Idarubicin hydrochloride, NSC-256439, IMI-30, DMDR, Idamycin, Zavedos, -Drug Synthesis Database

【结构式】

【药物名称】Idarubicin hydrochloride, NSC-256439, IMI-30, DMDR, Idamycin, Zavedos

【化学名称】(1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside hydrochloride
　　　　　　(7S,9S)-9-Acetyl-7-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenedione hydrochloride
　　　　　　4-Demethoxydaunomycin hydrochloride
　　　　　　4-Demethoxydaunorubicin hydrochloride

【CA登记号】58957-92-9

【分子式】C₂₆H₂₈ClNO₉

【分子量】533.96736

【开发单位】Pfizer (Originator)

【药理作用】Oncolytic Drugs, Anthracyclines

合成路线1 合成路线2

合成路线1

The condensation of chiral tetraline (I) with phthalic anhydride (II) by means of AlCl3 at 180 C gives the naphthacenedione (III), which is ketalized at the acetyl group with ethylene glycol and p-toluenesulfonic acid yielding the dioxolane (IV). The hydroxylation of (IV) with Br2 and AIBN in CCl4/CHCl3 affords the 4-demethoxy-7-epidaunomycinone (V), which is isomerized with TFA yielding 4-demethoxydaunomycinone (VI) . The condensation of (VI) with the acylated hexopyranosyl chloride (VII) by means of CF3SO3Ag of Br2Hg affords the trifluoroacetylated 4-demethoxydaunomycin (VIII), which is finally treated with NaOH in order to eliminate the trifluoroacetyl groups

参考文献中间体

【1】 Arcamone, F.; et al.; Synthesis and antitumour activity of new daunorubicin and adriamycin analogues. Experientia 1978, 34, 1255.
【2】 Bernardi, L.; Arcamone, F.; Patelli, B.; Di Marco, A. (Pharmacia Corp.); Daunomycin analogues, their preparation and use. DE 2525633; US 4046878 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(I)	34606	1-[(2R)-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-1-ethanone		C₁₄H₁₈O₄	详情	详情
(II)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(III)	34607	(8R)-8-acetyl-6,8,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione		C₂₀H₁₆O₆	详情	详情
(IV)	34608	(8R)-6,8,11-trihydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydro-5,12-naphthacenedione		C₂₂H₂₀O₇	详情	详情
(V)	34609	(2S,4R)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₀H₁₄O₈	详情	详情
(VI)	34610	(2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₀H₁₄O₈	详情	详情
(VII)	34611	(2S,3S,4S,6S)-6-chloro-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate		C₁₀H₁₀ClF₆NO₄	详情	详情
(VIII)	34612	(3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-4,6,11-trioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate		C₃₀H₂₃F₆NO₁₂	详情	详情

合成路线2

The reaction of daunomycinone (IX) with AlCl3 in dichloromethane gives 4-demethyldaunomycinone (X), which is ketalized with ethylene glycol as before yielding the dioxolane (XI). The selective sulfonation of (XI) with TsCl, DIEA and DMAP in pyridine affords the 4-tosyloxy derivative (XII), which is treated with 4-methoxybenzylamine (XIII) in pyridine providing the secondary benzylamine (XIV). Elimination of the benzyl protecting group of (XIV) with TFA gives 4-amino-4-demethoxydaunomycinone ethylene ketal (XV), which is deaminated by reaction with TFA, NaNO2 and H3PO2 to give 4-demethoxydaunomycinone (XVI). Finally, this compound is submitted to fermentation with Streptomyces peucetius corneus, S. Peucetius caesius, S. Caeruleus, S. Peucetius, S. Coeruleorubidus, and other chemical or radio-induced mutants thereof.

参考文献中间体

【1】 Francalanci, F.; Martinengo, T.; de Bernardinis, S.; Cabri, W. (Pharmacia Corp.); Process for the preparation of 4-demethoxydaunomycinone, the aglycone of 4-demethoxy-daunorubicin. EP 0328399 .
【2】 Mitscher, L.A.; Lednicer, D. (Pharmacia Corp.); Biosynthesis of simplified anthracyclines. US 4471052 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(IX)	34613	(2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-7-methoxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₁H₁₆O₉	详情	详情
(X)	34614	(2S,4S)-2-acetyl-2,4,5,7,12-pentahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₀H₁₄O₉	详情	详情
(XI)	34615	(2R,4S)-2,4,5,7,12-pentahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₂H₁₈O₁₀	详情	详情
(XII)	34616	(8R,10S)-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-5,7,12-trioxo-5,7,8,9,10,12-hexahydro-1-naphthacenyl 4-methylbenzenesulfonate		C₂₉H₂₄O₁₂S	详情	详情
(XIII)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(XIV)	34617	(2R,4S)-2,4,5,12-tetrahydroxy-7-[(4-methoxybenzyl)amino]-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₃₀H₂₇NO₁₀	详情	详情
(XV)	34618	(2R,4S)-7-amino-2,4,5,12-tetrahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₂H₁₉NO₉	详情	详情
(XVI)	34610	(2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione		C₂₀H₁₄O₈	详情	详情

Extended Information