【药物名称】RB-360-II
化学结构式(Chemical Structure):
参考文献No.412275
标题:Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor
作者:Blommaert, A.G.S.; Dhotel, H.; Ducos, B.; Durieux, C.; Goudreau, N.; Bado, A.; Garbay, C.; Roques, B.P.
来源:J Med Chem 1997,40(5),647-658
合成路线图解说明:

8-Bromooctanoic acid (I) was treated with 2-methylpropene (II) in the presence of sulfuric acid to afford tert-butyl ester (III). Alkylation of the benzylidene derivative of glycine methyl ester (IV) with bromide (III) using lithium diisopropylamide (LDA) and hexamethylphosphoramide (HMPA) in THF at -78 C, followed by imine hydrolysis with aqueous citric acid provided the racemic aminoester (V). This was condensed with Boc-a-methyl(R)tryptophan (VI) using (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as the coupling reagent, in the presence of diisopropylethylamine (DIEA) to give the protected dipeptide (VII) as a diastereomeric mixture, and further treatment with trifluoroacetic acid in dichloromethane and anisole removed both tert-butyl groups. The resulting linear compound (VIII) was cyclized by treatment with BOP and NaHCO3 in DMF to give (IX), which was then hydrolyzed with NaOH to afford acid (X). Coupling with the dipeptide Asp(OBzl)PheNH2 (XI) yielded (XII), and the obtained benzyl ester was finally deprotected by catalytic hydrogenolysis to provide the target compound, after separation of isomers by semipreparative HPLC.

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