Gedatolisib的合成
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摘要
本研究合成了抗肿瘤药物gedatolisib。三聚氯氰(2)与吗啉在丙酮/水中反应得2-氯-4,6-二(吗啉-4-基)-1,3,5-三嗪,与4-氨基苯硼酸频哪醇酯在四三苯基膦钯催化下,经Suzuki偶联得4-[4,6-二(吗啉-4-基)-1,3,5-三嗪-2-基]苯胺(5),本步反应中钯催化剂的用量由文献的5%减少至0.8%,后处理用乙酸乙酯重结晶代替柱色谱纯化,保证收率的同时,简化了操作。用价廉的N,N'-羰基二咪唑代替高毒的氯甲酸苯酯作羰基化试剂与化合物5反应后,再与(4-氨基苯基)[4-(二甲胺基)哌啶-1-基]甲酮缩合得目标化合物,降低了生产成本,且环境更友好。本工艺路线短,原料易得,条件温和,操作简便,总收率40.1%(以2计)。
The antitumor drug gedatolisib was prepared by taking cyanuric chloride(2) as the starting material. Compound 2 reacted with morpholine in acetone/water to give 2-chloro-4,6-bis(morpholin-4-yl)-1,3,5-triazine, which was followed by a Suzuki coupling with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in the presence of Pd(PPh3)4 to afford 4-[4,6-bis(morpholin-4-yl)-1,3,5-triazine-2-yl]aniline. In this step, the amount of the catalyst Pd(PPh3)4 was reduced from 5% to 0.8%, the crude was purified by recrystallization in ethyl acetate. Then the latter was subjected to an amidation with N,N'-carbonyl diimidazole and a condensation with(4-aminophenyl)[4-(dimethylamino)-piperidin-1-yl]methanone to prepare the target compound with a total yield of 40.1%(based on 2). This process has short synthetic route, accessible materials, mild conditions and handy operations, which makes it suitables for the scale-up preparation.
The antitumor drug gedatolisib was prepared by taking cyanuric chloride(2) as the starting material. Compound 2 reacted with morpholine in acetone/water to give 2-chloro-4,6-bis(morpholin-4-yl)-1,3,5-triazine, which was followed by a Suzuki coupling with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in the presence of Pd(PPh3)4 to afford 4-[4,6-bis(morpholin-4-yl)-1,3,5-triazine-2-yl]aniline. In this step, the amount of the catalyst Pd(PPh3)4 was reduced from 5% to 0.8%, the crude was purified by recrystallization in ethyl acetate. Then the latter was subjected to an amidation with N,N'-carbonyl diimidazole and a condensation with(4-aminophenyl)[4-(dimethylamino)-piperidin-1-yl]methanone to prepare the target compound with a total yield of 40.1%(based on 2). This process has short synthetic route, accessible materials, mild conditions and handy operations, which makes it suitables for the scale-up preparation.
引文
[1]VENKATESAN A M,DEHNHARDT C M,DELOS S E,et al.Bis(morpholino-1,3,5-triazine)derivatives:potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors:discovery of compound 26(PKI-587),a highly efficacious dual inhibitor[J].J Med Chem,2010,53(6):2636-2645.
[2]GEDALY R,GALUPPO R,MUSGRAVE Y,et al.PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation[J].J Surg Res,2013,185(1):225-230.
[3]张晔,陈延峰,张丽霞,等.Gedatolisib的合成工艺改进[J].中国药物化学杂志,2017,27(4):283-287.
[4]ZHAO X,TAN Q,ZHANG Z,et al.1,3,5-Triazine inhibitors of histone deacetylases:synthesis and biological activity[J].Med Chem Res,2014,23(12):5188-5196.
[5]KHAFIZOVA G,POTOSKI J R.Process,purification and crystallization of 1-(4-{[4-(dimethylamino)piperidin-1-yl]-carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:WO,2010096619[P].2010-08-26.
[6]LIU X,ZHU G,LI L,et al.New and practical synthesis of gedatolisib[J].Org Process Res Dev,2018,22(1):62-66.
[7]KUMAR D,KHAN S I,PONNAN P,et al.Triazinepyrimidine based molecular hybrids:synthesis,docking studies and evaluation of antimalarial activity[J].New JChem,2014,38(10):5087-5095.
[8]LABORDA P,ZHAO Y,LING J,et al.Production of antifungal p-aminobenzoic acid in lysobacterantibioticus OH13[J].J Agr Food Chem,2018,66(3):630-636.
[2]GEDALY R,GALUPPO R,MUSGRAVE Y,et al.PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation[J].J Surg Res,2013,185(1):225-230.
[3]张晔,陈延峰,张丽霞,等.Gedatolisib的合成工艺改进[J].中国药物化学杂志,2017,27(4):283-287.
[4]ZHAO X,TAN Q,ZHANG Z,et al.1,3,5-Triazine inhibitors of histone deacetylases:synthesis and biological activity[J].Med Chem Res,2014,23(12):5188-5196.
[5]KHAFIZOVA G,POTOSKI J R.Process,purification and crystallization of 1-(4-{[4-(dimethylamino)piperidin-1-yl]-carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:WO,2010096619[P].2010-08-26.
[6]LIU X,ZHU G,LI L,et al.New and practical synthesis of gedatolisib[J].Org Process Res Dev,2018,22(1):62-66.
[7]KUMAR D,KHAN S I,PONNAN P,et al.Triazinepyrimidine based molecular hybrids:synthesis,docking studies and evaluation of antimalarial activity[J].New JChem,2014,38(10):5087-5095.
[8]LABORDA P,ZHAO Y,LING J,et al.Production of antifungal p-aminobenzoic acid in lysobacterantibioticus OH13[J].J Agr Food Chem,2018,66(3):630-636.