Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in HOAc, followed by the introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH(XVI), Boc-Hyp-OH(XVIII) and Boc-Pro-OH(XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28946801b).
The peptidic chain is elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Arg(Tos)-OH (XXII), Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXIV). (Scheme 28946801c).
Derivative (XXIV) is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole. (Schemes 28946801d).
Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH (XVI), Boc-Hyp-OH (XVIII) and Boc-Pro-OH (XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28947001b).
The peptidic chain is elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc Arg(Tos)-OH (XXII), and Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXV)(Scheme 28947001c).
The peptidic chain is elongated by deprotection with TFA/EDT and coupling of protected amino acid (Boc-Lys(COOCH2Ph)-OH (XXIV)) with BOP/DIEA, providing derivative (XXVI), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (Scheme 28947001d).
Synthesis of EN 290154: Cleavage of both the Fmoc protecting group and ethyl ester of (XV) by means of HBr in HOAc followed by Boc protection affords (XVI) which is then anchored to a chloromethylated resin to yield (XVII). Deprotection of dihydro-benzothiazepinone (XVII) with TFA in presence of ethanedithiol, followed by coupling with Boc-Ser-OH by means of BOP/DIEA in CH2Cl2, yields derivative (XVIII). Deprotection of (XVIIII) followed by coupling with intermediate (XIV) in the same conditions described for (XVII) affords derivative (XIX). Next steps include sequencial Boc removal and coupling with Boc-Arg(Tos)-OH and then Boc-Lys(Fmoc)-OH. Finally the product is cleaved from the resin by means of HF/anisole.
o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).
Aromatic nucleophilic substitution of o-fluoronitrobenzene (I) with N-Ac-cysteine (II) in EtOH in the presence of NaHCO3 yields (III). Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (1) (Scheme 28947001a). Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH, Boc-Gly-OH, Boc-Hyp-OH, Boc-Pro-OH, Boc Arg(Tos)-OH, Boc-Lys(COOCH2Ph)-OH (x2)) with BOP/DIEA, providing derivative (XIV), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (2,3) (Scheme 28947001[b-d]).