PlAzOMICIN, -Drug Synthesis Database

【结构式】

【药物名称】PlAzOMICIN

【化学名称】1-[4-Amino-2(S)-hydroxybutyryl]-6'-(2-hydroxyethyl)sisomicin；4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-[3(R)-amino-6-(2-hydroxyethylaminomethyl)-3,4-dihydro-2H-pyran 2(S)-yloxy]-2-[3-deoxy-4-C-methyl-3-(methylamino)-b-l-arabinopyranosyloxy]-3-hydroxycyclohexyl]-2(S)-hydroxybutyramide

【CA登记号】1154757-24-0

【分子式】C₂₅H₄₈N₆O₁₀

【分子量】592.6828

【开发单位】　

【药理作用】Aminoglycoside antibiotic

合成路线1 合成路线2

合成路线1

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 .

参考文献中间体

【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

合成路线2

N-Acylation of sisomicin (I) with ethyl trifluorothioacetate (XII) in MeOH gives 6-trifluoroacetyl-sisomicin (XIII) (2-4), which by selective N-protection with CbzOSu in the presence of zn(OAc)2 and Et3N in MeOH/THF yields 2’,3-diCbz-sisomicin (XIV). N-Acylation of compound (XIV) with the activated carboxylic acid (XV) provides 6'-(trifluoroacetamido)-2’,3-diCbz-1-[4-amino-2(S)-hydroxybutryl]sisomicin (XVI). Hydrolysis of the trifluoroacetamide group in compound (XVI) with NH4OH in acetonitrile, followed by reductive alkylation with Obenzoylglycoaldehyde (XVII) in the presence of NaBH3CN in MeOH affords the secondary amino alcohol (XVIII). Finally, compound (XVIII) is deprotected by removal the O-benzoyl group by means of NaOH in MeOH/H2O, followed by catalytic hydrogenolysis with H2 over Pd/C in AcOH .

参考文献中间体

【1】 Nagabhushan, T.l. (Schering Corp.). Process for the manufacture of 6’-Nalkyl derivatives of sisomicin and verdamicin; novel intermediates useful therein, and novel 6’-N-alkylverdamicins prepared thereby. US 3997524.
【2】 Aggen, J.B., Armstrong, E.S., Goldblum, A.A. et al. Synthesis, structure and in vivo activity of the neoglycoside ACHN-490. 49th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 12-15, San Francisco) 2009, Abst F1-840.
【3】 Aggen, J.B., Armstrong, E.S., Goldblum, A.A. et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 2010, 54(11): 4636-42.

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)	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
(XII)	43223	S-ethyl 2,2,2-trifluoroethanethioate	383-64-2	C₄H₅F₃OS	详情	详情
(XIII)	67697	N-(((2R,3S)-3-amino-2-(((1S,2R,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)-2,2,2-trifluoroacetamide		C₂₁H₃₆F₃N₅O₈	详情	详情
(XIV)	67698	2’,3-diCbz-sisomicin		C₃₇H₄₈F₃N₅O₁₂	详情	详情
(XV)	67699	(2S)-2,5-dioxotetrahydrofuran-3-yl 4 -(((benzyloxy)carbonyl)amino)-2-hydroxybutanoate (XVI) C49H61F3N6O16 6’-(trifluoroacetamido)-2',3- diCbz-1-[4-amino-2(S)-hydroxybutryl]sisomicin		C₁₆H₁₇NO₈	详情	详情
(XVI)	67701			C₄₉H₆₁F₃N₆O₁₆	详情	详情
(XVII)	15605	2-oxoethyl benzoate		C₉H₈O₃	详情	详情
(XVIII)	67700			C₅₆H₇₀N₆O₁₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)