3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol -Drug Synthesis Database

【结构式】

【分子编号】35937

【品名】3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol

【CA登记号】

【分子式】C₁₄H₁₂ClN₃O

【分子量】273.7216

【元素组成】C 61.43% H 4.42% Cl 12.95% N 15.35% O 5.85%

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：(VI)

The reaction of 3-trifluoromethylbenzaldehyde (I) with morpholine (II) and potassium cyanide by means of p-toluenesulfonic acid in refluxing THF gives alpha-(3-trifluoromethylphenyl)-4-morpholineacetonitrile (III), which is condensed with ethyl acrylate (IV) by means of KOH in THF yielding gamma-cyano-gamma-(3-trifluoromethylphenyl)-4-morpholinebutyric acid ethyl ester (V). The cyclization of (V) with hydrazine in refluxing ethanol affords 4,5-dihydro-6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VI), which is dehydrogenated by treatment with Br2 in hot acetic acid to give 6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VII). The reaction of (VII) with POCl3 at 100 C affords 3-chloro-6-(3-trifluoromethylphenyl)pyridazine (VIII), which is finally cyclized with acetylhydrazine (IX) in refluxing n-butanol.

参考文献中间体

合成目标

【1】 Allen, G.R. Jr.; Hanifin, J.W. Jr.; Moran, D.B.; Albright, J.D.; 6-Phenyl-1,2,4-triazolo{8 4,3-b{9 pyridazine hypotensive agents. US 4112095 .
【2】 Albright, J.D.; et al.; Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines. J Med Chem 1981, 24, 5, 592-600.
【3】 Owen, R.T.; Serradell, M.N.; Blancafort, P.; Castaner, J.; CL-218,872. Drugs Fut 1983, 8, 3, 191.

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)	35964	3-(trifluoromethyl)benzaldehyde	454-89-7	C₈H₅F₃O	详情	详情
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(III)	35965	2-(4-morpholinyl)-2-[3-(trifluoromethyl)phenyl]acetonitrile		C₁₃H₁₃F₃N₂O	详情	详情
(IV)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(V)	35966	ethyl 4-cyano-4-(4-morpholinyl)-4-[3-(trifluoromethyl)phenyl]butanoate		C₁₈H₂₁F₃N₂O₃	详情	详情
(VI)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(VII)	35968	6-[3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone		C₁₁H₇F₃N₂O	详情	详情
(VIII)	35969	3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine		C₁₁H₆ClF₃N₂	详情	详情
(IX)	29262	acetohydrazide	1068-57-1	C₂H₆N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.

参考文献中间体

合成目标

【1】 Gall, M.; Hester, J.B.; US 3947466 .
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.

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)	10279	(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone	719-59-5	C₁₃H₁₀ClNO	详情	详情
(II)	35936	2-benzoyl-4-chlorophenylformamide		C₁₄H₁₀ClNO₂	详情	详情
(III)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(IV)	35938	[5-chloro-2-(4H-1,2,4-triazol-4-yl)phenyl](phenyl)methanone		C₁₅H₁₀ClN₃O	详情	详情
(V)	35939	[2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]-5-chlorophenyl](phenyl)methanone		C₁₇H₁₄ClN₃O₃	详情	详情
(VI)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(VII)	35940	2-([4-(2-benzoyl-4-chlorophenyl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4H-1,2,4-triazol-3-yl]methyl)-1H-isoindole-1,3(2H)-dione		C₃₃H₂₀ClN₅O₅	详情	详情
(VIII)	35941	(8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methylamine; (8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methanamine		C₁₇H₁₄ClN₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The reaction of (III) with (XI) by means of pyridine in THF gives 1,3-dioxo-2-isoindolineacetic acid [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (XVI), which by cyclization by means of trifluoroacetic acid in refluxing toluene yields 5-chloro-2-[3-(phtalimidomethyl)-4H-1,2,4-triazol-4-yl-benzophenone (XVII). The reaction of (XVII) with N,N,N',N'-tetramethyldiaminomethane (A) by means of acetyl chloride in DMF affords 5-chloro-2-[3-[(dimethylamino)methyl-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (XVIII), which is finally cyclized by means of hydrazine in hot ethanol.

参考文献中间体

合成目标

【1】 Gall, M.; Hester, J.B.; US 3957761 .
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.

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)	14349	N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine	51-80-9	C₅H₁₄N₂	详情	详情
(III)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(XI)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(XVI)	35944	N-(2-benzoyl-4-chlorophenyl)-N,N'-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]hydrazonoformamide		C₃₄H₂₂ClN₅O₇	详情	详情
(XVII)	35945	2-[[4-(2-benzoyl-4-chlorophenyl)-4H-1,2,4-triazol-3-yl]methyl]-1H-isoindole-1,3(2H)-dione		C₂₄H₁₅ClN₄O₃	详情	详情
(XVIII)	35946	2-([4-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-3-yl]methyl)-1H-isoindole-1,3(2H)-dione		C₂₇H₂₂ClN₅O₃	详情	详情

Extended Information