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【结 构 式】 
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【分子编号】24273 【品名】2-[(2-hydroxyethyl)amino]-1-ethanol 【CA登记号】111-42-2 |
【 分 子 式 】C4H11NO2 【 分 子 量 】105.13688 【元素组成】C 45.7% H 10.55% N 13.32% O 30.44% |
合成路线1
该中间体在本合成路线中的序号：(D)Compound can be prepared in several different ways, all starting from 3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (I): 1) The condensation of (I) with N-(3-bromopropyl)-N'-(m-chlorophenyl)piperazine (B) by means of NaNH2, NaH or sodium alcoholate in an organic solvent (DMSO, DMF, dioxane, benzene, alcohol, tetralin, etc.). 2) The condensation of (I) with 1-chloro-3-bromopropane (A) by means of sodium alcoholate in alcohol gives 1-(3-chloropropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (II), which is then condensed with an inert solvent by means of HCl acceptor. 3) The condensation of (II) with diethanolamine (C) affords 1-(3-bishydroxyethylaminopropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (III), which is then converted into the corresponding dichlorocompound (IV) by means of SOCl2. Finally, (IV) is cyclized with m-chloroaniline (E).
| 【1】 Palazzo, G.; 1-[3-(4-Metrachlorophenyl-1-piperazinyl)propyl]-3,4-diethyl-delta2-1,2,4-triazolin-5-one. DE 2351739; FR 2202702; GB 1438337; US 3857845 . |
| 【2】 de Angelis, L.; Castaner, J.; Etoperidone. Drugs Fut 1977, 2, 3, 164. |
| 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) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (E) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (D) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (B) | 33592 | 1-(3-bromopropyl)-4-(4-chlorophenyl)piperazine | C13H18BrClN2 | 详情 | 详情 | |
| (I) | 33588 | 4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | 52883-26-8 | C6H11N3O | 详情 | 详情 |
| (II) | 33589 | 2-(3-chloropropyl)-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C9H16ClN3O | 详情 | 详情 | |
| (III) | 33591 | 2-[3-[bis(2-hydroxyethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C13H26N4O3 | 详情 | 详情 | |
| (IV) | 33590 | 2-[3-[bis(2-chloroethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one | C13H24Cl2N4O | 详情 | 详情 | |
| (C) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The alkylation of 5,5-pentamethylenehydantoin (I) with 1-bromo-2-chloroethane (II) by means of KOH in refluxing ethanol gives 3-(2-chloroethyl)-5,5-pentamethylenehydantoin (II), which is condensed with diethanolamine (IV) by means of NaI in hot DMF yielding 3-[2-[bis(2 hydroxyethyl)amino]ethyl] 5,5-pentamethylenehydantoin (V) Finally, this compound is treated with hot POCl3.
| 【1】 Peng, G.W.; et al.; Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 1975, 18, 8, 846. |
| 【2】 Prous, J.; Castaner, J.; Spiromustine. Drugs Fut 1986, 11, 9, 773. |
| 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) | 24270 | 1,3-diazaspiro[4.5]decane-2,4-dione | 702-62-5 | C8H12N2O2 | 详情 | 详情 |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 24272 | 3-(2-chloroethyl)-1,3-diazaspiro[4.5]decane-2,4-dione | C10H15ClN2O2 | 详情 | 详情 | |
| (IV) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (V) | 24274 | 3-[2-[bis(2-hydroxyethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione | C14H25N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Protection of the amino group of diethanolamine (I) with diethyl chlorophosphate in the presence of triethylamine gave N-(diethoxyphosphoryl)ethanolamine (II). Further treatment of (II) with methanesulfonyl chloride yielded the corresponding bis(mesylate) (III). Reaction of 2,6-bis(bromomethyl) pyridine (IV) with NaCN in the presence of cetyl trimethylammonium bromide under phase-transfer conditions produced dinitrile (V), which was hydrogenated over Raney Nickel to afford diamine (VI). Subsequent condensation of (VI) with p-toluenesulfonyl chloride gave bis(sulfonamide) (VII). Cyclization of bis(mesylate) (III) with bis(sulfonamide) (VII) in the presence of Cs2CO3 gave rise to macrocycle (VIII). Selective deprotection of the diethoxyphosphoryl group by means of HBr in AcOH gave (IX). This was dimerized with alpha,alpha'-dibromo-p-xylene (X) in the presence of K2CO3 in refluxing acetonitrile to give the tosyl-protected dimer (XI). Deprotection of the tosyl groups of (XI) was achieved by reductive treatment with sodium amalgam. The title compound was then isolated after conversion to the octahydrobromide tetrahydrate salt.
| 【1】 Witvrouw, M.; Henson, G.W.; Padmanabhan, S.; De Clercq, E.; Struyf, S.; Martellucci, S.A.; Bridger, G.J.; Skerlj, R.T.; Schols, D.; Synthesis and structure-activity relationships of phenylenebis (methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4. J Med Chem 1999, 42, 19, 3971. |
| 【2】 Bridger, G.J.; Padmanabhan, S.; Skerlj, R.T. (Johnson Matthey plc); Cyclic polyamines. EP 0739345; JP 1997509407; US 5698546; WO 9518808 . |
| 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) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (II) | 34633 | C8H20NO5P | 详情 | 详情 | ||
| (III) | 34634 | 2-((diethoxyphosphoryl)[2-[(methylsulfonyl)oxy]ethyl]amino)ethyl methanesulfonate | C10H24NO9PS2 | 详情 | 详情 | |
| (IV) | 34635 | 2,6-bis(bromomethyl)pyridine | 7703-74-4 | C7H7Br2N | 详情 | 详情 |
| (V) | 34636 | 2-[6-(2-nitriloethyl)-2-pyridinyl]acetonitrile | C9H7N3 | 详情 | 详情 | |
| (VI) | 34637 | 2-[6-(2-aminoethyl)-2-pyridinyl]-1-ethanamine; 2-[6-(2-aminoethyl)-2-pyridinyl]ethylamine | C9H15N3 | 详情 | 详情 | |
| (VII) | 34638 | 4-methyl-N-[2-[6-(2-[[(4-methylphenyl)sulfonyl]amino]ethyl)-2-pyridinyl]ethyl]benzenesulfonamide | C23H27N3O4S2 | 详情 | 详情 | |
| (VIII) | 34639 | diethyl 4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-ylphosphonate | C31H43N4O7PS2 | 详情 | 详情 | |
| (IX) | 34640 | 4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene | C27H34N4O4S2 | 详情 | 详情 | |
| (X) | 18697 | 1,4-bis(bromomethyl)benzene | 623-24-5 | C8H8Br2 | 详情 | 详情 |
| (XI) | 34641 | 7-(4-[[4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl]methyl]benzyl)-4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene | C62H74N8O8S4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)The reaction of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (I) with piperidine (A) at room temperature gives 2,6-dichloro-4,8-di(N-piperidino)pyrimido[5,4-d]pyrimidine (II), which is treated with diethanolamine (B) at 200 C to yield 2,6-bis(diethanolamino)-4,8-di(N-piperidino)pyrimido[5,4-d])pyrimidine (III) (1). The reduction of (III) with Zn in hot formic or acetic acid or in hot aqueous HCl gives 2,6-bis(diethanolamino)-8-(N-piperidino)-1,2,3,4-tetrahydropyrimido[5,4-d]pyrimidine (IV), which is then dehydrogenated with I2 - KI in water.
| 【1】 Castañer, J.; Serradell, M.N.; Blancafort, P.; Owen, R.T.; Mopidamol. Drugs Fut 1980, 5, 11, 550. |
| 【2】 US 3322755 . |
| 【3】 Fischer, F.G.; et al.; US 3031450 . |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (B) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (I) | 36173 | 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine | C6Cl4N4 | 详情 | 详情 | |
| (II) | 39202 | 2,6-dichloro-4,8-di(1-piperidinyl)pyrimido[5,4-d]pyrimidine | C16H20Cl2N6 | 详情 | 详情 | |
| (III) | 39203 | 2-[[6-[bis(2-hydroxyethyl)amino]-4,8-di(1-piperidinyl)pyrimido[5,4-d]pyrimidin-2-yl](2-hydroxyethyl)amino]-1-ethanol | 58-32-2 | C24H40N8O4 | 详情 | 详情 |
| (IV) | 39204 | 2-[[6-[bis(2-hydroxyethyl)amino]-4-(1-piperidinyl)-5,6,7,8-tetrahydropyrimido[5,4-d]pyrimidin-2-yl](2-hydroxyethyl)amino]-1-ethanol | C19H35N7O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Pyrimidopyrimidine tetraone (I) was converted to the disodium salt (II), which was then treated with PCl5 in refluxing POCl3 to provide the tetrachloro pyrimidopyrimidine (III). Displacement of the more reactive 4- and 8-chlorine atoms of (III) by 4-methoxybenzylamine (IV) in THF at room temperature gave the 4,8-di(4-methoxybenzylamino) derivative (V). Finally, the remainig chlorine atoms of (V) were displaced by diethanolamine (VI) at 110 C, yielding the title compound.
| 【1】 Barlow, H.C.; et al.; Resistance-modifying agents. Part 7: 2,6-Disubstituted-4,8-dibenzylaminopyrimido[5,4-d]pyrimidines that inhibit nucleoside transport in the presence of alpha1-acid glycoprotein (AGP). Bioorg Med Chem Lett 2000, 10, 6, 585. |
| 【2】 Calvert, A.H.; Griffin, R.J.; Curtin, N.J.; Golding, B.T.; Newell, D.R. (University of Newcastle upon Tyne); Pyrimidopyrimidine cpds.. WO 9843974 . |
| 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) | 41123 | 1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetrone | 6713-54-8 | C6H4N4O4 | 详情 | 详情 |
| (II) | 41124 | disodium 2,6-dioxo-1,2,6,7-tetrahydropyrimido[5,4-d]pyrimidine-4,8-diolate | C6H2N4Na2O4 | 详情 | 详情 | |
| (III) | 36173 | 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine | C6Cl4N4 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 41125 | 2,6-dichloro-N(4),N(8)-bis(4-methoxybenzyl)pyrimido[5,4-d]pyrimidine-4,8-diamine; N-[2,6-dichloro-8-[(4-methoxybenzyl)amino]pyrimido[5,4-d]pyrimidin-4-yl]-N-(4-methoxybenzyl)amine | C22H20Cl2N6O2 | 详情 | 详情 | |
| (VI) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(A)Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.
| 【1】 Hester, J.B.; Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential. J Med Chem 2001, 44, 7, 1099. |
| 【2】 Hester, J.B. Jr.; Gibson, J.K. (Pharmacia Corp.); Antiarrhythmic (S)-enantiomers of methanesulfonamides. EP 0802900; JP 1999500418; WO 9621643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (A) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (I) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (IV) | 48114 | N-ethyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C13H18N2O4S | 详情 | 详情 | |
| (V) | 48115 | (4S)-N-ethyl-4-hydroxy-4-[4-[(methylsulfonyl)amino]phenyl]butanamide | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 48116 | N-[4-[(1S)-4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide | C13H22N2O3S | 详情 | 详情 | |
| (VII) | 48117 | 5-chloro-1-pentanol | C5H11ClO | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 48118 | 2-[(5-chloropentyl)oxy]tetrahydro-2H-pyran; 5-chloropentyl tetrahydro-2H-pyran-2-yl ether | C10H19ClO2 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 48119 | 2-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexanol | C12H24O3 | 详情 | 详情 | |
| (XII) | 48120 | 5-fluoro-5-methylhexyl tetrahydro-2H-pyran-2-yl ether; 2-[(5-fluoro-5-methylhexyl)oxy]tetrahydro-2H-pyran | C12H23FO2 | 详情 | 详情 | |
| (XIII) | 48121 | 6-fluoro-6-methyl-1-heptanol | C8H17FO | 详情 | 详情 | |
| (XIV) | 48122 | 1-bromo-6-fluoro-6-methylheptane | C8H16BrF | 详情 | 详情 | |
| (XV) | 48123 | N-(4-[(1S)-4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-hydroxybutyl]phenyl)methanesulfonamide | C21H37FN2O3S | 详情 | 详情 | |
| (XVI) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Dichlorophenylpiperazine (III) was prepared from aniline (I) by dehydrative cyclization with diethanolamine (II) in the presence of P2O5 and Et3N-HCl at 200 C. Alkylation of piperazine (III) with N-(4-bromobutyl) phthalimide (IV) gave (V), and subsequent hydrazinolysis of the phthalimide provided the (4-aminobutyl)piperazine (VI). Finally, condensation of (VI) with fluorene-2-carboxylic acid (VII) yielded the target amide.
| 【1】 Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.; Wasley, W.F.; Thurkauf, A.; NGB 2904 and NGB 2849: Two highly selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 19, 2715. |
| 【2】 Yuan, J.; Chen, X. (Neurogen Corp.); Novel N-aminoalkylfluorenecarboxamides; a new class of dopamine receptor subtype specific ligands. EP 0873329; JP 1998511114; US 5659033; WO 9710229 . |
| 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) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 13943 | 1-(2,3-Dichlorophenyl)piperazine | 41202-77-1 | C10H12Cl2N2 | 详情 | 详情 |
| (IV) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (V) | 28563 | 2-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H23Cl2N3O2 | 详情 | 详情 | |
| (VI) | 28564 | 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butylamine | C14H21Cl2N3 | 详情 | 详情 | |
| (VII) | 28566 | 9H-fluorene-2-carboxylic acid | C14H10O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The reaction of 5-bromo-1(R)-methyl-2-(triphenylmethyl)-2,3-dihydro-1H-isoindole (I) with; BuLi, triisopropyl borate and diethanolamine (II) gives the boronic ester (III), which is condensed with 1-cyclopropyl-7-bromo-8-(difluoromethoxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (IV) by means of PdCl2(PPh3)2 to yield the precursor (V). Finally, this compound is deprotected by a treatment with HCl in ethanol/water to provide the target Garenoxacin.
| 【1】 Hayashi, K.; Takahata, M.; Kawamura, Y.; Todo, Y.; Synthesis, antibacterial activity, and toxicity of 7-(isoindolin-5-yl)-4-oxoquinoline-3-carboxylic acids. Discovery of the novel des-F(6)-quinolone antibacterial agent garenoxacin (T-3811 or BMS-284756). Arzneim Forsch Drug Res. 2002, 52, 12, 903. |
| 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) | 30634 | (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole | C28H24BrN | 详情 | 详情 | |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 61570 | (1R)-5-(1,3,6,2-dioxazaborocan-2-yl)-1-methyl-2-trityl-2,3-dihydro-1H-isoindole | C32H33BN2O2 | 详情 | 详情 | |
| (IV) | 61571 | ethyl 7-bromo-1-cyclopropyl-8-(2,2-difluoroethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C17H16BrF2NO3 | 详情 | 详情 | |
| (V) | 61572 | ethyl 1-cyclopropyl-8-(2,2-difluoroethyl)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C45H40F2N2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VI)The condensation of 2,6-dichloropurine (I) with 4-methoxybenzylamine (II) in butanol at 120 C gives 2-chloro-6-(4-methoxybenzylamino)purine (II), which is treated with isopropyl iodide (IV) and NaH in DMF yielding 2-chloro-9-isopropyl-6-(4-methoxybenzylamino)purine (V). Finally, this compound is condensed with diethanolamine (VI) in DMSO at 160 C.
| 【1】 Schow, S.R.; et al.; Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg Med Chem Lett 1997, 7, 21, 2697. |
| 【2】 Lum, R.T.; Blum, C.L.; Mackman, R.; Wick, M.M.; Schow, S.R. (CV Therapeutics, Inc.); Purine inhibitors of cyclin dependent kinase 2 and IkappaB-alpha. EP 1021186; US 5866702; WO 9805335 . |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (II) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (III) | 38022 | N-(2-chloro-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine | C13H12ClN5O | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 38023 | 2-chloro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine; N-(2-chloro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine | C16H18ClN5O | 详情 | 详情 | |
| (VI) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Dichlorophenylpiperazine (III) was prepared from aniline (I) by dehydrative cyclization with diethanolamine (II) in the presence of P2O5 and Et3N-HCl at 200 C. Alkylation of piperazine (III) with N-(4-bromobutyl) phthalimide (IV) gave (V), and subsequent hydrazinolysis of the phthalimide provided the (4-aminobutyl)piperazine (VI). Finally, condensation of (VI) with biphenylene-2-carboxylic acid (VII) yielded the target amide.
| 【1】 Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.; Wasley, W.F.; Thurkauf, A.; NGB 2904 and NGB 2849: Two highly selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 19, 2715. |
| 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) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 23943 | 2-methoxyisonicotinonitrile | C7H6N2O | 详情 | 详情 | |
| (IV) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (V) | 28563 | 2-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H23Cl2N3O2 | 详情 | 详情 | |
| (VI) | 28564 | 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butylamine | C14H21Cl2N3 | 详情 | 详情 | |
| (VII) | 28565 | 2-biphenylenecarboxylic acid | C13H8O2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of phenyl isocyanate (I) with diethanolamine (II) produced 1,1-bis(2-hydroxyethyl)-3-phenylurea (III), which was converted into the bis(chloroethyl) derivative (IV) upon treatment with SOCl2. Cyclization of this compound at 140 C furnished imidazolinone (V). Finally, condensation of (V) with benzisoxazolylpiperidine (VI) in the presence of K2CO3 and KI in refluxing methyl isobuyl ketone yielded the title compound.
| 【1】 Audinot, V.; Millan, M.; Brocco, M.; Peglion, J.-L. (ADIR et Cie.); 3-(Piperid-4-yl)-1,2-benzisoxazole and 3-(piperazin-4-yl)-1,2-benzisoxazole cpds.. EP 0811622; FR 2749304; US 5780474 . |
| 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) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 36999 | N,N-bis(2-hydroxyethyl)-N'-phenylurea | C11H16N2O3 | 详情 | 详情 | |
| (IV) | 37000 | N,N-bis(2-chloroethyl)-N'-phenylurea | C11H14Cl2N2O | 详情 | 详情 | |
| (V) | 37001 | 1-(2-chloroethyl)-3-phenyl-2-imidazolidinone | C11H13ClN2O | 详情 | 详情 | |
| (VI) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)In an alternative method, p-nitroaniline (I) is reacted with ethylene oxide (II) to afford diol (III). This compound can also be prepared by condensation of 1-fluoro-4-nitrobenzene (IV) with diethanolamine (V). Chlorination of diol (III) to provide (VI) is accomplished with either mesyl chloride or SOCl2 in the presence of pyridine. Then, nitro group reduction in (VI) by means of iron and HCl affords aniline (VII).
| 【1】 Jordan, A.M.; Khan, T.H.; Malkin, H.; Osborn, H.M.I.; Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT). Bioorg Med Chem 2002, 10, 8, 2625. |
| 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) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (II) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (III) | 64080 | 2-[(2-hydroxyethyl)-4-nitroanilino]-1-ethanol | C10H14N2O4 | 详情 | 详情 | |
| (IV) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (V) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (VI) | 64081 | N,N-bis(2-chloroethyl)-4-nitroaniline; N,N-bis(2-chloroethyl)-N-(4-nitrophenyl)amine | C10H12Cl2N2O2 | 详情 | 详情 | |
| (VII) | 64082 | N~1~,N~1~-bis(2-chloroethyl)-1,4-benzenediamine; N-(4-aminophenyl)-N,N-bis(2-chloroethyl)amine | C10H14Cl2N2 | 详情 | 详情 |