固-液结合法合成布舍瑞林

Synthesis of Buserelin Using Solid-liquid Combination Method

采用固-液结合法,通过4+5片段缩合合成九肽布舍瑞林。以2-Cl-Trt树脂为固相载体,分别合成四肽(p Glu-HisTrp-Ser-OH)和保护五肽(Fmoc-Tyr(Bzl)-D-Ser(But)-Leu-Arg(NO2)-Pro-OH)。保护五肽与乙胺溶液在DCC/HOBt作用下得到Fmoc-Tyr(Bzl)-D-Ser(But)-Leu-Arg(NO2)-Pro-NHEt,随后脱除Fmoc保护基和在pd/C催化作用下脱除侧链保护基得Tyr-DSer(But)-Leu-Arg-Pro-NHEt,所得五肽与四肽在HBTU/HOBT作用下合成得到九肽布舍瑞林。所得粗品经高压制备液相分离纯化得纯度98%产品,经与标准品比对和质谱分析,确证产物为布舍瑞林。

Nanopeptide buserelin was synthesized by segment condensation strategy( 4 + 5) using solid-liquid combination method. Tetrapeptide( p Glu-His-Trp-Ser-OH) and protected pentapeptide( Fmoc-Tyr( Bzl)-D-Ser( But)-Leu-Arg( NO2)-Pro-OH) were synthesized in solid phase and using 2-Cl-Trt resin as carrier. And obtained protected pentapeptide coupled with ethylamine under the action of DCC/HOBt in solution phase to give Fmoc-Tyr( Bzl)-D-Ser( But)-Leu-Arg( NO2)-Pro-NHEt. After removing Fmoc-protection group and the side chain protector under the catalysis of pd/C,the obtained pentapeptide( Tyr-D-Ser( But)-Leu-Arg-Pro-NHEt) reacted with tetrapeptide to give the target product buserelin. The purity of the obtained buserelin could reach 98% after purified by the preparation HPLC,and the structure was confirmed by mass spectroscopy and after comparing with standard product.