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【结 构 式】 
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【分子编号】21164 【品名】methyl (3S)-3-(3-nitrophenyl)pentanoate 【CA登记号】 |
【 分 子 式 】C12H15NO4 【 分 子 量 】237.25544 【元素组成】C 60.75% H 6.37% N 5.9% O 26.97% |
合成路线1
该中间体在本合成路线中的序号：(X)1) The condensation of 1-phenylhexan-3-one (I) with ethyl acetate by means of butyllithium and diisopropylamine in THF gives racemic 3-hydroxy-3-(2-phenylethyl)hexanoic acid ethyl ester (II), which is hydrolyzed with NaOH in methanol to the corresponding free acid (III). The optical resolution of (III) with (1R,2S)-(-)-norephedrine (IV) followed by treatment with aqueous HCl yields the chiral (R)-acid (V), which is treated with 4-biphenylyloxymethyl chloride (VI) and diisopropylethylamine in toluene affording the protected ester (VII). The reduction of the ester group of (VII) with diisobutylaluminum hydride (DIBAL) in toluene gives the monoprotected diol (VIII), which is oxidized at the primary hydroxy group with 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) and NaOCl yielding the corresponding aldehyde (IX). The condensation of (IX) with (R)-3-(3-nitrophenyl)pentanoic acid methyl ester (X) by means of sodium hexamethyldisilazide (NaHMDS) in THF gives the hydroxyester (XI) as a mixture of four diastereomers. This mixture is oxidized with pyridinium chlorochromate (PCC) in dichloromethane to afford the ketoester (XII) also as a mixture of two diastereomers. Elimination of the biphenylyloxymethyl protecting group with H2SO4 in methanol yields the hydroxy ketoester (XIII).
| 【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 | |
| (I) | 17233 | 1-phenyl-3-hexanone | C12H16O | 详情 | 详情 | |
| (II) | 21156 | ethyl 3-hydroxy-3-phenethylhexanoate | C16H24O3 | 详情 | 详情 | |
| (III) | 21157 | 3-hydroxy-3-phenethylhexanoic acid | C14H20O3 | 详情 | 详情 | |
| (IV) | 13355 | 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine | 37577-28-9 | C9H13NO | 详情 | 详情 |
| (IV) | 21158 | (1R,2S)-2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (V) | 21159 | (3R)-3-hydroxy-3-phenethylhexanoic acid | C14H20O3 | 详情 | 详情 | |
| (VI) | 21160 | [1,1'-biphenyl]-4-yl chloromethyl ether; 4-(chloromethoxy)-1,1'-biphenyl | C13H11ClO | 详情 | 详情 | |
| (VII) | 21161 | ([1,1'-biphenyl]-4-yloxy)methyl (3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethylhexanoate | C40H40O5 | 详情 | 详情 | |
| (VIII) | 21162 | (3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethyl-1-hexanol | C27H32O3 | 详情 | 详情 | |
| (IX) | 21163 | (3R)-3-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-phenethylhexanal | C27H30O3 | 详情 | 详情 | |
| (X) | 21164 | methyl (3S)-3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XI) | 21165 | methyl (5R)-5-[([1,1'-biphenyl]-4-yloxy)methoxy]-3-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-5-phenethyloctanoate | C39H45NO7 | 详情 | 详情 | |
| (XII) | 21166 | methyl (5R)-5-[([1,1'-biphenyl]-4-yloxy)methoxy]-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate | C39H43NO7 | 详情 | 详情 | |
| (XIII) | 21167 | methyl (5R)-5-hydroxy-2-[(1S)-1-(3-nitrophenyl)propyl]-3-oxo-5-phenethyloctanoate | C26H33NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)2) The chiral intermediate (X) has been obtained by two different ways: a) The Knovenagel condensation of dimethyl malonate (XVII) with 3-nitrobenzaldehyde (XVIII) gives the corresponding benzylidenemalonate (XIX), which is alkylated with diethyl zinc and CuBr in DMSO yielding 2-[1-(3-nitrophenyl)propyl]malonic acid dimethyl ester (XX). The partial decarboxylation of (XX) with 6N HCl affords racemic 3-(3-nitrophenyl)pentanoic acid (XXI), which is esterified with methanol/HCl to the racemic methyl ester (XXII). Finally, this racemate is resolved by chromatography over a chiral (R,R)Whelk-O1 column giving the desired intermediate (X). b) The regioselective acetylation of 1-(3-nitrophenyl)-1-propanol (XXIII) with isopropenyl acetate (XXIV) catalyzed by Amano P30 lipase gives a mixture of the (S)-acetate (XXV) and unreacted (R)-alcohol (XXVI). After separation, (XXVI) was mesylated with mesyl chloride as usual yielding mesylate (XXVII), which was condensed with the sodium salt of diethyl malonate (XXVIII) affording the chiral malonic ester (XXIX). Partial decarboxylation of (XXIX) with 6N HCl gives the chiral pentanoic acid (XXX), which is finally esterified to the desired intermediate (X) with methanol/HCl.
| 【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 21164 | methyl (3S)-3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XVII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (XVIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XIX) | 21173 | dimethyl 2-(3-nitrobenzylidene)malonate | C12H11NO6 | 详情 | 详情 | |
| (XX) | 21174 | dimethyl 2-[1-(3-nitrophenyl)propyl]malonate | C14H17NO6 | 详情 | 详情 | |
| (XXI) | 21175 | 3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 | |
| (XXII) | 21176 | methyl 3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XXIII) | 21177 | 1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXIV) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XXV) | 21179 | (1S)-1-(3-nitrophenyl)propyl acetate | C11H13NO4 | 详情 | 详情 | |
| (XXVI) | 21180 | (1R)-1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXVII) | 21181 | (1R)-1-(3-nitrophenyl)propyl methanesulfonate | C10H13NO5S | 详情 | 详情 | |
| (XXVIII) | 21182 | Diethyl malonate sodium salt | C7H11NaO4 | 详情 | 详情 | |
| (XXIX) | 21183 | diethyl 2-[(1S)-1-(3-nitrophenyl)propyl]malonate | C16H21NO6 | 详情 | 详情 | |
| (XXX) | 21184 | (3S)-3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 |