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【结 构 式】 
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【药物名称】Ketanserin, R-41468, Perketal, Taseron, Serefrex, Sufrexal 【化学名称】3-[2-[4-(4-Fluorobenzoyl)piperidin-1-yl]ethyl]quinazoline-2,4(1H,3H)-dione 【CA登记号】74050-98-9 【 分 子 式 】C22H22FN3O3 【 分 子 量 】395.43734 |
【开发单位】Janssen (Originator), Barrier Therapeutics (Formulation) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, 5-HT2 Antagonists |
合成路线1
The condensation of N-(2-bromoethyl)-2-nitrobenzamide (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of Na2CO3 in refluxing methyl isobutyl ketone gives N-[2-[4-(4-fluorobenzoyl)-2-piperidinyl]ethyl]-2-nitrobenzamide (III), which is reduced with H2 over Pt/C in methanol yielding the corresponding amino derivative (IV). Finally, this compound is cyclized with urea (V) in refluxing xylene.
| 【1】 Janssen, C.G.M.; Lenoir, H.A.C.; Thijssen, J.B.A.; Knaeps, A.G.; Verluyten, W.L.M.; Heykants, J.J.P.; Synthesis of 3H- and 14C-ketanserin. J Label Compd Radiopharm 1988, 25, 7, 783-92. |
| 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) | 21496 | N-(2-bromoethyl)-2-nitrobenzamide | C9H9BrN2O3 | 详情 | 详情 | |
| (II) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (III) | 21498 | N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-nitrobenzamide | C21H22FN3O4 | 详情 | 详情 | |
| (IV) | 21499 | 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide | C21H24FN3O2 | 详情 | 详情 | |
| (V) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
合成路线2
By condensation of 2,3-dihydro-5H-oxazole[2,3-b]quinazolin-5-one (I) with 4-(4-fluorobenzoyl)piperidine (II) in refuxing toluene.
| 【1】 Signorini, R.; Verga, A. (Ravizza SpA); Process for preparing ketanserine. EP 0098499; IT 1155357 . |
合成路线3
By reaction of 4-(p-fluorobenzoyl)piperidine (I) with 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (II) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting compounds are prepared as follows: 1) The Grignard reaction of N-benzyl-4-cyanopiperidine (III) with p-fluorophenylmagnesium bromide (IV) ethyl ether gives N-benzyl-4-p-fluorobenzoyl)piperidine (V), which by reaction with Na2CO3 and ethyl chloroformate (A) is converted into N-ethoxycarbonyl-4-(p-fluorobenzoyl)piperidine (VI). Finally, this compound is hydrolyzed with 48% HBr to give (I). 2) The reaction of ethyl anthranilate (VII) with ethyl chloroformate (A) in refluxing xylene gives ethyl 2-(ethoxycarbonylamino)benzoate (VIII), which is cyclized with 2-aminoethanol (B) at 170 C to afford 3-(2-hydroxyethyl)-2,4-(1H,3H)-quinazolinedione (IX). Finally, this compound is treated with SOCl2 in refluxing chloroform to afford (II).
| 【1】 Van Der, M.; Keninis, L.; Vandenberk, J.; Van Heertum, A. (Janssen Pharmaceutica NV); Piperidinylalkyl quinazoline compounds, composition and method of use. EP 0013612; JP 55105679; US 4335127 . |
| 【2】 Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; Ketanserin. Drugs Fut 1981, 6, 11, 684. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (B) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (I) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (II) | 32277 | 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione | 5081-87-8 | C10H9ClN2O2 | 详情 | 详情 |
| (III) | 29013 | 1-benzyl-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (IV) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (V) | 29014 | (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone | C19H20FNO | 详情 | 详情 | |
| (VI) | 29015 | ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C15H18FNO3 | 详情 | 详情 | |
| (VII) | 32278 | ethyl 2-aminobenzoate | 87-25-2 | C9H11NO2 | 详情 | 详情 |
| (VIII) | 32279 | ethyl 2-[(ethoxycarbonyl)amino]benzoate | C12H15NO4 | 详情 | 详情 | |
| (IX) | 32280 | 3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione | C10H10N2O3 | 详情 | 详情 |