ethyl (E)-2-butyryl-3-ethoxy-2-propenoate -Drug Synthesis Database

【结构式】

【分子编号】12517

【品名】ethyl (E)-2-butyryl-3-ethoxy-2-propenoate

【CA登记号】

【分子式】C₁₁H₁₈O₄

【分子量】214.26152

【元素组成】C 61.66% H 8.47% O 29.87%

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)

The synthesis of SK&F 96067 can be achieved in five stages: Reaction of ethyl butyrylacetate with triethyl orthoformate and acetic anhydride gives ethyl 2-butyryl-3-ethoxyacrylate (II) as a mixture of (E)- and (Z)-isomers. Treatment of (II) with o-anisidine provides the acyclic quinolone precursor (III), which on thermal cyclization in diphenyl ether gives the quinolone (IV). Conversion to the 4-chloroquinoline (V) is achieved by treatment with phosphorus oxychloride. Reaction of the chloroquinoline (V) with o-toluidine gives SK&F 96067 (VI).

参考文献中间体

合成目标

【1】 Ife, R.J.; Brown, T.H.; Leach, C.A. (SmithKline Beecham plc); 4-Amino-3-substituted quinolines as inhibitors of gastric acid secretion. AU 8778741; EP 0259174; JP 1989500664; US 4806549; US 4806550; WO 8801621 .
【2】 Brown, T.H.; Reavill, D.R.; Wiggall, K.J.; Ife, R.J.; Keeling, D.J.; Leach, C.A.; Meeson, M.L.; Parsons, M.E.; Theobald, C.J.; Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-Substituted-4-phenylaminoquinolines. J Med Chem 1992, 35, 18, 3413.
【3】 Ife, R.J.; SK&F-96067. Drugs Fut 1992, 17, 9, 796.

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)	12516	ethyl 3-oxohexanoate; ethyl butyrylacetate	3249-68-1	C₈H₁₄O₃	详情	详情
(II)	12517	ethyl (E)-2-butyryl-3-ethoxy-2-propenoate		C₁₁H₁₈O₄	详情	详情
(III)	12518	ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate		C₁₆H₂₁NO₄	详情	详情
(IV)	12519	3-Butyryl-8-methoxy-4(1H)-quinolinone		C₁₄H₁₅NO₃	详情	详情
(V)	12520	1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone		C₁₄H₁₄ClNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

This compound has been obtained by several related ways: 1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II), which by reaction with o-toluidine (III) yields the aminoacrylate (IV). The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V), which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI). The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII), which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX). Finally, this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3. 2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII), which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).

参考文献中间体

合成目标

【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	21304	Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether	122-51-0	C₇H₁₆O₃	详情	详情
(I)	12516	ethyl 3-oxohexanoate; ethyl butyrylacetate	3249-68-1	C₈H₁₄O₃	详情	详情
(II)	12517	ethyl (E)-2-butyryl-3-ethoxy-2-propenoate		C₁₁H₁₈O₄	详情	详情
(III)	25193	2-methoxyphenylamine; 2-methoxyaniline	517-28-2	C₇H₉NO	详情	详情
(IV)	12518	ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate		C₁₆H₂₁NO₄	详情	详情
(V)	12519	3-Butyryl-8-methoxy-4(1H)-quinolinone		C₁₄H₁₅NO₃	详情	详情
(VI)	12520	1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone		C₁₄H₁₄ClNO₂	详情	详情
(VII)	32800	1-(4-chloro-8-hydroxy-3-quinolinyl)-1-butanone		C₁₃H₁₂ClNO₂	详情	详情
(VIII)	15511	o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine	95-53-4	C₇H₉N	详情	详情
(IX)	32801	1-[8-hydroxy-4-(2-toluidino)-3-quinolinyl]-1-butanone		C₂₀H₂₀N₂O₂	详情	详情
(X)	10059	Ethylene bromohydrin; 2-Bromo-1-ethanol	540-51-2	C₂H₅BrO	详情	详情
(XI)	32802	1,3-dioxolan-2-one	96-49-1	C₃H₄O₃	详情	详情
(XII)	32799	1-[8-methoxy-4-(2-toluidino)-3-quinolinyl]-1-butanone		C₂₁H₂₂N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The condensation of 2-methoxypyridine-3-amine (I) with ethyl 2-(ethoxymethylene)-3-oxohexanoate (II) by heating at 120-30 C gives the aminoacrylate ewster (III), which is cyclized by heating in refluxing diphenyl ether to yield the naphthyridinone (IV). The reaction of (IV) with methanesulfonyl chloride and triethylamine in dichloromethane affords the methanesulfonyloxy naphthyridine (V), which is finally condensed with (R)-1-phenylethylamine (VI) in refluxing acetonitrile.

参考文献中间体

合成目标

【1】 Sohn, S.K.; Chang, M.S.; Kim, S.G.; Chung, K.J.; Kang, D.P.; Kim, Y.H.; Kang, B.G.; Choi, W.S.; Seo, K.H.; Yoo, H.Y.; Paek, J.H. (Yung-Jin Pharmaceutical Co., Ltd.); 4-Amino-3-acylnaphthyridine derivs.. WO 9703074 .

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)	25075	2-methoxy-3-pyridinamine		C₆H₈N₂O	详情	详情
(II)	12517	ethyl (E)-2-butyryl-3-ethoxy-2-propenoate		C₁₁H₁₈O₄	详情	详情
(III)	25076	ethyl (Z)-2-butyryl-3-[(2-methoxy-3-pyridinyl)amino]-2-propenoate		C₁₅H₂₀N₂O₄	详情	详情
(IV)	25077	3-butyryl-8-methoxy[1,7]naphthyridin-4(1H)-one		C₁₃H₁₄N₂O₃	详情	详情
(V)	25078	8-methoxy-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1-propylvinyl)[1,7]naphthyridine		C₁₇H₂₂N₂O₂S	详情	详情
(VI)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情

Extended Information