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【结 构 式】 
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【分子编号】24694 【品名】N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine 【CA登记号】120-43-4 |
【 分 子 式 】C7H14N2O2 【 分 子 量 】158.20044 【元素组成】C 53.15% H 8.92% N 17.71% O 20.23% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 2,6-dichloro-3-nitropyridine (I) with N-ethoxycarbonylpiperidine (II) by means of triethylamine in CHCl gives 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (III), which is treated with ethanolic NH3 at 120 C in a sealed tube to afford 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (IV). The acetylation of (IV) with acetic anhydride - acetic acid at 90 C yields the corresponding 6-acetamido derivative (V), which is reduced with H2 over Pd/C in acetic acid giving 3-amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (VI). The diazotation of (VI) with isoamyl nitrite (A) and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII), which by heat treatment at 120 C in toluene is converted into 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine (VIII). The hydrolysis of (VIII) with HCl in methanol yields the corresponding 6-aminopyridine derivative (IX), which is condensed with diethyl ethoxymethylenemalonate (X) by heating at 130 C to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI). The cyclization of (XI) by heating at 255 C yields ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XII), which is N-alkylated by means of ethyl iodide and K2CO3 in hot DMF to afford ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XIII). Finally, this compound is hydrolyzed by means of NaOH in refluxing ethanol.
| 【1】 Matsumoto, J.; et al. (Aventis Pharma SA; Dainippon Pharmaceutical Co., Ltd.); Novel naphthyridine derivatives, intermediates thereof, processes for preparation thereof and use thereof. EP 0009425; ES 483629; US 4359578 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Castaner, J.; Leeson, P.A.; AT-2266. Drugs Fut 1981, 6, 3, 129. |
| 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) | 32169 | 3-Methyl-1-nitrobutane; Isoamyl nitrite | 543-87-3 | C5H11NO2 | 详情 | 详情 |
| (I) | 13574 | 2,6-Dichloro-3-nitropyridine | 16013-85-7 | C5H2Cl2N2O2 | 详情 | 详情 |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 32165 | 6-Chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine; Ethyl 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylate | C12H15ClN4O4 | 详情 | 详情 | |
| (IV) | 32166 | Ethyl 4-(6-amino-3-nitro-2-pyridinyl)-1-piperazinecarboxylate; 6-Amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine | C12H17N5O4 | 详情 | 详情 | |
| (V) | 32167 | ethyl 4-[6-(acetamido)-3-nitro-2-pyridinyl]-1-piperazinecarboxylate | C14H19N5O5 | 详情 | 详情 | |
| (VI) | 32168 | Ethyl 4-[6-(acetamido)-3-amino-2-pyridinyl]-1-piperazinecarboxylate; 3-Amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine | C14H21N5O3 | 详情 | 详情 | |
| (VII) | 32170 | 6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate; 6-Acetamido-2-[4-(ethoxycarbonyl)pipderazin-1-yl]pyridin-3-yldiazonium tetrafluoroborate | C14H19BF4N6O3 | 详情 | 详情 | |
| (VIII) | 32171 | 6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine; Ethyl 4-[6-(acetamido)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylate | C14H19FN4O3 | 详情 | 详情 | |
| (IX) | 32172 | ethyl 4-(6-amino-3-fluoro-2-pyridinyl)-1-piperazinecarboxylate | C12H17FN4O2 | 详情 | 详情 | |
| (X) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (XI) | 32173 | N-[2-(4-EthoxycarbonyI-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate; Diethyl 2-[([6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro-2-pyridinyl]amino)methylene]malonate | C20H27FN4O6 | 详情 | 详情 | |
| (XII) | 32174 | Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate; Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C18H21FN4O5 | 详情 | 详情 | |
| (XIII) | 32175 | Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate; Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate | C20H25FN4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 7-chloro-1-(p-fluorophenyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3 carboxylic acid (I) with N-carboethoxypiperazine (II) in hot 1-methyl-2-pyrrolidinone yields 7-(4-carboethoxypiperazinyl)-1-(p-fluorophenyl)-6-fluoro-1,4-dihydro-4 oxoquinoline-3-carboxylic acid (III). Hydrolysis of (III) with aqueous sodium hydroxide in ethanol followed by treatment with dilute hydrochloric acid gives A-56620.
| 【1】 Clairbone, A.K.; Pihuleac, E.; Nordeen, C.; Fernandes, P.B.; Pernet, A.; Chu, D.T.W.; O'Donell, T.J.; A-56619 and A-56620: Synthesis and antibacterial activities of the novel aryl-fluoro-quinolones and their analogs. 24th Intersci Conf Antimicrob Agents Chemother (Oct 8-10, Washington, D.C) 1984, Abs 72. |
| 【2】 Chu, D.T.W.; Fernandes, P.B.; Granneman, G.R.; Abbott-56620. Drugs Fut 1985, 10, 7, 546. |
| 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) | 24579 | 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H8ClF2NO3 | 详情 | 详情 | |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 24695 | 7-[4-(ethoxycarbonyl)-1-piperazinyl]-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C23H21F2N3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)The reaction of O-(p-chlorophenoxy)aniline hydrochloride (I) with ethyl chlorocarbonate (A) in pyridine ether gives ethyl O-(p-chlorophenoxy)phenylcarbanilate (II), which is condensed with N-carbetoxypiperazine (B) by means of Na2O or NaOCH3 in refluxing benzene to afford ethyl 4-[(O-(p-chlorophenoxy)phenyl)carbamoyl]-1-piperazine carboxylate (III). This product is finally decarboxylated and cyclized with P2O5 in refluxing POCl3.
| 【1】 Howell, C.F.; et al.; Treatment of depression with 2-chloro-11-(pipeazinyl)dibenz[b,f][1,4]oxazepines and acid addition salts thereof. BE 0698690; FR 7845M; GB 1192812; GB 1192812; NL 6706970; US 3663696; US 3681357 . |
| 【2】 Playle, A.C.; Castaner, J.; Amoxapine. Drugs Fut 1976, 1, 11, 511. |
| 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) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (B) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (I) | 34008 | 1-(2,6-dimethylphenoxy)acetone oxime | C11H15NO2 | 详情 | 详情 | |
| (II) | 34089 | ethyl 4-[[2-(4-chlorophenoxy)anilino]carbonyl]-1-piperazinecarboxylate; Ethyl-4-[(o-(p-Chlorophenoxy)phenyl)carbamoyl]-1-piperazine carboxylate | C20H22ClN3O4 | 详情 | 详情 | |
| (III) | 34090 | 2-chlorodibenzo[b,f][1,4]oxazepin-11-amine; 2-chlorodibenzo[b,f][1,4]oxazepin-11-ylamine | C13H9ClN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of 2-chloro-5-fluoro-4-(methylsulfanyl)pyrimidine (I) with N-carbethoxypiperazine (II) yields (III), which upon treatment with Raney Nickel affords ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate (IV). Hydrolysis and decarboxylation of (IV) generates 5-fluoro-2-(1-piperazinyl)pyrimidine (V). The reaction of (V) with the alpha-chloroketal (VI) generates the butyrophenone derivative (VII). Sodium borohydride reduction of (VII) and treatment with ethanolic hydrochloric acid yields BMY-14802-1.
| 【1】 Lobeck, W.G. Jr.; Yevich, J.P. (Bristol-Myers Squibb Co.); Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives. AU 8539449; BE 0901880; CH 663022; DE 3507983; ES 8607254; FR 2560878; GB 2155925; JP 1986000075; US 4605655 . |
| 【2】 Yocca, F.D.; Yevich, J.P.; New, J.S.; BMY-14802-1. Drugs Fut 1987, 12, 8, 752. |
| 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) | 28200 | 2-chloro-5-fluoro-4-(methylsulfanyl)pyrimidine | C5H4ClFN2S | 详情 | 详情 | |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 28201 | ethyl 4-[5-fluoro-4-(methylsulfanyl)-2-pyrimidinyl]-1-piperazinecarboxylate | C12H17FN4O2S | 详情 | 详情 | |
| (IV) | 28202 | ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate | C11H15FN4O2 | 详情 | 详情 | |
| (V) | 11426 | 5-Fluoro-2-piperazinopyrimidine | C8H11FN4 | 详情 | 详情 | |
| (VI) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (VII) | 28204 | 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanone | C18H20F2N4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(D)The starting 3-fluorothiophenol (I) is obtained either from 3-fluoro-1-bromobenzene (II) by reaction with Mg and a following treatment with S, or from 3-fluoroaniline (III) by the Leuckart method via 3-fluorobenzenediazonium xanthate and 3-fluorophenyl xanthate. Two different ways were described for obtaining the acid (VI): 1) Reaction of (I) with 5-chloro-2-iodobenzoic acid (A) in a boiling aqueous KOH solution in the presence of Cu, which leads to the acid (IV). This is transformed in three steps (reduction with sodium dihydrodibis(2-methoxyethoxy)aluminate, followed by reaction with SOCl2 in pyridine, and final reaction with NaCN in boiling aqueous ethanol) to the nitrile (V), which is hydrolyzed with a boiling solution of KOH in aqueous ethanol. 2) Reaction of (I) with 2,5-dichloro acetophenone (B) in dimethylformamide at 150 C in the presence of Cu. The resulting ketone (VII) is proceased by the Kindler's modification of the Willgerodt reaction: treatment with S in boiling morpholine (C) gives the thiomorpholide (VIII), which is hydrolyzed either with a boiling ethanolic KOH solution or with a refluxing mixture of dilute H2SO4 and acetic acid. The acid (VI), obtained by both routes, is cyclized with polyphosphoric acid at 150 C to the ketone (IX), which is reduced with sodium borohydride in aqueous ethanol to the alcohol (X). Treatment with HCl in benzene in the presence of CaCl2 affords the reactive chloride (XI), which can be converted to the final product (XIV) by two methods: (b) substitution reaction of (XI) with 1-(ethoxycarbonyl)piperazine (D), followed by alkaline hydrolysis of the carbamate (XII) and addition of the secondary amine (XIII) to acrylamide in tert-butyl alcohol in the presence of benzyltriethylammonium hydroxide. (a) substitution reaction with 3-(1-piperazinyl)propionamide (E) in boiling chloroform gives directly (XIV);
| 【1】 Rand, K.H.; Houck, H.; Coll Czech Chem Commun 1975, 40, 2887. |
| 【2】 Nagaoka, M.R.; et al.; Coll Czech Chem Commun 1968, 33, 1852. |
| 【3】 Coll Czech Chem Commun 1978, 43, 1276. |
| 【4】 Parola, M.; Robino, G.; Pastacaldi, S.; Gentilini, P.; Pinzani, M.; Marra, F.; Coll Czech Chem Commun 1986, 51, 2598. |
| 【5】 Yu, D.; Mortin, L.I.; Zhang, X.; Alder, J.; Li, T.; Coll Czech Chem Commun 1967, 32, 2021. |
| 【6】 Ghiro, L.; et al.; Z Physik Chem (Leipzig) 1931, 156 A, 3, 397. |
| 【7】 Pomykácek, J.; Diabac, A.; Protiva, M.; Valchár, M.; Jilek, J.; Cervena, I. (SPOFA - United Pharmaceutical Works); N-Substd.-2-chloro-7-fluoro-10-piperazino-10, 11-dihydrobenzo[b,f]thiepins and acid addition salts thereof. EP 0189310; JP 1986204181; US 4678788 . |
| 【8】 Protiva, M.; VUFB-15496. Drugs Fut 1987, 12, 7, 636. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (F) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (D) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (A) | 28004 | 5-chloro-2-iodobenzoic acid | 13421-00-6 | C7H4ClIO2 | 详情 | 详情 |
| (B) | 28005 | 1-(2,5-dichlorophenyl)-1-ethanone | 2476-37-1 | C8H6Cl2O | 详情 | 详情 |
| (E) | 28016 | 3-(1-piperazinyl)propanamide | C7H15N3O | 详情 | 详情 | |
| (I) | 28003 | 3-fluorobenzenethiol | 2557-77-9 | C6H5FS | 详情 | 详情 |
| (II) | 28002 | 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene | 1073-06-9 | C6H4BrF | 详情 | 详情 |
| (III) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (IV) | 28006 | 5-chloro-2-[(3-fluorophenyl)sulfanyl]benzoic acid | C13H8ClFO2S | 详情 | 详情 | |
| (V) | 28007 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetonitrile | C14H9ClFNS | 详情 | 详情 | |
| (VI) | 28008 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]acetic acid | C14H10ClFO2S | 详情 | 详情 | |
| (VII) | 28009 | 1-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-ethanone | C14H10ClFOS | 详情 | 详情 | |
| (VIII) | 28010 | 2-[5-chloro-2-[(3-fluorophenyl)sulfanyl]phenyl]-1-(4-morpholinyl)-1-ethanethione | C18H17ClFNOS2 | 详情 | 详情 | |
| (IX) | 28011 | 2-chloro-7-fluorodibenzo[b,f]thiepin-10(11H)-one | C14H8ClFOS | 详情 | 详情 | |
| (X) | 28012 | 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-ol | C14H10ClFOS | 详情 | 详情 | |
| (XI) | 28013 | 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine | C14H9Cl2FS | 详情 | 详情 | |
| (XII) | 28014 | ethyl 4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylate | C21H22ClFN2O2S | 详情 | 详情 | |
| (XIII) | 28015 | 1-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine | C18H18ClFN2S | 详情 | 详情 | |
| (C) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The cyclization of pyridine-3-carbaldehyde (I) with L-cysteine (II) gives 2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid (II), which is finally condensed with 1-(3-phenylpropyl)piperazine (IV) by means of DCC and HOBT in DMF. The intermediate 1-(3-phenylpropyl)piperazine (IV) has been obtained as follows: The condensation of piperazine-1-carboxylic acid ethyl ester (V) with 3-phenylpropyl bromide (VI) by means of K2CO3 in 2-butanone gives 4-(3-phenylpropyl)piperazine-1-carboxylic acid ethyl ester (VII), which is decarboxylated with NaOH in refluxing ethanol.
| 【1】 Mase, T.; Hara, H.; Nagaoka, H.; Takahasi, T.; Suzuki, T.; Tomioka, K.; Yamada, T. (Yamanouchi Pharmaceutical Co., Ltd.); Saturated heterocyclic carboxamide derivs.. AU 8812080; EP 0279681; JP 1988208582; US 4987132 . |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 38633 | (2S)-2-amino-2-(methylsulfanyl)ethanoic acid | C3H7NO2S | 详情 | 详情 | |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 38636 | 1-(3-phenylpropyl)piperazine | C13H20N2 | 详情 | 详情 | |
| (V) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (VI) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (VII) | 38635 | ethyl 4-(3-phenylpropyl)-1-piperazinecarboxylate | C16H24N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The cyclization of pyridine-3-carbaldehyde (I) with L-cysteine (II) gives 2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid (III), which is finally condensed with 1-(3-methyl-3-phenylbutyl)piperazine (IV) by means of DCC and HOBT In DMF. The intermediate 1-(3-methyl-3-phenylbutyl)piperazine (IV) has been obtained as follows: The reduction of 3-methyl-3-phenylbutyric acid (IV) with LiAlH4 in THF gives the corresponding butanol (V), which is treated with refluxing 48% HBr to yield the 3-methyl-3-phenylbutyl bromide (VI). The condensation of (VI) with piperazine-1-carboxylic acid ethyl ester (VII) by means of K2CO3 in 2-butanone gives 4-(3-methyl-3-phenylbutyl)piperazine-1-carboxylic acid ethyl ester (VIII), which is decarboxylated with NaOH in refluxing ethanol.
| 【1】 Mase, T.; Hara, H.; Nagaoka, H.; Takahasi, T.; Suzuki, T.; Tomioka, K.; Yamada, T. (Yamanouchi Pharmaceutical Co., Ltd.); Saturated heterocyclic carboxamide derivs.. AU 8812080; EP 0279681; JP 1988208582; US 4987132 . |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 38633 | (2S)-2-amino-2-(methylsulfanyl)ethanoic acid | C3H7NO2S | 详情 | 详情 | |
| (III) | 38634 | (4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid | C9H10N2O2S | 详情 | 详情 | |
| (IV) | 38637 | 3-methyl-3-phenylbutyric acid | C11H14O2 | 详情 | 详情 | |
| (IV) | 38641 | 1-(3-methyl-3-phenylbutyl)piperazine | C15H24N2 | 详情 | 详情 | |
| (V) | 38638 | 3-methyl-3-phenyl-1-butanol | C11H16O | 详情 | 详情 | |
| (VI) | 38639 | 1-(3-bromo-1,1-dimethylpropyl)benzene | C11H15Br | 详情 | 详情 | |
| (VII) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (VIII) | 38640 | ethyl 4-(3-methyl-3-phenylbutyl)-1-piperazinecarboxylate | C18H28N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVII)The intermediate 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) has been obtained as follows: a) The condensation of 5-fluoro-1H-indole (VIII) with acrylic acid (IX) by means of acetic anhydride gives 3-(1H-indol-5-yl)propionic acid (X), which is reduced with LiAlH4 to 3-(1H-indol-5-yl)-1-propanol (XI). The tosylation of (XI) with tosyl chloride yields the tosylate (XII), which is condensed with 1-benzylpiperazine (XIII) in refluxing butyl acetate affording 3-[3-(4-benzylpiperazin-1-yl)propyl]-5-fluoro-1H-indole (XIV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C yielding the target intermediate (V). b) The tosylate intermediate (XII) can also be condensed with ethyl piperazine-1-carboxylate (XVII) in refluxing butyl acetate giving 4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine-1-carboxylic acid ethyl ester (XVIII), which is then decarboxylated with NaOH to the target intermediate (V). The intermediate 3-(1H-indol-5-yl)-1-propanol (XI) can also be obtained by direct cyclization of 4-fluorophenylhydrazine (XV) with dihydropyran (XVI) in hot propyleneglycol.
| 【1】 Anderson, N.G.; et al.; Process development of 5-fluoro-3[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride. Org Process Res Dev 1997, 1, 4, 300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 32385 | 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole | C15H20FN3 | 详情 | 详情 | |
| (VIII) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 32389 | 3-(5-fluoro-1H-indol-3-yl)propionic acid | C11H10FNO2 | 详情 | 详情 | |
| (XI) | 32390 | 3-(5-fluoro-1H-indol-3-yl)-1-propanol | C11H12FNO | 详情 | 详情 | |
| (XII) | 32391 | 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate | C18H18FNO3S | 详情 | 详情 | |
| (XIII) | 28542 | N-Benzylpiperazine; 1-Benzylpiperazine | 2759-28-6 | C11H16N2 | 详情 | 详情 |
| (XIV) | 32392 | 3-[3-(4-benzyl-1-piperazinyl)propyl]-5-fluoro-1H-indole | C22H26FN3 | 详情 | 详情 | |
| (XV) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (XVI) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (XVII) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (XVIII) | 32393 | ethyl 4-[3-(5-fluoro-1H-indol-3-yl)propyl]-1-piperazinecarboxylate | C18H24FN3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Alkylation of ethyl 1-piperazinecarboxylate (I) with 2-bromo-4'-chloroacetophenone (II) afforded disubstituted piperazine (III). Further cleavage of the carbamate group of (III) in refluxing HCl produced piperazine (IV). Bromide (VII) was prepared by reduction of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (V) with NaBH4, followed by treatment of the resulting alcohol (VI) with PBr3. Piperazine (IV) was then condensed with bromide (VII) to give adduct (VIII). Finally, ketone reduction using LiAlH4 furnished the title alcohol.
| 【1】 Collis, M.P.; Robertson, A.D.; Kenche, V.B.; Jackson, W.R.; Jarrott, B.; Beart, P.M. (Monash University); Arylalkylpiperazine cpds. as antioxidants. JP 2000510126; WO 9743259 . |
| 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) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (II) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (III) | 37704 | ethyl 4-[2-(4-chlorophenyl)-2-oxoethyl]-1-piperazinecarboxylate | C15H19ClN2O3 | 详情 | 详情 | |
| (IV) | 37705 | 1-(4-chlorophenyl)-2-(1-piperazinyl)-1-ethanone | C12H15ClN2O | 详情 | 详情 | |
| (V) | 14875 | 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde | 1620-98-0 | C15H22O2 | 详情 | 详情 |
| (VI) | 37706 | 2,6-di(tert-butyl)-4-(hydroxymethyl)phenol | 88-26-6 | C15H24O2 | 详情 | 详情 |
| (VII) | 37707 | 4-(bromomethyl)-2,6-di(tert-butyl)phenol | C15H23BrO | 详情 | 详情 | |
| (VIII) | 37708 | 1-(4-chlorophenyl)-2-[4-[3,5-di(tert-butyl)-4-hydroxybenzyl]-1-piperazinyl]-1-ethanone | C27H37ClN2O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The reductocondensation of 2,3,4-trimethoxybenzaldehyde (I) with ethyl piperazine-1-carboxylate (II) by means of NaBH3CN in AcOH gives the corresponding benzyl derivative (III), which is decarboxylated with aqueous KOH at 130 C yielding 1-(2,3,4-trimethoxybenzyl)piperazine (IV). The acylation of (IV) with chloroacetyl chloride in dichloromethane affords 1-(2-chloroacetyl)-4-(2,3,4-trimethoxybenzyl)piperazine (V)., which is finally condensed with diosmetin (VI) by means of KHCO3 in DMF.
| 【1】 Ferté, J.; Kühnel, J.-M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M.A.; Flavonoid-related modulators of multidrug resistance: Synthesis, pharmacological activity, and structure-activity relationships. J Med Chem 1999, 42, 3, 478. |
| 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) | 22119 | 2,3,4-trimethoxybenzaldehyde | 2103-57-3 | C10H12O4 | 详情 | 详情 |
| (II) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (III) | 30010 | ethyl 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarboxylate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 24354 | 2,3-dimethoxy-4-(1-piperazinylmethyl)phenyl methyl ether | C14H22N2O3 | 详情 | 详情 | |
| (V) | 30011 | 2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone | C16H23ClN2O4 | 详情 | 详情 | |
| (VI) | 30012 | 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one | 520-34-3 | C16H12O6 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Reaction of piperazine-1-carboxylic acid ethyl ester (I) with nitric oxide in the presence of NaOMe in a pressure bottle gives rise to the sodium piperazinyldiazenium diolate (II). This is finally condensed with 2,4-dinitrofluorobenzene (III) to produce the title compound.
| 【1】 Saavedra, J.E.; et al.; The secondary amine/nitric oxide complex ion R2N[N(O)NO](-) as nucleophile and leaving group in S(N)Ar reactions. J Org Chem 2001, 66, 9, 3090. |
| 【2】 Keefer, L.K.; Saavedra, J.E.; Srinivasan, A.; Rice, W.G.; Bogdan, C.; Ji, X. (US Department of Health & Human Services); O2-Arylated or O2-glycosylated 1-substd. diazen-1-ium-1,2-diolates and O2-substd. 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates. JP 2002506421; WO 9813358 . |
| 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) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (II) | 58979 | C7H13N4NaO4 | 详情 | 详情 | ||
| (III) | 58980 | 1-Fluoro-2,4-dinitrobenzene; Sanger's reagent; 2,4-Dinitro-1-fluorobenzene; 2,4-Dinitrofluorobenzene | 70-34-8 | C6H3FN2O4 | 详情 | 详情 |