AT-2433 A1, -Drug Synthesis Database

【结构式】

【药物名称】AT-2433 A1

【化学名称】1-Chloro-13-[6-O-[2,4-dideoxy-4-(methylamino)-alpha-L-threo-pentofuranosyl]-4-O-methyl-beta-D-glucopyranosyl]-6-methyl-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione

【CA登记号】102644-20-2

【分子式】C₃₄H₃₅ClN₄O₉

【分子量】679.13245

【开发单位】Schering-Plough (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS

合成路线1 合成路线2

合成路线1

The Grignard condensation of pyrrolinedione (I) with 7-chloroindol-1-ylmagnesium bromide (II) in toluene gives the monoaddition product (III), which is condensed with indol-1-ylmagnesium bromide (IV) to yield the disubstituted compound (V). The hydrogenation of (V) with H2 over Pd/C in DMF affords the tetrahydro derivative (VI), which is condensed with the aminosugar (VII) in DMF and dehydrogenated with DDQ or DBU to afford the adduct (VIII). Finally, the methylamino group of (VIII) is deprotected by means of TBAF in THF.

参考文献中间体

【1】 Van Vranken, D.L.; Chisholm, J.D.; Regiocontrolled synthesis of the antitumor antibiotic AT2433-A1. J Org Chem 2000, 65, 22, 7541.

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)	31468	3,4-dibromo-1-methyl-1H-pyrrole-2,5-dione		C₅H₃Br₂NO₂	详情	详情
(II)	45582	bromo(7-chloro-1H-indol-1-yl)magnesium		C₈H₅BrClMgN	详情	详情
(III)	45583	3-bromo-4-(7-chloro-1H-inden-3-yl)-1-methyl-1H-pyrrole-2,5-dione		C₁₄H₉BrClNO₂	详情	详情
(IV)	45584	bromo(1H-indol-1-yl)magnesium		C₈H₆BrMgN	详情	详情
(V)	45585	3-(7-chloro-1H-indol-3-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione		C₂₁H₁₄ClN₃O₂	详情	详情
(VI)	45586	(4bR,4cR,7aR,12bS)-1-chloro-6-methyl-7a,12,12b,13-tetrahydro-4bH-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(4cH,6H)-dione	577-59-3	C₂₁H₁₆ClN₃O₂	详情	详情
(VII)	45587	2-(trimethylsilyl)ethyl (3S,4S,6S)-4-hydroxy-6-[[(2R,3S,4R,5R,6R)-4,5,6-trihydroxy-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-yl(methyl)carbamate		C₁₉H₃₇NO₁₀Si	详情	详情
(VIII)	45588	2-(trimethylsilyl)ethyl (3S,4S,6S)-6-[[(2R,3S,4R,5R,6R)-6-(11-chloro-6-methyl-5,7-dioxo-5,6,7,13-tetrahydro-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-12-yl)-4,5-dihydroxy-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]-4-hydroxytetrahydro-2H-pyran-3-yl(methyl)carbamate		C₄₀H₄₇ClN₄O₁₁Si	详情	详情

合成路线2

The intermediate aminosugar (VII) has been obtained as follows: The protection of the alcohol (IX) with Bn-Br and NaH in DMF gives the benzyl ether (X), which is oxidized with OsO4 and NaIO4 in acetone/THF to yield the aldehyde (XI). The cyclization of (XI) by means of Ts-OH in dioxane/water affords the lactol (XII), which is treated with diethylamino sulfurtrifluoride (DAST) to provide the glycosyl fluoride (XIII). The condensation of (XIII) with the benzylated glucose derivative (XIV) by means of AgClO4 and SnCl2 in THF/ethyl ether gives the disaccharide (XV). The reduction of the carbamoyl group of (XV) with LiAlH4 in refluxing THF yields the methylamino derivative (XVI), which is protected at the methylamino group with trimethylsilylethyl(p-methylphenyl)carbonate (teoc-O-PNP) to afford the carbamate (XVII). Finally, this compound is debenzylated by hydrogenation over Pd/C in ethanol/THF to afford the target aminosugar (VIII).

参考文献中间体

【1】 Van Vranken, D.L.; Chisholm, J.D.; Regiocontrolled synthesis of the antitumor antibiotic AT2433-A1. J Org Chem 2000, 65, 22, 7541.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	45587	2-(trimethylsilyl)ethyl (3S,4S,6S)-4-hydroxy-6-[[(2R,3S,4R,5R,6R)-4,5,6-trihydroxy-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-yl(methyl)carbamate		C₁₉H₃₇NO₁₀Si	详情	详情
(IX)	45589	tert-butyl (4S)-4-(1-hydroxy-3-butenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₁₄H₂₅NO₄	详情	详情
(X)	45590	tert-butyl (4S)-4-[1-(benzyloxy)-3-butenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate	15930-53-7	C₂₁H₃₁NO₄	详情	详情
(XI)	45591	tert-butyl (4S)-4-[1-(benzyloxy)-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate		C₂₀H₂₉NO₅	详情	详情
(XII)	45592	tert-butyl (3S,4S)-4-(benzyloxy)-6-hydroxytetrahydro-2H-pyran-3-ylcarbamate		C₁₇H₂₅NO₅	详情	详情
(XIII)	45593	tert-butyl (3S,4S)-4-(benzyloxy)-6-fluorotetrahydro-2H-pyran-3-ylcarbamate		C₁₇H₂₄FNO₄	详情	详情
(XIV)	45594	[(2R,3S,4S,5R,6R)-4,5,6-tris(benzyloxy)-3-methoxytetrahydro-2H-pyran-2-yl]methanol		C₂₈H₃₂O₆	详情	详情
(XV)	45595	tert-butyl (3S,4S,6S)-4-(benzyloxy)-6-[[(2R,3S,4S,5R,6R)-4,5,6-tris(benzyloxy)-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-ylcarbamate		C₄₅H₅₅NO₁₀	详情	详情
(XVI)	45596	N-((3S,4S,6S)-4-(benzyloxy)-6-[[(2R,3S,4S,5R,6R)-4,5,6-tris(benzyloxy)-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-yl)-N-methylamine; (3S,4S,6S)-4-(benzyloxy)-N-methyl-6-[[(2R,3S,4S,5R,6R)-4,5,6-tris(benzyloxy)-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-amine		C₄₁H₄₉NO₈	详情	详情
(XVII)	45597	2-(trimethylsilyl)ethyl (3S,4S,6S)-4-(benzyloxy)-6-[[(2R,3S,4S,5R,6R)-4,5,6-tris(benzyloxy)-3-methoxytetrahydro-2H-pyran-2-yl]methoxy]tetrahydro-2H-pyran-3-yl(methyl)carbamate		C₄₇H₆₁NO₁₀Si	详情	详情

Extended Information