Phortress, 5F-DF-203-L-lysinamide, NSC-710305
(2S)-2,6-二氨基-N-[4-(5-氟-1,3-苯并噻唑-2-基)-2-甲基苯基]己酰胺二盐酸盐Chemical Name: N1-[4-(5-Fluorobenzothiazol-2-yl)-2-methylphenyl]-L-lysinamide dihydrochloride
CAS No. 328087-38-3
项目整合开发状态: Preclinical
项目研究机构: University of Nottingham (Originator), Cancer Research UK (Codevelopment)
合成路线:The reaction of 5-fluorobenzothiazol-2-amine (I) with KOH in refluxing water gives the disulfide (II),which is treated with 3-methyl-4-nitrobenzoyl chloride (III) in refluxing pyridine to yield the bis-benzamide (IV).Finally,this compound is reductively cyclized by reaction with SnCl2 and HCl in ethanol/water to afford the target aminophenyl benzothiazole.
合成路线:Synthesis of intermediate (VII): Conversion of 3-fluoroaniline (I) into 2-amino-5-fluorobenzothiazole (III) can be achieved by first coupling with isocyanate (II) followed by hydrolysis with NaOH,reaction with Br2 and finally heating treatment.Dimerization of substituted benzothiazole (III) by means of refluxing aqueous KOH yields disulfide derivative (IV),which is then condensed with substituted benzoyl chloride (V) in refluxing pyridine to afford derivative (VI).Finally,(VI) is converted into intermediate (VII) by treatment with SnCl2 dihydrate in refluxing HCl/EtOH.Alternatively,intermediate (VII) can be synthesized as follows: substituted aniline (VIII) is first brominated via a Sandmeyer reaction with NaNO2 in HBr and CuBr,and then the nitro group is reduced with SnCl2 in refluxing EtOH to provide derivative (IX).Condensation of (IX) with substituted benzoyl chloride (V) in refluxing pyridine yields amide (X),which is then first treated with Lawesson's reagent and HMPA and then with NaH in NMP to afford benzothiazole derivative (XI).Finally,the nitro group of (XI) is reduced with SnCl2 in refluxing EtOH to yield intermediate (VII).Synthesis of EN 295753: The desired compound can finally be obtained by coupling of intermediate (VII) with Boc-Lys(Boc)-OH (XII) by means of carbodiimide WSC.HCl and HOBt in CH2Cl2,followed by Boc removal with HCl (gas) in CH2Cl2.
📌 参考资料/链接：
参考文献标题:Substd.2-arylbenzazole cpds.and their use as antitumour agents
文献作者:Chua,M.-S.; Westwell,A.D.; Hutchinson,I.P.; Stevens,M.F.G.; Poole,T.D.(Cancer Research Campaign Technology Ltd.)
参考来源:WO 0114354
📄 详细内容
合成路线:Synthesis of intermediate (VII): Conversion of 3-fluoroaniline (I) into 2-amino-5-fluorobenzothiazole (III) can be achieved by first coupling with isocyanate (II) followed by hydrolysis with NaOH,reaction with Br2 and finally heating treatment.Dimerization of substituted benzothiazole (III) by means of refluxing aqueous KOH yields disulfide derivative (IV),which is then condensed with substituted benzoyl chloride (V) in refluxing pyridine to afford derivative (VI).Finally,(VI) is converted into intermediate (VII) by treatment with SnCl2 dihydrate in refluxing HCl/EtOH.Alternatively,intermediate (VII) can be synthesized as follows: substituted aniline (VIII) is first brominated via a Sandmeyer reaction with NaNO2 in HBr and CuBr,and then the nitro group is reduced with SnCl2 in refluxing EtOH to provide derivative (IX).Condensation of (IX) with substituted benzoyl chloride (V) in refluxing pyridine yields amide (X),which is then first treated with Lawesson's reagent and HMPA and then with NaH in NMP to afford benzothiazole derivative (XI).Finally,the nitro group of (XI) is reduced with SnCl2 in refluxing EtOH to yield intermediate (VII).Synthesis of EN 295753: The desired compound can finally be obtained by coupling of intermediate (VII) with Boc-Lys(Boc)-OH (XII) by means of carbodiimide WSC.HCl and HOBt in CH2Cl2,followed by Boc removal with HCl (gas) in CH2Cl2.
参考文献标题:Antitumor benzothiazoles.16.Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid produgs
文献作者:Hutchinson,I.; Jennings,S.A.; Vishnuvajjala,B.R.; Westwell,A.D.; Stevens,M.F.
参考来源:J Med Chem 2002,45(3),744
产品链接: CAS No. 328087-38-3››