| 摘要 |
Preparation of N-acetyl- (L)-p-amidinophenylalanine cyclohexylglycine-~b-(3-N-methylpyridinium)-alanine (Ac-(L)-pAph- Chg-PalMe(3)-NH2) (I) or its salt, comprises: (a) reacting N-acetyl-(D,L)-4-cyanophenylalanine ethyl ester in an aqueous solution with acetonitrile and subtilisin, maintaining pH appropriately, to form N-acetyl-(L)-4 cyanophenylalanine (III); (b) coupling (III) with compound (IV) and (c) converting cyano group thus obtained compound into amidino and methylating the nitrogen or pyridyl to give (I). Step (a) is also claimed per se. In step (a), the aqueous solution comprises 10-15vol.% of 1M solution of an inorganic salt, preferably KCl. The amount of acetonitrile is 5-95 (preferably 50-60) vol.% of the aqueous solution. The amount of subtilisin is 0.5-10 mEquivs. by wt. of the amount of (I). pH is adjusted and maintained at 5-9 (preferably 6.5-7.5) using a base, preferably NaOH, or phosphate buffer, and the mixture is stirred for 15 minutes to 4 hours. Compound (III) may be isolated from the reaction medium. |
