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【结 构 式】 
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【药物名称】S-8921 【化学名称】1-(3,4-Dimethoxyphenyl)-3-(3-ethylpentanoyl)-4-hydroxy-6,7,8-trimethoxy-2-naphthalenecarboxylic acid methyl ester 【CA登记号】151165-96-7 【 分 子 式 】C30H36O9 【 分 子 量 】540.61602 |
【开发单位】Shionogi (Originator) 【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Ileal Bile Acid Transporter Inhibitors |
合成路线1
The Wadsworth-Emmons condensation of 3-pentanone (I) with phosphonate (II) affords the conjugated ester adduct (III). Subsequent double bond hydrogenation in (III), in the presence of Pd/C, leads to the saturated ester (IV). After basic hydrolysis of the ethyl ester group of (IV), the resultant carboxylic acid (V) is activated as the corresponding acid chloride (VI) upon treatment with SOCl2. Then, acylation of the silver acetylide of methyl propiolate (VII) with acid chloride (VI) gives rise to the oxo ester intermediate (VIII).
| 【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 . |
| 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) | 32415 | Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone | 96-22-0 | C5H10O | 详情 | 详情 |
| (II) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 57428 | ethyl 3-ethyl-2-pentenoate | C9H16O2 | 详情 | 详情 | |
| (IV) | 57429 | ethyl 3-ethylpentanoate | C9H18O2 | 详情 | 详情 | |
| (V) | 57433 | 3-ethylpentanoic acid | C7H14O2 | 详情 | 详情 | |
| (VI) | 57430 | 3-ethylpentanoyl chloride | C7H13ClO | 详情 | 详情 | |
| (VII) | 57431 | (3-methoxy-3-oxo-1-propynyl)silver | C4H3AgO2 | 详情 | 详情 | |
| (VIII) | 57432 | methyl 6-ethyl-4-oxo-2-octynoate | C11H16O3 | 详情 | 详情 |
合成路线2
Protection of 3,4,5-trimethoxybenzaldehyde (IX) with ethylene glycol (X) affords acetal (XI). After lithiation of (XI) by means of butyllithium, addition to veratraldehyde (XII) furnishes carbinol (XIII). Finally, cyclization of hydroxy acetal (XIII) with alkyne (VIII) under acidic conditions provides the title naphthol derivative.
| 【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 . |
| 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) | 57432 | methyl 6-ethyl-4-oxo-2-octynoate | C11H16O3 | 详情 | 详情 | |
| (IX) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (X) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XI) | 57434 | 2-(3,4,5-trimethoxyphenyl)-1,3-dioxolane; 4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl methyl ether | C12H16O5 | 详情 | 详情 | |
| (XII) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (XIII) | 57435 | (3,4-dimethoxyphenyl)[6-(1,3-dioxolan-2-yl)-2,3,4-trimethoxyphenyl]methanol | C21H26O8 | 详情 | 详情 |
合成路线3
In an alternative procedure, the known hydroxynaphthalene dicarboxylate (I) is protected as the methoxymethyl ether (III) using chloromethyl methyl ether (II) and diisopropyl ethylamine. Subsequent partial hydrolysis of diester (III) with KOH leads to acid (IV). Removal of the methoxymethyl protecting group of (IV) to produce naphthol (V) is accomplished by treatment with in situ generated iodotrimethylsilane. Hydroxy acid (V) is then converted to the dioxinone derivative (VI) employing diiodomethane and CsF in hot DMF. Finally, addition of the Grignard reagent (VII) to the lactone function of (VI) yields the desired 2-ethylbutyl ketone.
| 【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 . |
| 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) | 57436 | dimethyl 4-(3,4-dimethoxyphenyl)-1-hydroxy-5,6,7-trimethoxy-2,3-naphthalenedicarboxylate | C25H26O10 | 详情 | 详情 | |
| (II) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (III) | 57437 | dimethyl 4-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-1-(methoxymethoxy)-2,3-naphthalenedicarboxylate | C27H30O11 | 详情 | 详情 | |
| (IV) | 57438 | 4-(3,4-dimethoxyphenyl)-5,6,7-trimethoxy-3-(methoxycarbonyl)-1-(methoxymethoxy)-2-naphthoic acid | C26H28O11 | 详情 | 详情 | |
| (V) | 57439 | 4-(3,4-dimethoxyphenyl)-1-hydroxy-5,6,7-trimethoxy-3-(methoxycarbonyl)-2-naphthoic acid | C24H24O10 | 详情 | 详情 | |
| (VI) | 57440 | methyl 6-(3,4-dimethoxyphenyl)-7,8,9-trimethoxy-4-oxo-4H-naphtho[1,2-d][1,3]dioxine-5-carboxylate | C25H24O10 | 详情 | 详情 | |
| (VII) | 57441 | bromo(2-ethylbutyl)magnesium | C6H13BrMg | 详情 | 详情 |
合成路线4
A different synthetic strategy requires the precursor phthalide derivative (V), which is prepared by two related ways. 3,4,5-Trimethoxybenzoyl chloride (I) is condensed with 2-amino-2-methyl-1-propanol (II), and the resultant hydroxy amide is further cyclized with SOCl2 to the oxazoline (III). Lithiation of (III), followed by addition to veratraldehyde (IV) and acidic oxazoline hydrolysis, leads to the target lactone (V). Alternatively, isobenzofuranone (V) is obtained by direct condensation between trimethoxybenzoic acid (VI) and veratraldehyde (IV) in the presence of polyphosphoric acid.
| 【1】 Mori, S.; et al.; Convergent synthesis of S-8921, a new potent hypocholesterolemic arylnapththalene lignan analog. Tetrahedron Lett 1999, 40, 6, 1165. |
| 【2】 Mori, S.; Takechi, S.; Kida, S. (Shionogi & Co. Ltd.); Process for producing lignan cpd.. EP 0646570; WO 9424087 . |
| 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) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
| (II) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (III) | 57442 | 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2,6-dimethoxyphenyl methyl ether; 4,4-dimethyl-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-oxazole | C14H19NO4 | 详情 | 详情 | |
| (IV) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (V) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (VI) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |
合成路线5
Addition of the lithium acetylide prepared from methyl propiolate (VIII) to 3-ethylpentanal (VII) gives methyl 6-ethyl-4-hydroxy-2-octynoate (IX), which is further oxidized to the corresponding keto ester (X) employing the Jones reagent in acetone. Cycloaddition between alkyne (X) and the lithium derivative of the isobenzofuranone (V) gives rise to the 1,4-epoxy dihydronaphthalene adduct (XI). Subsequent acidic hydrolysis of (XI) furnishes the hydroxy naphthalenone (XII). Finally, reductive aromatization of (XII) using TiCl3 produces the title naphthol compound.
| 【1】 Mori, S.; Takechi, S.; Kida, S. (Shionogi & Co. Ltd.); Process for producing lignan cpd.. EP 0646570; WO 9424087 . |
| 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) | 57444 | 3-ethylpentanal | C7H14O | 详情 | 详情 | |
| (VIII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (IX) | 57445 | methyl 6-ethyl-4-hydroxy-2-octynoate | C11H18O3 | 详情 | 详情 | |
| (X) | 57432 | methyl 6-ethyl-4-oxo-2-octynoate | C11H16O3 | 详情 | 详情 | |
| (XI) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (XII) | 57446 | methyl 8-(3,4-dimethoxyphenyl)-10-(3-ethylpentanoyl)-4,5,6-trimethoxy-1-[(trimethylsilyl)oxy]-11-oxatricyclo[6.2.1.0~2,7~]undeca-2,4,6,9-tetraene-9-carboxylate | C33H44O10Si | 详情 | 详情 |
合成路线6
In a related procedure, malic acid (I) is converted into the O-acetylated monomethyl ester (IV) by a sequence involving O-acetylation with acetic anhydride, followed by dehydration of the resultant O-acetyl malic acid (II) to the cyclic anhydride (III), which undergoes further methanolysis to mono ester (IV). Mono-acid (IV) is then chlorinated with SOCl2, yielding acid chloride (V). Subsequent Li2CuCl4-catalyzed cross-coupling of acid chloride (V) with 2-ethylbutylmagnesium bromide (VI) affords ketone (VII). Elimination of the acetate group of (VII) with triethylamine in toluene leads to the acyl propenoate (VIII). This is subjected to cycloaddition reaction with the lithium derivative of phthalide (IX) producing the dihydroxydihydronaphthalene adduct (X). Finally, dehydration of (X) under acidic conditions furnishes the title compound.
| 【1】 Mori, S.; et al.; Convergent synthesis of S-8921, a new potent hypocholesterolemic arylnapththalene lignan analog. Tetrahedron Lett 1999, 40, 6, 1165. |
| 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) | 22743 | Hydroxysuccinic acid; Malic acid; Hydroxybutanedioic acid | 617-48-1 | C4H6O5 | 详情 | 详情 |
| (II) | 57448 | 2-(acetyloxy)succinic acid | C6H8O6 | 详情 | 详情 | |
| (III) | 57449 | 2,5-dioxotetrahydro-3-furanyl acetate | C6H6O5 | 详情 | 详情 | |
| (IV) | 57450 | 3-(acetyloxy)-4-methoxy-4-oxobutanoic acid | C7H10O6 | 详情 | 详情 | |
| (V) | 57451 | methyl 2-(acetyloxy)-4-chloro-4-oxobutanoate | C7H9ClO5 | 详情 | 详情 | |
| (VI) | 57441 | bromo(2-ethylbutyl)magnesium | C6H13BrMg | 详情 | 详情 | |
| (VII) | 57452 | methyl 2-(acetyloxy)-6-ethyl-4-oxooctanoate | C13H22O5 | 详情 | 详情 | |
| (VIII) | 57453 | methyl (E)-6-ethyl-4-oxo-2-octenoate | C11H18O3 | 详情 | 详情 | |
| (IX) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (X) | 57454 | methyl (1S,2R)-1-(3,4-dimethoxyphenyl)-3-(3-ethylpentanoyl)-1,4-dihydroxy-6,7,8-trimethoxy-1,2-dihydro-2-naphthalenecarboxylate | C30H38O10 | 详情 | 详情 |