新型氨基糖苷类抗菌药plazomicin的合成

发布时间：2018-08-18 18:49

【摘要】：硫酸西索米星(2)经游离后,用4-硝基苄氧羰基(PNZ)选择性保护6'-位氨基,然后依次用叔丁氧羰基(Boc)保护2'-和3-位氨基,芴甲氧羰基(Fmoc)保护1-位氨基,及Boc保护3"-位氨基得[6'-(4-硝基苄氧羰基)-2',3,3"-三叔丁氧羰基-1-芴甲氧羰基]西索米星(6),再依次经脱除Fmoc、与N-叔丁氧羰基-4-氨基-2(S)-羟基丁酸(12)缩合和脱除PNZ得[2',3,3"-三叔丁氧羰基-1-[N-叔丁氧羰基-4-氨基-2(S)-羟基丁酰基]]西索米星(9),9与苯甲酰氧基乙醛(13)和三乙酰氧基硼氢化钠进行还原氨化制得[6'-苯甲酰氧基乙基-2',3,3"-三叔丁氧羰基-1-[N-叔丁氧羰基-4-氨基-2(S)-羟基丁酰基]]西索米星(10),脱除苯甲酰基保护得[6'-羟乙基-2',3,3"-三叔丁氧羰基-1-[N-叔丁氧羰基-4-氨基-2(S)-羟基丁酰基]]西索米星(11),最后脱除Boc保护得plazomicin(1),总收率3.8%(以2计)。其中10、11未见文献报道。
[Abstract]:After dissociation, sisomicin sulfate (2) was selectively protected by 4-nitrobenzoxy carbonyl (PNZ), then protected by tert-butoxycarbonyl (Boc) (2- and 3-position amino groups), fluorene methoxycarbonyl (Fmoc) (Fmoc) protected 1-position amino groups. And Boc protected 3 "-position amino to [6- (4-nitrobenzoxy carbonyl) -2tbutylmethoxycarbonyl] sisomicin (6), then removed Fmocmocloxycarbonyl -4amino-2-hydroxybutyric acid (12) and condensed with Nt-tert-butoxy carbonyl -4amino -2 (S) -hydroxybutyric acid (12) to obtain [2tbutylcarbonyl 3" -tert-butyloxycarbonyl] sisomicin (6). Carbonyl [N- tert-butyloxycarbonyl -4amino -2 (S)-hydroxybutylol] sisomicin (9) -9 was reduced and ammoniated with benzoyl acetaldehyde (13) and triacetyl sodium borohydride to obtain [6N-benzoyloxyethyl-233 "-tri-tert-butyloxycarbonyl-1- [N- tert-butyloxycarbonyl] -1- [N- tert-butyloxyacetaldehyde (13) and triacetyl sodium borohydride] by reductive ammoniation of carbonyl -1- [N- tert-butyloxyacetaldehyde (13) and triacetyl sodium borohydride] [6-HYDROXYL-HYDROXYL-2HYDROXYL 3 "-TRIMETHYDROxycarbonyl -1- [N- tert-butoxycarbonyl -4- amino -2 (S)-hydroxybutyloyl] sisomicin (11) was obtained by removing benzoyl group (10). Finally, plazomicin (1) was obtained by removing Boc protection. The overall yield was 3.8% (based on 2). Of these, 10 / 11 were not reported in the literature.
【作者单位】：中国医药工业研究总院上海医药工业研究院创新药物与制药工艺国家重点实验室;
【分类号】：R914.5

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