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PROCESS FOR THE PREPARATION OF D-ARGINYL-L-ARGINYL-L-PROLYL-L [(4R)-4-HYDROXYPROLYL]-GLYCYL-L[3-(2-THIENYL)ALANYL]-L-SERYL-D-(1,2,3,4-TETRAHYDROISOQUINOLIN-3- YLCARBONYL)-L[(3AS,7AS)-OCTAHYDROINDOL-2-YLCARBONYL]-L-ARGININE, ACETATE SALT

IP.com Disclosure Number: IPCOM000235528D
Publication Date: 2014-Mar-06
Document File: 3 page(s) / 57K

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The IP.com Prior Art Database

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  PROCESS FOR THE PREPARATION OF D-ARGINYL-L-ARGINYL-L- PROLYL-L [(4R)-4-HYDROXYPROLYL]-GLYCYL-L[3-(2- THIENYL)ALANYL]-L-SERYL-D-(1,2,3,4-TETRAHYDROISOQUINOLIN-3- YLCARBONYL)-L[(3AS,7AS)-OCTAHYDROINDOL-2-YLCARBONYL]-L-

ARGININE, ACETATE SALT

    D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]- glycyl-L[3-(2- thienyl)alanyl]-L-seryl-D-(1,2,3,4-tetrahydroisoquinolin-3- ylcarbonyl)-L[(3aS,7aS)- octahydroindol-2-ylcarbonyl]-L-arginine, acetate salt, referred as to 'Compound I', has the following structure:

For the purpose of clarity and as an aid in the understanding of the following description, the following terms and abbreviations are defined below:

DDM dodecylmercaptane

DIC N,N'-Diisopropylcarbodiimide

DIPEA diisopropylethylamine

DMF dimethylformamide

Fmoc 9-fluorenylmethoxycarbonyl

HOBt N-hydroxybenzotriazole

HPLC High Performance Liquid Chromatography

MTBE methyl-t-butyl ether

SPPS solid phase peptide synthesis

t-Bu tert-butyl

TFA trifluoroacetic acid

TBTU 2-[1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate


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Described hereinafter, is a process for the synthesis of Compound I.

The synthesis is based on sequential SPPS (solid phase peptide synthesis) technology. The synthesis is done using Fmoc chemistry and is performed on the solid support (2- Cl-Trt-chloride resin or Wang resin).

After completion of the synthesis, the peptide is cleaved from the resin with simultaneous deprotection of the side chain protecting groups. The crude peptide is purified by preparative RP-HPLC using water/acetonitrile mobile phases, followed by exchange of counterions to acetate, optional concentration on rotovapor and lyophilization to obtain final product.

The peptide is prepared from amino residues by employing Fmoc as a protecting group for the α-amino residues. Other functiona...