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【结 构 式】 
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【分子编号】14213 【品名】N-Ethylpiperazine; 1-Ethylpiperazine 【CA登记号】5308-25-8 |
【 分 子 式 】C6H14N2 【 分 子 量 】114.19064 【元素组成】C 63.11% H 12.36% N 24.53% |
合成路线1
该中间体在本合成路线中的序号：(X)1) The condensation of 2,4-dichloro-5-fluoro-benzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially decarboxylated with p-toluenesulfonic acid yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) by means of refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol giving ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(cyclopropylamino)acrylate (VII). The cyclization of (VII) by means of NaH in refluxing dioxane yields 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX), which is finally condensed with N-ethylpiperazine (X) by heating at 140 C in DMSO.
| 【1】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 . |
| 【2】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 . |
| 【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305. |
| 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) | 22093 | 2,4-dichloro-5-fluorobenzoyl chloride | 86393-34-2 | C7H2Cl3FO | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 22095 | diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate | C14H13Cl2FO5 | 详情 | 详情 | |
| (IV) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (V) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (VI) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (VII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (VIII) | 22100 | ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate | C15H14Cl2FNO3 | 详情 | 详情 | |
| (IX) | 22101 | 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 86393-33-1 | C13H9ClFNO3 | 详情 | 详情 |
| (X) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)This compound can be prepared by two related ways: 1) The reaction of 2-nitrobenzoic acid (I) with PCl5 at 50 C gives the corresponding acyl chloride (II), which by a Friedel-Craft's condensation with benzene and AlCl3 yields 2-nitrobenzophenone (III). The reduction of (III) with H2 over Pd/C in ethanol affords 2-aminobenzophenone (IV), which is acylated with acetic anhydride sodium acetate to give 2-acetamidobenzophenone (V). The cyclization of (V) by means of sodium methoxide in refluxing ethanol yields 4-phenylquinoline-2(1H)-one (VI), which by reaction with SOCl2-DMF in hot CHCl3 is converted to 2-chloro-4-phenylquinoline (VII). Finally, this compound is condensed with N-ethylpiperazine (VIII) at 130 C. 2) Quinoline (VII) is condensed with piperazine (IX) as before to give 4-phenyl-2-(1-piperazinyl)quinoline (X), which is finally alkylated with ethyl iodide and sodium carbonate in refluxing butanone.
| 【1】 Uno, H.; Nagai, Y.; Karasawa, T.; Furukawa, K. (Dainippon Pharm. Co.; Ltd.); 2-(4-Ethyl-1-piperazinyl)-4-phenylquinoline and its salts with acids, process for their preparation and their use as antidepressant agents. DE 2912414 . |
| 【2】 Uno, H.; Nagai, Y.; Hino, K.; Kawashima, K.; Oka, M.; Matsumoto, J.; A novel class of antiulcer agents. 4-Phenyl-2-(1-piperazinyl)quinolines. Chem Pharm Bull 1989, 37, 1, 110. |
| 【3】 Prous, J.; Castaner, J.; AD-2646. Drugs Fut 1989, 14, 8, 735. |
| 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) | 20951 | 2-nitrobenzoic acid；o-Nitrobenzoic acid | 552-16-9 | C7H5NO4 | 详情 | 详情 |
| (II) | 21099 | o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride | 610-14-0 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 21100 | (2-nitrophenyl)(phenyl)methanone | 2243-79-0 | C13H9NO3 | 详情 | 详情 |
| (IV) | 21101 | (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone | 2835-77-0 | C13H11NO | 详情 | 详情 |
| (V) | 21102 | N-(2-benzoylphenyl)acetamide | 85-99-4 | C15H13NO2 | 详情 | 详情 |
| (VI) | 21103 | 4-phenyl-2(1H)-quinolinone | C15H11NO | 详情 | 详情 | |
| (VII) | 21104 | 2-chloro-4-phenylquinoline | C15H10ClN | 详情 | 详情 | |
| (VIII) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
| (IX) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (X) | 21107 | 4-phenyl-2-(1-piperazinyl)quinoline | C19H19N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation of cyclooctanone (I) with 4-fluorobenzoylacetonitrile (II) by heating with polyphosphoric acid at 120 C gives 4-fluorophenyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one (III), which is converted to the corresponding 2-chloro derivative (IV) by treatment with refluxing phosphoryl chloride. The reaction of (IV) with 1-ethylpiperazine (V) at 170 C affords AD-5423.
| 【1】 Hino, K.; Kai, N.; Sakamoto, M.; Kon, T.; Oka, M.; Furakawa, K.; Ochi, Y. (Dainippon Pharmaceutical Co., Ltd.); 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivs., processes for the production thereof, and pharmaceutical compsn. containing the same. EP 0385237; JP 1991007257; JP 1994041079; US 5021421 . |
| 【2】 Oka, M.; Hino, K.; AD-5423. Drugs Fut 1992, 17, 1, 9. |
| 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) | 14209 | Cyclooctanone | 502-49-8 | C8H14O | 详情 | 详情 |
| (II) | 14210 | 3-(4-Fluorophenyl)-3-oxopropanenitrile | C9H6FNO | 详情 | 详情 | |
| (III) | 14211 | 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one | C17H18FNO | 详情 | 详情 | |
| (IV) | 14212 | 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine | C17H17ClFN | 详情 | 详情 | |
| (V) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Cyclization of 2-ethoxybenzamidine (I) with 2-butyramidopropionic acid (II) and ethoxalyl chloride (III) by means of DMAP in refluxing pyridine gives 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-4-one (IV), which is sulfonated with chlorosulfonic acid to provide the sulfonyl chloride (V). Finally, this compound is condensed with 1-ethylpiperazine (VI) in dichloromethane.
| 【1】 Niewohner, U.; Bischoff, E.; Es-Sayed, M.; Schenke, T.; Schmidt, G.; Lampe, T.; Haning, H.; Imidazo[5,1-f][1,2,4]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg Med Chem Lett 2002, 12, 6, 865. |
| 【2】 Castaner, J.; Martin, L.; Rabasseda, X.; Sorbera, L.A.; Vardenafil. Drugs Fut 2001, 26, 2, 141. |
| 【3】 Perzborn, E.; Keldenich, J.; Schlemmer, K.-H.; Haning, H.; Serno, P.; Bischoff, E.; El-Sayed, M.; Niewöhner, U.; Nowakowski, M.; Schenke, T.; Dembowsky, K. (Bayer AG); 2-Phenyl substd. imidazotriazinones as phosphodiesterase inhibitors. DE 19750085; DE 19812462; EP 1049695; WO 9924433 . |
| 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) | 44352 | 2-ethoxybenzenecarboximidamide | 53623-81-7 | C9H12N2O | 详情 | 详情 |
| (II) | 44353 | N-butyrylalanine | C7H13NO3 | 详情 | 详情 | |
| (III) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IV) | 44354 | 2-(2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one | C17H20N4O2 | 详情 | 详情 | |
| (V) | 44355 | 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride | C17H19ClN4O4S | 详情 | 详情 | |
| (VI) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)Reaction of 2-chloronicotinic acid (I) with an ethanolic solution of potassium tert-butoxide affords 2-ethoxynicotinic acid (II), which is further converted to the corresponding ethyl ester (III) by alkylation with iodoethane in the presence of Cs2CO3. Nitration of (III) employing ammonium nitrate and trifluoroacetic anhydride leads to ethyl 2-ethoxy-5-nitropyridine-3-carboxylate (IV). This is then reduced to the aminopyridine (V) by catalytic hydrogenation over Raney Ni. Diazotization of amine (V), followed by treatment with SO2 and CuCl2 gives rise to the sulfonyl chloride (VI). Acid chloride (VI) is subsequently coupled to N-ethylpiperazine (VII), producing sulfonamide (VIII). Alkaline hydrolysis of ethyl ester (VIII) yields the intermediate pyridinecarboxylic acid (IX)
| 【1】 Street, S.D.A.; Wood, A.; Bunnage, M.E.; Mathias, J.P. (Pfizer Inc.; Pfizer Ltd.); Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction. WO 9954333 . |
| 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) | 28827 | 2-(2-chloroethyl)-4-methyl-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione | C11H13ClN2OS | 详情 | 详情 | |
| (II) | 62092 | 2-ethoxynicotinic acid | C8H9NO3 | 详情 | 详情 | |
| (III) | 62093 | ethyl 2-ethoxynicotinate | C10H13NO3 | 详情 | 详情 | |
| (IV) | 62094 | ethyl 2-ethoxy-5-nitronicotinate | C10H12N2O5 | 详情 | 详情 | |
| (V) | 62095 | ethyl 5-amino-2-ethoxynicotinate | C10H14N2O3 | 详情 | 详情 | |
| (VI) | 62096 | ethyl 5-(chlorosulfonyl)-2-ethoxynicotinate | C10H12ClNO5S | 详情 | 详情 | |
| (VII) | 14213 | N-Ethylpiperazine; 1-Ethylpiperazine | 5308-25-8 | C6H14N2 | 详情 | 详情 |
| (VIII) | 62097 | ethyl 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinate | C16H25N3O5S | 详情 | 详情 | |
| (IX) | 62098 | 2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]nicotinic acid | C14H21N3O5S | 详情 | 详情 |