ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】25694

【品名】ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate

【CA登记号】

【分子式】C₁₂H₂₁NO₄

【分子量】243.30308

【元素组成】C 59.24% H 8.7% N 5.76% O 26.3%

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：(II)

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：(II)

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：(II)

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