E-6123
4H-吡啶[4',3':4,5]噻吩[3,2-f][1,2,4]三唑并[4,3-a]Chemical Name: (+)-6-(2-Chlorophenyl)-9-(cyclopropylcarbonyl)-1,4(S)-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
CAS No. 131614-02-3
项目整合开发状态: Phase II
项目研究机构: Eisai (Originator)
合成路线:1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II).Treatment of (II) with 2-bromopropionyl bromide gives the amide (III),which on reaction with ammonia gives the amine (IV).Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V).Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI),which is reacted with acetic hydrazide to give the triazole (VII).Basic hydrolysis of the amide of (VII) produces the amine (VIII),which is resolved to give the S-enantiomer (IX).Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).
📌 参考资料/链接：
参考文献标题:1,4-Diazepine deriv.and its pharmaceutical use
文献作者:Okano,K.; Miyazawa,S.; Clark,R.S.J.; Abe,S.; Kawahara,T.; Shimomura,N.; Asano,O.; Yoshimura,H.; Miyamoto,M.; Sakuma,Y.; Muramoto,K.; Obaishi,H.; Harada,K.; Tsunoda,H.; Katayama,S.; Yamada,K.; Souda,S.; et al.(Eisai Co.,Ltd.)
参考来源:AU 8943761; EP 0367110; EP 0606103; EP 0677524; JP 1990256682; US 5221671; US 5304553; US 5382579; US 5409909; US 5438045; US 5468740; US 5482937
📄 详细内容
合成路线:1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II).Treatment of (II) with 2-bromopropionyl bromide gives the amide (III),which on reaction with ammonia gives the amine (IV).Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V).Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI),which is reacted with acetic hydrazide to give the triazole (VII).Basic hydrolysis of the amide of (VII) produces the amine (VIII),which is resolved to give the S-enantiomer (IX).Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).
参考文献标题:E6123
文献作者:Clark,R.S.J.
参考来源:Drugs Fut 1991,16(4),310
合成路线:A large-scale production method (kg scale) for E-6123 has been reported: The optical resolution of racemic 6-(2-chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (I),prepared by the previously reported method,by crystallization of its salt with (+)-(D)-dibenzoyltartaric acid in ethanol and treatment with aqueous NaHCO3 gives the corresponding (S)-isomer (II),which is then acylated with cyclopropanecarbonyl chloride (III) and pyridine in dichloromethane.
参考文献标题:A practical synthesis of optically active platelet-activating factor antagonist,E6123,and its absolute configuration
文献作者:Miyazawa,S.; Shimomura,N.; Okano,K.; et al.
参考来源:Chem Pharm Bull 1992,40(2),521
产品链接: CAS No. 131614-02-3››