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【结 构 式】 
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【分子编号】11163 【品名】5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 【CA登记号】 |
【 分 子 式 】C12H9N3O 【 分 子 量 】211.22308 【元素组成】C 68.24% H 4.29% N 19.89% O 7.57% |
合成路线1
该中间体在本合成路线中的序号：(IV)Synthesis of the intermediate 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (IV) is accomplished by condensation of 3-amino-2-chloropyridine (I) and the anthranilic ester (II) using potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene furnishes the corresponding chloroacetamide (V). The diamine part of AF-DX 116 is prepared starting from 2-(hydroxymethyl)piperidine (VI). Reaction with thionylchloride in dichloromethane affords the pipecolylchloride hydrochloride (VII), which is converted with diethylamine to the required 2-[(diethylamino)methyl]piperidine (IX) via nucleophilic ring opening of the intermediate aziridine (VIII). Minor amounts of 3-(diethylamino)hexahydroazepine (X), formed by a side reaction, are separated by thorough fractional distillation of the diamine (IX) and/or recrystallization of its hydrochloride (XI). Coupling of (V) and (XI) in the presence of sodium carbonate yields AF-DX 116 as its free base.
| 【1】 Schmidt, G.; Hammer, R.; Giachetti, A.; Engel, W.; Trummlitz, G.; Eberlein, W.; Mihm, G. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8539815; EP 0156191; ES 8607282; ES 8702908; JP 1985215683; US 4550107 . |
| 【2】 Mattson, R.J.; Yevich, J.P.; Eison, M.S. (Bristol-Myers Squibb Co.); Cerebral function enhancing diazinylpiperidine derivs. AU 8659787; BE 0905061; CH 671579; DE 3622842; FR 2584408; GB 2177692; US 4826843 . |
| 【3】 Eberlein, W.G.; Trummlitz, G.; Mihm, G.; Engel, W.W.; Hammer, R.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1718-24. |
| 【4】 Engel, W.; Doods, H.; Wetzel, B.; AF-DX 116. Drugs Fut 1990, 15, 1, 9. |
| 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) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (II) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (III) | 11162 | 2-Amino-N-(2-chloro-3-pyridinyl)benzamide | C12H10ClN3O | 详情 | 详情 | |
| (IV) | 11163 | 5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C12H9N3O | 详情 | 详情 | |
| (V) | 11164 | 11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C14H10ClN3O2 | 详情 | 详情 | |
| (VI) | 11165 | 2-Piperidinylmethanol; 2-Piperidinemethanol | 3433-37-2 | C6H13NO | 详情 | 详情 |
| (VII) | 11166 | 2-(Chloromethyl)piperidine | C6H12ClN | 详情 | 详情 | |
| (VIII) | 11167 | 1-Azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 | |
| (IX) | 11168 | N-Ethyl-N-(2-piperidinylmethyl)-1-ethanamine; N-(2-Piperidylmethyl)-diethylamine; N,N-Diethyl-N-(2-piperidinylmethyl)amine | 64168-09-8 | C10H22N2 | 详情 | 详情 |
| (X) | 11169 | N,N-Diethyl-3-azepanamine; N-(3-Azepanyl)-N,N-diethylamine | C10H22N2 | 详情 | 详情 | |
| (XI) | 11170 | N-Ethyl-N-(2-piperidinylmethyl)-1-ethanamine hydrochloride | C10H23ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.
| 【1】 Eberlein, W.; Engel, W.; Trummlitz, G.; Mihm, G.; Mayer, N.; Doods, H. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8824122; DE 3735895; EP 0312895; JP 1989230580; US 5175158 . |
| 【2】 Eberlein, W.; Doods, H.; Wetzel, B.; AQ-RA-741. Drugs Fut 1990, 15, 8, 786. |
| 【3】 LaMontagne, M.P.; et al.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1728-32. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (I) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (II) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (III) | 11162 | 2-Amino-N-(2-chloro-3-pyridinyl)benzamide | C12H10ClN3O | 详情 | 详情 | |
| (IV) | 11163 | 5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C12H9N3O | 详情 | 详情 | |
| (V) | 11164 | 11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C14H10ClN3O2 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 31151 | N-(3-chloropropyl)-N,N-diethylamine; 3-chloro-N,N-diethyl-1-propanamine | C7H16ClN | 详情 | 详情 | |
| (VIII) | 31152 | N,N-diethyl-N-[4-(4-pyridinyl)butyl]amine; N,N-diethyl-4-(4-pyridinyl)-1-butanamine | C13H22N2 | 详情 | 详情 | |
| (IX) | 31153 | N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine | C13H28N2 | 详情 | 详情 |