| 摘要 |
PURPOSE: Conventional methods for producing N-methyl-D-phenylalanyl-N-£1-£3-££bisamino|methylene|amino|propyl|-3,3-difluorO-2-oxohexyl|-L-prolineamide, have difficulties in producing 4-guanyl-1-nitrobutane intermediate in process of using proper nitro intermediate. And hydrolyzed nitrite should be separated from nitrobutylphthalimide, and excessive hydrazine should be removed from phthaloimido group. Also the obtainment of suitable purity is difficult and many chromatography purification is required during synthesizing process. CONSTITUTION: A producing method of N-methyl-D-phenylalanyl-N-£1-£3-£(aminoiminomethyl)amino|propyl| comprises the steps of:(1) providing N-9-£1-£3-£bisamino|methylene|amino|-6-amino-5-hydroxy-4,4 -difluorononan by reacting 9,6-siamino-5-hydroxy-4,4-difluorononan or its pharmaceutically allowable salt with proper guanylating agent, (2) providing N-K2-protected-N-methyl-D-phenylalanyl-N-£1-£3-££bisamino|methylene|amino|propyl|-3,3-difluorO-2-hydroxyhexyl|-L-prolineamide by coupling the material of step (1) with N-K2-protected-N-methyl-D-phenylalanyl-L-prolineamide, (3) providing N-K2-protected-N-methyl-D-phenylalanyl-N-£1-£3-££bisamino|methylene|amino|propyl|-3,3-difluorO-2-oxohexyl|-L-prolineamide by reacting the material of step (2) with proper oxidizer, and (4) providing N-methyl-D-phenylalanyl-N-£1-£3-££bisamino|methylene|amino|propyl|-3,3-difluorO-2-oxohexyl|-L-prolineamide or its pharmaceutically allowable salt by deprotecting the material of step (3) with proper deprotecting agent.
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