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【结 构 式】

【分子编号】11162

【品名】2-Amino-N-(2-chloro-3-pyridinyl)benzamide

【CA登记号】

【 分 子 式 】C12H10ClN3O

【 分 子 量 】247.68372

【元素组成】C 58.19% H 4.07% Cl 14.31% N 16.97% O 6.46%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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:(III)

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
Extended Information