【结 构 式】 |
【分子编号】47355 【品名】4-(2-hydroxyethyl)phenol 【CA登记号】501-94-0 |
【 分 子 式 】C8H10O2 【 分 子 量 】138.1662 【元素组成】C 69.55% H 7.3% O 23.16% |
合成路线1
该中间体在本合成路线中的序号:(VI)The intermediate carboxylic acid (XIII) was prepared as follows: 2-(4-Hydroxyphenyl)ethanol (VI) was selectively protected at the phenolic hydroxyl with benzyl bromide, yielding (VII). Subsequent oxidation of the aliphatic alcohol group of (VII) with Dess-Martin periodinane reagent provided aldehyde (VIII). Wadsworth-Emmons condensation of (VIII) with the sodium derivative of phosphonate (IX) furnished adduct (X), which was further hydrogenated over Pd/C to the saturated ester (XI). The phenolic hydroxyl group of (XI), which was concomitantly debenzylated in the preceding hydrogenation step, was further reprotected as the methoxymethyl ether (XII). Acid (XIII) was then obtained by basic hydrolysis of ester (XII).
【1】 Takaoka, E.; et al.; Catalytic asymmetric synthesis of arbutamine. Heterocycles 1997, 46, 157. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
(VII) | 33328 | 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol | C15H16O2 | 详情 | 详情 | |
(VIII) | 55597 | 2-[4-(benzyloxy)phenyl]acetaldehyde | C15H14O2 | 详情 | 详情 | |
(IX) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(X) | 55598 | ethyl (E)-4-[4-(benzyloxy)phenyl]-2-butenoate | C19H20O3 | 详情 | 详情 | |
(XI) | 55599 | ethyl 4-(4-hydroxyphenyl)butanoate | C12H16O3 | 详情 | 详情 | |
(XII) | 55600 | ethyl 4-[4-(methoxymethoxy)phenyl]butanoate | C14H20O4 | 详情 | 详情 | |
(XIII) | 55601 | 4-[4-(methoxymethoxy)phenyl]butanoic acid | C12H16O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)Condensation of 4-hydroxyphenylethanol (I) with 2-(chloromethyl)quinoline (II) in ethanolic KOH provided ether (III). The free hydroxyl group of (III) was then converted to the corresponding mesylate (IV) by treatment with methanesulfonyl chloride and Et3N. Alkylation of 11-(4-piperidinylidene)-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-methanol (V) with mesylate (IV) in the presence of NaHCO3 gave adduct (VI). The primary alcohol of (VI) was oxidized to aldehyde (VII) using MnO2 in CH2Cl2. Finally, aldehyde (VII) was further oxidized to the title methyl ester by means of MnO2 in the presence of sodium cyanate in HOAc-MeOH.
【1】 Janssens, F.E.; Leenaerts, J.E.; Sommen, F.M.; Surleraux, D.L.N.G. (Janssen Pharmaceutica NV); Fused imidazole derivs. as multidrug resistance modulators. EP 0888352; JP 2000505477; US 6218381; WO 9734897 . |
【2】 Snoeck, H.J.M. (Janssen Pharmaceutica NV); Fused imidazole derivs. for improving oral bioavailability of pharmaceutical agents. WO 9913871 . |
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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
(II) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
(III) | 47356 | 2-[4-(2-quinolinylmethoxy)phenyl]-1-ethanol | C18H17NO2 | 详情 | 详情 | |
(IV) | 47357 | 4-(2-quinolinylmethoxy)phenethyl methanesulfonate | C19H19NO4S | 详情 | 详情 | |
(V) | 47358 | [11-(4-piperidinylidene)-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepin-3-yl]methanol | C18H21N3O | 详情 | 详情 | |
(VI) | 47359 | (11-[1-[4-(2-quinolinylmethoxy)phenethyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepin-3-yl)methanol | C36H36N4O2 | 详情 | 详情 | |
(VII) | 47360 | 11-[1-[4-(2-quinolinylmethoxy)phenethyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carbaldehyde | C36H34N4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)The reaction of 2-(4-hydroxyphenyl)ethyl alcohol (I) with Ms-Cl and TEA in dichloromethane gives the bis-methanesulfonate (II), which is condensed with 4-hydroxybenzaldehyde (III) by means of K2CO3 in acetonitrile to yield the substituted benzaldehyde (IV). The condensation of (IV) with phosphonium salt (V) by means of tetramethylguanidine (TMG) in chloroform affords the acrylic ester (VI), which is reduced with H2 over Pd/C in ethyl acetate to provide the propionic ester (VII). The hydrolysis of (VII) with LiOH in THF/water gives the propionic acid (VIII) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to yield the amide (X) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XI) is treated with H2SO4 in hot dioxane/water to furnish 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 |
---|---|---|---|---|---|---|
(I) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
(II) | 50403 | 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate | C10H14O6S2 | 详情 | 详情 | |
(III) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
(IV) | 50404 | 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate | C16H16O5S | 详情 | 详情 | |
(V) | 50405 | (Ethoxy(ethoxycarbonyl)methyl)triphenylphosphonium chloride | C24H26ClO3P | 详情 | 详情 | |
(VI) | 50406 | ethyl (E)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]-2-propenoate | C22H26O7S | 详情 | 详情 | |
(VII) | 50407 | ethyl 2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate | C22H28O7S | 详情 | 详情 | |
(VIII) | 50408 | 2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propionic acid | C20H24O7S | 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 |
(X) | 50409 | 4-[2-[4-(2-ethoxy-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-oxopropyl)phenoxy]ethyl]phenyl methanesulfonate | C28H33NO7S | 详情 | 详情 | |
(XI) | 50410 | 4-[2-[4-((2S)-2-ethoxy-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-oxopropyl)phenoxy]ethyl]phenyl methanesulfonate | C28H33NO7S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)2-(4-Hydroxyphenyl)ethanol (I) was protected at the aliphatic hydroxyl group by the following sequence. Reaction of (I) with methoxymethyl chloride and NaH blocked the phenolic hydroxyl as the methoxymethyl ether (II), which was subsequently treated with benzyl bromide to produce the fully protected compound (III). Further hydrolysis of the methoxymethyl ether using trifluoroacetic acid gave rise to 4-(2-benzyloxyethyl)phenol (IV). Condensation of phenol (IV) with 1,1,1-trichloro-2-methyl-2-propanol (V) under basic conditions generated the 2-(aryloxy)isobutyric acid (VI). After esterification of (VI) with SOCl2 in EtOH to give (VII), its O-benzyl protecting group was removed by catalytic hydrogenation to produce (VIII). Alcohol (VIII) was then converted into alkyl bromide (IX) by using CBr4 and PPh3. Alkylation of (-)-4'-hydroxynorephedrine (X) with bromide (IX) in hot DMF afforded the secondary amine (XI). The ethyl ester group of (XI) was finally hydrolyzed with NaOH to the title carboxylic acid.
【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265. |
【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hiribayashi, A. (Kissei Pharmaceutical Co., Ltd.); 2-Methylpropionic acid derivs. and medicinal compsns. containing the same. EP 1072583; WO 9952856 . |
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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
(II) | 56061 | sodium 2-[4-(methoxymethoxy)phenyl]-1-ethanolate | C10H13NaO3 | 详情 | 详情 | |
(III) | 56062 | benzyl 4-(methoxymethoxy)phenethyl ether; 1-[2-(benzyloxy)ethyl]-4-(methoxymethoxy)benzene | C17H20O3 | 详情 | 详情 | |
(IV) | 56063 | 4-[2-(benzyloxy)ethyl]phenol | C15H16O2 | 详情 | 详情 | |
(V) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
(VI) | 56064 | 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoic acid | C19H22O4 | 详情 | 详情 | |
(VII) | 56065 | ethyl 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoate | C21H26O4 | 详情 | 详情 | |
(VIII) | 56066 | ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropanoate | C14H20O4 | 详情 | 详情 | |
(IX) | 56067 | ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
(X) | 46836 | 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol | C9H13NO2 | 详情 | 详情 | |
(XI) | 56068 | ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropanoate | C23H31NO5 | 详情 | 详情 |