PD-173212

N-[[4-叔丁基苯基]甲基]-N-甲基-L-亮氨酰-N-叔丁基-O-苄基-L-酪氨酰胺Chemical Name: N-(4-tert-Butylbenzyl)-N-methyl-L-leucyl-4-O-(benzyl)-L-tyrosine tert-butylamide
CAS No. 217171-01-2
项目整合开发状态: Preclinical
项目研究机构: Elan (Originator), Pfizer (Originator)
合成路线:Coupling of N-Boc-O-benzyl-L-tyrosine (I) with tert-butylamine by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) afforded amide (II).Subsequent acid cleavage of the Boc group of (II) gave O-benzyltyrosine tert-butyl amide (III).

合成路线:N-Methyl-L-leucine (IV) was converted to tert-butyl ester (V) by treatment with isobutylene and H2SO4.Formation of the N,N-dialkyl derivative (VIII) was achieved by either alkylation of (V) with p-tert-butylbenzyl bromide (VI) or by reductive condensation of (V) with p-tert-butylbenzaldehyde (VII) and NaBH(OAc)3.Deprotection of the tert-butyl ester of (VIII) with trifluoroacetic acid gave amino acid (IX),which was activated as the mixed anhydride (X) upon treatment with isobutyl chloroformate and a polymer-supported morpholine base.Coupling of (X) with tyrosine amide (III) then afforded the title dipeptide amide.Unreacted starting materials were captured by the addition of polymer-supported polyamine and isocyanate resins.

合成路线:The precursor amino acid derivatives were obtained as follows:The condensation of N-Boc-O-benzyltyrosine (I) with tert-butylamine using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) gave amide (II).Subsequent deprotection of the Boc group of (II) by means of trifluoroacetic acid provided O-benzyltyrosine tert-butyl amide (III).N-Methyl leucine benzyl ester (IV) was alkylated with 3-bromocyclohexene (V),yielding the cyclohexenyl amine (VI).Hydrogenation of the olefinic double bond of (VI) with concomitant benzyl ester hydrogenolysis in the presence of Pd/C furnished N-cyclohexyl-N-methylleucine (VII).The title dipeptide was finally obtained by HBTU-promoted coupling of amino acids (III) and (VII).

合成路线:Alternatively,the compound was prepared using polymer-supported resins.Dialkyl leucine (VII) was first treated with isobutyl chloroformate and morpholine resin,tyrosine derivative (III) was added,and was then treated with isocyanate resin and tris(2-aminomethyl)amine resin.Filtration of the insoluble resins provided a solution of pure dipeptide derivative.