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【结 构 式】

【分子编号】50154

【品名】(1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-12-[2-(4-morpholinyl)ethyl]-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate

【CA登记号】

【 分 子 式 】C47H75NO10Si2

【 分 子 量 】870.28424

【元素组成】C 64.87% H 8.69% N 1.61% O 18.38% Si 6.45%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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.

1 Iimura, S.; et al.; Synthesis and antitumor activity of non-prodrug water-soluble taxoid: 10-C-Aminoalkylated docetaxel analogs. Heterocycles 2000, 53, 12, 2719.
2 Chiba, J.; Ohsuki, S.; Jimbo, T.; Iwahana, M.; Terasawa, H.; Yoshino, T.; Uoto, K.; Soga, T.; Iimura, S.; Orally active docetaxel analogue: Synthesis of 10-deoxy-10-C-morpholinoethyl docetaxel analogues. Bioorg Med Chem Lett 2001, 11, 3, 407.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50147 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-12-(3-hydroxypropyl)-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C38H56O10Si 详情 详情
(II) 50148 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-12-(3-[[(4-methylphenyl)sulfonyl]oxy]propyl)-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C45H62O12SSi 详情 详情
(III) 50149 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-12-[3-(methylsulfinyl)propyl]-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C39H58O10SSi 详情 详情
(IV) 50150 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-12-allyl-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C38H54O9Si 详情 详情
(V) 50151 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-12-allyl-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C44H68O9Si2 详情 详情
(VI) 50152 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-12-(2-oxoethyl)-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H66O10Si2 详情 详情
(VII) 50153 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-12-(2-hydroxyethyl)-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H68O10Si2 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 50154 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-12-[2-(4-morpholinyl)ethyl]-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C47H75NO10Si2 详情 详情
(X) 50155 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-12-[2-(4-morpholinyl)ethyl]-11-oxo-15-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H65NO10SSi 详情 详情
(XI) 50156 (1S,2S,3R,4S,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-9-methoxy-10,14,17,17-tetramethyl-12-[2-(4-morpholinyl)ethyl]-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C36H49NO10 详情 详情
(XII) 50157 tert-butyl (3R,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-4-phenyl-1-azetidinecarboxylate C20H31NO4Si 详情 详情
Extended Information