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【结 构 式】 
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【分子编号】50418 【品名】ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate 【CA登记号】 |
【 分 子 式 】C13H18O4 【 分 子 量 】238.28352 【元素组成】C 65.53% H 7.61% O 26.86% |
合成路线1
该中间体在本合成路线中的序号：(XX)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：(XX)Reaction of chloroacetic acid (XXII) with sodium ethoxide (XXIII) in ethanol gives 2-ethoxyacetic acid ethyl ester (XXIV), which is condensed with 4-methoxybenz-aldehyde (XXV) by means of t-BuOK in THF to yield 2-ethoxy-3-(4-methoxyphenyl)-2-propenoic acid ethyl ester (XXVI). Hydrolysis of ester (XXVI) with NaOH in hot ethanol/water affords the propenoic acid derivative (XXVII), which is reduced with H2 over Pd/C in ethanol to provide racemic 2-ethoxy-3-(4-methoxyphenyl)propionic acid (XXVIII). Optical resolution of mixture (XXVIII) is performed by salt formation with 1(S)-(1-naphthyl)ethylamine (XXIX) followed by crystallization to give the diastereomeric salt (XXX), which is treated with NaOH, followed by acidification with HCl to yield 2(S)-ethoxy-3-(4-methoxyphenyl)propionic acid (XXXI). Demethylation of compound (XXXI) by reaction with NaOH and octanethiol in NMP affords 2(S)-ethoxy-3-(4-hydroxyphenyl)propionic acid (XXXII), which is esterified with ethanol/HCl to provide the corresponding ethyl ester (XXXIII). Condensation of ester (XXXIII) with the bismesylate (II) by means of either K2CO3 in 2-butanone or Na2CO3 in acetone provides 2(S)-ethoxy-3-[4-[2-[4-(methanesulfonyloxy)-phenyl]ethoxy]phenyl]propionic acid ethyl ester (XXI), which is finally hydrolyzed with NaOH or LiOH in acetone/water.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959. |
| 【2】 Ioannidis, P.; Ehrl, R.; MacKintosh, W. (AstraZeneca AB); Process for the preparation 3-aryl-2-hydroxypropionic acid deriv.. WO 0296865 . |
| 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 | |
| (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 | |
| (XXII) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (XXIII) | 63048 | sodium 1-ethanolate | C2H5NaO | 详情 | 详情 | |
| (XXIV) | 63049 | ethyl 2-ethoxyacetate | C6H12O3 | 详情 | 详情 | |
| (XXV) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XXVI) | 63050 | ethyl (E)-2-ethoxy-3-(4-methoxyphenyl)-2-propenoate | C14H18O4 | 详情 | 详情 | |
| (XXVII) | 63051 | (E)-2-ethoxy-3-(4-methoxyphenyl)-2-propenoic acid | C12H14O4 | 详情 | 详情 | |
| (XXVIII) | 63052 | 2-ethoxy-3-(4-methoxyphenyl)propanoic acid | C12H16O4 | 详情 | 详情 | |
| (XXIX) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
| (XXX) | 63053 | (1S)-1-(1-naphthyl)-1-ethanaminium (2S)-2-ethoxy-3-(4-methoxyphenyl)propanoate | C24H29NO4 | 详情 | 详情 | |
| (XXXI) | 63054 | (2S)-2-ethoxy-3-(4-methoxyphenyl)propanoic acid | C12H16O4 | 详情 | 详情 | |
| (XXXII) | 63055 | (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid | C11H14O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of 2-(carbazol-9-yl)ethanol (I) with (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate (II) under Mitsunobu conditions using tributylphosphine and 1,1'-(azodicarbonyl)dipiperidine gave ether (III). Basic hydrolysis of the ethyl ester group of (III) provided carboxylic acid (IV), which was finally isolated as the corresponding arginine salt.
| 【1】 Sauerberg, P.; Pettersson, I.; Jeppesen, L.; et al.; Novel tricyclic-alpha-alkyloxyphenylpropionic acids: Dual PPAR/gamma alpha agonists with hypolipidemic and antidiabetic activity. J Med Chem 2002, 45, 4, 789. |
| 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) | 55092 | 2-(9H-carbazol-9-yl)-1-ethanol | C14H13NO | 详情 | 详情 | |
| (II) | 50418 | ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 55093 | ethyl (2S)-3-{4-[2-(9H-carbazol-9-yl)ethoxy]phenyl}-2-ethoxypropanoate | C27H29NO4 | 详情 | 详情 | |
| (IV) | 55094 | (2S)-3-{4-[2-(9H-carbazol-9-yl)ethoxy]phenyl}-2-ethoxypropanoic acid | C25H25NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The Horner-Emmons condensation of 4,4'-dibromobenzophenone (I) with triethyl phosphonoacetate leads to the 3,3-diarylpropenoate (II). Ester (II) is subsequently reduced to the allylic alcohol (III) employing DIBAL in cold THF. Suzuki coupling of aryl bromide (III) with phenylboronic acid (IV) furnishes 3,3-bis-(biphenyl-4-yl)-2-propen-1-ol (V). Coupling of allylic alcohol (V) with (S) ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate (VI) by means of 1,1'-(azodicarbonyl)dipiperidine (ADDP) and tributylphosphine under Mitsunobu conditions gives rise to the ether adduct (VII). Finally, saponification of the ethyl ester group of (VII) provides the target carboxylic acid.
| 【1】 Mogensen, J.P.; Jeppesen, L.; Bury, P.S.; Pettersson, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K.S.; Albrektsen, T.; Din, N.; Mortensen, S.B.; Svensson, L.A.; Wasserman, K.; Wulff, E.M.; Ynddal, L.; Sauerberg, P.; Design and synthesis of novel PPARalpha/gamma/delta triple activators using a known PPARalpha/gamma dual activator as structural template. Bioorg Med Chem Lett 2003, 13, 2, 257. |
| 【2】 Sauerberg, P.; Jeppesen, L.; Bury, P.S.; Murray, A.; Pettersson, I. (Novo Nordisk A/S); New cpds., their preparation and use. EP 1171414; JP 2002542218; WO 0063153 . |
| 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) | 34447 | bis(4-bromophenyl)methanone | 3988-03-2 | C13H8Br2O | 详情 | 详情 |
| (II) | 63223 | ethyl 3,3-bis(4-bromophenyl)acrylate | C17H14Br2O2 | 详情 | 详情 | |
| (III) | 63224 | 3,3-bis(4-bromophenyl)-2-propen-1-ol | C15H12Br2O | 详情 | 详情 | |
| (IV) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (V) | 63225 | 3,3-di[1,1'-biphenyl]-4-yl-2-propen-1-ol | C27H22O | 详情 | 详情 | |
| (VI) | 50418 | ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (VII) | 63226 | ethyl (2S)-3-{4-[(3,3-di[1,1'-biphenyl]-4-yl-2-propenyl)oxy]phenyl}-2-ethoxypropanoate | C40H38O4 | 详情 | 详情 |