Habekacin, Arbekacin, Habekacin, -Drug Synthesis Database

【结构式】

【药物名称】Habekacin, Arbekacin, Habekacin

【化学名称】1-N-[(S)-4-Amino-2-hydroxybutyryl]dibekacin
　　　　　　1-N-[(S)-4-Amino-2-hydroxybutyryl]-3',4'-dideoxykanamycin B
　　　　　　O-3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1--4)-O-[2,6-diamino-2,3,4,6-tetradeoxy-alpha-D-erythro-hexopyranosyl-(1--6)]-N'-[(2S)-4-amino-2-hydroxybutyryl]-2-deoxy-L-streptamine

【CA登记号】51025-85-5, 75282-65-4 (carbonate(1:2) salt)

【分子式】C₂₂H₄₄N₆O₁₀

【分子量】552.63018

【开发单位】Meiji Seika (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Aminoglycosides

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

The acylation of 3',4'-dideoxykanamycin B (dibekacin) (I) with N-benzyloxycarbonyloxysuccinimide (II) and zinc acetate in DMSO gives 3,2,6'-tri-N-benzyloxycarbonydibekacin (III), which is then treated with the N-hydroxysuccinimide ester of 2-hydroxy-4-aminobutyric acid (IV) and finally deprotected by hydrogenation with H2 over Pd/C in acidic water dioxane.

参考文献中间体

【1】 Umezawa, H.; Umezawa, S.; Tsuchiya, T.; Takagi, Y.; Jikihara, T. (Microbial Chemistry Research Foundation); Production of a selectively protected N-acylated derivative of an aminoglycosidic antibiotic. BE 0879925; DE 2945010; FR 2441631; FR 2482109; GB 2036020; GB 2065123; JP 80164696; JP 8064598; US 4297485 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

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)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	30664	3,2,6'-tri-N-benzyloxycarbonydibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-4-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexylcarbamate		C₄₂H₅₅N₅O₁₄	详情	详情
(IV)	30665	1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione		C₈H₁₂N₂O₅	详情	详情

合成路线2

The acylation of 3',4'-dideoxykanamycin B (dibekacin) (I) with benzyloxycarbonyl chloride in water gives 6'-N-benzyloxycarbonyldibekacin (V), which is then acylated with (IV) as before and deprotected by hydrogenolysis with H2 over Pd/C in water - acetic acid.

参考文献中间体

【1】 Umezawa, H.; Umezawa, S.; Maeda, K.; Tsuchiya, O.; Kondo, S.; Fukatsu, S. (Microbial Chemistry Research Foundation); 1-N-[(S)-alpha-hydroxy-omega-aminoacyl]. DE 2530169; FR 2201875; GB 1426908; JP 7462442; JP 7480039; JP 7494648; JP 7733629; JP 8003357; US 4001208; US 4107424 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(I)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(IV)	30665	1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione		C₈H₁₂N₂O₅	详情	详情
(V)	30666	6'-N-benzyloxycarbonyldibekacin; benzyl [(2S,5R,6R)-5-amino-6-[((1R,2S,3S,4R,6S)-4,6-diamino-3-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]tetrahydro-2H-pyran-2-yl]methylcarbamate		C₂₆H₄₃N₅O₁₀	详情	详情

合成路线3

The acylation of 3,2,6'-tri-N-benzyloxycarbonydibekacin (III) with ethyl trifluoroacetate and K2CO3 gives 3,2',6'-tri-N-benzyloxycarbonyl-3''-trifluoroacetyldibekacin (VI), which is acylated again with (IV) yielding the protected habekacin (VII). Finally, this compound is deprotected by hydrolysis with ammonia in aqueous THF, followed by hydrogenolysis with H2 over Pd/C.

参考文献中间体

【1】 Tsuchiya, T.; Takagi, Y.; Umezawa, S.; 1-N-Acylation of aminocyclitol antibiotics via zinc chelation and regiospecific N-trifluoroacetylation. Tetrahedron Lett 1979, 51, 4951-54.
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

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)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	30664	3,2,6'-tri-N-benzyloxycarbonydibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-4-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexylcarbamate		C₄₂H₅₅N₅O₁₄	详情	详情
(IV)	30665	1-[[(2S)-4-amino-2-hydroxybutanoyl]oxy]-2,5-pyrrolidinedione		C₈H₁₂N₂O₅	详情	详情
(VI)	30667	3,2',6'-tri-N-benzyloxycarbonyl-3''-trifluoroacetyldibekacin; Benzyl (1S,2R,3S,4S,5R)-5-amino-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4-([(2R,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl]oxy)-3-hydroxycyclohexylcarbamate		C₄₄H₅₄F₃N₅O₁₅	详情	详情
(VII)	30668	benzyl (1S,2R,3S,4S,5R)-5-[[(2S)-4-amino-2-hydroxybutanoyl]amino]-2-[[(2R,3R,6S)-3-[[(benzyloxy)carbonyl]amino]-6-([[(benzyloxy)carbonyl]amino]methyl)tetrahydro-2H-pyran-2-yl]oxy]-4-([(2R,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl]oxy)-3-hydroxycyclohexylcarbamate		C₄₈H₆₁F₃N₆O₁₇	详情	详情

合成路线4

The acylation of 3',4'-dideoxykanamycin B (dibekacin) (I) with tert-butyl-S-(4,6-dimethylpyrimid-2-yl)thiocarbonate (VIII) by means of triethylamine in isopropanol gives 3,2',6'-tri-N-tert-butyloxycarbonyldibekacin (IX), which is acylated again with 4-benzyloxycarbonylamino-2-hydroxybutyric acid N-hydroxysuccinimide ester (X) in THE yielding the protected habekacin (XI). Finally, this compound is deprotected by a treatment with trifluoroacetic acid, followed by hydrogenolysis with H2 over Pd/C in methanol - acetic acid.

参考文献中间体

【1】 Umezawa, H.; Kondo, S. (Microbial Chemistry Research Foundation); Process for the preparation of 1-N-isoseryl- or 1-N-(L-4-amino-2-hydroxybutyryl)-3',4'-dideoxykanamycin B and intermediates thereof. DE 2950020; FR 2444046; GB 2038329; GB 2072676; GB 2072677; JP 55081897; US 4268664 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

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)	30662	Dibekacin; 3',4'-Dideoxykanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₇N₅O₈	详情	详情
(VIII)	30669	tert-butyl-S-(4,6-dimethylpyrimid-2-yl)thiocarbonate; O-(tert-butyl) S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate	41840-28-2	C₁₁H₁₆N₂O₂S	详情	详情
(IX)	30670	3,2',6'-tri-N-tert-butyloxycarbonyldibekacin; tert-Butyl (2R,3R,4S,5S,6R)-2-([(1S,2S,3R,4S,6R)-6-amino-4-[(tert-butoxycarbonyl)amino]-3-[((2R,3R,6S)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]tetrahydro-2H-pyran-2-yl)oxy]-2-hydroxycyclohexyl]oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-ylcarbamate		C₃₈H₆₉N₅O₁₆	详情	详情
(X)	30671	4-Benzyloxycarbonylamino-2-hydroxybutyric acid N-hydroxysuccinimide ester; Benzyl (3S)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-3-hydroxy-4-oxobutylcarbamate		C₁₆H₁₈N₂O₇	详情	详情
(XI)	30672	benzyl (3S)-4-[((1R,2S,3S,4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-[((2R,3R,6S)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]tetrahydro-2H-pyran-2-yl)oxy]-2-[[(2R,3R,4S,5S,6R)-4-[(tert-butoxycarbonyl)amino]-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexyl)amino]-3-hydroxy-4-oxobutylcarbamate		C₅₀H₈₂N₆O₂₀	详情	详情

合成路线5

The acylation of 3',4'-dideoxy-3',4'-didehydrokanamycin B (XII) with tert-butyl-S-(4,6-dimethylpyrimid-2-yl)thiocarbonate (VIII) as before gives 3,2',6'-tri-N-butoxycarbonyl-3',4'-dideoxy-3',4'-didehydrokanamycin B (XIII), which is acylated again with (X) as before yielding the fully protected 3',4'-didehydrohabekacin (XIV). Partial deprotection of (XIV) with trifluoroacetic acid affords 1-N-(4-benzyloxycarbonylamino-2-hydroxybutyryl)-3',4'-dideoxy-3',4'-didehydrokanamycin B (XV), which is finally debenzylated and reduced by a treatment with H2 over PtO2 in aqueous acetic acid.

参考文献中间体

【1】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Habekacin. Drugs Fut 1983, 8, 5, 410.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	30669	tert-butyl-S-(4,6-dimethylpyrimid-2-yl)thiocarbonate; O-(tert-butyl) S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate	41840-28-2	C₁₁H₁₆N₂O₂S	详情	详情
(X)	30671	4-Benzyloxycarbonylamino-2-hydroxybutyric acid N-hydroxysuccinimide ester; Benzyl (3S)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-3-hydroxy-4-oxobutylcarbamate		C₁₆H₁₈N₂O₇	详情	详情
(XII)	30673	3',4'-dideoxy-3',4'-didehydrokanamycin B; (2R,3R,4S,5S,6R)-4-amino-2-[((1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)-3,6-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol		C₁₈H₃₅N₅O₈	详情	详情
(XIII)	30674	3,2',6'-tri-N-butoxycarbonyl-3',4'-dideoxy-3',4'-didehydrokanamycin B; tert-Butyl (2R,3R,4S,5S,6R)-2-([(1S,2S,3R,4S,6R)-6-amino-4-[(tert-butoxycarbonyl)amino]-3-[((2R,3R,6S)-3-[(tert-butoxycarbonyl)amino]-6-[[(tert-butoxycarbonyl)amino]methyl]-3,6-dihydro-2H-pyran-2-yl)oxy]-2-hydroxycyclohexyl]oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-ylcarbamate		C₃₈H₆₇N₅O₁₆	详情	详情
(XIV)	30675	tert-butyl (1S,2R,3S,4S,5R)-2-[[(2R,3R,6S)-3-amino-6-(aminomethyl)-3,6-dihydro-2H-pyran-2-yl]oxy]-5-[((2S)-4-[[(benzyloxy)carbonyl]amino]-2-hydroxybutanoyl)amino]-4-[[(2R,3R,4S,5S,6R)-4-[(tert-butoxycarbonyl)amino]-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexylcarbamate		C₄₀H₆₄N₆O₁₆	详情	详情
(XV)	30676	1-N-(4-benzyloxycarbonylamino-2-Hydroxybutyryl)-3',4'-dideoxy-3',4'-didehydrokanamycin B; Benzyl (3S)-4-[((1R,2S,3S,4R,5S)-5-amino-4-[[(2R,3R,6S)-3-amino-6-(aminomethyl)-3,6-dihydro-2H-pyran-2-yl]oxy]-2-[[(2R,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-3-hydroxycyclohexyl)amino]-3-hydroxy-4-oxobutylcarbamate		C₃₀H₄₈N₆O₁₂	详情	详情

Extended Information