JMV-1609

Chemical Name: N-[2-[3(S)-[D-Arginyl-L-arginyl-L-prolyl-L-[4(R)-hydroxy]prolyl-glycyl-L-(2-thienyl)alanyl-L-serylamino]-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl]acetyl]-L-arginine
项目整合开发状态: Biological Testing
项目研究机构: Fournier (Originator)
合成路线:Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III).After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid,the resulting amine (IV) was protected as the benzyl carbamate (V).Reduction of the nitro group of (V) provided amino acid (VI),which was cyclized to the benzothiazepinone (VII) using EDC.Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1).Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH,followed by introduction of the N-Boc group afforded intermediate (X) (2).Optionally,hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI).This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII).Then,basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).

合成路线:An alternative access to intermediate (XX) consisted in coupling of arginine-resin (XVI) with building block (XIV) by means of BOP reagent,followed by trifluoroacetic acid deprotection of the Boc group.

合成路线:Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI),N-Boc-glycine (XXIII),N-Boc-4-hydroxyproline (XXV),N-Boc-proline (XXVII),Nalpha-Boc-Ngamma-tosyl-arginine (XXIX) and Nalpha-Boc-Ngamma-nitro-D-arginine (XXXI) to produce peptide resins (XXII),(XXIV),(XXVI),(XXVIII),(XXX) and (XXXII),respectively.The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

合成路线:Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI),N-Boc-glycine (XXIII),N-Boc-4-hydroxyproline (XXV),N-Boc-proline (XXVII),Nalpha-Boc-NG-tosyl-arginine (XXIX) and Nalpha-Boc-NG-nitro-D-arginine (XXXI) to produce peptide resins (XXII),(XXIV),(XXVI),(XXVIII),(XXX) and (XXXII),respectively.The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.