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CAS No. : | 4263-93-8 | MDL No. : | MFCD03001752 |
Formula : | C10H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JNJCEALGCZSIGB-UHFFFAOYSA-N |
M.W : | 180.20 | Pubchem ID : | 193387 |
Synonyms : |
|
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid | ||
With toluene-4-sulfonic acid In toluene for 2h; Reflux; | General procedure: A mixture of mandelic acid(12 mmol), alcohol (1.5 eq) , TsOH (500 mg) and toluene(20mL) wasrefluxed for 2 h. The resultant mixture was diluted with NaHCO3(sat.aq.)(3X10mL) and water( 2X10mL) and dried over Na2SO4.Flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether =6:1) gave the correspondingracemic mandelate ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide; acetic acid | ||
With sodium hypochlorite; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; toluene at 25℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine In ethyl acetate for 16h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With hydrogen In ethanol; water for 4h; Ambient temperature; other catalyst: Ni on Kieselguhr; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 43% 2: 52% | With hydrogen In ethanol at 45 - 50℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogen In ethanol at 20℃; for 9h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyrographite In tetrahydrofuran at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine at 0 - 5℃; for 6h; | |
With pyridine; dmap In diethyl ether at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: DMAP; pyridine / diethyl ether / 0 - 20 °C 2: SOCl2 / CH2Cl2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: DMAP; pyridine / diethyl ether / 0 - 20 °C 2: SOCl2 / CH2Cl2 3: Hunig's base / tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 78 percent Chromat. / NaOH / temp. <=10 deg C 2: 77 percent / hydrogen / Ni-Raney / ethanol; H2O / 4 h / Ambient temperature; other catalyst: Ni on Kieselguhr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1) LDA / 1) THF, -60 deg C, 10 min 2: 89 percent / xylene / Heating 3: 1) ozone, 2) dimethyl sulfide, water / 1) acetone, -60 deg C, 2) room temperature | ||
Multi-step reaction with 3 steps 1.1: lithium / tetrahydrofuran / 12 h / 0 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: saccharin / dichloromethane / Reflux; Inert atmosphere 3.1: cesium fluoride / N,N-dimethyl-formamide / 24 h / 140 °C / 760.05 Torr | ||
Multi-step reaction with 2 steps 1.1: sodium hydrogensulfite; water / diethyl ether / 2 h / 20 °C 1.2: 20 °C 2.1: water; hydrogenchloride / 1,4-dioxane / 6 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 23 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h 4: 87 percent / trifluoroacetic acid / 5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 23 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h 4: 87 percent / trifluoroacetic acid / 5 h / Ambient temperature 5: 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / CH2Cl2 / 16 h / Ambient temperature 6: pyrrolidine, 3A molecular sieves / acetonitrile / 6 h / Ambient temperature 7: H2 / 10percent Pd/C / ethanol / 16 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 28 percent / triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h 4: HCl / diethyl ether / 18 h / Ambient temperature 5: 27 percent / 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / 18 h / Ambient temperature 6: 22 percent / pyrrolidine, 3A molecular sieves / acetonitrile / 24 h / Ambient temperature 7: 36 percent / H2 / 10percent Pd/C / ethanol / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 28 percent / triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h 4: HCl / diethyl ether / 18 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 28 percent / triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h 4: HCl / diethyl ether / 18 h / Ambient temperature 5: 27 percent / 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / 18 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 28 percent / triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h 4: HCl / diethyl ether / 18 h / Ambient temperature 5: 27 percent / 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / 18 h / Ambient temperature 6: 22 percent / pyrrolidine, 3A molecular sieves / acetonitrile / 24 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 27 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 23 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 23 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h 4: 87 percent / trifluoroacetic acid / 5 h / Ambient temperature 5: 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / CH2Cl2 / 16 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 23 percent / triethylamine / CH2Cl2 / 1.) RT, 16 h, 2.) reflux, 1 h 4: 87 percent / trifluoroacetic acid / 5 h / Ambient temperature 5: 1-hydroxybenzotriazole, dicyclohexylcarbodiimide / CH2Cl2 / 16 h / Ambient temperature 6: pyrrolidine, 3A molecular sieves / acetonitrile / 6 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: 28 percent / triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 46 percent / triethylamine / ethyl acetate / 16 h / Heating 2: 1.) pyridine / 1.) dichloromethane, -22 deg C, 15 min, 2.) RT, 1 h 3: triethylamine / CH2Cl2 / 1.) RT, 1 h, 2.) reflux, 2.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogencarbonate In <i>N</i>-methyl-acetamide; ethanol; water | 2.a 5-Methyl-1,3-dioxolen-2-on-4-ylmethyl 2R-hydroxy-4-phenylbutyrate 2a 5-Methyl-1,3-dioxolen-2-on-4-ylmethyl 2R-hydroxy-4-phenylbutyrate 9.0 g (0.05 mol) of 2R-hydroxy-4-phenylbutyric acid are dissolved in 200 ml of absolute dimethylformamide, 10.0 g (0.10 mol) of potassium bicarbonate are added, the mixture is stirred at 50° C. for 90 minutes and then, while cooling in ice at 0° C., a solution of 11.6 g (0.06 mol) of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one in 50 ml of absolute dimethylformamide is added dropwise. The mixture is stirred at 0° C. for one hour and then at room temperature for 30 minutes, and is poured into 1 l of water, and the mixture is extracted twice with ethyl acetate. The combined extracts are washed twice with saturated sodium bicarbonate solution and twice with water, dried over sodium sulfate and concentrated, and impurities are removed form the crude product by column chromatography on 600 g of silica gel (mobile phase toluene/ethanol 199:1). 12.6 g (60%) of colorless oil are obtained. [α]D25 =-8.2° (C=1, methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-hydroxy-4-phenylbutanoic acid With caesium carbonate In methanol; water for 0.166667h; Stage #2: bromomethyl resin In DMF (N,N-dimethyl-formamide) at 60℃; for 18h; | 5 Example 5: Process for the preparation of (E)-2-[4-(2-ethoxycarbonyl- vinyl)-2-methoxyphenoxy]-4-phenylbutanoic acid (Example 66 of the table); A 20% solution of caesium carbonate in water (23 ml, 14.4 mmol) is added to a solution of 2-hydroxy-4-phenylbutanoic acid (7 g, 3.8 mmol) in methanol (200 ml). After stirring for 10 minutes, the solvents are evaporated off and the residue is taken up in toluene, which is then evaporated off. The residue is taken up in dimethylformamide (DMF) (125 ml), and is then added to a suspension of resin (23.7 g, 18 mmol) in DMF (125 ml). The reaction is stirred for 18 hours at 60°C. The resin is then washed several times with tetrahydrofuran (THF) (3 x 150 ml, 2 minutes), 1/1 THF/H20 (3 x 150 ml, 2 minutes), methanol (3 x 150 ml, 2 minutes), dichloromethane (3 x 150 ml, 2 minutes) and methanol (3 x 150 ml, 2 minutes). The resin is dried under vacuum at 50°C. A solution of ethyl (E)-3-(4-hydroxy-2-methoxy)phenylpent-2-enoate (1 mmol) in dichloromethane (2 ml) is added to grafted resin (150 mg, 0.1 mmol). A solution of 4,4-dimethyl-2-(triphenylphosphanyl)-1,2,5-thiadia- zo-li-dine (1 mmol) in dichloromethane (8 ml) is then added and the suspension is stirred at room temperature for 18 hours. The resin is filtered off and washed with DMF (5 ml), 50/50 DMF/H20 (5 ml), methanol (2 x 5 ml) and 80/20 dichloromethane/dichloroethane (DCM/DCE) (3 x 5 ml). The resin is then treated with 20/80 trifluoroacetic acid/dichloromethane (TFA/DCM) solution for 15 minutes. The resin is filtered off and washed with dichloromethane (2 x 5 ml). The filtrate is evaporated to give 1.9 mg of an oil, which is purified by preparative LCMS (liquid chromatography/mass spectrometry). Mass spectrometry: ES-: 383.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridinium p-toluenesulfonate In chloroform at 70℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrachloromethane at 20℃; for 16h; | Nitrosation using Method B General procedure: The carboxamide (0.25 mmol) was dissolved in CCl4 (2.5 mL) in a 25 mL RBF.The solution was cooled to 0 deg C, then NaOAc (0.75 mmol) was added. Stiring was stopped while gaseous N2O4 was bubbled into the cold suspension using a 5" disposable pipette (~2 bubbles/sec) for 5 min. The mixture was stirred vigorously for 3 h at 0 deg C, then for 16 h at rt. The bulk of solvent was removed using a rotary evaporator and the product isolated as in Method A. (For compounds 1f, 1g, and 1h, the acidified aqueous layer was saturated with NaCl before ether extraction to maximize the yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; for 5h;Inert atmosphere; Reflux; | General procedure: The catalyst [RuCl(benzene)(S)-SunPhos]Cl (40 mg, 0.04 mmol) was dissolved in degassed THF (40 mL) containing 1 M of aq HBr (480 muL), and then the solution was put into eight vials equally. To these vials 2-oxo-4-arylbutanoic acids 1 (1 mmol) were introduced, and then the vials were taken into an autoclave. The autoclave was purged three times with H2, and the pressure of H2 was set to 400 psi. The autoclave was stirred under specified reaction conditions. After being cooled to ambient temperature and release of hydrogen, the autoclave was opened and the solvent was evaporated. The residue 2 were refluxed in EtOH with a drop of concentrated sulfuric acid for 5 h, and the corresponding esters were passed through a short pad of silica gel with petroleum ether and ethyl acetate before the ees were determined by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: LACTIC ACID With potassium hydroxide In water; toluene Cooling with ice; Heating; Dean-Stark apparatus; Stage #2: benzyl alcohol With nickel(II) acetate tetrahydrate at 155 - 165℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 26% 2: 71% | With sodium hypochlorite; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; acetonitrile at 20℃; for 4h; Inert atmosphere; | |
1: 29 %Spectr. 2: 71 %Spectr. | Stage #1: 4-phenylbutane-1,2-diol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In 1,4-dioxane; aq. phosphate buffer at 25℃; Stage #2: With sodium hypochlorite; sodium chlorite In 1,4-dioxane; aq. phosphate buffer at 25℃; for 22h; chemoselective reaction; | |
1: 84 %Spectr. 2: 13 %Spectr. | Stage #1: 4-phenylbutane-1,2-diol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; chloroform at 25℃; Stage #2: With sodium hypochlorite; sodium chlorite In aq. phosphate buffer; chloroform at 25℃; for 3h; chemoselective reaction; |
Stage #1: 4-phenylbutane-1,2-diol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; ethyl acetate at 25℃; for 0.0833333h; Stage #2: With sodium hypochlorite; sodium chlorite In aq. phosphate buffer; water; ethyl acetate; benzene at 25℃; for 7h; | 13 In vitro, 4-phenylbutane-1,2-diol(26.3 mg, 0.158 mmol), and was dissolved in Kanto Chemical Co.toluene (790μl), to this solution, manufactured by Tokyo Chemical Industry Co.,Ltd. TEMPO " 2,2,6,6-tetramethylpiperidine 1-oxyl free radical"(trade name) (1.24mg, 7.92μmol) and, pH 6.8 for 1M- phosphate buffer and(565μl) was added, at 25°C the mixture was stirred for 5 minutes .Then, while stirring the mixture, 80% sodium chlorite (53.7mg, 0.475 mmol) and an aqueous solution dissolved in water (200 μl), an aqueous solution of sodium hypochlorite (7.92μmol) (0 .168M, and 47.1μl) and,simultaneously, was added dropwise over 1 minute.Thereafter, the reaction system as a 25 ° C., was carriedout for 4 hours the reaction was continued stirring. Then, a 0.1M- phosphatebuffer pH 2.1 (3 ml), and sodium chloride was added to complete the oxidationreaction.Then, extracted with ethyl acetate, to recover an organiclayer containing the α- hydroxy carboxylic acids of interest. Then, washing theorganic layer with saturated brine, dried over anhydrous magnesium sulfate,then, under reduced pressure, and Datsu to give the crude product. This crudeproduct, n- octyl ether was subjected to NMR measurement as a standardsubstance, and the target product of 2-hydroxy-4-phenylbutyric acid (95%), aby-product, 3-phenylpropionic acid it was found that (4.7%) and hasbeen included (see Figure 1 and Table 1). Therefore, the crude product waspurified by silica gel column chromatography (SO3H), to give2-hydroxy-4-phenylbutyric acid shown in the following (26.9mg). The yield was86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride In N,N-dimethyl-formamide at 140℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: saccharin / dichloromethane / Reflux; Inert atmosphere 2: cesium fluoride / N,N-dimethyl-formamide / 24 h / 140 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water In 1,4-dioxane for 6h; Reflux; | General procedure: A mixture of cyanohydrin (14 mmol), 37% HCl (5mL) and dioxane (10 mL) was refluxed for 6 h. The resultant mixture was dilutedwith water (10mL) and extracted with ethyl acetate (3X10mL).The pH value of the organic phase was adjusted to pH=2 with NaHCO3(sat.aq.). The aqueous phase was extracted with ethyl acetate (3X10mL).Thecombined organic phase was washed with brine (3×10 mL) and dried over Na2SO4. Flash chromatographyon silica gel (eluent: ethyl acetate/petroleum ether =2:1) gave the corresponding racemicmandelic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; caesium carbonate; methanol / tetrahydrofuran / 6 h / 70 °C 1.2: 1 h / 0 °C 2.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / toluene; aq. phosphate buffer / 25 °C / pH 6.8 2.2: 4 h / 25 °C | ||
Multi-step reaction with 2 steps 1.1: bis(pinacol)diborane; caesium carbonate / methanol; tetrahydrofuran / 12 h / 70 °C / Inert atmosphere 1.2: 1 h / 0 °C / Inert atmosphere 2.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium chlorite / water; aq. phosphate buffer; toluene / 3 h / 20 °C / pH 6.8 / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-phenylbutane-1,2-diol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; toluene at 25℃; Stage #2: With sodium hypochlorite; sodium chlorite In aq. phosphate buffer; toluene at 25℃; for 4h; chemoselective reaction; | |
Stage #1: 4-phenylbutane-1,2-diol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; benzene at 25℃; for 0.0833333h; Stage #2: With sodium hypochlorite; sodium chlorite In aq. phosphate buffer; water at 25℃; for 2.5h; | 3 In vitro, 4-phenylbutane-1,2-diol(26.3 mg, 0.158 mmol), and was dissolved in Kanto Chemical Co.toluene (790μl), to this solution, manufactured by Tokyo Chemical Industry Co.,Ltd. TEMPO " 2,2,6,6-tetramethylpiperidine 1-oxyl free radical"(trade name) (1.24mg, 7.92μmol) and, pH 6.8 for 1M- phosphate buffer and(565μl) was added, at 25°C the mixture was stirred for 5 minutes .Then, while stirring the mixture, 80% sodium chlorite (53.7mg, 0.475 mmol) and an aqueous solution dissolved in water (200 μl), an aqueous solution of sodium hypochlorite (7.92μmol) (0 .168M, and 47.1μl) and,simultaneously, was added dropwise over 1 minute.Thereafter, the reaction system as a 25 ° C., was carriedout for 4 hours the reaction was continued stirring. Then, a 0.1M- phosphatebuffer pH 2.1 (3 ml), and sodium chloride was added to complete the oxidationreaction.Then, extracted with ethyl acetate, to recover an organiclayer containing the α- hydroxy carboxylic acids of interest. Then, washing theorganic layer with saturated brine, dried over anhydrous magnesium sulfate,then, under reduced pressure, and Datsu to give the crude product. This crudeproduct, n- octyl ether was subjected to NMR measurement as a standardsubstance, and the target product of 2-hydroxy-4-phenylbutyric acid (95%), aby-product, 3-phenylpropionic acid it was found that (4.7%) and hasbeen included (see Figure 1 and Table 1). Therefore, the crude product waspurified by silica gel column chromatography (SO3H), to give2-hydroxy-4-phenylbutyric acid shown in the following (26.9mg). The yield was86% As the organic solvent, using Kanto Chemical Co. benzene inplace of toluene, except that the reaction time was 2.5 hours, by performingthe same operations as in Example 1, was synthesized 2-hydroxy-4-phenylbutyricacid . Table 1 shows the yield of 2-hydroxy-4-phenylbutyric acid in the crudeproduct (99%). | |
With sodium hypochlorite; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; water; toluene at 20℃; for 3h; Inert atmosphere; chemoselective reaction; |
6 %Spectr. | With 9-benzyl-9-norazaadamantane N-oxyl; sodium nitrite In acetonitrile at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 2-azatricyclo[3.3.1.13,7]dec-2-yloxidanyl; sodium nitrite In aq. phosphate buffer; water; acetonitrile at 25℃; for 2h; chemoselective reaction; | |
With 2,2,6,6-tetramethylpiperidin-1-oxoammonium chloride In aq. phosphate buffer; toluene at 25℃; for 1h; | ||
With 2-azatricyclo[3.3.1.13,7]decan-2-ol; sodium nitrite In aq. phosphate buffer; water; acetonitrile at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
737 mg | Stage #1: 2-hydroxy-4-phenylbutanoic acid; p-Methoxybenzyl bromide With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With Dess-Martin periodane In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 44% 2: 40% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate In dichloromethane at 25℃; for 6h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 16% 2: 10% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; iodosylbenzene; scandium tris(trifluoromethanesulfonate) In dichloromethane at 25℃; for 5h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 34% 2: 37% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 25℃; for 4h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; for 0.5h; | General procedures for enantioseparation of 2-hydroxy-4-phenylbutyric acid by (1R,2S)-2-amino-1,2-diphenylethanol (ADPE) General procedure: Rac-HPBA (1.00 mmol) and (1R,2S)-ADPE (1.00 mmol) were dissolved in methanol. After concentration, the resulting white solids were recrystallized from an appropriate solvent to obtain the salt crystals, which were filtered and dried under reduced pressure. The yield was calculated based on the 1H NMR data, considering the amount of the included solvent. A portion of the salt (ca. 20 mg) was decomposed by the addition of 1 M aqueous HCl solution and the aqueous layer was extracted with diethyl ether. After drying over anhydrous Na2SO4, the organic layer was concentrated to obtain enantio-enriched HPBA. To a solution of HPBA in methanol (1 ml) was added TMSCHN2 (hexane or ether solution) until the solution remained yellow. The mixture was stirred for 30 min at room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel PTLC (hexane/ethyl acetate = 2 :1) to produce methyl ester of HPBA. The ee value of the ester was determined by chiral HPLC analysis (Daicel Chiralcel OD-3, hexane/2-propanol=90:10, 1.0 mL/min; tr(S) = 8.3 min, tr(R) = 11.3 min). Methyl ester of (S)-HPBA: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.35-7.10 (m, 5H), 4.25-4.15 (m, 1H), 3.75 (s, 3H), 2.85-2.65 (m, 3 H), 2.20-1.85 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 175.6, 141.1, 128.6, 128.4, 126.1, 69 .7, 52.6, 35.9, 31.0. Methyl ester of (R)-HPBA: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.35-7.10 (m, 5H), 4.25-4.15 (m, 1H), 3.74 (s, 3H), 2.90-2.6 5 (m, 3 H), 2.20-1.85 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 175.6, 141.1, 128.6 128.4, 126.1, 69.7, 52.5, 35.9, 31.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 0.713 g 2: 0.241 g | In methanol | Successive enantioseparation of HPBA According to the general procedure mentioned above, rac-HPBA (1.601 g, 8.88 mmol ) and (1R,2S)-ADPE (1.890 g, 8.86 mmol ) were dissolved in methanol (30 mL). After concentration, the resulting white solid was recrystallized from tert-butanol (240 mL) to obtain the salt crystals, which were filtered and dried overnight to afford (S)-enriched salt (1.231 g, 75%ee ). The solvent tert-butanol was removed from the filtrate and the residual white solid was recrystallized from 50% aqueous ethanol (40 mL). The obtained solid was dried over night to afford (R)-enriched salt (1.579 g, 66%ee ). The (S)-enriched salt was further recrystallized from tert-butanol twice (amount of the solvent: 80 mL (1st) and 60 mL (2nd)) and afforded diastereopure salt of (S)-HPBA (0.713 g, >98%ee). On the other hand, recrystallization of the (R)-enriched salt from 50% aqueous ethanol four times (amount of the solvent: 40 mL (1st), 30 mL (2nd), 20 mL (3rd), and 16 mL (4th)) afforded diastereopure salt of (R)-HPBA (0.241 g, >98%ee). Enantio-enriched HPBA was isolated from the salts and the enantiopurity was determined by HPLC analysis as described above. Characterization of the diastereomeric salts. Each diastereomeric salt was prepared from the methanol solution of equimolar mixture of HPBA and ADPE. (S)-HPBA*(1R,2S)-ADPE: mp: 152-153 °C. 1H NMR (400 MHz, CD3OD): δ (ppm) 7.35-6.95 (m, 15H), 5.19 (s, 1H), 4.43 (s, 1H), 4.00-3.85 (m, 1H), 2.80-2.60 (m, 2H), 2.10-1.75 (m, 2H). 13C NMR (100 MHz, CD3OD): δ (ppm) 181.2, 143.7, 141.3, 135.2, 129.8, 129.7, 129.5, 129.3, 129.2, 129.1, 128.9, 127.6, 126.7, 75.0, 72.9, 61.7, 38.3, 32.7. IR (KBr): νmax = 3435, 1628, 1568, 1452, 1390, 1297, 1185, 1103, 1053, 744, 702, 568 cm-1. [α]D = -83.5 (c 0.496, methanol). (R)-HPBA*(1R,2S)-ADPE: mp: 151-152 °C. 1H NMR (400 MHz, CD3OD): δ (ppm) 7.45-6.90 (m, 15H), 5.18 (s, 1H), 4.43 (s, 1H), 4.00-3.85 (m, 1H), 2.80-2.60 (m, 2H), 2.10-1.75 (m, 2H). 13C NMR (100 MHz, CD3OD): δ (ppm) 181.1, 143.7 141.3, 135.2, 129.8, 129.8, 129.6, 129.3, 129.2, 129.1, 128.9, 127.6, 126.7, 75.0, 72.8, 61.8, 38.3, 32.7. IR (KBr): νmax = 3399, 1589, 1453, 1412, 1329, 1204, 1089, 1052, 701, 568 cm-1. [α]D = -65.1 (c 0.501, methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 60℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 60℃; for 18h; Inert atmosphere; |
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