【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% |
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 |