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【结 构 式】

【分子编号】25696

【品名】ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate

【CA登记号】

【 分 子 式 】C12H16N2O2

【 分 子 量 】220.27132

【元素组成】C 65.43% H 7.32% N 12.72% O 14.53%
与该中间体有关的原料药合成路线共 3 条
合成路线1合成路线2合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required butyl thioether was then obtained by reaction with sodium hydrosulfide and n-butyl bromide in DMF. Finally, resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.

参考文献 中间体
合成目标
【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538.
【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 .
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) 25693 ethyl 3-piperidinecarboxylate 5006-62-2 C8H15NO2 详情 详情
(II) 25694 ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate C12H21NO4 详情 详情
(III) 25695 1-azabicyclo[3.2.1]octan-6-one C7H11NO 详情 详情
(IV) 25696 ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate C12H16N2O2 详情 详情
(V) 25697 ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate C12H18N2O2 详情 详情
(VI) 25698 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt C9H13N3O 详情 详情
(VII) 25699 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H11Cl2N3S 详情 详情
(VIII) 25700 (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H12ClN3S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF. Finally, resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.

参考文献 中间体
合成目标
【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538.
【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 .
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) 25693 ethyl 3-piperidinecarboxylate 5006-62-2 C8H15NO2 详情 详情
(II) 25694 ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate C12H21NO4 详情 详情
(III) 25695 1-azabicyclo[3.2.1]octan-6-one C7H11NO 详情 详情
(IV) 25696 ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate C12H16N2O2 详情 详情
(V) 25697 ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate C12H18N2O2 详情 详情
(VI) 25698 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt C9H13N3O 详情 详情
(VII) 25699 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H11Cl2N3S 详情 详情
(VIII) 25700 (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H12ClN3S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF. Finally, resolution with L-tartaric acid yielded the title (5S,6S) enantiomer.

参考文献 中间体
合成目标
【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538.
【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 .
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) 25693 ethyl 3-piperidinecarboxylate 5006-62-2 C8H15NO2 详情 详情
(II) 25694 ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate C12H21NO4 详情 详情
(III) 25695 1-azabicyclo[3.2.1]octan-6-one C7H11NO 详情 详情
(IV) 25696 ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate C12H16N2O2 详情 详情
(V) 25697 ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate C12H18N2O2 详情 详情
(VI) 25698 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt C9H13N3O 详情 详情
(VII) 25699 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H11Cl2N3S 详情 详情
(VIII) 25700 (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane C9H12ClN3S 详情 详情
Extended Information