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【结 构 式】 
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【分子编号】33774 【品名】10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide 【CA登记号】28721-07-5 |
【 分 子 式 】C15H12N2O2 【 分 子 量 】252.27256 【元素组成】C 71.42% H 4.79% N 11.1% O 12.68% |
合成路线1
该中间体在本合成路线中的序号：(IV)Reaction of 10-methoxy-5H-dibenzo[b,f]azepine (I) with phosgene in toluene produced the dibenzoazepine-5-carbonyl chloride (II). This was converted to urea (III) upon treatment with ethanolic ammonia. Acidic hydrolysis of the enol ether function of (III) afforded ketone (IV). Then, reduction of the ketone (IV) to the target alcohol was accomplished either by catalytic hydrogenation over copper chromite or by means of NaBH4 in aqueous EtOH.
| 【1】 Garrett, J.; Soares-da-Silva, P.; Freitas, A.P.; Cunha, R.A.; Benes, J.; Parada, A.; Learmonth, D.A.; Alves, P.C.; Figueiredo, A.; Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem 1999, 42, 14, 2582. |
| 【2】 Schindler, W. (Novartis AG); Process for the preparation of a new azepine deriv.. DE 2011045; GB 1310120 . |
| 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) | 24333 | 10-methoxy-5H-dibenzo[b,f]azepine;10-Methoxyiminostilbene | 4698-11-7 | C15H13NO | 详情 | 详情 |
| (II) | 24334 | 10-methoxy-5H-dibenzo[b,f]azepine-5-carbonyl chloride | C16H12ClNO2 | 详情 | 详情 | |
| (III) | 24335 | 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxamide | C16H14N2O2 | 详情 | 详情 | |
| (IV) | 33774 | 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | 28721-07-5 | C15H12N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Oxcarbazepine (I) was reduced with NaBH4 to afford the racemic alcohol (IIa-b). Esterification with (-)-menthoxyacetic acid chloride (III) in the presence of dimethylaminopyridine provided the diastereomeric mixture of esters (IV) and (V), from which the desired isomer (V) was isolated by fractional crystallization from CH2Cl2/EtOAc. Basic hydrolysis of (V) then provided pure (R)-alcohol (VI). Finally, esterification of (VI) with acetyl chloride led to the title acetate ester.
| 【1】 Garrett, J.; Soares-da-Silva, P.; Freitas, A.P.; Cunha, R.A.; Benes, J.; Parada, A.; Learmonth, D.A.; Alves, P.C.; Figueiredo, A.; Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem 1999, 42, 14, 2582. |
| 【2】 Benes, J.; Vieira Araujo Soares da Silva, P.M. (Portela & Ca., SA); Substd. dihydrodibenzo[b,f]azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compsns. containing them. EP 0751129; US 5753646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 33775 | (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (IIb),(VI) | 33779 | (10R)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (I) | 33774 | 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | 28721-07-5 | C15H12N2O2 | 详情 | 详情 |
| (III) | 33776 | 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetyl chloride | 15356-62-4 | C12H21ClO2 | 详情 | 详情 |
| (IV) | 33777 | (10S)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetate | C27H34N2O4 | 详情 | 详情 | |
| (V) | 33778 | (10R)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetate | C27H34N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Reduction of oxcarbazepine (I) using NaBH4 yields the racemic alcohol (II). Resolution of the enantiomers is then achieved by means of fractional crystallization of the diastereomeric esters obtained from alcohol (II) and menthoxyacetyl chloride (III). Alkaline hydrolysis of the desired diastereoisomer (IV) provides the (S)-alcohol (V). This compound is finally converted into the corresponding acetate by esterification with acetyl chloride.
| 【2】 Benes, J.; Vieira Araujo Soares da Silva, P.M. (Portela & Ca., SA); Substd. dihydrodibenzo[b,f]azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compsns. containing them. EP 0751129; US 5753646 . |
| 【1】 Loareesuwan, S.; Management of multi drug-resistant falciparum malaria. J Antimicrob Chemother 1999, 44, Suppl. A. |
| 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) | 33774 | 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | 28721-07-5 | C15H12N2O2 | 详情 | 详情 |
| (II) | 58231 | 10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (III) | 33776 | 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetyl chloride | 15356-62-4 | C12H21ClO2 | 详情 | 详情 |
| (IV) | 33777 | (10S)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetate | C27H34N2O4 | 详情 | 详情 | |
| (V) | 33775 | (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reduction of oxcarbazepine (I) using NaBH4 in ethanol/water yields the racemic alcohol (II), which is resolved into its enantiomers by means of fractional crystallization of the diastereomeric esters obtained from alcohol (II) and menthoxyacetyl chloride (III). Alkaline hydrolysis of the desired diastereoisomer (IV) provides the (S)-alcohol (V) , which is finally acylated with acetyl chloride and DMAP in pyridine/CH2Cl2 .
Condensation of racemic alcohol (II) with di-O-acetyl-L-tartaric acid anhydride (VI) – obtained by treatment of L-tartaric (VII) acid with hot AcO2 and trace H2SO4 – gives a disastereomeric mixture of tartrate monoesters (VIII), which is separated into diastereomeric alcohol esters by fractional crystallization in water and then the desired (S)-diastereomer hydrolyzed under alkaline conditions to afford alcohol (V) .
| 【1】 Benes, J., Vieira Araujo Soares da Silva, P.M. (Bial – Portela & Ca., SA). Substituted dihydrodibenzo[b,f]azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them. CA 2180301, EP 0751129, JP 1997110836, JP 2004256516, US 5753646, WO 199700250. |
| 【2】 Benes, J., Parada, A., Figueiredo, A. et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem 1999, 42(14): 2582-7. |
| 【3】 Learmonth, D.A. (Portela & Ca., SA). Method for preparation of (S)-(+)-and (R)-(-)-10,11-dihydro-10-hydroxy-5H, dibenz[b,f]azepine-5-carboxamide. CA 2447980, EP 1385826, GB 2377440, JP 2004534753, US 2004162280, US 2007073057, US 7119197, WO 2002092572. |
| 【4】 Learmonth, D.A., Grasa, G.A., Zanotti-Gerosa, A. (Bial – Portela & Ca.,SA). Asymmetric catalytic reduction of oxcarbazepine. CA 2616984, EP 1915346, JP 2009502893, WO 2007012793. |
| 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) | 33774 | 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | 28721-07-5 | C15H12N2O2 | 详情 | 详情 |
| (II) | 58231 | 10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (III) | 33776 | 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetyl chloride | 15356-62-4 | C12H21ClO2 | 详情 | 详情 |
| (IV) | 33777 | (10S)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl 2-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]acetate | C27H34N2O4 | 详情 | 详情 | |
| (V) | 33775 | (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide | C15H14N2O2 | 详情 | 详情 | |
| (VI) | 69302 | di-O-acetyl-L-tartaric acid anhydride;(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate | C8H8O7 | 详情 | 详情 | |
| (VII) | 28379 | (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid | 87-69-4 | C4H6O6 | 详情 | 详情 |
| (VIII) | 69303 | (2S,3S)-4-((5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl)oxy)-2,3-dihydroxy-4-oxobutanoic acid | C19H18N2O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Alcohol (V) can also be obtained by enantioselective reduction of oxcarbazepine (I) by transfer hydrogenation with formic acid/triethylamine in the presence of the chiral Noyori catalyst [(S,S)-N-tosyl-1,2-diphenylethylenediamino](η6-p-cymene)chlororuthenium .
Alternatively, treatment of oxcarbazepine (I) with acetic anhydride and DMAP in pyridine/CH2Cl2 yields the enol acetate (IX), which is submitted to asymmetric hydrogenation with H2 in the presence of a chiral rhodium(I) catalyst .
| 【3】 Yu, B., Li, W., Learmonth, D. (Bial – Portela & Ca., SA). Preparation of eslicarbazepine and related compounds by asymmetric hydrogenation. CA 2648916, EP 2004610, GB 2437078, WO 2007117166. |
| 【1】 Learmonth, D.A., Grasa, G.A., Zanotti-Gerosa, A. (Bial – Portela & Ca.,SA). Asymmetric catalytic reduction of oxcarbazepine. CA 2616984, EP 1915346, JP 2009502893, WO 2007012793. |
| 【2】 Mathes, C., Sedelmeier, G., Blatter, F., Pfeffer, S., Grimler, D. (Novartis AG; Novartis Pharma GmbH). Enantioselective process for the preparation of both enantiomers of 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and new crystal forms thereof. CA 2501237, EP 1551808, JP 2006504710, US 2006142566, WO 2004031155. |