ES-242-5, -Drug Synthesis Database

【结构式】

【药物名称】ES-242-5

【化学名称】7,7',9,9'-Tetramethoxy-3,3'-dimethyl-5,5'-bi(3,4-dihydro-1H-naphtho[2,3-c]pyran)-4,10,10'-triol

【CA登记号】136565-66-7

【分子式】C₃₂H₃₄O₉

【分子量】562.62238

【开发单位】Kyowa Hakko (Originator)

【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, NMDA Antagonists

合成路线1 合成路线2

合成路线1

The title compound was originally isolated from the culture broths of Verticillum sp. The synthesis of this compound has been further described. The unsaturated lactone (I) was isomerized at the C-4 hydroxyl group, and subsequently protected as the methoxymethyl ether (II). Condensation of (II) with benzoate ester (III) in a tandem Michael addition-Dieckmann cyclization reaction afforded the tricyclic compound (IV), which was aromatized to the naphthopyranone (V) by treatment with cyclohexene and Pd/C. Protection of the hydroxyl group of (V) with benzyl bromide and K2CO3 gave benzyl ether (VI). After reduction of the lactone function of (VI) to the corresponding lactol by means of DIBAL, further deoxygenation with triethylsilane and trifluoroacetic acid provided the cyclic ether (VII). The benzyl group of (VII) was removed by hydrogenolysis with cyclohexadiene (VIII) and Pd/C, and the resulting hydroxynaphthopyran (IX) was oxidatively dimerized, affording (X) as a diasteromeric mixture. Aromatization of (X) by NaOH produced the bisnaphthol (XI).

参考文献中间体

【1】 Yamazaki, T.; Yoshimoto, T.; Tatsuta, K.; Synthesis and biological evaluation of the analogs of bioxanthracenes ES-242s, N-methyl-D-aspartate antagonists. J Antibiot 1998, 51, 3, 383.
【2】 Yamazaki, T.; Nagai, T.; Tamura, T.; Tatsuta, K.; Mase, T.; Synthesis of an N-methyl-D-aspartate receptor antagonist, ES-242-5, and its analogs. J Antibiot 1999, 52, 4, 422.
【3】 Nakamura, H.; Absolute and atropisomeric structure of ES-242s, N-methyl-D-aspartate receptor antagonists. J Antibiot 1999, 52, 4, 433.

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)	31509	(5R,6S)-5-hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one		C₆H₈O₃	详情	详情
(II)	31510	(5S,6S)-5-(methoxymethoxy)-6-methyl-5,6-dihydro-2H-pyran-2-one		C₈H₁₂O₄	详情	详情
(III)	31511	methyl 2,4-dimethoxy-6-methylbenzoate	6110-37-8	C₁₁H₁₄O₄	详情	详情
(IV)	31512	(3S,4S,4aR)-10-hydroxy-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4,4a,5-tetrahydro-1H-benzo[g]isochromen-1-one		C₁₈H₂₂O₇	详情	详情
(V)	31513	(3S,4S)-10-hydroxy-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-1-one		C₁₈H₂₀O₇	详情	详情
(VI)	31514	(3S,4S)-10-(benzyloxy)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-1-one		C₂₅H₂₆O₇	详情	详情
(VII)	31515	(3S,4S)-10-(benzyloxy)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromene; benzyl (3S,4S)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-10-yl ether		C₂₅H₂₈O₆	详情	详情
(VIII)	31516	1,4-cyclohexadiene	628-41-1	C₆H₈	详情	详情
(IX)	31517	(3S,4S)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-10-ol		C₁₈H₂₂O₆	详情	详情
(X)	31518	5,5'-Bis[7,9-dimethoxy-4(S)-(methoxymethoxy)-3(S)-methyl-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-10-one]		C₃₆H₄₂O₁₂	详情	详情
(XI)	31519	5,5'-Bis[7,9-dimethoxy-4(S)-(methoxymethoxy)-3(S)-methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-10-ol]		C₃₆H₄₂O₁₂	详情	详情

合成路线2

Bisnaphthol (XI) was chromatographically separated into atropisomers (XII) and (XIII). The required isomer (XII) was benzylated with NaH and benzyl bromide, and the methoxymethyl group was removed by treatment with HCl, generated from acetyl chloride in MeOH, to furnish diol (XIV). Reduction of one hydroxyl group of (XIV) was then effected by the sequence of conversion to the S-methyl dithiocarbonate (XV), followed by radical deoxygenation with n-Bu3SnH and AIBN to yield (XVI). The O-benzyl groups of (XVI) were finally removed by hydrogenation over Pd/C.

参考文献中间体

【1】 Yamazaki, T.; Yoshimoto, T.; Tatsuta, K.; Synthesis and biological evaluation of the analogs of bioxanthracenes ES-242s, N-methyl-D-aspartate antagonists. J Antibiot 1998, 51, 3, 383.
【2】 Yamazaki, T.; Nagai, T.; Tamura, T.; Tatsuta, K.; Mase, T.; Synthesis of an N-methyl-D-aspartate receptor antagonist, ES-242-5, and its analogs. J Antibiot 1999, 52, 4, 422.
【3】 Nakamura, H.; Absolute and atropisomeric structure of ES-242s, N-methyl-D-aspartate receptor antagonists. J Antibiot 1999, 52, 4, 433.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	31519	5,5'-Bis[7,9-dimethoxy-4(S)-(methoxymethoxy)-3(S)-methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-10-ol]	C₃₆H₄₂O₁₂	详情	详情
(XII)	63846	(3S,4S,5S,10S,10aS)-5-{(3S,4S,7S)-10-hydroxy-7,9-dimethoxy-3-methyl-4-[(methylperoxy)methoxy]-3,4,7,8-tetrahydro-1H-benzo[g]isochromen-5-yl}-7,9-dimethoxy-3-methyl-4-[(methylperoxy)methoxy]-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isochromen-10-ol	C₃₆H₄₈O₁₄	详情	详情
(XIII)	63847	(3S,4S,5R,10R,10aR)-5-{(3S,4S,7R)-10-hydroxy-7,9-dimethoxy-3-methyl-4-[(methylperoxy)methoxy]-3,4,7,8-tetrahydro-1H-benzo[g]isochromen-5-yl}-7,9-dimethoxy-3-methyl-4-[(methylperoxy)methoxy]-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isochromen-10-ol	C₃₆H₄₈O₁₄	详情	详情
(XIV)	31522	(3S,4S)-10-(benzyloxy)-5-[(3S,4S)-10-(benzyloxy)-4-hydroxy-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-5-yl]-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-4-ol	C₄₆H₄₆O₁₀	详情	详情
(XV)	31523	O-[(3S,4S)-10-(benzyloxy)-5-[(3S,4S)-10-(benzyloxy)-4-hydroxy-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-5-yl]-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-4-yl] S-methyl carbonodithioate	C₄₈H₄₈O₁₀S₂	详情	详情
(XVI)	31524	(3S,4S)-10-(benzyloxy)-5-[(3S)-10-(benzyloxy)-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-5-yl]-7,9-dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-4-ol	C₄₆H₄₆O₉	详情	详情

Extended Information