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【结 构 式】

【分子编号】67690

【品名】4-nitrobenzyl (((2R,3S)-3-amino-2-(((1S,3R,4S,6R)-4,6-diamino-3-(((2S,3S,4S,5S)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexyl)oxy)-3,4-dihydro-2H-pyran-6-yl)methyl)carbamate

【CA登记号】 

【 分 子 式 】C27H42N6O11

【 分 子 量 】626.664

【元素组成】C 51.75% H 6.76% N 13.41% O 28.08%

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: (II)

Selective N-protection of sisomicin (I) with HONB-pNz (prepared in situ by reaction of N-hydroxy-5-norbornene-2,3-dicarboximide [HONB] with p-nitrobenzylchloroformate [pNzCl] and Et3N in THF) by means of zn(OAc)2 in MeOH/CH2Cl2 gives 6’-pNz-sisomicin (II), which is selectively protected at the glycosidyl amino groups with HONB-Boc (prepared by reacting HONB with Boc2O and Et3N in THF) by means of zn(OAc)2 and Et3N in MeOH/THF to yield 6’-pNz-2’,3-diBoc-sisomicin (III). Protection of the remaining amino groups of compound (III) with HONB-Fmoc (prepared by reacting HONB with Fmoc-Cl by means of NMM in THF) and Boc2O in the presence of NMM in THF provides 6’-pNz-2’,3,3’’-triBoc-1-Fmoc-sisomicin (IV), which is selectively deprotected by removing the Fmoc-group by means of N(CH2CH2NH2)3 in CH2Cl2 to afford 6’-pNz-2’,3,3’’-triBoc-sisomicin (V). Condensation of protected sisomicin (V) with N-Boc-4- amino-2(S)-hydroxybutyric acid (VI) [prepared by N-protection of 4-amino-2(S)-hydroxybutyric acid (VII) with Boc2O and K2CO3 in diox-ane/H2O] in the presence of HONB and EDC in DMF generates 6’-pNz-2’,3,3’’-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutyryl)sisomicin (VIII). Basic hydrolysis of the 6’-pNz group of compound (VIII) by means of NaOH and Na2S2O4 in EtOH/H2O at 70 °C results in 2’,3,3’’-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutryl)sisomicin (IX), which then undergoes reductive alkylation with tert-butyldimethylsilyloxy acetaldehyde (X) in the presence of silica-supported cyanoboro -hydride (Si-CBH) in MeOH at 100 °C (microwave) to give the 6’-[2-(tert-butyldimethylsilyl oxy)ethyl]sisomicin derivative (XI). Finally, compound (IX) is completely deprotected by means of TFA in CH2Cl2 .

1 Aggen, J., Goldblum, A.A., linsell, M., Dozzo, P., Moser, H.E., Hildebrandt, D., Gliedt, M. (Achaogen, Inc.). Antibacterial aminoglycoside analogs. CN 101868472, CN 103360440, EP 2217610, JP 2011504508, JP 2011219498, KR 2010110297, US 8383596, US 2013217642, WO 2009067692.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 67690 4-nitrobenzyl (((2R,3S)-3-amino-2-(((1S,3R,4S,6R)-4,6-diamino-3-(((2S,3S,4S,5S)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexyl)oxy)-3,4-dihydro-2H-pyran-6-yl)methyl)carbamate   C27H42N6O11 详情 详情
(I) 44199 (2R,3R,4R,5R)-2-[((1S,2R,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol; Sisomicin 32385-11-8 C19H37N5O7 详情 详情
(III) 67691     C37H58N6O15 详情 详情
(IV) 67692     C57H76N6O19 详情 详情
(V) 67693     C42H66N6O17 详情 详情
(VI) 67688 N-Boc-4-amino-2(S)-hydroxybutyric acid 207305-60-0 C9H17NO5 详情 详情
(VII) 67689 4-amino-2(S)-hydroxybutyric acid 7013-05-0 C4H9NO3 详情 详情
(VIII) 67694 6'-pNz-2’,3,3''-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutyryl)sisomicin   C51H81N7O21 详情 详情
(IX) 67695 2',3,3''-triBoc-1-(N-Boc-4-amino-2(S)-hydroxybutryl)sisomicin   C43H76N6O17 详情 详情
(X) 61170 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde;tert-butyldimethylsilyloxy acetaldehyde 102191-92-4 C8H18O2Si 详情 详情
(XI) 67696 6'-[2-(tert-butyldimethylsilyl oxy)ethyl]sisomicin   C51H94N6O18Si 详情 详情
Extended Information