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【结 构 式】 
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【分子编号】43191 【品名】ethyl 2-cyano-2-cyclopentylideneacetate 【CA登记号】5407-83-0 |
【 分 子 式 】C10H13NO2 【 分 子 量 】179.21876 【元素组成】C 67.02% H 7.31% N 7.82% O 17.85% |
合成路线1
该中间体在本合成路线中的序号：(I)Treatment of ethyl cyanoacetate derivative (I) with cyanoacetamide (II) in EtOH in the presence of NaOEt provides dicyano derivative (III), which is then converted into diimide (IV) by treatment with refluxing sulfuric acid. Alternatively, (IV) can also be obtained by reaction between cyclopentanone (V), cyanoacetamide (II) and piperidine by means of KOH or NaOH in H2O (or H2O/EtOH) to provide mononitrile derivative (VI), which is then refluxed with H2SO4. Double N-alkylation of compound (IV) with chloride (VII) by heating with NaH or alkaline carbonate in DMF yields dialkylated compound (VIII), which is reduced with LiAlH4 or Red-Al in refluxing THF/toluene to furnish the free base (IX). Finally, (IX) is converted into the desired dihydrochloride by treatment with HCl in isopropanol.
| 【1】 McElvain, S.M.; Clemens, D.H.; Piperidine derivatives. XXX. 1,4-Dialkyl-4-arylpiperidines. J Am Chem Soc 1958, 80, 3915. |
| 【2】 Thole, F.B.; Thorpe, J.F.; The formation and reactions of imino-compounds. Part XV. The production of imino-derivatives of piperidine leading to the formation of the betabeta-disubstituted glutaric acids. J Chem Soc 1911, 99, 422. |
| 【3】 Schon, U.; et al.; Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9-tetraalkylbispidines: Derivatives with specific bradycardic activity. J Med Chem 1998, 41, 3, 318. |
| 【4】 Shon, U.; Hachmeister, B.; Kehrbach, W.; Kuhl, U.; Buschmann, G. (Kali-Chemie AG); New 3,7-diazabicylo[3.3.1]nonanes. DE 3234697; EP 0103833; JP 1993247039 . |
| 【5】 Schon, U.; Heitmann, W.; Matzel, U. (Kali-Chemie AG); Medicament containing crystalline fumaric acid salts or 9,9-alkylen-3-7-diazabicyclononane cpds.. DE 4139763; EP 0550383; JP 1993247040 . |
| 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) | 43191 | ethyl 2-cyano-2-cyclopentylideneacetate | 5407-83-0 | C10H13NO2 | 详情 | 详情 |
| (II) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (III) | 49455 | 7,9-Dioxo-8-azaspiro[4.5]decane-6,10-dicarbonitrile | C11H11N3O2 | 详情 | 详情 | |
| (IV) | 49456 | C11H12N2O4 | 详情 | 详情 | ||
| (V) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VI) | 49457 | 10-cyano-7-imino-9-oxo-8-azaspiro[4.5]decane-6-carboxamide | C11H14N4O2 | 详情 | 详情 | |
| (VII) | 29776 | 1-(chloromethyl)cyclopropane | 5911-08-0 | C4H7Cl | 详情 | 详情 |
| (VIII) | 49458 | C19H24N2O4 | 详情 | 详情 | ||
| (IX) | 49459 | C19H32N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.
| 【1】 Scott, K.R.; Nicholson, J.M.; Edafiogho, I.O.; Farrar, V.A.; Hinko, C.N.; Moore, J.A.; Imidooxy anticonvulsants: Structural analogs with special emphasis on N-(benzyloxy)-2-azaspiro[4,4]nonane-1,3-dione. Drugs Fut 1992, 17, 5, 395. |
| 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) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 43191 | ethyl 2-cyano-2-cyclopentylideneacetate | 5407-83-0 | C10H13NO2 | 详情 | 详情 |
| (IV) | 43192 | 1-(cyanomethyl)cyclopentanecarbonitrile | C8H10N2 | 详情 | 详情 | |
| (V) | 43193 | 1-(carboxymethyl)cyclopentanecarboxylic acid | C8H12O4 | 详情 | 详情 | |
| (VI) | 27158 | 2-oxaspiro[4.4]nonane-1,3-dione | C8H10O3 | 详情 | 详情 | |
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 43194 | 2-hydroxy-2-azaspiro[4.4]nonane-1,3-dione | C8H11NO3 | 详情 | 详情 | |
| (IX) | 43195 | sodium 1,3-dioxo-2-azaspiro[4.4]nonan-2-olate | C8H10NNaO3 | 详情 | 详情 | |
| (X) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |