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【结 构 式】 
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【分子编号】61620 【品名】4-Methoxy-3-(3-methoxypropoxy)benzaldehyde 【CA登记号】172900-75-3 |
【 分 子 式 】C12H16O4 【 分 子 量 】224.25664 【元素组成】C 64.27% H 7.19% O 28.54% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivative (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is reduced with diisobutylaluminum hydride in toluene to provide the unsaturated alcohol (VI). Finally, this compound is enantioselectively reduced with H2 over a chiral biphenylyl diphenylphosphine catalyst and a [Rh(norbornadiene)Cl]2 catalyst in toluene to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-1-propanol (VII). (see scheme 26758001d, intermediate (XXIX)).
| 【1】 Herold, P.; Stutz, S.; Spindler, F. (Speedel Pharma Inc.); Process for the preparation of (R)-2-alkyl-3-phenyl-1-propanols. WO 0202487 . |
| 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) | 61620 | 4-Methoxy-3-(3-methoxypropoxy)benzaldehyde | 172900-75-3 | C12H16O4 | 详情 | 详情 |
| (II) | 61621 | propyl 3-methylbutanoate | C8H16O2 | 详情 | 详情 | |
| (III) | 61622 | propyl 2-{hydroxy[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C20H32O6 | 详情 | 详情 | |
| (IV) | 61623 | propyl 2-{(acetyloxy)[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C22H34O7 | 详情 | 详情 | |
| (V) | 61624 | propyl (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoate | C20H30O5 | 详情 | 详情 | |
| (VI) | 61625 | (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propen-1-ol | C17H26O4 | 详情 | 详情 | |
| (VII) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivate (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is hydrolyzed with KOH in ethanol to provide the unsaturated free acid (VI). Finally, this compound is enantioselectively reduced with H2 over several chiral Rh catalysts {[Rh(NBD)2BF4, [Rh(NBD)(OCOCF3)2], [Rh(NBD)Cl2], etc} to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid (VII). (see scheme 26758001a, intermediate (VII)).
| 【1】 Herold, P.; Stutz, S. (Speedel Pharma Inc.); Preparation of (R)-2-alkyl-3-phenylpropionic acids. WO 0202500 . |
| 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) | 61620 | 4-Methoxy-3-(3-methoxypropoxy)benzaldehyde | 172900-75-3 | C12H16O4 | 详情 | 详情 |
| (II) | 61621 | propyl 3-methylbutanoate | C8H16O2 | 详情 | 详情 | |
| (III) | 61622 | propyl 2-{hydroxy[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C20H32O6 | 详情 | 详情 | |
| (IV) | 61623 | propyl 2-{(acetyloxy)[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutanoate | C22H34O7 | 详情 | 详情 | |
| (V) | 61624 | propyl (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoate | C20H30O5 | 详情 | 详情 | |
| (VI) | 61626 | (E)-2-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid | C17H24O5 | 详情 | 详情 | |
| (VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)
| 【1】 Dorg H, Zhang ZL, Huang JH, et al. 2005. Practical synthesisi of an orally active renin inhibitory aliskiren. Tetrahedron Lett, 46(37): 6337～6340 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 67017 | 2-cyano-2-methylpropanamide | 7505-93-3 | C5H8N2O | 详情 | 详情 |
| (I) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (II) | 67010 | 3-methoxypropyl methanesulfonate | C5H12O4S | 详情 | 详情 | |
| (III) | 61620 | 4-Methoxy-3-(3-methoxypropoxy)benzaldehyde | 172900-75-3 | C12H16O4 | 详情 | 详情 |
| (IV) | 28116 | [4-methoxy-3-(3-methoxypropoxy)phenyl]methanol | 172900-74-2 | C12H18O4 | 详情 | 详情 |
| (V) | 28117 | 3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether | 172900-73-1 | C12H17BrO3 | 详情 | 详情 |
| (VI) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (VII) | 28118 | (4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C27H35NO6 | 详情 | 详情 | |
| (VIII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
| (IX) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
| (X) | 28120 | 3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 172900-69-5 | C17H27BrO3 | 详情 | 详情 |
| (XI) | 67009 | (S)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine | 134870-62-5 | C11H20N2O2 | 详情 | 详情 |
| (XII) | 67011 | 3,6-diethoxy-2-isopropyl-5-(2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutyl)-2,5-dihydropyrazine | C28H46N2O5 | 详情 | 详情 | |
| (XIII) | 67012 | ethyl 2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoate | C21H35NO5 | 详情 | 详情 | |
| (XIV) | 28122 | methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate | C25H41NO7 | 详情 | 详情 | |
| (XV) | 67013 | tert-butyl (1-hydroxy-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexan-2-yl)carbamate | C24H41NO6 | 详情 | 详情 | |
| (XVI) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
| (XVII) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (XVIII) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
| (XIX) | 23285 | (4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (XX) | 67014 | 4-benzyl-3-(2-((benzyloxy)methyl)-3-methylbutanoyl)oxazolidin-2-one | C23H27NO4 | 详情 | 详情 | |
| (XXI) | 67015 | (R)-2-((benzyloxy)methyl)-3-methylbutanoic acid | C13H18O3 | 详情 | 详情 | |
| (XXII) | 67016 | 2-((benzyloxy)methyl)-3-methylbutan-1-ol | C13H20O2 | 详情 | 详情 | |
| (XXIII) | 66991 | (R)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene | C13H19BrO | 详情 | 详情 | |
| (XXIV) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (XXVI) | 67018 | benzyl (3-amino-2,2-dimethyl-3-oxopropyl)carbamate | C13H18N2O3 | 详情 | 详情 | |
| (XXVII) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
| (XXVIII) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
| (XXIX) | 67019 | tert-butyl (6-hydroxy-8-(hydroxymethyl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate | C30H53NO7 | 详情 | 详情 | |
| (XXX) | 67004 | tert-butyl (1-(4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)carbamate | C30H49NO7 | 详情 | 详情 | |
| (XXXI) | 67020 | tert-butyl (8-((1-amino-2-methyl-1-oxopropan-2-yl)carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate | C34H59N3O8 | 详情 | 详情 |