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【结 构 式】 
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【分子编号】10793 【品名】[(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium 【CA登记号】 |
【 分 子 式 】C10H10LiNO2 【 分 子 量 】183.13594 【元素组成】C 65.59% H 5.5% Li 3.79% N 7.65% O 17.47% |
合成路线1
该中间体在本合成路线中的序号：(IV)The synthesis of [14C]-labeled pravastatin has been reported: The reaction of propylmagnesium bromide (I) with (14)CO2 gives [14C]-butyric acid sodium salt (II), which is converted to the corresponding acyl chloride (III) by reaction with oxalyl chloride. The condensation of (III) with 4(S)-benzyloxazolidin-2-one (IV) in THF yields the corresponding acylation product (V), which is methylated with sodium hexamethyldisilazide and methyliodide to afford a mixture of tautomeric N-[4(S)-benzyl-3-[2(R and S)-methylbutyryl]oxazolidin-2-ones, which are separated by preparative HPLC to obtain the optically pure diastereomer (VI). The oxidative cleavage of (VI) with H2O2 and LiOH, followed by acidification and treatment with NaOH, yields sodium 2(S)-methylbutyrate (VII), which is treated with oxalyl chloride to afford the corresponding acyl chloride (VIII). The condensation of (VIII) with 4(R)-(tert-butyldimethylsilyloxy)-6(R)-[2-[8(S)-hydroxy-2(S)-methyl-1,2,6,7,8,8a(R)-hexahydronaphth-1(S)-yl]ethyl]tetrahydropyran-2-one (IX) by means of 4-(dimethylamino)pyridine in CH2Cl2 gives the esterified compound (X), which is deprotected with tetrabutylammonium fluoride and acetic acid, yielding the hydroxylated pyrone (XI). Finally, this compound is submitted to an asymmetric hydroxylation with a culture broth of Mucor hiemalis MF-5021. The final product is extracted from the culture broth and purified by preparative HPLC to give a final radiochemical purity of 95%.
| 【1】 Wallace, M.A.; Dean, D.C.; White, R.F.; Ellsworth, R.L.; Melillo, D.G.; Marks, T.; The synthesis of carbon-14 labeled pravastatin. J Label Compd Radiopharm 1993, 33, 8, 697. |
| 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) | 10790 | Bromo(propyl)magnesium；bromopropylMagnesium；4-propylbutyrolactone；propylmagnesiumbromide；n-propylmagnesium bromide；Bromopropylmagnesium; | 927-77-5 | C3H7BrMg | 详情 | 详情 |
| (II) | 10791 | Butyric acid sodium salt | C4H7NaO2 | 详情 | 详情 | |
| (II) | 44674 | sodium butyrate | C4H7NaO2 | 详情 | 详情 | |
| (III) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 44675 | butanoyl chloride | C4H7ClO | 详情 | 详情 | |
| (IV) | 10793 | [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (V) | 10794 | (4S)-4-Benzyl-3-butyryl-1,3-oxazolan-2-one | C14H17NO3 | 详情 | 详情 | |
| (V) | 44676 | (4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one | C14H17NO3 | 详情 | 详情 | |
| (VI) | 10795 | (4S)-4-Benzyl-3-[(2S)-2-methylbutanoyl]-1,3-oxazolan-2-one | C15H19NO3 | 详情 | 详情 | |
| (VI) | 44677 | (4S)-4-benzyl-3-[(2S)-2-methylbutanoyl]-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (VII) | 10796 | 2(S)-Methylbutyric acid sodium salt | C5H9NaO2 | 详情 | 详情 | |
| (VII) | 44678 | sodium (2S)-2-methylbutanoate | C5H9NaO2 | 详情 | 详情 | |
| (VIII) | 10797 | (2S)-2-Methylbutanoyl chloride | 57526-28-0 | C5H9ClO | 详情 | 详情 |
| (VIII) | 44679 | (2S)-2-methylbutanoyl chloride | C5H9ClO | 详情 | 详情 | |
| (IX) | 10798 | (4R,6R)-6-[2-[(1S,2S,8S,8aR)-8-Hydroxy-2-methyl-1,2,6,7,8,8a-hexahydro-1-naphthalenyl]ethyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-one | C24H40O4Si | 详情 | 详情 | |
| (X) | 10799 | (1S,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C29H48O5Si | 详情 | 详情 | |
| (X) | 44680 | (1S,7S,8S,8aR)-8-[2-((2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-oxotetrahydro-2H-pyran-2-yl)ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C29H48O5Si | 详情 | 详情 | |
| (XI) | 10800 | (1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate; Mevastatin | 109785-28-6 | C23H34O5 | 详情 | 详情 |
| (XI) | 44681 | (1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate | C23H34O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)C7-C12 fragment.- The selective monoepoxidation of 1,7-octadiene (I) with m-chloroperbenzoic acid (MCPBA) gives the epoxide (II), which is oxidized with periodic acid to the aldehyde (III). Further oxidation of (III) by means of NaClO2 yields 6-heptenoic acid (IV), which is condensed with the lithium salt of the chiral oxazolidinone (V) by means of pivaloyl chloride affording the chiral imide (VI). The methylation of (VI) with methyl iodide and sodium hexamethyldisylazide (NaHMDS) in THF provides the methylated chiral imide (VII) as a single enantiomer. The hydrolysis of (VII) with H2O2 and LiOH gives the corresponding free acid (VIII), which is reduced with LiAlH4 to the primery alcohol (IX). Finally, (IX) is treated with Swern oxidant to afford the desired taret aldehyde (X).
| 【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580. |
| 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) | 27177 | 1,7-octadiene | 3710-30-3 | C8H14 | 详情 | 详情 |
| (II) | 27178 | 2-(5-hexenyl)oxirane | 19600-63-6 | C8H14O | 详情 | 详情 |
| (III) | 27179 | 6-heptenal | C7H12O | 详情 | 详情 | |
| (IV) | 27180 | 6-heptenoic acid | 1119-60-4 | C7H12O2 | 详情 | 详情 |
| (V) | 10793 | [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (VI) | 27181 | (4S)-4-benzyl-3-(6-heptenoyl)-1,3-oxazolidin-2-one | C17H21NO3 | 详情 | 详情 | |
| (VII) | 27182 | (4S)-4-benzyl-3-[(2S)-2-methyl-6-heptenoyl]-1,3-oxazolidin-2-one | C18H23NO3 | 详情 | 详情 | |
| (VIII) | 27183 | (2S)-2-methyl-6-heptenoic acid | C8H14O2 | 详情 | 详情 | |
| (IX) | 27184 | (2S)-2-methyl-6-hepten-1-ol | C8H16O | 详情 | 详情 | |
| (X) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Cyclization of 5-(2-nitrovinyl)-1,3-benzodioxole (I) with ethyl 2-(4-methoxybenzoyl)acetate (II) by means of DBU in THF gives the 4-nitrobutyrate (III), which is reduced with H2 over Ni in ethanol to the corresponding amine, which undergoes immediate cyclization to give the pyrroline carboxylate (IV). Reduction of pyrroline (IV) with NaCNBH3 in THF affords the expected pyrrolidine as a mixture of the (trans,trans)-(V), (cis,cis)-(VI) and (cis,trans)-(VII) isomers. Using chromatography on silica gel, only the (cis,cis)-isomer (VI) is separated and completely isomerized to the (trans,trans)-isomer (V) by treatment with NaOEt in refluxing ethanol. Pure (trans,trans)-isomer (V) or the remaining mixture of (trans,trans)-(V) and (cis,trans)-(VII) is N-protected with Boc2O in dichloromethane to provide a mixture of carbamates. Then hydrolysis of the esters is performed with NaOH in ethanol/water at room temperature, and under these conditions only the (trans,trans)-isomer hydrolyzes, giving the racemic (trans,trans)-acid (VIII). Unreacted (cis,trans)-ester (VII) is easily removed by conventional methods. Condensation of the racemic acid (VIII) with the lithium salt of the chiral oxazolidinone (IX) by means of pivaloyl chloride yields the corresponding amide as a diastereomeric mixture of (X) and (XI) that are separated by chromatography. The desired isomer (XI) is deprotected with HCl in dioxane to afford the chiral pyrrolidine (XII), which is condensed with 2-bromo-N,N-dibutylacetamide (XIII) by means of diisopropylamine in acetonitrile to give the adduct (XIV). Finally, the chiral auxiliary of (XIV) is eliminated by means of LiOOH (LiOH + H2O2) in water.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
| 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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
| (IV) | 20678 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C21H21NO5 | 详情 | 详情 | |
| (V) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VI) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VII) | 48684 | ethyl (2S,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (VIII) | 20681 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid | C24H27NO7 | 详情 | 详情 | |
| (IX) | 10793 | [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (X) | 48685 | tert-butyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
| (XI) | 20684 | tert-butyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
| (XII) | 48686 | (4S)-3-[[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidinyl]carbonyl]-4-benzyl-1,3-oxazolidin-2-one | C29H28N2O6 | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XIV) | 20686 | 2-[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidinyl]-N,N-dibutylacetamide | C39H47N3O7 | 详情 | 详情 |