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【结 构 式】 
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【分子编号】50411 【品名】ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate 【CA登记号】 |
【 分 子 式 】C20H22O4 【 分 子 量 】326.39228 【元素组成】C 73.6% H 6.79% O 19.61% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of 4-(benzyloxy)benzaldehyde (XII) with phosphonium salt (V) by means of TMG as before gives the acrylic ester (XIII), which is hydrogenated with H2 over Rh/C in methanol to yield the propionic ester (XIV). The hydrolysis of (XIV) with LiOH in dioxane/water affords the corresponding acid (XV) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to provide the amide (XVI) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XVII) is treated with H2SO4 in hot dioxane/water to furnish the chiral propionic acid (XVIII), which is esterified with EtOH and HCl to give the ethyl propionate (XIX). The hydrogenolysis of the benzyl ether group of (XIX) with H2 over Pd/C in ethyl acetate yields the phenolic derivative (XX), which is condensed with the bis-methanesulfonate by means of K2CO3 in acetonitrile to afford the adduct (XXI). Finally, the ester group of (XXI) is hydrolyzed with LiOH in THF/water to provide the target propionic acid.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959. |
| 【2】 Andersson, K.; Boije, M.; Inghardt, T.; Lindstedt Alstermark, E.-L.; Gottfries, J.; Li, L. (AstraZeneca plc); New 3-aryl-2-aryl propionic acid derivs. and analogs. EP 1084101; EP 1084102; EP 1084103; WO 9962870; WO 9962871; WO 9962872 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 50403 | 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate | C10H14O6S2 | 详情 | 详情 | |
| (V) | 50405 | (Ethoxy(ethoxycarbonyl)methyl)triphenylphosphonium chloride | C24H26ClO3P | 详情 | 详情 | |
| (IX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (XIII) | 50411 | ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (XIV) | 50412 | ethyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XV) | 50413 | 3-[4-(benzyloxy)phenyl]-2-ethoxypropionic acid | C18H20O4 | 详情 | 详情 | |
| (XVI) | 50414 | 3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVII) | 50415 | (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVIII) | 40516 | methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (XIX) | 50417 | ethyl (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XX) | 50418 | ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (XXI) | 50419 | ethyl (2S)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate | C22H28O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IIIa)Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.
| 【1】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 . |
| 【2】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 50411 | ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (IIIb) | 51683 | ethyl (Z)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (I) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (II) | 51675 | ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate | C10H21O6P | 详情 | 详情 | |
| (IV) | 51682 | ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (V) | 51676 | methyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C19H22O4 | 详情 | 详情 | |
| (VI) | 51677 | methyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate | C12H16O4 | 详情 | 详情 | |
| (VII) | 51678 | 2-(10H-phenoxazin-10-yl)ethyl methanesulfonate | C15H15NO4S | 详情 | 详情 | |
| (VIII) | 51679 | ethyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate | C27H29NO5 | 详情 | 详情 | |
| (IX) | 51680 | methyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate | C26H27NO5 | 详情 | 详情 | |
| (X) | 51681 | 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid | C25H25NO5 | 详情 | 详情 |