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【结 构 式】 
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【分子编号】58231 【品名】10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide 【CA登记号】 |
【 分 子 式 】C15H14N2O2 【 分 子 量 】254.28844 【元素组成】C 70.85% H 5.55% N 11.02% O 12.58% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(II)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 |