新产品编号:2079257

Chemical Name: N12-Hydroxy-N8-[2-(4-morpholinyl)-2-oxoethyl]-2,10-dioxo-11(R)-[2'-(trifluoromethyl)biphenyl-4-ylmethyl]-1-oxa-3,9-diazacyclopentadecane-8(S),12(S)-dicarboxamide
项目整合开发状态: Biological Testing
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:Esterification of 3-(4-hydroxyphenyl)propionic acid (I),followed by alkylation of the phenolic hydroxyl,provided methyl 3-(4-benzyloxyphenyl)propionate (II),which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH.Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V),which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI),yielding (VII).Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII).Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X).The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI).Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII).This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).

合成路线:Condensation of carbonate (XIV) with N-alpha-Cbz-lysine methyl ester (XV) afforded the carbamate (XVI).The benzyl ester and N-Cbz protecting groups of (XVI) were then removed by catalytic hydrogenolysis,yielding amino acid (XVII),which was subjected to intramolecular cyclization in the presence of BOP to furnish the macrocyclic compound (XVIII).After conversion of the phenolic hydroxyl of (XVIII) to the aryl triflate (XIX),Suzuki coupling with 2-(trifluoromethyl)phenylboronic acid (XX) provided the biphenyl derivative (XXI).

合成路线:Saponification of the methyl ester (XXI) using LiOH gave the carboxylic acid (XXII).This was coupled with the glycine amide (XXIII) to produce adduct (XXIV).The desired hydroxamic acid was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XXIV),followed by coupling of the resulting carboxylic acid (XXV) with hydroxylamine.