Process for preparing the releasing hormone of luteinizing hormone(lh)and of follicle stimulating hormone(fsh),salts and compositions thereof,and intermediates therefor

Abstract

Abstract A PROCESS FOR PREPARING THE LH- AND FSH-RELEASING HORMONE OF THE FORMULA I H-PYR-HIS-TRP-SER:TYR-GLY-LEU-ARG-PRO-GLY-NH2 WHICH COMPRISES THE FOLLOWING STEPS: CONDENSING N-(5OXO-L-PROPLYL)-L-HISTIDINE HYDRAZIDE BY MEANS OF THE AZIDE METHOD WITH L-TRYPTOPHAN BENZYL ESTER AND TREATING THE RESULTING COMPOUND WITH HYDRAZINE HYDRATE TO OBTAIN N(N-(5-OXO-L-PROPYL) - L-HISTIDYL)-L-TRYPTOPHAN HYDRAZIDE (II): TREATING N-(O-BENZYL-N-CARBOXY-L-TYROSYL)GLYCINE N-BENZYL ESTER WITH ETHYL CHLOROFORMATE TO OBTAIN THE CORRESPONDING MIXED ANHYDRIDE WHICH IS REACTED WITH TBUTYL CARBAZATE TO OBTAIN THE CORRESPONDING 2-CARBOXYHYDRAZIDE T-BUTYL ESTER WHICH IS HYDROGENOLYZED TO N-LTYROSYLGLYCINE 2-CARBOXYHYDRAZIDE T-BUTYL ESTER, AND CONDENSING THE LATER WITH N-CARBOXY-L-SERYL N-BENZYL ESTER 2,4-DINITROPHENYL ESTER FOLLOWED BY HYDROGENOLYSIS OF THE REACTION PRODUCT TO OBTAIN N-(N-L-SERYL-L-TYROSYL) GLYCINE 2-CARBOXYHYDRAZIDE T-BUTYL ESTER (III); CONDENSING N-CARBOXY-L-PROLINE N-BENZYL ESTER WITH GLYCINE ETHYL ESTER IN THE PRESENCE OF DICYCLOHEXLCARBODIIMIDE, TREATIN THE RESULTING PRODUCT WITH AMMONIA AND THEN HYDROGENOLYZING, TO OBTAIN 2-((L-PROPYL)AMINO)ACETAMIDE, WHICH IS CONDENSED WITH N-CARBOXY-NG-NITRO-L-ARGININE N-T-BUTYL ESTER IN THE PRESENCE OF DICYCLOHEXYLCARBODIIMIDE AND N-HYDROXYSUCCINIMIDE TO OBTAIN N-(N-(N-CARBOXY-NG-NITRO-L-ARGINYL)-L-PROPYL)GLYCINAMIDE N-T-BUTYLESTER (IV ; OR ALTERNATIVELY CONDENSING L-PROLINE METHYL ESTER WITH N-CARBOXY-NG-NITRO-ARGININE N-T-BUTYL ESTER IN THE PRESENCE OF DICYCLOHEXYLCARBODIIMIDE, CONDENSING THE RESULTING PRODUCT WITH GLYCINE ETHYL ESTER IN THE PRESENCE OF DICYCLOHEXYLCARBODIIMIDE, AND TREATING THE RESULTING PRODUCT WITH AMMONIA TO OBTAIN THE SAME COMPOUND IV AS ABOVE; TREATING SAID COMPOUND IV WITH ACID AND THEN WITH N-CARBOXY-L-LEUCINE N-BENZYL ESTER 2,4,5-TRICHLOROPHENYL ESTER AND HYDROGENOLYZING THE RESULTING PRODUCT IN ACETIC ACID, TO OBTAIN N-(N-(N-(N-L-LEUCYL)-L-ARGINYL)-L-PROPLYL)GLYCINAMIDE DIACETATE (V); CONDENSING COMPOUND II WITH COMPOUND III BY MEANS OF THE AZIDE METHOD TO OBTAIN THE HEXAPEPTIDE N-(N-(N-(N-(N-(5 OXO-L-PROLYL)-L-HISTIDYL)-L-TRYPTOPHYL)-L - SERYL)-L-TYROSLY)GLYCINE 2-CARBOXYHYDRAZIDE T-BUTYL ESTER, OR CONDENSING N-(N-(5= OXO-L-PROPLYL)-L-HISTIDYL)-L-TRYPTOPHAN WITH COMPOUND III IN THE PRESENCE OF DICYCLOHEXYLCARBODIIMIDE TO OBTAIN THE SAME HEXAPEPTIDE AS ABOVE, AND DEPROTECTING AND COONVERTING THE LATTER TO ITS TRIFLUOROACETATE SALT (IV); AND CONDENSING COMPOUND V WITH COMPOUND VI BY MEANS OOF THE AZIDE METHOD, TO OBTAIN THE DECAPEPTIDE OF FORMULA I WHICH IS ISOLATED AS THE SALT AND OPTIONALLY CONVERTED TO OTHER PHARMACEUTICALLY ACCEPTABLE SALTS.

Inventors

• 👤 M Goetz
• 👤 H Immer
• 👤 V Nelson

Bibliographic Details