ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate -Drug Synthesis Database

【结构式】

【分子编号】43472

【品名】ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate

【CA登记号】

【分子式】C₁₆H₂₂ClNO₄S

【分子量】359.87372

【元素组成】C 53.4% H 6.16% Cl 9.85% N 3.89% O 17.78% S 8.91%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXIV)

2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.

参考文献中间体

合成目标

【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	19493	2-aminobenzonitrile	1885-29-6	C₇H₆N₂	详情	详情
(XVI)	19367	2-bromo-2-methylpropanoyl bromide	20769-85-1	C₄H₆Br₂O	详情	详情
(XVII)	43466	2-bromo-N-(2-cyanophenyl)-2-methylpropanamide		C₁₁H₁₁BrN₂O	详情	详情
(XVIII)	43467	3,3-dimethyl-2,4(1H,3H)-quinolinedione		C₁₁H₁₁NO₂	详情	详情
(XIX)	43468	3,3-dimethyl-1,2,3,4-tetrahydroquinoline		C₁₁H₁₅N	详情	详情
(XX)	43469	6-iodo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline		C₁₁H₁₄IN	详情	详情
(XXI)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(XXII)	43470	ethyl (E)-3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate		C₁₆H₂₁NO₂	详情	详情
(XXIII)	43471	ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate		C₁₆H₂₃NO₂	详情	详情
(XXIV)	43472	ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate		C₁₆H₂₂ClNO₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIV)

Coupling between sulfonyl chloride (XXIV) and amine (XIV) provided sulfonamide (XXXIV). The ethyl ester group of (XXXIV) was then hydrolyzed to carboxylic acid (XXXV), which was finally coupled with N-(2-morpholin-4-yl-2-oxoethyl)piperazine (XXXVI) to furnish the title amide.

参考文献中间体

合成目标

【1】 Hayler, J.; LeGrand, D.; Kane, P.D.; et al.; The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors. Bioorg Med Chem Lett 2000, 10, 14, 1567.
【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	43465	(2S)-2-amino-3-(1,3-benzothiazol-2-yl)-1-[4-(2-fluoroethyl)-1-piperidinyl]-1-propanone	C₁₇H₂₂FN₃OS	详情	详情
(XXIV)	43472	ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate	C₁₆H₂₂ClNO₄S	详情	详情
(XXXIV)	43482	ethyl 3-[8-[([(1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethyl]amino)sulfonyl]-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate	C₃₃H₄₃FN₄O₅S₂	详情	详情
(XXXV)	43483	3-[8-[([(1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethyl]amino)sulfonyl]-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propionic acid	C₃₁H₃₉FN₄O₅S₂	详情	详情
(XXXVI)	43484	1-(4-morpholinyl)-2-(1-piperazinyl)-1-ethanone	C₁₀H₁₉N₃O₂	详情	详情

Extended Information