新产品编号:1011407
Chemical Name: 1-[2-[2,2-Bis(3-methyl-2-thienyl)vinyloxy]ethyl]piperidine-3(R)-carboxylic acid
项目整合开发状态: Preclinical
项目研究机构: Novo Nordisk (Originator)
合成路线:Treatment of 2-(trityloxy)ethanol (I) with bromoacetic acid (II) and n-BuLi in THF affords ethoxyacetic acid derivative (III),which is then converted into ethyl ester (IV) by means of EtOH and DCC in CH2Cl2 in the presence of 4-pyrrolidinopyridine.Reaction of (IV) with Grignard reagent,prepared from 2-bromo-3-methylthiophene (V) and Mg turnings in THF,provides compound (VI),which is then converted into the corresponding tosylate derivative (VII) by treatment with BuLi and p-toluenesulfonyl chloride (p-TsCl) in toluene.Reaction of (VII) with (R)-ethyl nipecotate (VIII) and K2CO3 yields ethyl ester (IX),which is finally hydrolyzed with aqueous NaOH in EtOH followed by treatment with diluted HCl.
📌 参考资料/链接：
参考文献标题:Novel N-substd.azaheterocyclic carboxylic acids
文献作者:Knutsen,L.J.S.; Jorgensen,A.S.; Andersen,K.E.; Sonnewald,U.(Novo Nordisk A/S)
参考来源:EP 0374801; JP 1990223551; US 5071859; US 5214057
📄 详细内容
合成路线:Treatment of 2-(trityloxy)ethanol (I) with bromoacetic acid (II) and n-BuLi in THF affords ethoxyacetic acid derivative (III),which is then converted into ethyl ester (IV) by means of EtOH and DCC in CH2Cl2 in the presence of 4-pyrrolidinopyridine.Reaction of (IV) with Grignard reagent,prepared from 2-bromo-3-methylthiophene (V) and Mg turnings in THF,provides compound (VI),which is then converted into the corresponding tosylate derivative (VII) by treatment with BuLi and p-toluenesulfonyl chloride (p-TsCl) in toluene.Reaction of (VII) with (R)-ethyl nipecotate (VIII) and K2CO3 yields ethyl ester (IX),which is finally hydrolyzed with aqueous NaOH in EtOH followed by treatment with diluted HCl.
参考文献标题:Synthesis of novel GABA uptake inhibitors.3.Diaryloximine and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents
文献作者:Knutsen,L.J.S.; Andersen,K.E.; Lau,J.; Lundt,B.F.; Henry,R.F.; Morton,H.E.; Naerum,L.; Petersen,H.; Stephensen,H.; Suzdak,P.D.; Swedberg,M.D.; Thomsen,C.; Sorensen,P.O.
参考来源:J Med Chem 1999,42(18),3447