【结 构 式】 |
【分子编号】20646 【品名】[3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone 【CA登记号】 |
【 分 子 式 】C20H23ClN2O 【 分 子 量 】342.8682 【元素组成】C 70.06% H 6.76% Cl 10.34% N 8.17% O 4.67% |
合成路线1
该中间体在本合成路线中的序号:(VII)Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.
【1】 Villani, F.J.; Wong, J.K. (Schering Corp.); Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines. WO 8503707 . |
【2】 Castaner, J.; Leeson, P.; Graul, A.; Desloratadine. Drugs Fut 2000, 25, 4, 339. |
【3】 Villani, F.J. (Schering Corp.); Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6. US 4282233 . |
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) | 16500 | 3-methyl-2-pyridinecarbonitrile | 20970-75-6 | C7H6N2 | 详情 | 详情 |
(II) | 16501 | N-(tert-butyl)-3-methyl-2-pyridinecarboxamide | C11H16N2O | 详情 | 详情 | |
(III) | 20642 | 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride | 620-20-2 | C7H6Cl2 | 详情 | 详情 |
(IV) | 20643 | N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide | C18H21ClN2O | 详情 | 详情 | |
(V) | 20644 | 3-(3-chlorophenethyl)-2-pyridinecarbonitrile | C14H11ClN2 | 详情 | 详情 | |
(VI) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
(VII) | 20646 | [3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone | C20H23ClN2O | 详情 | 详情 | |
(VIII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
(IX) | 34056 | 8-chloro-11-(1-cyano-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C20H18ClN3 | 详情 | 详情 | |
(X) | 17877 | ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | 79794-75-5 | C22H23ClN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VI)N-tert-Butyl-3-methyl-2-pyridinecarboxamide (I) was treated with two equivalents of butyllithium at -40 C, and the resulting dianion was C-alkylated with 3-chlorobenzyl chloride (II) to provide the phenetylpyridine (III). Further refluxing with phosphoryl chloride afforded nitrile (IV), which was condensed with the piperidinyl Grignard reagent (V) to yield, after hydrolysis, ketone (VI). Acid-catalyzed cyclization of ketone (VI) produced the tricyclic compound (VII). Demethylation was then accomplished by conversion to the ethyl carbamate (VIII) by treatment with ethyl chloroformate, followed by hydrolysis to the N-unsubstituted piperidine (IX). Finally, acetylation of (IX) in the presence of pyridine provided the target amide.
【1】 Billah, M.M.; Green, M.J.; Wong, J.K.; Piwinski, J.J.; West, R.E. Jr.; Ganguly, A.K.; Kreutner, W.; Dual antagonists of platelet activating factor and histamine. Identification of structural requirements for dual activity of N-acyl-4-(5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidines. J Med Chem 1991, 34, 1, 457. |
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) | 16501 | N-(tert-butyl)-3-methyl-2-pyridinecarboxamide | C11H16N2O | 详情 | 详情 | |
(II) | 20642 | 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride | 620-20-2 | C7H6Cl2 | 详情 | 详情 |
(III) | 20643 | N-(tert-butyl)-3-(3-chlorophenethyl)-2-pyridinecarboxamide | C18H21ClN2O | 详情 | 详情 | |
(IV) | 20644 | 3-(3-chlorophenethyl)-2-pyridinecarbonitrile | C14H11ClN2 | 详情 | 详情 | |
(V) | 20645 | chloro(1-methyl-4-piperidinyl)magnesium | C6H12ClMgN | 详情 | 详情 | |
(VI) | 20646 | [3-(3-chlorophenethyl)-2-pyridinyl](1-methyl-4-piperidinyl)methanone | C20H23ClN2O | 详情 | 详情 | |
(VII) | 20647 | 8-chloro-11-(1-methyl-4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 38092-89-6 | C20H21ClN2 | 详情 | 详情 |
(VIII) | 17877 | ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate | 79794-75-5 | C22H23ClN2O2 | 详情 | 详情 |
(IX) | 17840 | 8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19ClN2 | 详情 | 详情 |