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【结 构 式】 
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【分子编号】16312 【品名】1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether 【CA登记号】38212-30-5 |
【 分 子 式 】C11H16N2O 【 分 子 量 】192.26092 【元素组成】C 68.72% H 8.39% N 14.57% O 8.32% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(benzoyloxymethyl)-1,3-dioxolane (I) with triazole (II) by means of NaH in DMSO, followed by hydrolysis with NaOH in dioxane water gives 2-(2,4-dichlorophenyl)-2-(1H)-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol (III), which is acylated with methanesulfonyl chloride in pyridine affording the corresponding 4-mesyloxymethyldioxolane (IV). Finally, this compound is condensed with 4-(4-isopropylpiperazin-1-yl)phenol (V) by means of NaH in hot DMSO. Compound (V) is obtained as follows: 4-(4-methoxyphenyl)piperazine (VI) is reductocondensed with acetone (A) by means of H2 over Pd/C giving 1-isopropyl-4-(4-methoxyphenyl)piperazine (VII), which is then demethylated with refluxing aqueous 48% HBr yielding (V)
| 【1】 Van Cutsem, J.; Heeres, J.; Hendrickx, R.; Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal. J Med Chem 1983, 26, 4, 611-613. |
| 【2】 Heeres, J.; Backx, L.J.J.; Mostmans, J.H. (Janssen Pharmaceutica NV); Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles. BE 0863382; FR 2378778; GB 1594859; JP 7895973; US 4144346; US 4223036 . |
| 【3】 Serradell, M.N.; Castaner, J.; Fromtling, R.A.; Terconazole. Drugs Fut 1984, 9, 7, 529. |
| 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) | 30488 | 4-(4-isopropyl-1-piperazinyl)phenol; 1-Isopropyl-4-(4-hydroxyphenyl)piperazine | C13H20N2O | 详情 | 详情 | |
| (I) | 30485 | [(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate | C18H15BrCl2O4 | 详情 | 详情 | |
| (II) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (III) | 30486 | [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol | C13H13Cl2N3O3 | 详情 | 详情 | |
| (IV) | 30487 | 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole | C16H19Cl2N3O3S | 详情 | 详情 | |
| (V) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (VI) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (VII) | 30489 | 1-isopropyl-4-(4-methoxyphenyl)piperazine; 4-(4-isopropyl-1-piperazinyl)phenyl methyl ether | C14H22N2O | 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 intermediate (I) can be obtained as follows:1) The condensation of 1-(4-methoxyphenyl)piperazine (III) with chloronitrobenzene (IV) by means of K2CO3 in DMSO gives 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), which is reduced with H2 over Pt/C to the corresponding amine (VI). The reaction of (VI) with phenyl chloroformate and pyridine in CHCl3 affords the corresponding carbamate (VII), which is treated with hydrazine in dioxane/water yielding the semicarbazide (VIII). The cyclization of (VIII) with formamidine and sodium acetate in butanol gives 4-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]-3,4-dihydro-2H-1,2,4-triazol-3-one (IX) (2), which is alkylated with 1-ethylpropyl tosylate (X) by means of KOH in DMSO yielding the corresponding 2-alkyl compound (XI). Finally, this compound is demethylated to (I) by refluxing in 48% HBr.
| 【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900. |
| 【2】 Castañer, J.; Fromtling, R.A.; SCH 51048. Drugs Fut 1995, 20, 3, 241. |
| 【3】 Saksena, A.K.; Girijavallabhan, V.M.; Ganguly, A.K.; Lovey, R.G. (Schering Corp.); Tri-substd. tetrahydrofuran antifungals. EP 0610377; JP 1995500605; WO 9309114 . |
| 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) | 16310 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (III) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (IV) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (V) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (VI) | 16315 | 4-[4-(4-methoxyphenyl)piperazino]phenylamine; 4-[4-(4-methoxyphenyl)piperazino]aniline; 1-(4-Aminophenyl)-4-(4-methoxyphenyl)piperazine | 74852-62-3 | C17H21N3O | 详情 | 详情 |
| (VII) | 16316 | phenyl N-[4-[4-(4-methoxyphenyl)piperazino]phenyl]carbamate | C24H25N3O3 | 详情 | 详情 | |
| (VIII) | 16317 | N-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-1-hydrazinecarboxamide | C18H23N5O2 | 详情 | 详情 | |
| (IX) | 16318 | 4-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C19H21N5O2 | 详情 | 详情 | |
| (X) | 16319 | 1-ethylpropyl 4-methylbenzenesulfonate | C12H18O3S | 详情 | 详情 | |
| (XI) | 16320 | 2-(1-ethylpropyl)-4-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H31N5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.
| 【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359. |
| 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) | 26628 | 1-bromo-4-nitrobenzene | 99-99-0 | C6H4BrNO2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (IV) | 63436 | 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether | C7H7BrO | 详情 | 详情 | |
| (V) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (VI) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (VII) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (VIII) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (IX) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (X) | 43156 | 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether | 6793-92-6 | C13H11BrO | 详情 | 详情 |
| (XI) | 64373 | 1-[4-(benzyloxy)phenyl]piperazine; benzyl 4-(1-piperazinyl)phenyl ether | C17H20N2O | 详情 | 详情 | |
| (XII) | 64372 | benzyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether; 1-[4-(benzyloxy)phenyl]-4-(4-nitrophenyl)piperazine | C23H23N3O3 | 详情 | 详情 | |
| (XIII) | 64371 | 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine | C23H25N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The cyclization of 2-(3-bromophenyl)ethyl alcohol (I) with ethyl 3,3-diethoxypropionate by means of TiCl4 in dichlromethane gives racemic 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (III), which is regioselectively hydrolyzed by means of Amano P-30 lipase in apH 7 buffer yielding 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1(S)-yl)acetic acid (IV). The condensation of (IV) with 1-(4-methoxyphenyl)piperazine (V) by means of diethyl cyanophosphate in dichloromethane affords the acylated piperazine (VI), which is reduced with the complex BH3.THF in THF to 6-bromo-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-3,4-dihydro-1H-2-benzopyran (VII). The reaction of (VII) with trimethylsilyl isocyante (VIII) by means of BuLiDMF gives the crboxamide (IX), which is treated with di-tert-butyl dicarbonate and dimethylaminopyridine (DMAP) in dichloromethane to yield the N,N-bis(tert-butoxycarbonyl) derivative (X). Finally, this compound is treated with an excess of methylamine.
| 【1】 Ennis, M.D.; Tenbrink, R.E. (Pharmacia & Upjohn AB); 1,6-Disubstd. isochromans for treatment of migraine headaches. EP 0836599; JP 1999509532; WO 9702259 . |
| 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) | 19969 | 2-(3-bromophenyl)-1-ethanol; 3-Bromophenethyl alcohol | 28229-69-8 | C8H9BrO | 详情 | 详情 |
| (II) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
| (III) | 19971 | ethyl 2-(6-bromo-3,4-dihydro-1H-isochromen-1-yl)acetate | C13H15BrO3 | 详情 | 详情 | |
| (IV) | 19972 | ethyl 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]acetate | C13H15BrO3 | 详情 | 详情 | |
| (V) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (VI) | 19974 | 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]-1-[4-(4-methoxyphenyl)-1-piperazinyl]-1-ethanone | C22H25BrN2O3 | 详情 | 详情 | |
| (VII) | 19975 | 1-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-4-(4-methoxyphenyl)piperazine; 4-(4-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-1-piperazinyl)phenyl methyl ether | C22H27BrN2O2 | 详情 | 详情 | |
| (VIII) | 19976 | isocyanato(trimethyl)silane; trimethylsilyl isocyanate | C4H9NOSi | 详情 | 详情 | |
| (IX) | 19977 | (1S)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-3,4-dihydro-1H-isochromene-6-carboxamide | C23H29N3O3 | 详情 | 详情 | |
| (X) | 19978 | 1-[2-((1S)-6-[[bis(tert-butoxycarbonyl)amino]carbonyl]-3,4-dihydro-1H-isochromen-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine | C33H45N3O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of 1-(4-methoxyphenyl)piperazine (I) with ethyl chloroacetate (II) gives the expected condensation product (III), which by treatment with hydrazine in converted into the corresponding hydrazide (IV). The cyclization of (IV) with benzimidate (V) by heating at 180 C affords the triazole (VI), which is finally condensed with 4-fluorobenzyl chloride (VII) by means of NaH in DMF.
| 【1】 Chytiroglou-Lada, A.; Filippatos, E.C.; Papakonstantinou-Garoufalias, S.S.; Papadaki-Valiraki, A.E.; Todoulou, O.G.; Synthesis, antifungal activity and antibacterial evaluation of some 3-piperazinylmethyl-5-aryl-1H-1,2,4-triazoles. Arzneim-Forsch Drug Res 1998, 48, 10, 1019. |
| 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) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 25573 | ethyl 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetate | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 25574 | 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetohydrazide | C13H20N4O2 | 详情 | 详情 | |
| (V) | 14225 | ethyl benzenecarboximidoate | C9H11NO | 详情 | 详情 | |
| (VI) | 25575 | 1-(4-methoxyphenyl)-4-[(5-phenyl-1H-1,2,4-triazol-3-yl)methyl]piperazine; methyl 4-[4-[(5-phenyl-1H-1,2,4-triazol-3-yl)methyl]-1-piperazinyl]phenyl ether | C20H23N5O | 详情 | 详情 | |
| (VII) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The condensation of 1-(4-methoxyphenyl)piperazine (I) with ethyl chloroacetate (II) gives the expected condensation product (III), which by treatment with hydrazine in converted into the corresponding hydrazide (IV). The cyclization of (IV) with 4-methylbenzimidate (V) by heating at 180 C affords the triazole (VI), which is finally condensed with 4-fluorobenzyl chloride (VII) by means of NaH in DMF.
| 【1】 Chytiroglou-Lada, A.; Filippatos, E.C.; Papakonstantinou-Garoufalias, S.S.; Papadaki-Valiraki, A.E.; Todoulou, O.G.; Synthesis, antifungal activity and antibacterial evaluation of some 3-piperazinylmethyl-5-aryl-1H-1,2,4-triazoles. Arzneim-Forsch Drug Res 1998, 48, 10, 1019. |
| 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) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 25573 | ethyl 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetate | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 25574 | 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetohydrazide | C13H20N4O2 | 详情 | 详情 | |
| (V) | 25576 | ethyl 4-methylbenzenecarboximidoate | C10H13NO | 详情 | 详情 | |
| (VI) | 25577 | methyl 4-(4-[[5-(4-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl]-1-piperazinyl)phenyl ether; 1-(4-methoxyphenyl)-4-[[5-(4-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl]piperazine | C21H25N5O | 详情 | 详情 | |
| (VII) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |