RGD-891
N-乙基-N-[4-(4-哌啶)丁烯酰]-甘基-L-蒺氨酸-L-(3-环己基)阿拉尼酰胺Chemical Name: N-Ethyl-N-[4-(4-piperidyl)butyryl]-glycyl-L-aspartyl-L-(3-cyclohexyl)alaninamide
CAS No. 169512-56-5, 194933-81-8 (monotrifluoroacetate)
项目整合开发状态: Phase I
项目研究机构: Aventis Pharma (Originator)
合成路线:Treatment of N-Boc-beta cyclohexylalanine (I) in THF with Et3N,isobutyl chloroformate (IBCF) and NH3/MeOH,followed by reaction with HCl gas,yields beta-cyclohexyl alaninamide hydrochloride (II).Amino acid (II) is then converted into dipeptide (IV) by first coupling with protected L-aspartic acid (III) by means of isopropyl chloroformate (IPCF) and N-methyl piperidine (A) in CH2Cl2,followed by Boc removal with TFA in CH2Cl2.Condensation of (IV) with Boc-protected N-ethylglycine (V) and successive Boc removal are performed under the same conditions as for the synthesis of (IV) to furnish tripeptide (VI).Then (VI) is coupled to carboxylic acid (VII) by means BOPCl and Et3N in CH2Cl2 to afford intermediate (VIII).Finally the target compound is obtained by debenzylation of (VIII) with H2 over Pd/C in MeOH/AcOH,followed by Boc removal with TFA in CH2Cl2.
合成路线:Intermediate (VII) can be obtained by following two different pathways:1.Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X),which is then protected with Boc2O and NaOH in THF to yield (XI).Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII),which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2,followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM),to provide crotonate (XIV).Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV),which is finally hydrolyzed with NaOH in MeOH.2.Alternatively,intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII),which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX).Finally,(XIX) is protected by reaction with Boc2O and NaOH in THF.
📌 参考资料/链接：
参考文献标题:Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
文献作者:Klein,S.I.; Molino,B.F.(Aventis Pharma SA)
参考来源:EP 0812205; JP 1997507213; US 5866685; WO 9510295
📄 详细内容
合成路线:Treatment of N-Boc-beta cyclohexylalanine (I) in THF with Et3N,isobutyl chloroformate (IBCF) and NH3/MeOH,followed by reaction with HCl gas,yields beta-cyclohexyl alaninamide hydrochloride (II).Amino acid (II) is then converted into dipeptide (IV) by first coupling with protected L-aspartic acid (III) by means of isopropyl chloroformate (IPCF) and N-methyl piperidine (A) in CH2Cl2,followed by Boc removal with TFA in CH2Cl2.Condensation of (IV) with Boc-protected N-ethylglycine (V) and successive Boc removal are performed under the same conditions as for the synthesis of (IV) to furnish tripeptide (VI).Then (VI) is coupled to carboxylic acid (VII) by means BOPCl and Et3N in CH2Cl2 to afford intermediate (VIII).Finally the target compound is obtained by debenzylation of (VIII) with H2 over Pd/C in MeOH/AcOH,followed by Boc removal with TFA in CH2Cl2.
合成路线:Intermediate (VII) can be obtained by following two different pathways:1.Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X),which is then protected with Boc2O and NaOH in THF to yield (XI).Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII),which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2,followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM),to provide crotonate (XIV).Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV),which is finally hydrolyzed with NaOH in MeOH.2.Alternatively,intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII),which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX).Finally,(XIX) is protected by reaction with Boc2O and NaOH in THF.
参考文献标题:Design of a new class of orally active fibrinogen receptor antagonists
文献作者:Klein,S.I.; Molino,B.F.; Czekaj,M.; Gardner,C.J.; Chu,V.; Brown,K.; Sabatino,R.D.; Bostwick,J.S.; Kasiewski,C.; Bentley,R.; Windisch,V.; Perrone,M.H.; Dunwiddie,C.T.; Leadley,R.J.
参考来源:J Med Chem 1998,41(14),2492
产品链接: CAS No. 169512-56-5››