3. Reduction of the amide carbonyl group of (XIV) by means of LiAlH4 furnished the title compound. In a related strategy, amide (XII) was initially reduced to diamine (VI) by using LiAlH4. Subsequent condensation of (VI) with dibromoethane (XIII) led to the target tetracyclic derivative
| 【1】 Haider, A.; Bollinger, H.; Fischer, A. (Sochinaz SA); Process for the preparation of a tetracyclic compound and application of this process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin. FR 2647114 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62397 | 6,11-dihydro-5H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine | C16H18N2 | 详情 | 详情 | |
| (VIII) | 62399 | 2-chloro-2-phenylacetyl chloride | C8H6Cl2O | 详情 | 详情 | |
| (IX) | 62400 | 2-chloro-N-methyl-2-phenylacetamide | C9H10ClNO | 详情 | 详情 | |
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XI) | 62401 | 2-[2-(hydroxymethyl)anilino]-N-methyl-2-phenylacetamide | C16H18N2O2 | 详情 | 详情 | |
| (XII) | 62402 | N-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide | C16H16N2O | 详情 | 详情 | |
| (XIII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XIV) | 62403 | 2-methyl-3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepin-1(2H)-one | C18H18N2O | 详情 | 详情 |
合成路线3
In a different method, reaction of styrene oxide (XV) with methylamine provided amino alcohol (XVI), which was further condensed with ethylene oxide (XVII) to afford amino diol (XVIII). Alternatively, diol (XVIII) was prepared by a more direct procedure by condensation of epoxide (XV) with 2-(methylamino)ethanol (XIX). Chlorination of (XVIII) employing SOCl2 yielded the dichloro derivative (XX), which was subsequently condensed with 2-aminobenzyl alcohol (X) leading to piperazine (XXI). Cyclization of (XXI) to the title compound was accomplished by treatment with hot polyphosphoric acid. Optionally, alcohol (XXI) was converted to chloride (XXII), which was then cyclized in the presence of AlCl3. In a related method, alcohol (XXI) was esterified with AcOH, and the resultant acetate ester (XXIII) was then cyclized in the presence of polyphosphoric acid
| 【1】 Olivié, J.; Synthesis for the preparation of tetracyclic cpds.. US 4217452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XV) | 23017 | 2-phenyloxirane | 96-09-3 | C8H8O | 详情 | 详情 |
| (XVI) | 62404 | 2-(methylamino)-1-phenyl-1-ethanol | C9H13NO | 详情 | 详情 | |
| (XVII) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (XVIII) | 62405 | 2-[(2-hydroxyethyl)(methyl)amino]-1-phenyl-1-ethanol | C11H17NO2 | 详情 | 详情 | |
| (XIX) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (XX) | 62406 | 2-chloro-N-(2-chloroethyl)-N-methyl-2-phenyl-1-ethanamine; N-(2-chloroethyl)-N-(2-chloro-2-phenylethyl)-N-methylamine | C11H15Cl2N | 详情 | 详情 | |
| (XXI) | 62407 | [2-(4-methyl-2-phenyl-1-piperazinyl)phenyl]methanol | C18H22N2O | 详情 | 详情 | |
| (XXII) | 62408 | 1-[2-(chloromethyl)phenyl]-4-methyl-2-phenylpiperazine | C18H21ClN2 | 详情 | 详情 | |
| (XXIII) | 62409 | 2-(4-methyl-2-phenyl-1-piperazinyl)benzyl acetate | C20H24N2O2 | 详情 | 详情 |
合成路线4
The key intermediate (XXI) was also prepared by several related procedures. Chlorination of aminoalcohol (XVI) gave chloro amine (XXIV), which was condensed with 2-aminobenzyl alcohol (X) to afford diamine (XXV). Then, alkylation of diamine (XXV) with dibromoethane (XIII) in hot pyridine gave rise to the target piperazine (XXI). Alternatively, diamine (XXV) was condensed with ethyl chloroacetate or with diethyl oxalate to produce the mono- or dioxopiperazines (XXVII) and (XXVI), respectively, which were then reduced to (XXI) by means of LiAlH4. Cyclization of alcohol (XXI) to the title compound was achieved by treatment with concentrated sulfuric acid
| 【1】 Olivié, J.; Synthesis for the preparation of tetracyclic cpds.. US 4217452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 | |
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XIII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XVI) | 62404 | 2-(methylamino)-1-phenyl-1-ethanol | C9H13NO | 详情 | 详情 | |
| (XXI) | 62407 | [2-(4-methyl-2-phenyl-1-piperazinyl)phenyl]methanol | C18H22N2O | 详情 | 详情 | |
| (XXIV) | 62410 | C10H16ClN | 详情 | 详情 | ||
| (XXV) | 62411 | (2-{[2-(methylamino)-1-phenylethyl]amino}phenyl)methanol | C16H20N2O | 详情 | 详情 | |
| (XXVI) | 62413 | 4-[2-(hydroxymethyl)phenyl]-1-methyl-5-phenyl-2,3-piperazinedione | C18H18N2O3 | 详情 | 详情 | |
| (XXVII) | 62412 | 1-[2-(hydroxymethyl)phenyl]-4-methyl-6-phenyl-2-piperazinone | C18H20N2O2 | 详情 | 详情 |
合成路线5
In a further procedure, styrene oxide (XV) was condensed with 2-(benzylamino)ethanol (XXVIII) to give amino diol (XXIX). After chlorination of (XXIX) using SOCl2 and DMAP, dichloro derivative (XXX) was condensed with 2-aminobenzyl alcohol (X) yielding piperazine (XXXI). Cyclization of (XXXI) in hot sulfuric acid afforded the tetracyclic compound (XXXII). The N-benzyl group of (XXXII) was then removed by treatment with butyl chloroformate producing carbamate (XXXIII), which was further hydrolyzed and decarboxylated to (XXXIV) under basic conditions. Finally, methylation of the secondary amine (XXXIV) was performed by reductive alkylation with formaldehyde either in the presence of formic acid under Leuckart-Wallach conditions or by catalytic hydrogenation
| 【1】 Grafe, I.; Ahrens, K.-H.; Morsdorf, J.P.; Kisielowski-Ruppert, L. (Heumann Pharma GmbH); Process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and their salts. DE 4305659; EP 0612745 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XV) | 23017 | 2-phenyloxirane | 96-09-3 | C8H8O | 详情 | 详情 |
| (XXVIII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXIX) | 62414 | 2-[benzyl(2-hydroxyethyl)amino]-1-phenyl-1-ethanol | C17H21NO2 | 详情 | 详情 | |
| (XXX) | 62415 | N-benzyl-2-chloro-N-(2-chloroethyl)-2-phenyl-1-ethanamine; N-benzyl-N-(2-chloroethyl)-N-(2-chloro-2-phenylethyl)amine | C17H19Cl2N | 详情 | 详情 | |
| (XXXI) | 62416 | [2-(4-benzyl-2-phenyl-1-piperazinyl)phenyl]methanol | C24H26N2O | 详情 | 详情 | |
| (XXXII) | 62417 | 2-benzyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C24H24N2 | 详情 | 详情 | |
| (XXXIII) | 62418 | butyl 3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepine-2(1H)-carboxylate | C22H26N2O2 | 详情 | 详情 | |
| (XXXIV) | 62419 | 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C17H18N2 | 详情 | 详情 |
合成路线6
11C-labelled mianserin is obtained by methylation of N-desmethyl mianserin hydrochloride (I) with 11C-Methyl iodide and NaOH in DMSO aminopyrazole (VI)
