Glaspimod, HP-5 dimer, SK&F-107647

(S)-5-氧代-L-脯氨酰-L-alpha-谷氨酰-L-alpha-天冬氨酰-N8-(5-氨基-1-羧基戊基)-8-氧代-N7-(N-(N-(5-氧代-L-脯氨酰)-L-alpha-谷氨酰)-L-alpha-天冬氨酰)-2,7,8-三氨基辛酰-L-赖氨酸Chemical Name: (2S,7S)-N2,N2'-[2,7-Bis(pyroglutamyl-glutamyl-aspartylamino)octanedioyl]bis(lysine)
CAS No. 134143-28-5
项目整合开发状态: Phase II
项目研究机构: Amersham Health (Originator), GlaxoSmithKline (Originator)
合成路线:The Kolbe electrolysis of N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-benzyl ester (I) gives 2(S),7(S)-bis(tert-butoxycarbonylamino)octanedioic acid dibenzyl ester (II),which is debenzylated with H2 over Pd/C in methanol yielding the free acid (III).The condensation of diacid (III) with N6-(benzyloxycarbonyl)-L-lysine benzyl ester (IV) affords the tripeptide (V),which is then treated with HCl in dioxane to eliminate the carbamate protecting groups so providing intermediate (VI).

合成路线:The esterification of N-(benzyloxycarbonyl)-L-aspartic acid 4-O-benzyl monoester (VII) with 2-(p-toluenesulfonyl)ethanol by means of DCC and pyridine gives the mixed diester (VIII),which is deprotected at the amino group with HCl in dioxane yielding compound (IX).The condensation of (IX) with protected glutamic acid (X) by means of HOBt,DIEA and WSC carbodiimide affords dipeptide (XI),which is deprotected with HCl as before giving (XII).The condensation of (XII) with pyroglutamic acid (XIII) as before yields tripeptide (XIV),which is deprotected at the terminal carboxy group by means of diazabicyclo[4.3.0]non-5-ene (DBN) providing tripeptide (XV).

合成路线:The condensation of tripeptide (XV) with intermediate tripeptide (VI) by means of TDBTU and DIEA in DMF gives the fully benzylated target compound,which is finally deprotected with H2 over Pd/C in DMF/AcOH.