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【结 构 式】 
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【分子编号】11620 【品名】2,4-Pentanedione;acetylacetone 【CA登记号】123-54-6 |
【 分 子 式 】C5H8O2 【 分 子 量 】100.11732 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号：(VII)The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 2H-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.
| 【1】 Threadgill, M.D.; Parveen, I.; Labelled compounds of interest as antitumour agents - VII. [H-2]- and [C-14]-curcumin. J Label Compd Radiopharm 2000, 43, 9, 883. |
| 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) | 45436 | 4-bromo-2-methoxyphenol | 7368-78-7 | C7H7BrO2 | 详情 | 详情 |
| (II) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (III) | 45437 | 5-bromo-2-(1-ethoxyethoxy)phenyl methyl ether; 4-bromo-1-(1-ethoxyethoxy)-2-methoxybenzene | C11H15BrO3 | 详情 | 详情 | |
| (IV) | 45438 | [4-(1-ethoxyethoxy)-3-methoxyphenyl]lithium | C11H15LiO3 | 详情 | 详情 | |
| (V) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (V) | 45439 | dimethylformamide | C3H7NO | 详情 | 详情 | |
| (VI) | 22701 | 4-hydroxy-3-methoxybenzaldehyde | 121-33-5 | C8H8O3 | 详情 | 详情 |
| (VI) | 45440 | 4-hydroxy-3-methoxybenzaldehyde | 21-59-0 | C8H8O3 | 详情 | 详情 |
| (VII) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The protection of 4-bromo-2-methoxyphenol (I) with ethyl vinyl ether (II) and TsOH in dichloromethane gives the ethoxyethyl ether (III), which is treated with n-BuLi in THF to yield the phenyl lithium compound (IV). The reaction of (IV) with 14C-labeled DMF (V), followed by hydrolysis with HCl, affords the labeled 4-hydroxy-3-methoxybenzaldehyde (VI), which is finally condensed with pentane-2,4-dione (VII) by means of B2O3 and tetrahydroquinoline in DMF.
| 【1】 Threadgill, M.D.; Parveen, I.; Labelled compounds of interest as antitumour agents - VII. [H-2]- and [C-14]-curcumin. J Label Compd Radiopharm 2000, 43, 9, 883. |
| 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) | 45436 | 4-bromo-2-methoxyphenol | 7368-78-7 | C7H7BrO2 | 详情 | 详情 |
| (II) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (III) | 45437 | 5-bromo-2-(1-ethoxyethoxy)phenyl methyl ether; 4-bromo-1-(1-ethoxyethoxy)-2-methoxybenzene | C11H15BrO3 | 详情 | 详情 | |
| (IV) | 45438 | [4-(1-ethoxyethoxy)-3-methoxyphenyl]lithium | C11H15LiO3 | 详情 | 详情 | |
| (V) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (V) | 45441 | dimethylformamide | C3H7NO | 详情 | 详情 | |
| (VI) | 22701 | 4-hydroxy-3-methoxybenzaldehyde | 121-33-5 | C8H8O3 | 详情 | 详情 |
| (VI) | 45442 | 4-hydroxy-3-methoxybenzaldehyde | C8H8O3 | 详情 | 详情 | |
| (VII) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A new synthesis of atipamezole has been described: The cyclization of alpha,alpha'-dibromo-o-xylene (I) with acetylacetone (II) by means of NaOH and tetrabutylammonium bromide in toluene/water at 80 C under phase-transfer conditions gives the unstable diacetyl derivative (III), which presumably undergoes cleavage to afford 2-acetylindane (IV). The alkylation of (IV) with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindane (V), which is brominated with Br2 to give 2-(bromoacetyl)-2-ethylindane (VI). Finally, this compound is cyclized with formamide at 160 C [some 2-ethyl-2-(4-oxazolyl)indane is also formed but is easily eliminated]; the cyclization can also be carried out with formamidine in liquid ammonia.
| 【1】 Wong, W.C.; Gluchowski, C.; A concise synthesis of atipamezole. Synthesis 1995, 2, 2, 139. |
| 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) | 11619 | 2,2-Bis(bromomethyl)indane | C11H12Br2 | 详情 | 详情 | |
| (II) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (III) | 11621 | 1-(2-Acetyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H14O2 | 详情 | 详情 | |
| (IV) | 11622 | 1-(2,3-Dihydro-1H-inden-2-yl)-1-ethanone | C11H12O | 详情 | 详情 | |
| (V) | 11612 | 1-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H16O | 详情 | 详情 | |
| (VI) | 11613 | 2-Bromo-1-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H15BrO | 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 intermediate 4-bromothiophene-3-carboxylic acid (II) was prepared in low yield by lithium-halogen exchange of 3,4-dibromothiophene (I) with n-BuLi in Et2O at -78 C, followed by quenching with solid CO2. Alternatively, lithiation of (I) at -116 C and further quenching with ethyl chloroformate provided ethyl ester (III) in moderate yields, accompanied by some byproducts that were separated by column chromatography. The required carboxylic acid (II) was then formed by saponification of (III) with NaOH. Subsequent condensation of bromoacid (II) with acetylacetone (IV) in the presence of potassium tert-butoxide and copper powder in refluxing tert-butanol provided the thienylpentanedione (V). Deacetylation with aqueous ammonia then gave the monoketone (VI). The target thienopyridinone was finally obtained by cyclization of (VI) with ammonium acetate in refluxing AcOH.
| 【1】 Shinkwin, A.E.; et al.; Synthesis of thiophenecarboxamides, thieno[3,4-c]p. Bioorg Med Chem 1999, 7, 2, 297. |
| 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) | 23826 | 3,4-dibromothiophene | 3141-26-2 | C4H2Br2S | 详情 | 详情 |
| (II) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (II) | 23827 | 4-bromo-3-thiophenecarboxylic acid | C5H3BrO2S | 详情 | 详情 | |
| (III) | 23828 | ethyl 4-bromo-3-thiophenecarboxylate | C7H7BrO2S | 详情 | 详情 | |
| (V) | 23832 | 4-[(Z)-1-acetyl-2-hydroxy-1-propenyl]-3-thiophenecarboxylic acid | C10H10O4S | 详情 | 详情 | |
| (VI) | 23833 | 4-(2-oxopropyl)-3-thiophenecarboxylic acid | C8H8O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)By condensation of 4-(methylsulfonyl)benzaldehyde (I) with pentane-2,4-dione (II) by means of SOCl2 in isopropanol.
| 【1】 Graul, A.; Wrobleski, T.; Castañer, J.; Orazipone. Drugs Fut 1998, 23, 1, 28. |
| 【2】 Backstrom, R.J.; Honkanen, E.J.; Pystynen, J.J.; Luiro, A.M.; Aho, P.A.; Linden, I.-B.Y.; Nissinen, E.A.O.; Pohto, P. (Orion Corporation); Substd. beta-diketones and their use. EP 0440324; JP 1992253933; US 5185370 . |
合成路线6
该中间体在本合成路线中的序号：(IX)The requisite nitrodiamine (VIII) was prepared via conversion of 4-methyl-1,2-phenylenediamine (V) to the selenocycle (VI) upon treatment with SeO2 and HCl, followed by nitration to afford regioselectively the nitro derivative (VII). Conversion to the diamine (VIII) was effected by treatment of (VII) with HI. Subsequent reaction of (VIII) with 2,4-pentanedione (IX) in the presence of HCl gave rise to the benzimidazole (X). Alkylation of (X) with bromide (IV) using K2CO3 in DMF provided adduct (XI) as the major regioisomer. Catalytic hydrogenation of the nitro group of (XI) then gave amine (XII). Finally, coupling of amine (XII) with 4'-(trifluoromethyl)biphenyl-2-carboxylic acid (XIII) was achieved via EDC activation or by previous conversion of (XIII) to the corresponding acid chloride with oxalyl chloride.
| 【1】 Sun, C.-Q.; Robl, J.A.; Sulsky, R.; et al.; A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors. J Med Chem 2001, 44, 6, 851. |
| 【3】 Sulsky, R.B.; Poss, M.A.; Slusarchyk, W.A.; Dickson, J.K.; Biller, S.A.; Tino, J.A.; Magnin, D.R.; Lawrence, R.M.; Robl, J.A.; Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. US 5760246 . |
| 【2】 Biller, S.A.; Dickson, J.K.; Lawrence, R.M.; Magnin, D.R.; Poss, M.A.; Robl, J.A.; Slusarchyk, W.A.; Sulsky, R.B.; Tino, J.A. (Bristol-Myers Squibb Co.); Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. EP 0904262; JP 2000502355; WO 9726240 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47746 | 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C20H19BrF3NO | 详情 | 详情 | |
| (V) | 47747 | 4-methyl-1,2-benzenediamine; 2-amino-4-methylphenylamine; 3,4-Diaminotoluene; 3,4-Toluenediamine; 4-methyl-1,2-phenylenediamine; 4-Methyl-O-Phenylenediamine; asym-o-Tolylenediamine; o-Toluylenediamine; ortho-toluenediamine; Tolylene-3,4-diamine | 496-72-0 | C7H10N2 | 详情 | 详情 |
| (VI) | 47748 | 5-methyl-2,1,3-benzoselenadiazole | C7H6N2Se | 详情 | 详情 | |
| (VII) | 47749 | 5-methyl-4-nitro-2,1,3-benzoselenadiazole | C7H5N3O2Se | 详情 | 详情 | |
| (VIII) | 47750 | 2-amino-4-methyl-3-nitrophenylamine; 4-methyl-3-nitro-1,2-benzenediamine | C7H9N3O2 | 详情 | 详情 | |
| (IX) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (X) | 47751 | 2,5-dimethyl-4-nitro-1H-benzimidazole | C9H9N3O2 | 详情 | 详情 | |
| (XI) | 47752 | 9-[4-(2,5-dimethyl-4-nitro-1H-benzimidazol-1-yl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C29H27F3N4O3 | 详情 | 详情 | |
| (XII) | 47753 | 9-[4-(4-amino-2,5-dimethyl-1H-benzimidazol-1-yl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C29H29F3N4O | 详情 | 详情 | |
| (XIII) | 41132 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid | C14H9F3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)2-Chloroaniline (I) is diazotized with NaNO2/HCl and the resultant diazonium salt (II) is further coupled to 2,4-pentanedione (III) to furnish the diketo hydrazone (IV). Subsequent bromination of (IV) with Br2 in Ac2O/AcOH gives rise to the hydrazonyl bromide (V). This is finally condensed with 3-ethynylaniline (VI) in DMF to provide the corresponding aryl amidrazone.
| 【1】 Wilson, D.M.; Termin, A.P.; Mao, L.; Ramirez-Weinhouse, M.M.; Molteni, V.; Gootenhuis, P.D.J.; Arylamidrazones as novel corticotropin releasing factor receptor antagonists. J Med Chem 2002, 45, 11, 2123. |
| 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) | 35804 | 2-chloroaniline; 2-chlorophenylamine | 95-51-2 | C6H6ClN | 详情 | 详情 |
| (II) | 63682 | 2-chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (III) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (IV) | 63683 | 2,3,4-pentanetrione 3-[N-(2-chlorophenyl)hydrazone] | C11H11ClN2O2 | 详情 | 详情 | |
| (V) | 63684 | N-(2-chlorophenyl)-2-oxopropanehydrazonoyl bromide | C9H8BrClN2O | 详情 | 详情 | |
| (VI) | 56445 | 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene | 54060-30-9 | C8H7N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)Condensation of 2-fluoro-4-nitrotoluene (I) with paraformaldehyde under basic conditions affords diol (II). Nitro group reduction in (II) by hydrogenation over Pd/C yields aniline (III), which is further protected with acetylacetone (IV), to produce the pyrrole derivative (V). After conversion of diol (V) into the mono-tosylate (VI), cyclization in the presence of BuLi furnishes the oxetane derivative (VII). Removal of the pyrrole moiety of (VII) by treatment with hydroxylamine provides amine (VIII), which is converted to the carbamate (IX) by acylation with benzyl chloroformate. Finally, condensation of (IX) with (S)-N,O-diacetyl-1-amino-3-chloro-2-propanol (X) in the presence of lithium t-butoxide produces the required oxazolidinone derivative.
| 【1】 Hao, Y.; Barbachyn, M.R.; Greene, M.L.; et al.; Synthesis and antibacterial activities of oxazolidinones incorporating C-ring oxetanes and thietanes. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1321. |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 62249 | 2-(2-fluoro-4-nitrophenyl)-1,3-propanediol | C9H10FNO4 | 详情 | 详情 | |
| (III) | 62250 | 2-(4-amino-2-fluorophenyl)-1,3-propanediol | C9H12FNO2 | 详情 | 详情 | |
| (IV) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (V) | 62251 | 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluorophenyl]-1,3-propanediol | C15H18FNO2 | 详情 | 详情 | |
| (VI) | 62252 | 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluorophenyl]-3-hydroxypropyl 4-methylbenzenesulfonate | C22H24FNO4S | 详情 | 详情 | |
| (VII) | 62253 | 1-[3-fluoro-4-(3-oxetanyl)phenyl]-2,5-dimethyl-1H-pyrrole | C15H16FNO | 详情 | 详情 | |
| (VIII) | 62254 | 3-fluoro-4-(3-oxetanyl)aniline; 3-fluoro-4-(3-oxetanyl)phenylamine | C9H10FNO | 详情 | 详情 | |
| (IX) | 62255 | benzyl 3-fluoro-4-(3-oxetanyl)phenylcarbamate | C17H16FNO3 | 详情 | 详情 | |
| (X) | 61915 | (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate | C7H12ClNO3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXXV)The triazolopyrimidine intermediate (IX) is prepared as follows. Cyclization of glycolic acid (XXXII) with aminoguanidine bicarbonate (XXXIII) in the presence of HNO3 at reflux yields 3-amino-5-(hydroxymethyl)-1,2,4-triazole (XXXIV) (1), optionally isolated as its glycolate salt , which then cyclizes with acetylacetone (XXXV) in refluxing AcOH/EtOH to afford the [1,2,4]triazolo[1,5-a]pyrimidine derivative (XXXVI) . Finally, alcohol (XXXVI) is oxidized by means of o-iodoxybenzoic acid (IBX) in DCE at 80 °C or with PhI(OAc)2 in the presence of TEMPO in CH2Cl2 .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 68338 | 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde | C8H8N4O | 详情 | 详情 | |
| (XXXII) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (XXXIII) | 68355 | aminoguanidine bicarbonate;aminoguanidine carbonate;1-aminoguanidine bicarbonate;aminoguanidine hydrogen carbonate | 2200-97-7 | CH6N4.CH2O3 | 详情 | 详情 |
| (XXXIV) | 68356 | 5-amino-1H-1,2,4-Triazole-3-methanol;3-amino-5-(hydroxymethyl)-1,2,4-triazole;5-amino-s-Triazole-3-methanol;(5-Amino-1H-[1,2,4]triazol-3-yl)methanol | 27277-03-8 | C3H6N4O | 详情 | 详情 |
| (XXXV) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (XXXVI) | 68357 | (5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol | C8H10N4O | 详情 | 详情 |