1,5-双(1-甲基-2-氧代-3-苄氧基-1,2-二氢吡啶-4-甲酰氨基)-3-氧杂戊烷的合成
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摘要
以2-吡咯烷酮与草酸二乙酯为起始原料,经开环/扩环、还原、甲基化、脱甲基、苄基化、酯键水解与缩合等反应,合成了新型螯合剂衍生物1,5-双(1-甲基-2-氧代-3-苄氧基-1,2-二氢吡啶-4-甲酰氨基)-3-氧杂戊烷,优化了第一步开环/扩环反应工艺。n(2-吡咯烷酮)∶n(草酸二乙酯)∶n(CH_3CH_2OK)=1∶1.1∶1.2为最佳投料比,最终总收率为8.6%,其结构经~1H NMR、~(13)C NMR和MS确证。
A novel chelator derivative, 1,5-bis(1-methyl-2-oxo-3-benzyloxy-1,2-dihydro-pyridine-4-carboxamide)-3-oxapentane,was synthesized with an overall yield of 8.6% via ring expansion, reduction, methylation, demethylation, benzylation, hydrolysis of ester bond and condensation reaction using 2-pyrrolidinone and diethyl oxalate as the starting materials. The optimization of the ring opening/expansion reaction and the optimum molar ratio 2-pyrrolidinone:diethyl oxalate:CH_3CH_2OK was 1:1.1:1.2. The structure was confirmed by ~1H NMR,~(13) C NMR and MS.
A novel chelator derivative, 1,5-bis(1-methyl-2-oxo-3-benzyloxy-1,2-dihydro-pyridine-4-carboxamide)-3-oxapentane,was synthesized with an overall yield of 8.6% via ring expansion, reduction, methylation, demethylation, benzylation, hydrolysis of ester bond and condensation reaction using 2-pyrrolidinone and diethyl oxalate as the starting materials. The optimization of the ring opening/expansion reaction and the optimum molar ratio 2-pyrrolidinone:diethyl oxalate:CH_3CH_2OK was 1:1.1:1.2. The structure was confirmed by ~1H NMR,~(13) C NMR and MS.
引文
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[2]Singh A N, Liu W, Hao G, et al. Multivalent bifunctional chelator scaffolds for Gallium-68 based positron emission tomography imaging probe design:signal amplification via multivalency[J]. Bioconjugate Chem., 2011, 22(8):1650-1662.
[3]Eriksson S E, Tomas O, Rune N, et al. Treatment with unlabeled mAb BR96 after radioimmunotherapy with 177LuDOTA-BR96 in a syngeneic rat colon carcinoma model[J].Cancer Biother Radiopharm, 2012, 27(3):175-182.
[4]Mier W, Hoffend J, Kr?mer S, et al. Conjugation of DOTA using isolated phenolic active esters:the labeling and biodistribution of albumin as blood pool marker[J].Bioconjugate Chem., 2005, 16(1):237-240.
[5]Shetty D, Jeong J M, Ju C H, et al. Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography[J]. Bioorg Med Chem., 2010, 18(21):7338-7347.
[6]Zhang K, Cui S, Wang J, et al. Study on antitumor activity of metal-based diketone complexes[J]. Med Chem Res., 2012,21(7):1071-1076.
[7]Mukai T, Suwada J, Sano K, et al. Design of Ga-DOTAbased bifunctional radiopharmaceuticals:two functional moieties can be conjugated to radiogallium-DOTA without reducing the complex stability[J]. Bioorg Med Chem., 2009,17(13):4285-4289.
[8]Arano Y, Yokoyama A, Magata Y, et al. Synthesis and evaluation of a new bifunctional chelating agent for 99mTc labeling proteins:p-carboxyethylphenylglyoxal-di(Nmethylthiosemicarbazone)[J]. Int J Nucl Med Bio., 1986,12(6):425-430.
[9]Barrett S, Jaen J, Caprathe B, et al. Efficient synthesis of exo-1-azabicyclo[2.2.1]heptan-3-ol[J]. Org Prep Proced Int.,1997, 29(3):330-335.
[10]Allen M J, Raines R T, Kiessling L L. Contrast agents for magnetic resonance imaging synthesized with ring-opening metathesis polymerization[J]. J Am Chem Soc., 2006,128(20):6534-6535.
[11]Ramdahl T, Bonge-Hansen H T, Ryan O B, et al. Efficient Chelator for Complexation of Thorium-227[J]. Bioorg Med Chem Lett., 2016, 26(17):4318-4321.
[12]Cuthbertson A. Radio-pharmaceutical complexes:US,0340759[P]. 2017-11-28.
[13]Baba A R, Gowda D C. Utilization of 3-ethyl-1(N,Ndimethyl)aminopropylcarbodiimide(EDCI)/1-hydroxybenzotriazole(HOBt)as a polymerizing agent[J].Lett Pept Sci., 2001, 8(6):309-318.
[14]Yu P, Hu J, Zhou T Y, et al. Synthesis, insecticidal evaluation of novel 1,3,4-thiadiazole chrysanthemamide derivatives formed by an EDCI/HOBt condensation[J]. J Chem Res., 2011, 35(12):703-706.