【结 构 式】 |
【分子编号】25699 【品名】6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane 【CA登记号】 |
【 分 子 式 】C9H11Cl2N3S 【 分 子 量 】264.17796 【元素组成】C 40.92% H 4.2% Cl 26.84% N 15.91% S 12.14% |
合成路线1
该中间体在本合成路线中的序号:(VII)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.
【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:(VII)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.
【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:(VII)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.
【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 |