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【结 构 式】 
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【药物名称】Rivastatin, Cerivastatin sodium, Bay-w-6228, Certa, Baycol, Lipobay(free acid) 【化学名称】(+)-(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt 【CA登记号】143201-11-0, 145599-86-6 (free acid) 【 分 子 式 】C26H33FNNaO5 【 分 子 量 】481.54481 |
【开发单位】Bayer (Originator), Fournier (Licensee), GlaxoSmithKline (Licensee), Takeda (Licensee) 【药理作用】Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, HMG-CoA Reductase Inhibitors |
合成路线1
The compound can be obtained in a multistep synthesis as outlined in Scheme 18923701a. The cyclization of ethyl 3-amino-4-methylpent-2-enoate and 4-(ethoxycarbonyl)-5-(4-fluorophenyl)-2-methylpent-4-en-3-one (II) in a conventional dihydropyridine synthesis gives the dihydropyridine (III), which is oxidized to the symmetric penta-substituted pyridine (IV). After selective monoreduction with Red-Al the pyridine alcohol (V) is methylated to (VI). The second ester group is converted to the aldehyde (VII) in a two-step reduction/oxidation procedure. trans-Selective Wittig-Horner reaction with diethyl 2-(cyclohexylamino)vinylphosphonate affords the alpha,beta-unsaturated aldehyde (VIII). The condensation of (VIII) with methyl acetoacetate and subsequent erythro-selective reduction with triethylborane and NaBH4 results in the racemic dihydroxyester (IX). The reaction of (IX) with (S)-(+)-phenylglycinol yields the two diastereomeric (S)-(+)-phenylglycinolamides which can be separated on a silical gel column. After hydrolysis of the phenylglycinolamide (X) the sodium salt of the (+)-enantiomer is obtained.
| 【1】 Angerbauer, R.; Fey, P.; Hubsch, W.; Philipps, T.; Bischoff, H.; Petzinna, D.; Schmidt, D.; Thomas, G. (Bayer AG); Substituted pyridines. AU 8928617; EP 0325130; JP 1989216974; US 5006530; US 5169857 . |
| 【2】 Angerbauer, R.; Fey, P.; Hubsch, W.; Philipps, T.; Bischoff, H.; Petzinna, D.; Schmidt, D.; Thomas, G. (Bayer AG); Substituted pyridyl-dihydroxy-heptenoic acid and its salts. DE 4040026; EP 0491226; JP 1992308573; US 5177080 . |
| 【3】 Bischoff, H.; Ritter, W.; Steinke, W.; Angerbauer, R.; BAY W 6228. Drugs Fut 1994, 19, 6, 537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 42234 | Diethyl 2-(cyclohexylamino)vinylphosphonate | C12H24NO3P | 详情 | 详情 | ||
| (I) | 15876 | ethyl (E)-3-amino-4-methyl-2-pentenoate | C8H15NO2 | 详情 | 详情 | |
| (II) | 15877 | ethyl (Z)-3-(4-fluorophenyl)-2-isobutyryl-2-propenoate | C15H17FO3 | 详情 | 详情 | |
| (III) | 15878 | diethyl 4-(4-fluorophenyl)-2,6-diisopropyl-1,4-dihydro-3,5-pyridinedicarboxylate | C23H30FNO4 | 详情 | 详情 | |
| (IV) | 15879 | diethyl 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-pyridinedicarboxylate | C23H28FNO4 | 详情 | 详情 | |
| (V) | 15880 | ethyl 4-(4-fluorophenyl)-5-(hydroxymethyl)-2,6-diisopropylnicotinate | C21H26FNO3 | 详情 | 详情 | |
| (VI) | 15881 | ethyl 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinate | C22H28FNO3 | 详情 | 详情 | |
| (VII) | 15882 | 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinaldehyde | C20H24FNO2 | 详情 | 详情 | |
| (VIII) | 15883 | (E)-3-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-2-propenal | C22H26FNO2 | 详情 | 详情 | |
| (IX) | 15884 | methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate | C27H36FNO5 | 详情 | 详情 | |
| (X) | 15885 | (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]-6-heptenamide | C34H43FN2O5 | 详情 | 详情 |
合成路线2
In an alternative approach, the racemic dihydroxymethyl ester (IX) is converted to the racemic lactone (XI), which can be separated into the pure enantiomers on a large-scale chromatography using the newly developed chiral phase Baychiral PM. Finally, the (+)-lactone (XII) is hydrolyzed to BAY W 6228.
| 【1】 Angerbauer, R.; Bischoff, H.; Bömer, B.; Fey, P.; Grosser, R.; Hübsch, W.; Lange, W.; Lautz, J.; Philipps, T.; Schmidt, D.; Stereoselective biological activity of the synthetic HMG-CoA reductase inhibitor BAY W 6228. 2nd Eur Med Chem Conf (March 31-April 4, Bad Nauheim) 1993, 1993. |
| 【2】 Bischoff, H.; Ritter, W.; Steinke, W.; Angerbauer, R.; BAY W 6228. Drugs Fut 1994, 19, 6, 537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 15884 | methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoate | C27H36FNO5 | 详情 | 详情 | |
| (XI) | 64684 | (rac)-[(4R*,6S*)-6-{(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one] | C26H32FNO4 | 详情 | 详情 | |
| (XII) | 15886 | (4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one | C26H32FNO4 | 详情 | 详情 | |
| (XIII) | 15888 | (4S,6R)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one | C26H32FNO4 | 详情 | 详情 |
合成路线3
A synthesis of [14C]-labeled cerivastatin has been developed: The decarboxylative bromination of 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine-3-carboxylic acid (I) gave the bromopyridine (II), which is treated with BuLi and [14C]-labeled CO2 affording the labeled carboxylic acid (III). The methylation of (III) with diazomethane gave the corresponding methyl ester (IV), which was reduced with LiAlH4 in ether to the alcohol (V). The reaction of (V) with SOCl2 afforded the chloromethyl derivative (VI), which was condensed with triethyl phosphite at 180 C to give the phosphonate (VII). The condensation of (VII) with the tetrahydropyran-2-carbaldehyde (VIII) by means of LDA in THF yielded the olefine (IX), which was treated with HCl in aqueous THF eliminating the protecting groups and thus, providing the epimeric mixture of hemiacetals (X). The oxidation of (X) with silver carbonate in refluxing toluene gave the lactone (XI), which was finally treated with NaOH in water/acetonitrile.
| 【1】 Angerbauer, R.; Radtke, M.; Synthesis of [C14]cerivastatin. J Label Compd Radiopharm 1999, 42, 2, 101. |
| 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),(III) | 24969 | 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinic acid | C20H24FNO3 | 详情 | 详情 | |
| (II) | 24970 | 3-bromo-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine; [5-bromo-4-(4-fluorophenyl)-2,6-diisopropyl-3-pyridinyl]methyl methyl ether | C19H23BrFNO | 详情 | 详情 | |
| (III) | 45279 | 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinic acid | C20H24FNO3 | 详情 | 详情 | |
| (IV) | 24972 | methyl 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinate | C21H26FNO3 | 详情 | 详情 | |
| (IV) | 45280 | methyl 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)nicotinate | C21H26FNO3 | 详情 | 详情 | |
| (V) | 24973 | [4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]methanol | C20H26FNO2 | 详情 | 详情 | |
| (V) | 45281 | [4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]methanol | C20H26FNO2 | 详情 | 详情 | |
| (VI) | 24974 | 3-(chloromethyl)-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine; [5-(chloromethyl)-4-(4-fluorophenyl)-2,6-diisopropyl-3-pyridinyl]methyl methyl ether | C20H25ClFNO | 详情 | 详情 | |
| (VI) | 45282 | 3-(chloromethyl)-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine; [5-(chloromethyl)-4-(4-fluorophenyl)-2,6-diisopropyl-3-pyridinyl]methyl methyl ether | C20H25ClFNO | 详情 | 详情 | |
| (VII) | 24975 | ethyl methyl [4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]methylphosphonate | C23H33FNO4P | 详情 | 详情 | |
| (VII) | 45283 | ethyl methyl [4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]methylphosphonate | C23H33FNO4P | 详情 | 详情 | |
| (VIII) | 24976 | (2S,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxytetrahydro-2H-pyran-2-carbaldehyde | C13H26O4Si | 详情 | 详情 | |
| (IX) | 24977 | 3-[(E)-2-((2S,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxytetrahydro-2H-pyran-2-yl)ethenyl]-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine | C33H50FNO4Si | 详情 | 详情 | |
| (IX) | 45284 | tert-butyl(dimethyl)silyl (2S,4R,6S)-2-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-6-methoxytetrahydro-2H-pyran-4-yl ether; 3-[(E)-2-((2S,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxytetrahydro-2H-pyran-2-yl)ethenyl]-4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine | C33H50FNO4Si | 详情 | 详情 | |
| (X) | 24978 | (4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]tetrahydro-2H-pyran-2,4-diol | C26H34FNO4 | 详情 | 详情 | |
| (X) | 45285 | (4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]tetrahydro-2H-pyran-2,4-diol | C26H34FNO4 | 详情 | 详情 | |
| (XI) | 15886 | (4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one | C26H32FNO4 | 详情 | 详情 | |
| (XI) | 45286 | (4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyridinyl]ethenyl]-4-hydroxytetrahydro-2H-pyran-2-one | C26H32FNO4 | 详情 | 详情 |