新产品编号:1982755
Chemical Name: [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-12b-Acetoxy-12-benzoyloxy-9-[3-(tert-butoxycarbonylamino)-2-hydroxy-3-phenylpropionyloxy]-11-hydroxy-4-methoxy-4a,8,13,13-tetramethyl-6-[2-(4-morpholinyl)ethyl]-2a,3,4,4a,5,
项目整合开发状态: Preclinical
项目研究机构: Daiichi Pharmaceutical (Originator)
合成路线:Tosylation of the primary hydroxyl group of (I) affords tosylate (II),which is then subjected to reaction with MeSNa and tetrabutylammonium iodide (n-Bu4NI) in THF followed by oxidation with NaIO4 in MeOH/H2O to provide sulfoxide (III).Derivative (III) is then heated with K2CO3 in 1,2-dichlorobenzene to yield olefin (IV),which is subjected to reaction with triethylsilyl chloride (TESCl) and imidazole in DMF to give the disilylated compound (V).Derivative (V) is then subjected to a Johnson-Remeiux reaction by first treatment with OsO4 and NMO in MeOH/THF/H2O followed by oxidation with NaIO4 in MeOH/THF/H2O to afford aldehyde (VI),which is then reduced by means of NaBH4 in MeOH to furnish alcohol (VII).Reaction between (VII) and morpholine (VIII) in refluxing MeOH affords baccatin III derivative (IX) (1),which is treated with TsOH in MeOH and then with acetic anhydride and DMSO to yield compound (X).Desulfurylation of (X) by refluxing with Raney-Ni in EtOH followed by removal of the TES protecting group by reaction with HF-pyridine affords intermediate (XI),which is finally converted into the desired compound by introduction of the phenylisoserine side-chain using protected beta-lactam (XII) and NaHMDS in THF followed by TBS removal by treatment with HF-pyridine.
📌 参考资料/链接：
参考文献标题:Orally active docetaxel analogue: Synthesis of 10-deoxy-10-C-morpholinoethyl docetaxel analogues
文献作者:Iimura,S.; Uoto,K.; Ohsuki,S.; Chiba,J.; Yoshino,T.; Iwahana,M.; Jimbo,T.; Terasawa,H.; Soga,T.
参考来源:Bioorg Med Chem Lett 2001,11(3),407
📄 详细内容
合成路线:Tosylation of the primary hydroxyl group of (I) affords tosylate (II),which is then subjected to reaction with MeSNa and tetrabutylammonium iodide (n-Bu4NI) in THF followed by oxidation with NaIO4 in MeOH/H2O to provide sulfoxide (III).Derivative (III) is then heated with K2CO3 in 1,2-dichlorobenzene to yield olefin (IV),which is subjected to reaction with triethylsilyl chloride (TESCl) and imidazole in DMF to give the disilylated compound (V).Derivative (V) is then subjected to a Johnson-Remeiux reaction by first treatment with OsO4 and NMO in MeOH/THF/H2O followed by oxidation with NaIO4 in MeOH/THF/H2O to afford aldehyde (VI),which is then reduced by means of NaBH4 in MeOH to furnish alcohol (VII).Reaction between (VII) and morpholine (VIII) in refluxing MeOH affords baccatin III derivative (IX) (1),which is treated with TsOH in MeOH and then with acetic anhydride and DMSO to yield compound (X).Desulfurylation of (X) by refluxing with Raney-Ni in EtOH followed by removal of the TES protecting group by reaction with HF-pyridine affords intermediate (XI),which is finally converted into the desired compound by introduction of the phenylisoserine side-chain using protected beta-lactam (XII) and NaHMDS in THF followed by TBS removal by treatment with HF-pyridine.
参考文献标题:Synthesis and antitumor activity of non-prodrug water-soluble taxoid: 10-C-Aminoalkylated docetaxel analogs
文献作者:Iimura,S.; et al.
参考来源:Heterocycles 2000,53(12),2719