BB-3497

Chemical Name: N2-[2(R)-(N-Formyl-N-hydroxyaminomethyl)hexanoyl]-N1,N1-dimethyl-L-tert-leucinamide; 2(R)-Butyl-N-formyl-N-hydroxy-beta-alanyl-N,N,3-trimethyl-L-valinamide
CAS No. 235784-88-0
项目整合开发状态: Preclinical
项目研究机构: Vernalis (Originator)
合成路线:Claisen reaction between ethyl caproate (I) and ethyl formate (II) in the presence of NaOEt affords formyl derivative (III),which is then condensed with O-benzyl hydroxylamine hydrochloride (IV) by means of NaOAc in EtOH/H2O to yield derivative (V).Hydrolysis of the ethyl ester moiety of (V) by treatment with aqueous NaOH in MeOH provides carboxylic acid (VI),which is coupled to tert-leucine N,N-dimethylamide (VII) by means of EDC and HOAt to furnish compound (VIII).Reduction of the oxime moiety of (VIII) with NaCNBH3 in HOAc affords a mixture of diastereoisomers from which (R)-(IX) is separated by flash chromatography.Finally,treatment of (R)-(IX) with N-formyl-benzotriazole (HCOBt) in THF provides formamide (X),whose benzyl group is then removed by hydrogenation over Pd/C in MeOH.

合成路线:Alternatively,compound (R)-(IX) can be obtained as follows: treatment of butylmalonic acid (XI) with formaldehyde (XII) in ethanol in the presence of piperidine provides 2-butyl acrylic acid (XIII),which is converted into oxazolidinone derivative (XVI) by first reaction with pivaloyl chloride (XIV) and Et3N in THF followed by treatment with derivative (XV) and BuLi in THF.Oxazolidinone (XVI) is then enantioselectively condensed with O-benzylhydroxylamine (XVII) and treated with p-TsOH to afford a single diastereoisomer (XVIII),which is then hydrolyzed with LiOH in THF to yield (XIX).Finally,hexanoic acid (XIX) is coupled to tert-Leucine-N,N-dimethylamide (VII) by means of EDC and HOBt in DMF.