YM-47142

Chemical Name: [3R-(3alpha,6beta,9beta,17alpha,18alpha)]-6-(Carbamoylmethyl)-9,14-diisobutyl-3,18-dimethyl-17-(3-methylbutyryl-L-phenylalanyl-L-threonylamino)-1-oxa-4,7,10,15-tetraazacyclooctadecane-2,5,8,11,12,13,16-heptaone
项目整合开发状态: Biological Testing
项目研究机构: Yamanouchi (Originator)
合成路线:Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III),which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV).After treatment of (IV) with Et3N,the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI).Acid deprotection of the N-Boc group of (VI) provided amine (VII),which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX).Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF,and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI).After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI),treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).

合成路线:The tert-butoxycarbonyl and 4,4'-dimethoxybenzhydryl groups of (XII) were then deprotected using trifluoroacetic acid,and the resulting compound (XIII) was coupled with the phenylacetyl dipeptide (XIV) to form (XV).Finally,the phosphorus ylide of (XV) was transformed to the desired carbonyl function by means of ozonolytic cleavage of the C=P double bond.

合成路线:Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III),which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV).After treatment of (IV) with Et3N,the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI).Acid deprotection of the N-Boc group of (VI) provided amine (VII),which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX).Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF,and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI).After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI),treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).

合成路线:The tert-butoxycarbonyl and 4,4'-dimethoxybenzhydryl groups of (XII) were then deprotected using trifluoroacetic acid,and the resulting compound (XIII) was coupled with the isovaleryl dipeptide (XIV) to form (XV).Finally,the phosphorus ylide of (XV) was transformed to the desired carbonyl function by means of ozonolytic cleavage of the C=P double bond.