diethyl 2-(2-cyanoethyl)malonate -Drug Synthesis Database

【结构式】

【分子编号】22941

【品名】diethyl 2-(2-cyanoethyl)malonate

【CA登记号】17216-62-5

【分子式】C₁₀H₁₅NO₄

【分子量】213.23344

【元素组成】C 56.33% H 7.09% N 6.57% O 30.01%

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：(II)

2-Chloro-3-nitropyridine (I) is condensed with diethyl 2-(2-cyanoethyl)malonate (II) by means of NaH in refluxing THF fo give 1-cyano-3,3-bis(ethoxycarbonyl)-3-(3-nitro-2-pyridinyl)propane (III), which is hydrolyzed with NaOH io aqueous ethanol and decarboxylated in aqueous HCl to afford 2-(3-cyanopropyl)-3-nitropyridine (IV). Hydrogenation of (IV) over Pd/C in ethanol gives 3 amino-2-(3-cyanopropyl)pyridine (V), which is diazotized with NaNO2 in dilute H2SO4 and hydrolyzed to 2-(3-cyanopropyl)-3-hydroxypyridine (VI). Methylation of (VI) with MeI by means of NaH in Me2SO yields 2-(3-cyanopropyl)-3-methoxypyridine (VII), which is then reduced with LiAlH4 to provide 2-(4-amino-butyl)-3-methoxypyridine (VIII). The final stage is to condense (VIII) with 2-nitroamino-5-(6-methyl)-3-pyridinylmethyl)-4-pyrimidinone (XIII) in refluxing pyridine. Synthesis of the pyrimidinone (XIII) reagent commences with 2-methylpyridine-4-aldehyde (IX), which is condensed with malonic acid and decarboxylated in pyridine containing piperidine to afford 3-(6-methyl-3pyridinyl)acrylic acid (X). Esterification of (X) with ethanol-H2SO4, followed by reduction with H2 over Pd/C in ethanol gives ethyl (2-mcthyl-5-pyridinyl)ethanoate (XI), which with ethyl formate in the presence of NaH in glyme furnishes 1-(ethoxycarbonyl)-1-formyl-2-(2 methyl-5-pyridinyl)ethane (XII). Condensation of (XII) with nitroguanidine in ethanol in the presence of NaOEt provides the 4-pyrimidinone (XIII).

参考文献中间体

合成目标

【1】 Durant, G.J.; Ganellin, C.R.; Sach, G.S. (SmithKline Beecham plc); Guanidines, thioureas and 1,1-diamino-2-nitroethyl. GB 1564502; US 4426526 .
【2】 Durant, G.J.; Brown, T.H.; Ganellin, C.R. (SmithKline Beecham plc); Pyridylalkylpyrimidone cpds., process for preparin. EP 0017679 .
【3】 Prous, J.; Castaner, J.; Icotidine trihydrochloride. Drugs Fut 1987, 12, 1, 24.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(I)	10321	2-Chloro-3-nitropyridine	5470-18-8	C₅H₃ClN₂O₂	详情	详情
(II)	22941	diethyl 2-(2-cyanoethyl)malonate	17216-62-5	C₁₀H₁₅NO₄	详情	详情
(III)	22942	diethyl 2-(2-cyanoethyl)-2-(3-nitro-2-pyridinyl)malonate		C₁₅H₁₇N₃O₆	详情	详情
(IV)	22943	4-(3-nitro-2-pyridinyl)butanenitrile		C₉H₉N₃O₂	详情	详情
(V)	22944	4-(3-amino-2-pyridinyl)butanenitrile		C₉H₁₁N₃	详情	详情
(VI)	22945	4-(3-hydroxy-2-pyridinyl)butanenitrile		C₉H₁₀N₂O	详情	详情
(VII)	22946	4-(3-methoxy-2-pyridinyl)butanenitrile		C₁₀H₁₂N₂O	详情	详情
(VIII)	22947	4-(3-methoxy-2-pyridinyl)-1-butanamine; 4-(3-methoxy-2-pyridinyl)butylamine		C₁₀H₁₆N₂O	详情	详情
(IX)	22949	6-methylnicotinaldehyde		C₇H₇NO	详情	详情
(X)	22950	(E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid		C₉H₉NO₂	详情	详情
(XI)	22951	ethyl 3-(6-methyl-3-pyridinyl)propanoate		C₁₁H₁₅NO₂	详情	详情
(XII)	22952	ethyl 2-formyl-3-(6-methyl-3-pyridinyl)propanoate		C₁₂H₁₅NO₃	详情	详情
(XIII)	22953	5-(6-Methylpyridin-3-ylmethyl)-2-(nitroamino)pyrimidin-4(1H)-one		C₁₁H₁₁N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of diethyl 2-(2-cyanoethyl)malonate (I) with 2-chloro-3-methyl-5-nitropyridine (II) by means of NaH in refluxing THF gives 4-(3-methyl-5-nitropyrid-2-yl)-4,4-bis(ethoxycarbonyl)butyronitrile (III), which is decarboxylated with NaOH in ethanol water yielding 4-(3-methyl-5-nitropyrid-2-yl)butyronitrile (IV). The reduction of (IV) with H2 over Pd/C in ethanol affords 4-(5-amino-3-methylpyrid-2-yl)butyronitrile (V), which is reduced further with LiAlH4 in ether-THF giving 5-amino-2-(4-aminobutyl)-3-methylpyridine (VI). The Sandmeyer reaction of (VI) with NaNO2, HBr and Cu2Br2 yields 5-bromo-2-(4-aminobutyl)-3-methylpyridine (VII), which is finally condensed with 2-nitroamino-5-(6-methylpyrid-2-ylmethyl)-4-pyrimidone (VIII) in refluxing pyridine.

参考文献中间体

合成目标

【1】 Sach, G.S. (SmithKline Beecham plc); Histamine H1-antagonists. DD 202291; EP 0068833; EP 0068834; JP 58008079; JP 61233616; JP 61233670; US 4444772; US 4486434; US 4535163; US 4584381 .
【2】 Serradell, M.N.; Castaner, J.; SKF-93944. Drugs Fut 1985, 10, 3, 209.

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)	22941	diethyl 2-(2-cyanoethyl)malonate	17216-62-5	C₁₀H₁₅NO₄	详情	详情
(II)	29072	2-chloro-3-methyl-5-nitropyridine		C₆H₅ClN₂O₂	详情	详情
(III)	29073	Diethyl 2-(2-cyanoethyl)-2-(3-methyl-5-nitro-2-pyridinyl)malonate		C₁₆H₁₉N₃O₆	详情	详情
(IV)	29074	4-(3-methyl-5-nitro-2-pyridinyl)butanenitrile		C₁₀H₁₁N₃O₂	详情	详情
(V)	29075	4-(5-amino-3-methyl-2-pyridinyl)butanenitrile		C₁₀H₁₃N₃	详情	详情
(VI)	29076	6-(4-aminobutyl)-5-methyl-3-pyridinamine		C₁₀H₁₇N₃	详情	详情
(VII)	29077	4-(5-bromo-3-methyl-2-pyridinyl)-1-butanamine		C₁₀H₁₅BrN₂	详情	详情
(VIII)	22953	5-(6-Methylpyridin-3-ylmethyl)-2-(nitroamino)pyrimidin-4(1H)-one		C₁₁H₁₁N₅O₃	详情	详情

Extended Information