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【结 构 式】 
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【分子编号】31153 【品名】N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine 【CA登记号】 |
【 分 子 式 】C13H28N2 【 分 子 量 】212.3788 【元素组成】C 73.52% H 13.29% N 13.19% |
合成路线1
该中间体在本合成路线中的序号：(IX)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 |
合成路线2
该中间体在本合成路线中的序号：(IX)Horner-Emmons reaction of 1-benzyl-4-piperidone (I) with triethyl 4-phosphonocrotonate (II) afforded the (piperidinylidene)butenoate (III). Catalytic hydrogenation of the double bond of (III) with concomitant N-debenzylation yielded the piperidinylbutanoate (IV). After reprotection as the N-benzyl derivative (V), reduction of the ester function of (V) using LiAlH4 gave alcohol (VI), which was further converted to mesylate (VII). Displacement of the mesylate group of (VII) with diethylamine produced diamine (VIII). The N-benzyl group of (VIII) was then deprotected by transfer hydrogenation to furnish piperidine (IX). The chloroacetyl derivative (XI) was prepared by acylation of iminodibenzyl (X) with chloroacetyl chloride. Chloride (XI) was finally condensed with piperidine (IX) in the presence of Na2CO3 and NaI to afford the title compound.
| 【1】 Maiorana, S.; Colibretti, M.L.; Terni, P.; Imbimbo, B.P.; Mandelli, G.R.; Lamperti, G.; Synthesis of new cardioselective M2 muscarinic receptor antagonists. Chem Pharm Bull 2000, 48, 11, 1611. |
| 【2】 Imbimbo, B.P.; Mandelli, G.R.; Terni, P.M.L.; Maiorana, S. (Mediolanum Farmaceutici); Selective M2 muscarinic receptor antagonists having 5H-dibenz[b,f]azepine structure. WO 0102386 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 22705 | ethyl (E)-4-(diethoxyphosphoryl)-2-butenoate | C10H19O5P | 详情 | 详情 | |
| (III) | 48038 | ethyl (E)-4-(1-benzyl-4-piperidinylidene)-2-butenoate | C18H23NO2 | 详情 | 详情 | |
| (IV) | 48039 | ethyl 4-(4-piperidinyl)butanoate | C11H21NO2 | 详情 | 详情 | |
| (V) | 48040 | ethyl 4-(1-benzyl-4-piperidinyl)butanoate | C18H27NO2 | 详情 | 详情 | |
| (VI) | 48041 | 4-(1-benzyl-4-piperidinyl)-1-butanol | C16H25NO | 详情 | 详情 | |
| (VII) | 48042 | 4-(1-benzyl-4-piperidinyl)butyl methanesulfonate | C17H27NO3S | 详情 | 详情 | |
| (VIII) | 48043 | 4-(1-benzyl-4-piperidinyl)-N,N-diethyl-1-butanamine; N-[4-(1-benzyl-4-piperidinyl)butyl]-N,N-diethylamine | C20H34N2 | 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 | |
| (X) | 47619 | Iminostilbene; 5H-dibenzo[b,f]azepine | 256-96-2 | C14H11N | 详情 | 详情 |
| (XI) | 48044 | 2-chloro-1-(5H-dibenzo[b,f]azepin-5-yl)-1-ethanone | C16H12ClNO | 详情 | 详情 |