bis(2,4,6-trichlorophenyl) malonate -Drug Synthesis Database

【结构式】

【分子编号】12956

【品名】bis(2,4,6-trichlorophenyl) malonate

【CA登记号】

【分子式】C₁₅H₆Cl₆O₄

【分子量】462.92644

【元素组成】C 38.92% H 1.31% Cl 45.95% O 13.82%

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：(IV)

This compound can be obtained by two related ways: 1) The cyclization of 3-cyclohexylpropionitrile (I) with thiosemicarbazide (II) by means of trifluoroacetic acid gives 5-(2-cyclohexylethyl)-1,3,4-thiadiazol-2-amino (III), which is submitted to a new cyclization process with bis(2,4,6-trichlorophenyl)malonate (IV) in refluxing xylene yielding 2-(2-cyclohexylethyl)-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (V) (1-3). The nitration of (V) with fuming nitric acid in acetic acid affords the corresponding 7-hydroxy-6-nitro derivative (VI), which is treated with POCl3 and tripropylamine to afford the 7-chloro-6-nitro derivative (VII). The reaction of (VII) with concentrated aqueous NH4OH in ethanol gives the corresponding 7-amino-6-nitro compound (VIII), which is reduced with Sn-HCl in dioxane-water to afford the 6,7-diamino derivative (IX). Finally, this compound is dissolved in aqueous HCl and treated with NaNO2. 2) The cyclization of 3-cyclohexylpropionic acid (X) with thiosemicarbazide (II) by means of hot H2SO4 gives the thiadiazole (III), which is cyclized again with malonic acid (XI) by means of POCl3 in hot toluene to afford the previously obtained thiadiazolopyrimidine (V).

参考文献中间体

合成目标

【1】 Isoda, S.; Aibara, S.; Miwa, T.; Fujiwara, H.; Yokohama, S.; Matsumoto, H. (Daiichi Pharmaceutical Co., Ltd.); Tricyclic triazolopyrimidine derivatives. AU 9052298; EP 0279298; JP 1989000086; JP 1989006264; US 4898943 .
【2】 Narabayashi, Y. (Daiichi Pharmaceutical Co., Ltd.); Agents for treatment of gastrointestinal diseases. JP 1990138216 .
【3】 Aihara, S. (Daiichi Pharmaceutical Co., Ltd.); Antiallergic and antiinflammatory agents. JP 1990138215 .
【4】 Yokohama, S.; Miwa, T.; Aibara, S.; Fujiwara, H.; Matsumoto, H.; Nakayama, K.; Iwamoto, T.; Mori, M.; Moroi, R.; Tsukada, W.; Isoda, S.; Synthesis and antiallergy activity of [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one derivatives. II. 6-Alkyl- and 6-cycloalkylalkyl derivatives. Chem Pharm Bull 1992, 40, 9, 2391-8.
【5】 Rabasseda, X.; Castaner, J.; Mealy, N.; DS-4574. Drugs Fut 1994, 19, 10, 901.

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)	12953	3-Cyclohexylpropanenitrile		C₉H₁₅N	详情	详情
(II)	12954	1-Hydrazinecarbothioamide; Thiosemicarbazide	79-19-6	CH₅N₃S	详情	详情
(III)	12955	5-(2-Cyclohexylethyl)-1,3,4-thiadiazol-2-ylamine; 5-(2-Cyclohexylethyl)-1,3,4-thiadiazol-2-amine		C₁₀H₁₇N₃S	详情	详情
(IV)	12956	bis(2,4,6-trichlorophenyl) malonate		C₁₅H₆Cl₆O₄	详情	详情
(V)	12957	2-(2-Cyclohexylethyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one		C₁₃H₁₇N₃O₂S	详情	详情
(VI)	12958	2-(2-Cyclohexylethyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one		C₁₃H₁₆N₄O₄S	详情	详情
(VII)	12959	7-Chloro-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one		C₁₃H₁₅ClN₄O₃S	详情	详情
(VIII)	12960	7-Amino-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one		C₁₃H₁₇N₅O₃S	详情	详情
(IX)	12961	6,7-Diamino-2-(2-cyclohexylethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one		C₁₃H₁₉N₅OS	详情	详情
(X)	12962	3-Cyclohexylpropionic acid	701-97-3	C₉H₁₆O₂	详情	详情
(XI)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Cyclization of the diaminoacrylate (I) with bis(2,4,6-trichlorophenyl) malonate (II) in hot toluene produced pyridone (III). This was then condensed with 2,6-dichlorobenzaldehyde (IV) in the presence of piperidine in refluxing EtOH to furnish the title bis-pyridyl derivative.

参考文献中间体

合成目标

【1】 Onnis, V.; Cocco, M.T.; Congiu, C.; Synthesis and antitumor activity of 4-hydroxy-2-pyridone derivatives. Eur J Med Chem 2000, 35, 5, 545.

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)	47074	ethyl (Z)-3-amino-3-(4-morpholinyl)-2-propenoate		C₉H₁₆N₂O₃	详情	详情
(II)	12956	bis(2,4,6-trichlorophenyl) malonate		C₁₅H₆Cl₆O₄	详情	详情
(III)	47075	ethyl 4-hydroxy-2-(4-morpholinyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate		C₁₂H₁₆N₂O₅	详情	详情
(IV)	27507	2,6-dichlorobenzaldehyde	83-38-5	C₇H₄Cl₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

2-Amino-3-hydroxypyridine (I) is alkylated with N-(2-chloroethyl)piperidine (II) under phase transfer conditions to provide ether (III). Subsequent cyclization of aminopyridine (III) with bis-trichlorophenyl malonate (IV) in refluxing acetone leads to the pyridopyrimidine (V). This is finally condensed with the N-(bromomethyl)saccharin derivative (VI) to furnish the title compound.

参考文献中间体

合成目标

【1】 Hermecz, I.; Kapui, Z.; Arányi, P.; Bátori, S.; Varga, M.; Dessilla, S.; Lévai, F.; Mikus, E.; Pascal, M.; Simonot, B.; Urbán Szabó, K.; Vasváriné Debreczy, L.; T. Nagy, L. (Sanofi-Synthélabo); Saccharin derivs. as orally active elastase inhibitors. WO 0144245 .

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)	37086	2-amino-3-pyridinol; 2-Amino-3-hydroxypyridine	16867-03-1	C₅H₆N₂O	详情	详情
(II)	10117	1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine	1932-03-2	C₇H₁₄ClN	详情	详情
(III)	62082	3-[2-(1-piperidinyl)ethoxy]-2-pyridinamine; 3-[2-(1-piperidinyl)ethoxy]-2-pyridinylamine		C₁₂H₁₉N₃O	详情	详情
(IV)	12956	bis(2,4,6-trichlorophenyl) malonate		C₁₅H₆Cl₆O₄	详情	详情
(V)	62083	2-hydroxy-9-[2-(1-piperidinyl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one		C₁₅H₁₉N₃O₃	详情	详情
(VI)	62084	2-(bromomethyl)-4-isopropyl-6-methoxy-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₂H₁₄BrNO₄S	详情	详情

Extended Information