methyl (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】34965

【品名】methyl (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate

【CA登记号】

【分子式】C₂₃H₂₆O₉

【分子量】446.45404

【元素组成】C 61.88% H 5.87% O 32.25%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(X)

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with the chiral dihydrofuranone (II) in hot acetonitrile gives the pentacyclic anhydride (III), which is opened with warm acetic acid yielding the carboxylic acid (IV). Hydrogenation of the benzylic double bond of (IV) with H2 over Pd/C affords (V), which is treated with lead tetraacetate and acetic acid in THF to give the acetoxy compound (VI). The hydrolysis of the acetoxy group and the menthol hemiacetal group with HCl in hot dioxane yields the diol (VII), which is treated with diazomethane in ether/methanol affording the aldehyde (VIII). The reduction of the aldehyde group of (VIII) with LiEt3BH in THF gives the diol (IX) as a diastereomeric mixture, which is treated with HCl in THF to afford the diol (X) with the right conformation. Finally, this compound is lactonized to the target compound with ZnCl2 in THF.

参考文献中间体

合成目标

【1】 Jones, D.W.; Bush, E.J.; Asymmetric total synthesis of (-)-podophyllotoxin. J Chem Soc Chem Commun 1993, 1200.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	34956	5-(3,4,5-trimethoxyphenyl)-7H-[1,3]dioxolo[4,5-g]isochromen-7-one	C₁₉H₁₆O₇	详情	详情
(II)	34957	(5R)-5-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]-2(5H)-furanone	C₁₄H₂₂O₃	详情	详情
(III)	34958	(1R,11R,12R,13R,16R)-13-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]-1-(3,4,5-trimethoxyphenyl)-5,7,14,17-tetraoxapentacyclo[9.5.2.0(2,10).0(4,8).0(12,16)]octadeca-2(10),3,8-triene-15,18-dione	C₃₃H₃₈O₁₀	详情	详情
(IV)	34959	(5R,5aR,6R)-6-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5-carboxylic acid	C₃₃H₃₈O₁₀	详情	详情
(V)	34960	(5R,5aR,6R,8aR,9R)-6-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5-carboxylic acid	C₃₃H₄₀O₁₀	详情	详情
(VI)	34961	(5R,5aS,6R,8aR,9R)-6-[[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl acetate	C₃₄H₄₂O₁₀	详情	详情
(VII)	34962	(5R,5aR,8R,8aS)-8,9-dihydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	C₂₂H₂₂O₉	详情	详情
(VIII)	34963	methyl (5R,6R,7S)-7-formyl-8-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate	C₂₃H₂₄O₉	详情	详情
(IX)	34964	methyl (5R,6R,7R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate	C₂₃H₂₆O₉	详情	详情
(X)	34965	methyl (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate	C₂₃H₂₆O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl maleate (LXIII) gives the expected adduct (LXIV), which by thermal extrusion of CO2 yields the dihydronaphthodioxole (LXV). This compound is then converted to dihydroxycompound (X), which is finally cyclized by means of ZnCl2 to provide the target compound. The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl fumarate (LXVI) gives the expected adduct (LXVII), which by hydrogenation with H2 over Pd/C yields the tricarboxylic acid derivative (LXVIII). The reaction of (LXVIII) with Pb(OAc)4 affords the acetoxy derivative (LXIX), which is selectively reduced with LiBEt3H providing the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to give the previously described (X) with the suitable configuration.

参考文献中间体

合成目标

【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(LXVLIII)	35016	(5R,6R,7R,8R)-6,7-bis(methoxycarbonyl)-8-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-5-carboxylic acid		C₂₅H₂₆O₁₁	详情	详情
(I)	34956	5-(3,4,5-trimethoxyphenyl)-7H-[1,3]dioxolo[4,5-g]isochromen-7-one		C₁₉H₁₆O₇	详情	详情
(X)	34965	methyl (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate		C₂₃H₂₆O₉	详情	详情
(LXI)	35011	methyl (5R,6R,7R,8S)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate		C₂₃H₂₆O₉	详情	详情
(LXIII)	17206	dimethyl (Z)-2-butenedioate; Dimethyl Maleate	23055-10-9	C₆H₈O₄	详情	详情
(LXIV)	35013	dimethyl (1S,11S,14R,15S)-13-oxo-11-(3,4,5-trimethoxyphenyl)-5,7,12-trioxatetracyclo[9.2.2.0(2,10).0(4,8)]pentadeca-2(10),3,8-triene-14,15-dicarboxylate		C₂₅H₂₄O₁₁	详情	详情
(LXV)	35014	dimethyl (5R,6R)-5-(3,4,5-trimethoxyphenyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylate		C₂₄H₂₄O₉	详情	详情
(LXVI)	35018	dimethyl (E)-2-butenedioate	624-49-7	C₆H₈O₄	详情	详情
(LXVII)	35015	dimethyl (1R,11R,14S,15S)-13-oxo-11-(3,4,5-trimethoxyphenyl)-5,7,12-trioxatetracyclo[9.2.2.0(2,10).0(4,8)]pentadeca-2(10),3,8-triene-14,15-dicarboxylate		C₂₅H₂₄O₁₁	详情	详情
(LXIX)	35017	dimethyl (5S,6S,7R,8R)-5-(acetoxy)-8-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylate		C₂₆H₂₈O₁₁	详情	详情

Extended Information