JMV-1645

合成路线: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).

合成路线: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).

合成路线:Derivative (XXIV) is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole.(Schemes 28946801d).

合成路线: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).

合成路线: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).

合成路线: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).

参考文献标题:Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists
文献作者:Amblard,M.; Bedos,P.; Olivier,C.; Daffix,I.; Luccarini,J.M.; Dodey,P.; Pruneau,D.; Paquet,J.L.; Martinez,J.
参考来源:J Med Chem 2000,43(12),2382


合成路线: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).

合成路线: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]).
参考文献标题:Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives
文献作者:Slade,J.; Mazzegna,G.C.; Ben-David,D.; Stanton,J.L.
参考来源:J Med Chem 1985,281517-1521