Study On Synthesis Of Goserelin In Liquid Phase

Goserelin is an artificial decapeptide, which derived from luteinizing hormone releasing hormone. The amino acid sequence is pGlu¹-His²-Trp³-Ser⁴-Tyr⁵ -D-Ser(But)⁶-Leu⁷-Arg⁸-Pro⁹-AzaGly¹⁰-NH₂, and it has been used in the treatment of prostate and breast cancer, hysteromyoma and so on. This drug has launched on the market in 1987, till 2008, the 1.138 billion U.S. dollars sales on the worldwide market make it"a blockbuster drug".In domestic, crude goserelin drug still can not be synthesized due to the technical reasons. Moreover, the high import price of which also restricts the exploitation of the formulations. Herein, a liquid fragments condensation synthetic route (( 2+2 ) + ( 3+3 ) = 4 + 6) was designed, as a good result, crude goserelin was obtained using natural or protected amino acids by 23 steps.(1) Synthetic to tetrapeptide pGlu-His-Trp-Ser-OMe: Dipeptide pGlu-His-OMe was synthesized from pyroglutamate and methyl L-histidinate dihydrochloride; another dipeptide Z-Trp-Ser-OMe was obtained from N-Z-L-tryptophan coupling with L-serine methyl ester hydrochloride. And which was hydrazinolysised and removed Z protecting group, respectively. Finally, titled tetrapeptide fragment was obtained through azide method in the yield of 43.1% ( based on Serine ).(2) Synthetic to hexapeptide A-Tyr(B)-D-Ser(But)-Leu-Arg(E)-Pro-AzaGly-NH2: Methyl L-leucinate hydrochloride coupled with Z-D-Ser(But)-OH, then the Z protecting group was removed to give dipeptide D-Ser(But)-leu-OMe, which reacted with A-Tyr(B)-OH to give the tripeptide. Another dipeptide Z-Pro-AzaGly-NH₂ was synthesized from Z-Pro-OH and semicarbazide hydrochloride, removal of its Z protecting group and coupled with D-Arg(E)-OH provided another protected tripeptide. The first tripeptide was saponification, and the obtained second tripeptide was deprotected the"D"group, respectively. Finally, these two tripeptides were coupled using mixed anhydride method to give title hexapeptide in an overall yield of 47.7% ( based on Leucine ).(3) Synthesis of goserelin: The tetrapeptide pGlu-His-Trp-Ser-OMe was hydrazinolysised while the hexapeptide's"A"protecting group was removed. And then the two peptide fragments coupled through azide method. Goserelin was obtained after removal of"B"and"E"protecting groups in the yield of 47.2% ( based on the hexapeptide fragment ).The structures of the key intermediates and the target goserelin in this work were determined by nuclear magnetic resonance spectra (NMR) and mass spectrometry (MS).