|
【结 构 式】 
|
【分子编号】23285 【品名】(4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C15H19NO3 【 分 子 量 】261.3208 【元素组成】C 68.94% H 7.33% N 5.36% O 18.37% |
与该中间体有关的原料药合成路线共 2 条
合成路线1
该中间体在本合成路线中的序号：(IV)3-Benzyloxy-4-methoxybenzaldehyde (I) was reduced to benzyl alcohol (II) with NaBH4, and then converted into bromide (III) using Me3SiBr. Alkylation of 4-(R)-benzyl-3-isovaleroyl-oxazolidinone (IV) with bromide (III) in the presence of lithium hexamethyldisilazide in THF at -70 C produced the (R,R) diastereoisomer (V). Then, hydrolysis of (V) with lithium hydroperoxide gave the (R)-acid (VI), which was reduced to alcohol (VII) by means of NaBH4 and I2. The reation of (VII) with NBS and PPh3 yielded bromide (VIII), which was condensed with dihydropyrazine (IX) in the presence of BuLi to give compound (X) as the major diastereoisomer. Subsequent acid hydrolysis of the dihydropyrazine (X) provided aminoester (XI), which was protected as the tert-butyl carbamate (XII) with Boc2O and DIEA. The carboxylate group of (XII) was reduced to aldehyde (XIII) with DIBAL-H in cold toluene. This aldehyde (XIII) was condensed with N-butyl methacrylamide (XIV) in the presence of butyllithium and chlorotitanium triisopropoxide at -75 C to give a mixture of diastereoisomeric aminoalcohols, from which the major threo compound (XV) was isolated by column chromatography.
| 【1】 Rasetti, V.; Wood, J.; Grütter, M.; Maibaum, J.; Goeschke, R.; Cohen, N.C.; Fuhrer, W.; Rahuel, J.; Stutz, S.; Novel 2,7-dialkyl substituted 5(S)-amino-4(S)-hydr. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.229. |
| 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) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (II) | 23283 | [3-(benzyloxy)-4-methoxyphenyl]methanol | C15H16O3 | 详情 | 详情 | |
| (III) | 23284 | 2-(benzyloxy)-4-(bromomethyl)-1-methoxybenzene; benzyl 5-(bromomethyl)-2-methoxyphenyl ether | C15H15BrO2 | 详情 | 详情 | |
| (IV) | 23285 | (4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (V) | 23286 | (4R)-4-benzyl-3-[(2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C30H33NO5 | 详情 | 详情 | |
| (VI) | 23287 | (2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyric acid | C20H24O4 | 详情 | 详情 | |
| (VII) | 23288 | (2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methyl-1-butanol | C20H26O3 | 详情 | 详情 | |
| (VIII) | 23289 | benzyl 5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenyl ether; 2-(benzyloxy)-4-[(2R)-2-(bromomethyl)-3-methylbutyl]-1-methoxybenzene | C20H25BrO2 | 详情 | 详情 | |
| (IX) | 10291 | (S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (2S)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3S)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether | 78342-42-4 | C9H16N2O2 | 详情 | 详情 |
| (X) | 23291 | benzyl 5-((2S)-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]-3-methylbutyl)-2-methoxyphenyl ether; (2S,5R)-2-[(2S)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | C29H40N2O4 | 详情 | 详情 | |
| (XI) | 23292 | methyl (2S,4S)-2-amino-4-[3-(benzyloxy)-4-methoxybenzyl]-5-methylhexanoate | C23H31NO4 | 详情 | 详情 | |
| (XII) | 23293 | methyl (2S,4S)-4-[3-(benzyloxy)-4-methoxybenzyl]-2-[(tert-butoxycarbonyl)amino]-5-methylhexanoate | C28H39NO6 | 详情 | 详情 | |
| (XIII) | 23294 | tert-butyl (1S,3S)-3-[3-(benzyloxy)-4-methoxybenzyl]-1-formyl-4-methylpentylcarbamate | C27H37NO5 | 详情 | 详情 | |
| (XIV) | 23295 | N-butyl-2-methylacrylamide | C8H15NO | 详情 | 详情 | |
| (XV) | 23296 | tert-butyl (1S,2S)-1-[(2S)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyl]-4-[(butylamino)carbonyl]-2-hydroxy-4-pentenylcarbamate | C35H52N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)
| 【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 |
Extended Information