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CAS No. : | 328-50-7 | MDL No. : | MFCD00004165 |
Formula : | C5H6O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KPGXRSRHYNQIFN-UHFFFAOYSA-N |
M.W : | 146.10 | Pubchem ID : | 51 |
Synonyms : |
Alpha-Ketoglutaric acid;α-Ketoglutaric Acid;NSC 17391;α-KGA;2-oxoglutaric acid;alpha-ketoglutarate
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 29.89 |
TPSA : | 91.67 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.83 cm/s |
Log Po/w (iLOGP) : | -0.09 |
Log Po/w (XLOGP3) : | -0.9 |
Log Po/w (WLOGP) : | -0.5 |
Log Po/w (MLOGP) : | -1.06 |
Log Po/w (SILICOS-IT) : | -0.62 |
Consensus Log Po/w : | -0.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | 0.09 |
Solubility : | 178.0 mg/ml ; 1.22 mol/l |
Class : | Highly soluble |
Log S (Ali) : | -0.54 |
Solubility : | 41.9 mg/ml ; 0.287 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.64 |
Solubility : | 632.0 mg/ml ; 4.33 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.61 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338+P310 | UN#: | N/A |
Hazard Statements: | H318 | Packing Group: | N/A |
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 |
---|---|---|
52.8% | With hydrogenchloride at 100℃; for 3h; | 175.1 Step 1 : Preparation of 1 -methyl-6-oxo-1 ,4,5,6-tetrahydropyridazine-3-carboxylic acid To a solution of 2-oxopentanedioic acid (10 g, 68 mmol) in 1 0% hydrogen chloride (40 ml_) was added methylhydrazine sulfate (9.8 g, 68 mmol) in three portions. Reaction was stirred at 100 °C for 3 h before it was cooled to room temperature and extracted with tetrahydrofuran (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 2), dried over sodium sulfate, filtered and concentrated. The crude solid was washed with petroleum ether (20 ml_) to offer 1 -methyl-6-oxo-1 ,4,5,6-tetrahydropyridazine-3-carboxylic acid as a white solid (5.6 g, 52.8%); LCMS (ESI) m/z: 157.1 [M+H]+. |
52.8% | With hydrogenchloride In water at 100℃; for 3h; | 175.1; 201.1; 200.1 Step 1 : Preparation of 1 -methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylic acid To a solution of 2-oxopentanedioic acid (10 g, 68 mmol) in 10% hydrogen chloride (40 ml_) was added methylhydrazine sulfate (9.8 g, 68 mmol) in three portions. Reaction was stirred at 100 °C for 3 h before it was cooled to room temperature and extracted with tetrahydrofuran (100 ml_ x 3). The combined organic layers were washed with brine (50 ml_ x 2), dried over sodium sulfate, filtered and concentrated. The crude solid was washed with petroleum ether (20 ml_) to offer 1 -methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylic acid as a white solid (5.6 g, 52.8%); LCMS (ESI) m/z: 157.1 [M+H]+. |
With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With carbazic acid; at 90℃; for 3.0h;Green chemistry; | General procedure: A 10.0 mmol for alpha-keto acid compound or a 5.2 mmol for beta-diketones or alpha-keto acids was mixed with 0.40 g of hydrazinium carboxylate (1a, 5.2 mmol), respectively. (For solid di-carbonyl compound, the mixture was ground using a pestle and a mortar.) The mixture was stored in a closed vial, and then heated to 70 - 90 C until the reaction was complete. Complete conversion to related product was dependent upon the nature of di-carbonyl compounds. Typically, those di-carbonyl compounds take about <3 h to complete the reactions. CO2 and water were released during the reaction. All products obtained from the reactions of 1a with di-carbonyl compounds were basically characterized by 1H and 13C NMR spectroscopy. The products have over 97% of purity of reaction mixture based on 1H NMR spectroscopy and isolation yields are over 97% based on di-carbonyl compounds. The melting points, elemental analysis and UV-Vis spectra for all azines, pyrazoles and pyridazinones, were measured after purification using appropriate solvent. |
62% | With sodium hydroxide; hydrazinium sulfate; In water; | Sodium hydroxide (0.69 g, 17.25 mmol)And hydrazine sulfate (1.02 g, 7.85 mmol)Was placed in a 10 mL double-necked flask,4.5 mL of hot water was added to dissolve,Magnetic stirring slowly dropping1.8 mL of a hot aqueous solution of alpha-ketoglutaric acid (1.14 g, 7.81 mmol)After completion of the dropwise addition, the reaction solution was heated to slightly boil,The reaction was over night.The reaction was stopped,Cooling under ice bath standing white solid precipitation,Filtration.The white solid obtained by suction filtration was recrystallized from 2N hydrochloric acid to give 691.1 mg of colorless needles.Yield: 62%; |
62.3% | With sodium hydroxide; hydrazinium sulfate; In water; at 105℃; | A well-stirred solution of alpha-ketoglutaric acid (1.14 g, 7.81 mmol) in hot water (1.8 mL) was added slowly, with stirring to a solution of sodium hydroxide (0.69 g, 17.25 mmol) and hydrazinium sulfate (1.02 g, 7.85 mmol) in hot water (4.5 mL). The mixture was heated to moderate boiling overnight, and then refrigerated in ice bath for several hours. The precipitate was collected by filtration and recrystallized with 2 N HCl to provide 11 as a colorless needle crystal (691.1 mg, yield 62.3%). Mp: 195.4-195.9 C (Ref. melting point 195-196 C [55]). |
With hydrazine hydrate; In ethanol; at 60℃; | General procedure: To a stirred solution of the suitable gamma-keto acid 1a-k (1.00 mmol) in EtOH (2 mL), hydrazine hydrate (1.00 mmol) was added dropwise. The mixture was heated at 60 C for 1-3h. After cooling, the precipitate was collected by suction and purified by recrystallization from either toluene or ethanol. | |
With hydrazine hydrate; In ethanol; at 60℃; for 2.0h; | Hydrazine hydrate (1.2 mL) was slowly added to [alpha] -ketoglutaric acid (0.014 mol, 2.00 g)In an ethanol solution at a constant temperature of 60 C for 2 h. After the reaction, decompression,The residue was washed with ethanol to give a white powder. | |
2.04 g | With hydrazine hydrate; In ethanol; at 60℃; for 2.0h; | To a solution of 2-oxoglutaric acid (2.00 g) in ethanol (10 mL) was added hydrazine monohydrate (ca. 80%, 1.20 mL), and the mixture was stirred at 60C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then the reaction mixture was cooled with ice. The precipitated solid was collected by filtration. The obtained solid was washed with diethyl ether to give the title compound(2.04 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydroxylamine hydrochloride; sodium hydroxide In water at 0 - 20℃; | N-Hydroxy-α-iminopentanedioic acid (4f) α-Ketoglutaric acid (1.0 g, 6.8 mmol) was added at 0°C to an aqueous solution containing hydroxylamine hydrochloride (953 mg, 15 mmol) and NaOH (1.0 g, 25 mmol) and the mixture was vigorously stirred at room temperature for 18 hrs. The pH was adjusted to 1.0 with concentrated HCl and reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to give the product in 86% yield. 1H NMR (500 M Hz, DMSO-d6) δ 12.44 (bs, 1H), 12.15 (bs, 1H), 2.65-2.62 (m, 2H), 2.39-2.35 (m, 2H); 13C NMR (125 M Hz, DMSO-d6) 173.3, 165.1, 150.6, 29.8, 20.0. |
35% | With hydroxylamine hydrochloride | |
With hydroxylamine |
With hydroxylamine lower-melting form; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Einw. eines Enzym-Praeparats aus Schweineherz; | ||
XIX Pathways for Production of 6-Aminocaproic acid from Succinic Semialdehyde and Pyruvate Succinic semialdehyde is formed from alpha-ketoglutarate by two enzymes: alpha-ketoglutarate decarboxylase and 4-aminobutyrate transaminase. | ||
With magnesium(II) chloride hexahydrate; M. smegmatis ketoglutarate decarboxylase; thiamine diphosphate In aq. phosphate buffer at 30℃; for 26h; Enzymatic reaction; | 1 Example 1: Activity of selected KGD enzymes utilizing KG as a substrate General procedure: In this example, various KGD enzymes are tested for the activity of degrading KG into SSA. The following reactants were added at the start of the 470 uL reaction: l5mM KG, 107 uM thiamine pyrophosphate (TPP), 4.5mM MgCl2-6H2O, 63 to 197 ug/mL KGD enzyme, 30mM Kphos (pH 8). Reactions were incubated at 30 °C with 300 rpm shaking for 21 hours, and then left on the bench for 5 hours before HPLC analysis. The degradation of KG over time is shown in Table 1 after normalization of starting KG concentrations. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water pH 6.8; | ||
With NH4al(SO4)2; water at 100℃; pH 5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron trifluoride at 65℃; for 0.333333h; | |
94% | With toluene-4-sulfonic acid In chloroform Heating; | |
90% | With sulfuric acid for 2h; Heating; |
90% | With Bronsted acidic, ionic liquid containing, heteropolyanion functionalized polysiloxane network POS-HPA-IL for 4h; Reflux; Green chemistry; | |
85% | With 2,2-dimethoxy-propane at 20℃; for 24h; Green chemistry; | |
78% | With toluene-4-sulfonic acid for 24h; Reflux; Inert atmosphere; | Synthesis of a-keto esters To a solution of α-ketoglutaric acid (6) (3.3 mmol,500 mg) in freshly distilled dry alcohol (methanol, ethanolor isopropanol) (10 mL) at room temperature, it wasadded p-toluenesulfonic acid (PTSA) (0.4 mmol, 65 mg).The mixture was refluxed 24 h and sequentially NaHCO3(0.8 mmol, 70 mg) was added. After stirring 30 min atroom temperature, the solvent was removed in vacuo andthe crude mixture was diluted with ethyl acetate (10 mL),dried over MgSO4 and concentrated under reduced pressure.Silica gel column chromatography (50% EtOAc in hexanes,v/v) of the crude product afforded the respective ester asa colorless oil. Dimethyl 2-oxoglutarate (3)Yield 78%; 1H NMR (CDCl3, 500 MHz) d 2.69 (t,J 5.9 Hz, 2H), 3.17 (t, J 5.9 Hz, 2H), 3.69 (s, 3H), 3.89(s, 3H); 13C NMR (CDCl3, 125 MHz) d 27.4, 34.2, 51.9,53.0, 160.9, 172.4, 192.2; IR (film) n / cm-1 3005, 2958,1782, 1732, 1438, 1168, 1083; GC (FID) tR: 39.3 min; TLC(EtOAc:hexane 1:1) Rf = 0.40. |
69% | With acetyl chloride at 0℃; for 2.5h; | |
65% | With toluene-4-sulfonic acid In toluene Heating; | |
With Novozym 435 lipase B from Candida antarctica at 30℃; | ||
4.76 g | With thionyl chloride at -5℃; | |
With sulfuric acid Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Amberlyst15; at 20℃; for 1h; | Add 250 ml of ethanol to a 500 ml third-flask.Add 2-oxoglutaric acid (43.8g, 0.3mol, 1.0eq) in sequence at room temperature,Amberlyst15 (wet type, ion exchange resin) (22g),After the addition, the reaction was stirred for 1 hour, and the reaction was followed by TLC to monitor the end of the reaction.The reaction solution was filtered and concentrated to obtain diethyl 2-oxopentane-1,5-dicarboxylate.57.8g, yield 95%. |
76% | With toluene-4-sulfonic acid; for 24h;Reflux; Inert atmosphere; | General procedure: To a solution of alpha-ketoglutaric acid (6) (3.3 mmol,500 mg) in freshly distilled dry alcohol (methanol, ethanolor isopropanol) (10 mL) at room temperature, it wasadded p-toluenesulfonic acid (PTSA) (0.4 mmol, 65 mg).The mixture was refluxed 24 h and sequentially NaHCO3(0.8 mmol, 70 mg) was added. After stirring 30 min atroom temperature, the solvent was removed in vacuo andthe crude mixture was diluted with ethyl acetate (10 mL),dried over MgSO4 and concentrated under reduced pressure.Silica gel column chromatography (50% EtOAc in hexanes,v/v) of the crude product afforded the respective ester asa colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In 1,4-dioxane; benzene for 168h; Heating; | |
82% | With toluene-4-sulfonic acid In toluene for 168h; Heating; | |
80% | In 1,4-dioxane; benzene Heating; |
68% | With toluene-4-sulfonic acid In 1,4-dioxane; toluene for 48h; Dean-Stark; Reflux; | Nb-benzylhexahydrocanthin-6-one (3). Nb-benzyltryptamine (320mg, 1.28 mmol) was dissolved in anhydrous toluene (30 mL) and dioxane (20 mL)in a round-bottom flask (100 mL) that was equipped with a Dean-Stark trap and a reflux condenser. A mixture of α-ketoglutaric (205 mg, 1.4 mmol) acid and p-TSA (24.32 mg, 0.128 mmol) was added, and the solution was heated to reflux for 48 h. The reaction solution was quenched with saturated aqueous NaHCO3 (20 mL) and diluted with EtOAc (20 mL). The organic layer was separated with EtOAc (30 mL×3) and washed sequentially with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure to afford a dark green residue which was purified by flash column chromatography using petroleum ether/ethyl acetate(8:1, v/v) as the eluent to give 276.79 mg (68%) of compound 3 as a green solid. m.p. 173-174oC; ESI-MS m/z 317.12 [M+H]+; 1HNMR (500 MHz, CD3OD) δ:8.31 (d, J = 8.5 Hz, 1H), 7.42-7.34(m, 5H), 7.30-7.26 (m, 3H), 4.26 (d, J= 13.4 Hz, 1H), 3.61 (d, J = 11.8Hz,1H), 3.47 (d, J = 13.3 Hz, 1H), 3.25(m, 1H), 2.86 (m, 2H), 2.74-2.53 (m, 4H), 1.85 (m, 1H); 13C NMR (125MHz, CD3OD) δ: 168.87, 137.35, 134.91, 134.32, 129.33, 129.17, 128.21, 127.21, 124.20, 123.87, 118.00, 115.73, 113.46, 57.45, 56.78, 49.63, 32.41, 26.95, 20.79. |
68% | With toluene-4-sulfonic acid In 1,4-dioxane; 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 48h; | synthesis of 3-benzyl-1,2,3,3a,4,5-hexahydrocanthin-6-one (3) Benzyl- [2- (lH-indol-3-yl) -ethyl] -amine (320 mg, 1.28 mmol),α-ketoglutaric acid (205 mg, 1.4 mmol),P-toluenesulfonic acid (24.32 mg, 0.128 mmol),1,4-dioxane: xylene (6: 4) 50mL mixed,The reaction was carried out for 48 hours at 150 ° C on a reflux device equipped with a water trap.TLC detection reaction is completed,To this was added 30 mL of saturated aqueous sodium bicarbonate solution,Add 50mL × 3 dichloromethane extraction,Saturated salt water,Dried over anhydrous sodium sulfate,filter,Concentrated under reduced pressure,Silica gel column chromatography,276.79 mg of green solid,Yield 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With toluene-4-sulfonic acid In toluene Heating; | |
76% | With toluene-4-sulfonic acid for 24h; Reflux; Inert atmosphere; | Synthesis of a-keto esters General procedure: To a solution of α-ketoglutaric acid (6) (3.3 mmol,500 mg) in freshly distilled dry alcohol (methanol, ethanolor isopropanol) (10 mL) at room temperature, it wasadded p-toluenesulfonic acid (PTSA) (0.4 mmol, 65 mg).The mixture was refluxed 24 h and sequentially NaHCO3(0.8 mmol, 70 mg) was added. After stirring 30 min atroom temperature, the solvent was removed in vacuo andthe crude mixture was diluted with ethyl acetate (10 mL),dried over MgSO4 and concentrated under reduced pressure.Silica gel column chromatography (50% EtOAc in hexanes,v/v) of the crude product afforded the respective ester asa colorless oil. |
75% | With toluene-4-sulfonic acid In toluene for 6h; Reflux; |
With Novozym 435 lipase B from Candida antarctica at 30℃; | ||
With toluene-4-sulfonic acid In toluene for 18h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In ethanol; for 0.1h;Microwave irradiation; | To a solution of 1.1g (10 mmoles) of o-fenilendiamina in ethanol (5 mL) in a microwave reaction tube was -ketoglutaric acid (1.5g; 10.30 mmol). The reaction mixture was irradiated with MW during 1 min. at 30 W followed by 5 min at 15 W. The crude product was filtered, washed with NaOH 5% and water. Compound 10 was obtained as a white solid (2.10, 98%) crystallized from ethanol; mp: 256-258 C; mp lit.: 257-258 C [2a,3]. IR (Film): 3435, 3102, 1730, 1666, 1608, 1502 cm-1.1H-NMR (300 MHz, DMSO-d6): 2.72 (t; J=6.30 Hz; 2H; CH2); 3.02 (t; J=6.30 Hz; 2H; CH2); 7.21-7.35 (m; 2H; ArH); 7.46 (t; J= 7.65 Hz; 1H; ArH), 7.69 (d; J= 8.06, 1H, ArH), 12.10 (bs; 1H; OH); 12.30 (bs; 1H; OH) ppm. 13C-NMR (75 MHz,DMSO-d6): delta 28.1; 30.4; 115.7; 123.5; 128.5; 129.9; 131.9, 132.1; 155.0 (C=N); 160.7; 174.4 (COOH) ppm. MS (m/z): 218.1. |
98% | In ethanol; for 0.0833333h;Microwave irradiation; | General procedure: In a typical reaction, o-phenyldiamine (10mmol) and the corresponding dicarbonylic compound (10mmol) were dissolved in ethanol (5ml) in a reaction glass tube equipped with a screw cap and magnetic agitation. The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300 reactor) at 30W for around 5-13min. After cooling, 10ml of ethanol was added to the reaction vessel. The product was recrystallized from ethanol, precipitating as a white solid. |
95.7% | In ethanol; at 20.0℃; for 1h; | Weigh o-phenylenediamine (10.81 g, 0.10 mol),Add 250ml of absolute ethanol,After stirring at room temperature for 15 min to dissolve, 2-oxoglutaric acid (16.11 g, 0.10 mol) was added, which was formed as a milky white solid, stirring was continued for 1 h, and the reaction was completed. Filtering,A white solid was obtained, which was crystallized from ethanol to give 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid (Compound 1) 20.73 g.95.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 70% 2: 19 % Spectr. | With [Ir(III)Cp*(bpy)(OH2)](SO4); ammonium formate In water at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In ethanol; | A) 30 g of 2-ketoglutaric acid were boiled under reflux for 3 hours in 500 ml of ethanol with the addition of 3 ml of sulfuric acid. The ethanol was then removed by evaporation, the residue was extracted with dichloromethane, and the dichloromethane phase was washed with water, dried and concentrated. 37 g of oily diethyl 2-ketoglutarate were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In water; | EXAMPLE 2 Preparation of 1-hydrazinophthalazine alpha-ketoglutarate Hydrazone 1-hydrazinophthalazine hydrochloride (395 mg; 2 mmol) is dissolved in 5 ml of water. To this an aqueous solution of alpha-ketoglutaric acid (1 g; 7 mmol) is added and the reaction mixture is allowed to stand overnight at room temperature. The solid precipitate is filtered off and dried in vacuo to yield 510 mg of 1-hydrazinophthalazine alpha-ketoglutarate hydrazone (88% theoretical yield). [British Journal of Clinical Pharmacology 5: 489-494 (1978)] |
88% | In water; | EXAMPLE 2 Preparation of 1-hydrazinophthalazine alpha-ketoglutarate hydrazone 1-hydrazinophthalazine hydrochloride (395 mg; 2 mmol) is dissolved in 5 ml of water. To this an aqueous solution of alpha-ketoglutaric acid (1 g; 7 mmol) is added and the reaction mixture is allowed to stand overnight at room temperature. The solid precipitate is filtered off and dried in vacuo to yield 510 mg of 1 -hydrazinophthalazine alpha-ketoglutarate hydrazone (88% theoretical yield). [British Journal of Clinical Pharmacology 5: 489-494 (1978)]. |
88% | In water; | EXAMPLE 2 Preparation of 1-hydrazinophthalazine alpha-ketoglutarate hydrazone 1-hydrazinophthalazine hydrochloride (395 mg; 2 mmol) is dissolved in 5 ml of water. To this an aqueous solution of alpha-ketoglutaric acid (1 g; 7 mmol) is added and the reaction mixture is allowed to stand overnight at room temperature. The solid precipitate is filtered off and dried in vacuo to yield 510 mg of 1-hydrazinophthalazine alpha-ketoglutarate hydrazone (88% theoretical yield). [British Journal of Clinical Pharmacology 5: 489-494 (1978)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In acetonitrile at 75 - 80℃; for 2h; | 4 Compound of Formula 1 (40 g, 64 mmol) and 2-ketoglutaric acid (8.8 g, 1 eq) were mixed in 400 mL acetonitrile. The mixture was heated at 75-80° C. for 2 hours. After cooled slowly to room temperature, the resulting slurry was filtered, washed with acetonitrile, and dried under vacuum to give a white solid (43.5 g, 89% yield). m.p. by DSC 136.3° C. (DSC onset). Rotamer ratio: 5:95. 1H NMR (400 MHz, D2O, mixture of rotamers) δ 8.73 (s, 1H), 7.26 (dd, J1=14.0 Hz, J2=7.2 Hz, 1 H), 6.96 (m, 3H), 4.45 (br d, J=12.3 Hz, 1H), 3.75 (d, J=10.5 Hz, 1H), 3.59 (d, J=11.1 Hz, 1H), 3.25 (m, 6H), 2.91 (m, 2H), 2.75 (m, 5H), 2.48 (t, J=6.5 Hz, 2H), 2.39 (m, 2H), 2.27 (m, 1H), 2.25 (s, 3H), 2.22 (s, 3H), 2.00 (m, 3H), 1.75 (d, J=12.5 Hz, 1H), 1.65 (m, 1H), 1.54 (m, 1H), 1.28 (s, 3H), 1.13 (d, J=5.8 Hz, 3H). 1.25 (m, 2H), 0.92 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; | EXAMPLE 8 N-(1,3-Dicarboxypropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong> 2-Oxoglutaric acid (1.46 g) and <strong>[13485-59-1]L-alanyl-L-proline</strong> (0.37 g) were treated with sodium cyanoborohydride (0.38 g) as described above. Crude N-(1,3-dicarboxypropyl)-<strong>[13485-59-1]L-alanyl-L-proline</strong> (0.47 g) was obtained, m.p. 140-160. The mass spectrum of silylated material showed an ion at 517 m/e equivalent to the molecular ion for the trisilylated derivative minus methyl (532-15). The nmr spectrum was consistent with structure. Methyl resonances were centered at 1.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | In isopropyl alcohol at 25 - 60℃; for 20h; | 20 Example 20 oxoglutarate [Show Image] 3.01 g base (10 mmoles) are dissolved in 90 ml isopropanol at 60°C. 1.46 g α-oxo-glutaric acid (10 mmoles) are added. The resulting solution is allowed to cool. Crystallization takes spontaneously place during cooling. The suspension is stirred at 25°C for 20 h and filtered. The crystals are washed with 30 ml isopropanol and dried first for 2 h at 50°C / ca. 10 mbar and then for 20 h at 80°C and ca. 10 mbar. Yield: 4.40 g white powder (98.4 %) Elemental analysis: Calc.: 56.37 % C; 6.53 % H; 15.65 % N; 21.45 % OFound: 56.41 % C; 6.63 % H; 15.72 % N; 21.40 % O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol Heating; | 51 Example 51Preparation of (+)-(lS,3'R)-quinuclidin-3'-yl l-phenyl-l,2,3,4-tetrahydro- isoquinoline-2-carboxylate gentisic acid salt In a dry 25 mL round bottom flask ethanol (45 mL), (+)-(lS,3'R)-quinuclidin-3'- yl 1 -phenyl- 1, 2,3 ,4-tetrahydro-isoquinoline-2-carboxylate (5.0 g, % chiral purity > 97.5 % ) were taken. To the clear solution gentisic acid (2.13 g) was added. It was warmed and stirred for 60-120 min. The solvent was distilled out at reduced pressure to obtain the semi-solid mass.Toluene was added and distilled out. The above steps were repeated till solid salt was obtained (Wt.- 6.8 g)Similarly Solifenacin acid salt with following acids were prepared. Some of the salts of Solifenacin were obtained as liquid and some of the salts were obtained as solid. Results are summarized in the table as below:Table 8: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With hydrogenchloride In water for 3h; Reflux; | 4.1. 4,5-Dihydro-1-methyl-6-oxopyridazine-3-carboxylic acid 3A 1.46 g (10 mmol) of α-Ketoglutaric acid was dissolved in 10% HCl and 0.46 g (10 mmol) of methylhydrazine was added dropwise. Then the reaction mixture was refluxed for 3 h. After cooling the reaction mixture was extracted with dichloromethane. The extracts were washed with water, dried (anhydrous MgSO4) and evaporated. Crude product was crystallized from ethanol. Yield 52% |
47% | With hydrogenchloride In water at 100℃; for 3h; | 200.1; 201.1 Step 1 : Preparation of 1 -methyl-6-oxo-1 ,4,5,6-tetrahydropyridazine-3-carboxylic acid To a solution of 2-oxopentanedioic acid (4.99 g, 34.1 mmol) in aqueous hydrogen chloride solution (50 mL, 10%) was added methylhydrazine (3.93 g, 34.1 mmol, 50% in water) dropwise. The mixture was stirred at 100 °C for 3 h. The mixture was extracted with dichloromethane (10 x 30 mL). The combined organic layers were dried and concentrated in vacuo to give a residue. The residue was re-crystallized from ethanol (20 mL) and filtered to give 1 -methyl-6-oxo-1 ,4,5,6-tetrahydropyridazine-3-carboxylic acid (2.5 g, 16.0 mmol, 47%) as white solid. 1H NMR (400 MHz, Chloroform-d) d 9.63 (br. s, 1 H), 3.46 (s, 3H), 2.98 - 2.83 (m, 2H), 2.67 - 2.54 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ATP; magnesium chloride; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid;SbnC (NIS synthetase); SbnE (NIS synthetase); SbnF (NIS synthetase); In water; at 20℃;pH 7.4;In the dark; | In Vitro Synthesis of Staphyloferrin BBioinformatic analyses of the predicted protein products from the staphyloferrin B biosynthesis operon identified three enzymes (SbnC, SbnE and SbnF) that belong to the NIS family of siderophore synthetase enzymes. These enzymes are thought to catalyze the ATP and Mg2+-dependent activation of carboxylate substrates, in a reaction that proceeds through an acyl-adenlyate intermediate that is then recognized by an amine substrate to yield an overall condensation reaction to an amide. To examine the activity of the SbnC, SbnE and SbnF enzymes, and to determine their role in staphyloferrin B synthesis, each was independently overexpressed in E. coli as a hexahistidine-tagged derivative, and subsequently purified using nickel-affinity chromatography. When the three synthetases were incubated together with staphyloferrin B components L-2,3-diaminopropionic acid (Dap), citrate, 1,2-diaminoethane (Dae), and alpha-ketoglutarate (alpha-KG), an ion corresponding to staphyloferrin B was not formed. Additional purified Sbn enzymes were added to the reaction. Notably, when SbnH, a putative PLP-dependent decarboxylase, was combined in reactions with the three synthetases and substrates, an ion corresponding to that of staphyloferrin B was produced. The staphyloferrin B ion was not produced when any of ATP, Mg2+, SbnC, SbnE, SbnF, SbnH, Dap, citrate or alpha-KG was omitted from the reaction (data not shown). Notably, staphyloferrin B synthesis could proceed without the addition of Dae in the reaction. ESI-MS/MS was used to confirm that staphyloferrin B produced in vitro was the same as that isolated from spent culture supernatants of iron-starved S. aureus. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride In methanol; water for 6h; Reflux; | 5.1.1. 4-(1H-Benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) A solution of o-phenylene diamine (0.01 mol), α-ketoglutaric acid (equimolar; 0.01 mol) in methanol/water mixture (1:1) and HCl (4N; 5 mL) was refluxed for 6 h and then left to cool to room temperature. The NaOH solution (10% w/v) was added slowly to neutralize the reaction mixture, when a solid mass precipitated out, which was filtered, washed with water and recrystallized with ethanol. Yield: 87%, m.p. 261-262 °C, Rf = 0.71 [toluene: ethyl acetate: formic acid (5:4:1)]. IR (KBr, cm-1): 3394 (O-H), 3326 (N-H), 3114 (C-H, Ar-H), 2972(C-H, CH2), 1728 (CO), 1600 (CN), 1562 (CC). 1H NMR (DMSO-d6): 12.97 (s, 1H, OH, D2O exchangeable), 12.34 (s, 1H, NH, D2O exchangeable), 7.66 (d, 1H, J = 7.5 Hz, H-4, benzimidazole), 7.48 (t, 1H, J = 7.2 Hz, H-7, benzimidazole), 7.27 (t, 2H, J = 8.7 Hz, H-5,6 benzimidazole), 3.05 (t, 2H, J = 6.9 Hz, CH2), 2.76 (t, 2H, J = 6.9 Hz, CH2). 13C NMR (DMSO-d6): 175.57 (CO), 168.21 (CO, COOH), 159.67 (CN), 138.27, 132.21, 130.19, 128.57, 124.65, 123.64 (Ar-C), 34.23 (CH2, CH2CO), 31.36 (CH2, CH2COOH). Anal. calcd. for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63; H, 4.65; N, 12.98. ESI-MS (m/z): 218 (M+). |
87% | With hydrogenchloride In methanol; water for 6h; Reflux; | Synthesis of 4-(1H-Benzo[d]imidazol-2-yl)-4-oxobutanoic acid(1) A solution of o-phenylenediamine (0.01 mol), α-ketoglutaric acid (equimolar; 0.01 mol)in methanol/water mixture (1:1) and HCl (4N; 5 mL) was refluxed for 6h and then left to cool to room temperature. 10% NaOH solution was added slowly to neutralize the reaction mixture, when a solid mass precipitated out, which was filtered, washed with water and recrystallized withethanol.Yield: 87%;Mp261-262°C;Rf 0.71 [toluene: ethyl acetate: formic acid (5:4:1)];IR (KBr, cm-1): 3394 (OH), 3326 (NH), 3114 (CH), 2972(CH2), 1728 (C=O), 1600 (C=N), 1562 (C=C);1H NMR (300 MHz,DMSO-d6): δ12.97 (s, 1H, OH,D2O exchangeable), 12.34 (s, 1H, NH, D2O exchangeable), 7.66 (d, 1H,J= 7.5Hz, H-4-benzimidazole), 7.48 (t, 1H,J= 7.2Hz,H-7-benzimidazole), 7.27 (t, 2H,J= 8.7Hz, H-5,6-benzimidazole), 3.05 (t, 2H,J= 6.9Hz, CH2), 2.76 (t, 2H,J= 6.9Hz, CH2);13C NMR(300 MHz,DMSO-d6):δ175.57 (C=O), 168.21 (C=O, COOH), 159.67 (C=N),138.27, 132.21, 130.19, 128.57, 124.65, 123.64 (Ar-C), 34.23 (CH2, CH2CO), 31.36 (CH2, CH2COOH);ESI MS (m/z): 218(M+);Anal. calcd. forC11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63; H, 4.65; N, 12.98. |
87% | With hydrogenchloride In methanol; water at 20℃; for 6h; Reflux; | 6.2.1 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) A solution of o-phenylenediamine (0.01 mol), α-ketoglutaric acid (equimolar; 0.01 mol) in methanol/ water mixture (1:1) and HCl (4 N; 5 mL) was refluxed for 6 h and then left to cool to room temperature. 10% NaOH solution was added slowly to neutralize the reaction mixture, when a solid mass precipitated out, which was filtered, washed with water and recrystallized with ethanol. Yield: 87%, m.p. 261-262 °C, Rf 0.71 [toluene:ethyl acetate:formic acid (5:4:1)]; IR (KBr, cm-1): 3394 (O-H), 3326 (N-H), 3114 (C-H, Ar-H), 2972 (C-H, CH2), 1728 (C=O), 1600 (C=N), 1562 (C=C); 1H NMR (DMSO-d6): 12.97 (s, 1H, OH, D2O exchangeable), 12.34 (s, 1H, NH, D2O exchangeable), 7.66 (d, 1H, J = 7.5 Hz, H-4, benzimidazole), 7.48 (t, 1H, J = 7.2 Hz, H-7, benzimidazole), 7.27 (t, 2H, J = 8.7 Hz, H-5,6, benzimidazole), 3.05 (t, 2H, J = 6.9 Hz, CH2), 2.76 (t, 2H, J = 6.9 Hz, CH2); 13C NMR (DMSO-d6): 175.57 (C=O), 168.21 (C=O, COOH), 159.67 (C=N), 138.27, 132.21, 130.19, 128.57, 124.65, 123.64 (Ar-C), 34.23 (CH2, CH2CO), 31.36 (CH2, CH2COOH); ESI MS (m/z): 218 (M+); Anal. calcd. for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63; H, 4.65; N, 12.98. |
87% | With hydrogenchloride In methanol; water for 6h; Reflux; | Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) A solution of o-phenylenediamine (0.01 mol, 1.08gm), α-ketoglutaricacid (equimolar; 0.01 mol, 1.46gm) in methanol/water mixture(1:1) and HCl (4 N; 5 mL) was refluxed for 6 h and then left to cool toroom temperature. The NaOH solution (10% w/v) was added slowly toneutralize the reaction mixture, a solid mass precipitated out, whichwas filtered, washed with water and recrystallized with ethanol. It gaveeffervescence when treated with sodium bicarbonate.Yield: 87% (traditional); Mp. 261-262 °C; Rf=0.71(T:E:F). IR (KBr,cm-1): 3394(O-H), 3326(N-H), 3114(C-H, Ar-H), 2972(C-H, CH2),1728(C=O), 1600(C=N), 1562(C=C). 1H NMR (DMSO-d6): δ 12.97 (s,1H, OH, D2O exchangeable), 12.34(s, 1H, NH, D2O exchangeable),7.66(d, 1H, J=7.5 Hz, H-4, benzimidazole), 7.48(t, 1H, J=7.2 Hz, H-7, benzimidazole), 7.27(t, 2H, J = 8.7 Hz, H-5,6, benzimidazole),3.05(t, 2H, J = 6.9 Hz, CH2), 2.76(t, 2H, J = 6.9 Hz, CH2). 13C NMR(DMSO-d6): δ 175.57(C=O), 168.21(C=O, COOH), 159.67(C=N),138.27, 132.21, 130.19, 128.57, 124.65, 123.64(Ar-C), 34.23(CH2,CH2CO), 31.36(CH2, CH2COOH). ESI-MS (m/z): 218 (M+). Anal. calcd.for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63; H, 4.65;N, 12.98. |
87% | With hydrogenchloride In methanol; water for 6h; Reflux; | |
87% | With hydrogenchloride In methanol; water for 6h; | 2.2.1. Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) A solution of o-phenylenediamine (0.01 mol), α-ketoglutaric acid (equimolar; 0.01 mol) in methanol/water mixture (1:1) and HCl (4N; 5 mL) was refluxed for 6 h and then left to cool to room temperature. The NaOH solution (10% w/v) was added slowly to neutralize the reaction mixture, a solid mass precipitated out, which was filtered, washed with water and recrystallized with ethanol. It gave effervescence when treated with sodium bicarbonate. Yield: 87%; Mp. 261-262°C; Rf = 0.71(T:E:F). IR (KBr, cm-1): 3394(O-H), 3326(N-H), 3114(C-H, Ar-H), 2972(C-H, CH2), 1728(C=O), 1600(C=N), 1562(C=C). 1H-NMR (DMSO-d6): δ 12.97 (s, 1H, OH, D2O exchangeable), 12.34(s, 1H, NH, D2O exchangeable), 7.66(d, 1H, J = 7.5Hz, H-4, benzimidazole), 7.48(t, 1H, J = 7.2Hz, H-7, benzimidazole), 7.27(t, 2H, J = 8.7Hz, H-5,6, benzimidazole), 3.05(t, 2H, J = 6.9Hz, CH2), 2.76(t, 2H, J = 6.9Hz, CH2). 13C-NMR (DMSO-d6): δ 175.57(C=O), 168.21(C=O, COOH), 159.67(C=N), 138.27, 132.21, 130.19, 128.57, 124.65, 123.64(Ar-C), 34.23(CH2, CH2CO), 31.36(CH2, CH2COOH). ESI-MS (m/z): 218 (M+). Anal. calcd. for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63; H, 4.65; N, 12.98. |
With hydrogenchloride In methanol; water for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 23 %Chromat. 2: 10 %Chromat. 3: 16 %Chromat. 4: 8 %Chromat. | With dihydrogen peroxide In water at 89.84℃; for 24h; Schlenk technique; Green chemistry; | 2.2.1. General procedure for oxidation of furfural, HMF, FuA andFDCA General procedure: Furfural, HMF, FuA and FDCA oxidation were carried out in aSchlenk glass tube attached with a reflux condenser. In each reactionsolid acid and/or solid base catalyst(s) and reactants wereloaded in the reactor followed by the addition of 30% H2O2 oxidantand water solvent. The reaction was performed with stirring underatmospheric pressure at a range of temperatures. After the reaction,the resultant reaction mixture were diluted 10-20 times withwater and the catalyst was filtered off using Millex-LG 0.20 m.The recovered catalyst was washed by 50 mL of water, and driedin vacuo at room temperature before further reuses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide In water at 89.84℃; for 24h; Schlenk technique; Green chemistry; | 2.2.1. General procedure for oxidation of furfural, HMF, FuA and FDCA General procedure: Furfural, HMF, FuA and FDCA oxidation were carried out in aSchlenk glass tube attached with a reflux condenser. In each reactionsolid acid and/or solid base catalyst(s) and reactants wereloaded in the reactor followed by the addition of 30% H2O2 oxidantand water solvent. The reaction was performed with stirring underatmospheric pressure at a range of temperatures. After the reaction,the resultant reaction mixture were diluted 10-20 times withwater and the catalyst was filtered off using Millex-LG 0.20 m.The recovered catalyst was washed by 50 mL of water, and driedin vacuo at room temperature before further reuses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 22 %Chromat. 2: 10 %Chromat. 3: 52 %Chromat. | With dihydrogen peroxide In water at 59.84℃; for 24h; Schlenk technique; Green chemistry; | 2.2.1. General procedure for oxidation of furfural, HMF, FuA andFDCA General procedure: Furfural, HMF, FuA and FDCA oxidation were carried out in aSchlenk glass tube attached with a reflux condenser. In each reactionsolid acid and/or solid base catalyst(s) and reactants wereloaded in the reactor followed by the addition of 30% H2O2 oxidantand water solvent. The reaction was performed with stirring underatmospheric pressure at a range of temperatures. After the reaction,the resultant reaction mixture were diluted 10-20 times withwater and the catalyst was filtered off using Millex-LG 0.20 m.The recovered catalyst was washed by 50 mL of water, and driedin vacuo at room temperature before further reuses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase; In aq. phosphate buffer; at 30℃; for 0.0166667h;pH 7.5;Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from alpha-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM alpha-ketoglutarate, 0.05 mM pyridoxal-5?-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With D-arginine; pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase In aq. phosphate buffer at 30℃; for 0.0166667h; Enzymatic reaction; | General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from α-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM α-ketoglutarate, 0.05 mM pyridoxal-5′-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 °C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 °C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile. | |
> 99 % ee | With D-amino acid transaminase; D-Alanine; R-selective ω-transaminase from Arthrobacter sp; (3-hydroxy-5-hydroxymethyl)-2-methylisonicotinic acid 5-phosphate; isopropylamine In aq. phosphate buffer for 5h; | |
With meso-diaminopimelate dehydrogenase; pyridoxal 5'-phosphate; NADH In isopropyl alcohol at 35℃; Enzymatic reaction; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With SbnB from Staphylococcus aureus; NADH In water-d2 at 25℃; Enzymatic reaction; | SbnA reactions were performed in 50 mM potassium phosphate pH 8.0 with 10 mM OPS and 10 mM L-glutamate overnight at room temperature SbnA was removed from the reaction by centrifugation through a Nanosep 3K Omega spin column (Pall) at 14,000 Χ g for 20 min. NMR analysis of reaction product (10 mM ACEGA in 50 mM phosphate/10% D2O pH 8.0) was performed at 25C on a Bruker Avance 600 MHz spectrometer with a cryoprobe.1H spectrum was obtained using water-presaturation. 13C, 1H-13C HSQC, and 1H-13C HMBC spectra were measured using standard methods provided by TopSpin software (Bruker). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To determine the catalytic efficiency of enzymes in the reduction of a-Ketoglutarate (a-KG), reactions were performed to determine Vmax and Km for a-KG. In these reactions, substrate was varied while the cofactor was held constant at 500 uM. All reactions were performed in 50 mM potassium phosphate buffer, pH 6.5, 10% glycerol, 0.03% (w/v) BSA, 5 mM MgC12, and 40mM sodium hydrocarbon- ate. Reaction progress was followed by spectroscopy at 340 nM monitoring the change in oxidation state of the cofactot Sufficient enzyme was added to give a linear change in absorbance for 10 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: α-ketoglutaric acid With tetra(n-butyl)ammonium hydroxide In water; isopropyl alcohol Cooling with ice; Stage #2: p-methoxybenzyl chloride In N,N-dimethyl acetamide at 20℃; for 65h; Inert atmosphere; regioselective reaction; | 12.a 2-Ketoglutaric acid 1-(p-methoxybenzyl) ester (3) a). 2-Ketoglutaric acid 1-(p-methoxybenzyl) ester (3) 2-Ketoglutaric acid (98.5%, 1.484 g, 10.0 mmol) was suspended in 2-propanol (25 mL), cooled in ice and neutralized with a 40% aqueous solution of tetrabutylammonium hydroxide (5.9 mL, 9.0 mmol). The resulting solution was diluted with hexane (7 mL), dried in vacuo (below 30° C.), dissolved in a mixture of 2-propanol (15 mL) and hexane (5 mL) and dried as above to a viscous syrup (4.834 g). The residue was protected with argon, dissolved in N,N-dimethylacetamide (5 mL), and p-methoxybenzyl chloride (1.25 mL, 9.0 mmol) was added. The mixture was allowed to react at room temperature under argon protection for 65 h. An 0.8 M aqueous solution of phosphoric acid (40 mL) was added, the mixture was extracted with ethyl acetate, the organic layer was washed with 0.8 M phosphoric acid, with water, and dried. The crude monoester (2.266 g) was purified by flash chromatography (silica-gel, chloroform-ethyl acetate, 100:0 to 1:1, containing 0.2% of acetic acid) and crystallized from ethyl acetate-hexane. Yield of 3: 1.330 g (56%), 1H NMR (CDCl3) detected 60% of the open tautomer 3a and 40% of the cyclic tautomer 3b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 180℃; for 48h; Dean-Stark; | 3-benzyl-10-methoxy-1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5]naphthyridin-6-one (3): A mixture of compound 2 (5.61 g, 20 mmol), a-ketoglutaric acid (3.51 g, 24 mmol), p-toluenesulfonic acid (0.69 g, 4 mmol), and a solution of toluene/dioxane (60 mL 3:2 v/v) was heated at 180 °Cfor 48 h, using a Dean-Stark trap for water removal. Upon completion, the reaction mixture was cooled to room temperature and the organic solvent removed. The residue was dissolved in a mixture of CH2Cl2 (60 mL) and saturated aqueous NaHCO3 (80 mL). The aqueous phase was separated and the product extracted with CH2Cl2 (3 × 50 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2SO4. The obtained crude product was chromatographed on silica gel eluting with dichloromethane to afford compound 3 as a white powder (5.75 g). Yield, 83%; m.p. 192.5-193.7 °C; Rf = 0.25 (1:2 EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 7.43-7.27 (m, 5H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 4.23 (d, J = 13.5 Hz, 1H), 3.85 (s, 3H), 3.56-3.52 (m, 1H), 3.39 (d, J = 13.5 Hz, 1H), 3.25-3.15 (m, 1H), 2.91-2.68 (m, 3H), 2.61-2.47 (m, 3H), 1.96-1.85 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 167.72, 156.91, 138.54, 135.45, 130.53, 129.60, 128.87, 128.46, 127.26, 116.87, 113.45, 112.01, 101.84, 57.74, 57.28, 55.75, 50.11, 32.80, 27.61, 21.36. HRMS (ESI) m/z calcd for C22H22N2O2 [M+H]+ 347.1754, found 347.1749. |
83% | With toluene-4-sulfonic acid In 1,4-dioxane; toluene Reflux; | |
5.75 g | With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 180℃; for 48h; Dean-Stark; | 3.2.2. Synthesis of Compound 3 A mixture of compound 2 (5.61 g, 20 mmol), a-ketoglutaric acid (3.51 g, 24 mmol), p-toluenesulfonic acid (0.69 g, 4 mmol), and a solution of toluene/dioxane (60 mL 3:2 v/v) was heated at 180 °C for 48 h, using a Dean-Stark trap for water removal. Upon completion, the reaction mixture was cooled to room temperature and the organic solvent removed. The residue was dissolved in a mixture of CH2Cl2 (60 mL) and saturated aqueous NaHCO3 (80 mL). The aqueous phase was separated and the product extracted with CH2Cl2 (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. The obtained crude product was chromatographed on silica gel eluting with dichloromethane to afford compound 3 as a white powder (5.75 g, yield 83%, m.p. 192.5-193.7 °C). 1H-NMR (500 MHz, CDCl3) δ: 8.26 (d, J = 8.8 Hz,1H), 7.43-7.27 (m, 5H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 4.23 (d, J = 13.5 Hz,1H), 3.85 (s, 3H), 3.56-3.52 (m, 1H), 3.39 (d, J = 13.5 Hz, 1H), 3.25-3.15 (m, 1H), 2.91-2.68 (m, 3H),2.61-2.47 (m, 3H), 1.96-1.85 (m, 1H). 13C-NMR (125 MHz, CDCl3) δ: 167.7, 156.9, 138.5, 135.4, 130.5,129.6, 128.9, 128.5, 127.3, 116.9, 113.4, 112.0, 101.8, 57.7, 57.3, 55.7, 50.1, 32.8, 27.6, 21.4. ESI-MS m/z:[M + H]+(found) = 347.23, [M + H]+(calcd) = 347.43. Elemental analysis calculated for C22H22N2O2 (%):C, 76.28; H, 6.40; N, 8.09 (found: C, 76.12; H, 6.51; N, 8.03). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: NBD chloride With hydrazine hydrate In methanol; chloroform at 20℃; for 0.5h; Stage #2: α-ketoglutaric acid | 1 Example 1: Preparation of fluorescent / UV molecular probes for alpha-ketoglutarate The 0.3gNBD-Cl dissolved to 50 ml in chloroform, then add 50 ml volume concentration of 0.6% hydrazine hydrate-methanol solution, mix, stir at room temperature 30 min, to obtain brown precipitation, filtration, the filter cake is acetic acid ethyl ester washing, drying, be 0.29g brown product, alpha-ketoglutarate is the fluorescence/ultraviolet molecular probe (probe HNBD), the yield is 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | After adding ethyl acetate (100ml), in 3- {7-cyano -5 -[(2R) -2- aminopropyl] -2,3-dihydro -1H- indol-1-yl} propyl benzoate monotartrate (10.0g; formula 2),Here it was added to an aqueous solution obtainedby dissolving potassium carbonate (27g) in water (100ml) to dissolve thecompound of formula 2. and The ethyl acetate layer was separated,and Theaqueous layer was further extracted with ethyl acetate (100 ml).After washingthe combined ethyl acetate layer was dissolved in an aqueous solution ofpotassium carbonate (2.7g) in water (100ml),And dried over anhydrous sodiumsulfate (20 g).After removing anhydrous sodium sulfate by filtration ,Thefiltrate was distilled under reduced pressure to remove the solvent.The resulting concentrate was dissolved in isopropyl alcohol(50 ml) and After addition of 1-ethyl-3-methylimidazolium bromide (10.0 g;Formula 4),Sodium carbonate (2.3 g) was added and the temperature was raised tothe reflux temperature. Then, 2- {2- (2,2,2-trifluoroethoxy) phenoxy} ethylmethanesulfonate (7.0 g;formula-3), was added,and It was refluxed for 22 hours. The reaction mixture was distilled under reduced pressure atroom temperature to remove the solvent,and Here it was added an aqueoussolution (50ml) dissolved in sodium hydrogen carbonate (3.5g) in water(70ml),And extracted with ethyl acetate (140 ml).The aqueous layer was furtherextracted with ethyl acetate (70 ml) and The collected mixture was washedsuccessively with an aqueous solution of sodium hydrogencarbonate (3.5 g)dissolved in water (70 ml) and saturated brine (70 ml),The residue wassubjected to vacuum distillation to obtain 3- {7-cyano-5 - [(2R) -2 - ({2- [2-(2,2,2- trifluoroethoxy) phenoxy] ethyl} amino,)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate (Formula 5). The compound thus obtained was dissolved in acetone (100 ml)2-oxoglutaric acid (2.84 g; Formula 7)Was dissolved in acetone (30 ml)[0099]The dissolved solution was slowly added to precipitate crystals. After stirring at room temperature for about 2 hours, the mixture was filtered,(10.7 g, 75%; formula 5b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | In acetone at 10 - 30℃; for 3h; | 1 Embodiment 1 darbey adds the group ester 2- alkone glutarate preparation of crystalline form I The darbey adds the group ester 1.0g (1.6mmol) is added to the 20 ml acetone, 25-30 °C lower stirring dissolution, dissolved with 2-ketoglutaric acid 0.21g (1.4mmol) propanone 3 ml, in the above-mentioned temperature stirring 1h, the temperature is then dropped to 10-15 °C stirring crystallization 2h, filtering, in the obtained precipitate is 40 °C drying in air-blast drying cabinet of 4h the above, to obtain 1.02g (yield 91.4%) of crystalline form I of darbey adds the group ester 2- alkone glutarate, HPLC purity to 99.60%, melting point: 133-135°C, moisture content: 0.35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.17% | In ethanol at 20℃; | 2.2.9 (5,7-dimethyl-1,8-naphthyridine-2-amine): (α-ketoglutaric acid): 2(H2O) [(HL+) · (Hktg-) · (H2O)2] (9) To an ethanol solution (8mL) of 5,7-dimethyl-1,8-naphthyridine-2-amine (34.8mg, 0.2mmol) was added α-ketoglutaric acid (29.2mg, 0.2mmol) in 8mL ethanol. The solution was stirred for 20min, then the solution was filtered into a test tube. The solution was left standing at room temperature for 15 days; colorless crystals were isolated after slow evaporation of the ethanol solution in air. The crystals were collected and dried in air to give [(HL+) · (Hktg-) · 2(H2O)] (9). Yield: 52mg, 73.17%. m. p. 149-151°C. Anal. Calcd for C15H21N3O7 (355.35): C, 50.65; H, 5.91; N, 11.82. Found: C, 50.54; H, 5.79; N, 11.70. Infrared spectrum (KBr disc, cm-1): 3658s(ν(OH)), 3461s(multiple, νas(NH)), 3370s(νs(NH)), 3245m, 3148m, 2992m, 2888m, 2689m, 2508w, 1897m, 1739s(ν(C=O)), 1680s, 1614m, 1584s(νas(COO-)), 1539m, 1498m, 1457m, 1416m, 1376s(νas(COO-)), 1334m, 1288s(ν(C-O)), 1246m, 1204m, 1162m, 1120m, 1078m, 1035m, 993m, 952m, 889m, 848m, 805m, 762m, 720m, 678m, 636m, 610m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: α-ketoglutaric acid; prenyl bromide With N-cyclohexyl-cyclohexanamine In N,N-dimethyl-formamide at 60℃; for 1h; Stage #2: diazodiphenylmethane In tetrahydrofuran at 20℃; for 7h; Cooling with ice; | 1.1 Step 1 Synthesis of compound 1b A solution of the compound 1a (43.8 g, 300 mmol) in DMF (307 mL) was warmed to 60°C. Dicyclohexylamine(59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol) were added to the solution. The mixture wasstirred at 60°C for 1 hour. Then, the precipitates were removed by filtration. Water was added to the filtrate, followed byextraction with ethyl acetate. The organic layer was washed by water and brine and then dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. Under ice cooling, diphenyldiazomethane (64.1 g, 330mmol) was added to a solution of the obtained residue in tetrahydrofuran (321 mL). The mixture was stirred at roomtemperature for 7 hours. The mixture was left standing at room temperature for 2 days. Then, the solvent was evaporatedunder reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethylacetate) to afford the compound 1b (104 g, yield 91%).1H-NMR (CDCl3) δ: 1.73 (3H, s), 1.76 (3H, s), 2.79 (2H, t, J = 6.2 Hz), 3.18 (2H, t, J = 6.2 Hz), 4.74 (2H, d, J = 7.3 Hz),5.38 (1H, t, J = 7.3 Hz), 6.86 (1H, s), 7.26-7.36 (10H, m). |
91% | Stage #1: α-ketoglutaric acid; prenyl bromide With N-cyclohexyl-cyclohexanamine In N,N-dimethyl-formamide at 60℃; for 1h; Stage #2: diazodiphenylmethane In tetrahydrofuran at 20℃; for 7h; Cooling with ice; | 1.1 Step 1 Synthesls of compound 1b A solutlon of the compound 1a (43.8 g, 300 mmol) ln DMF (307 ml) was warmed to 60°C. Dlcyclohexylamine(59.6 ml, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 ml, 300 mmol) were added to the solutlon. The mlxture wasstlrred at 60°C for 1 hour. Then, the preclpltates were removed by flltratlon. Water was added to the flltrate, followed byextractlon wlth ethyl acetate. The organlc layer was washed by water and brlne and then drled over anhydrous magneslumsulfate. The solvent was evaporated under reduced pressure. Under lce coollng, dlphenyldlazomethane (64.1 g, 330mmol) was added to a solutlon of the obtalned resldue ln tetrahydrofuran (321 ml). The mlxture was stlrred at roomtemperature for 7 hours. The mlxture was left standlng at room temperature for 2 days. Then, the solvent was evaporatedunder reduced pressure. The obtalned crude product was purlfled by slllca gel column chromatography (hexane-ethylacetate) to afford the compound 1b (104 g, yleld 91%). |
91% | Stage #1: α-ketoglutaric acid; prenyl bromide With N-cyclohexyl-cyclohexanamine In N,N-dimethyl-formamide at 60℃; for 1h; Stage #2: diazodiphenylmethane In tetrahydrofuran at 20℃; for 7h; | 1.1 Step 1 Synthesis of Compound 1b A solution of compound 1a (43.8 g, 300 mmol) in DMF (307 mL) was warmed to 60 ° C.Dicyclohexylamine (59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol) were added thereto. After stirring at 60 ° C for 1 hour,The precipitated solid was removed by filtration. Add water to the filtrate,Extraction was performed with ethyl acetate. After the organic layer was washed with water and saturated saline,Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and under ice cooling,Tetrahydrofuran (321 mL) on the obtained residueDiphenyldiazomethane (64.1 g, 330 mmol) was added to the solution,Stir at room temperature for 7 hours. After standing at room temperature for 2 days, the solvent was distilled off under reduced pressure.The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate).Obtaining compound 1b(104 g, 91% yield). |
91% | Stage #1: α-ketoglutaric acid; prenyl bromide With N-cyclohexyl-cyclohexanamine In N,N-dimethyl-formamide at 60℃; for 1h; Inert atmosphere; Stage #2: diazodiphenylmethane In tetrahydrofuran at 20℃; for 55h; Inert atmosphere; Cooling with ice; | 5.1.1. Synthesis of 5-benzhydryl 1-(3-methylbut-2-en-1-yl) 2-oxopentanedioate (8) A solution of compound 7 (43.8 g, 300 mmol) in DMF (307 mL) was warmed to 60 C. Dicyclohexylamine (59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol) were added to the solution.The mixture was stirred at 60 C for 1 h. The precipitates wereremoved by filtration. Water was added to the filtrate, followed byextraction with ethyl acetate. The organic layer was washed with waterand brine in this order and then dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. Under icecooling, diphenyldiazomethane (64.1 g, 330 mmol) was added to a solutionof the obtained residue in tetrahydrofuran (321 mL). The mixturewas stirred at room temperature for 7 h. The mixture was left standing atroom temperature for 2 days. Next, the solvent was evaporated underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane-ethyl acetate) to afford compound 8(104 g, yield 91%).1H-NMR (400 MHz, CDCl3) δ: 1.73 (3H, d, J = 0.6 Hz), 1.76 (3H, s),2.78 (2H, t, J = 6.5 Hz), 3.18 (2H, t, J = 6.5 Hz), 4.73 (2H, d, J = 7.5 Hz),5.35-5.40 (1H, m), 6.87 (1H, s), 7.27-7.33 (10H, m).13C-NMR{1H} (100 MHz,CDCl3) δ: 18.1, 25.8, 27.8, 34.3, 63.3, 77.5,117.3, 127.1, 128.0, 128.5, 139.9, 141.0, 160.5, 171.1, 192.5.MS (ESI) m/z: [M + H2O + H]+ calcd for C23H27O6 399; found 399. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetone; at 35 - 45℃; | (0263) [0231] 2.922 g (0.02 moles) of alpha-ketoglutaric acid was dissolved in 10 mL of dry acetone. A separate solution was made from 12.937 g (0.04 moles) of tris[2-(2-(methoxyethoxy)ethyl] amine (TMEEA) in 5 mL of dry acetone. The amine solution was added dropwise with stirring over the course of 2 minutes to the AKG solution; no visible indication of reaction was seen, but the resulting mixture became slightly warm (approximately 35 - 45° C). The mixture was shaken briefly but vigorously, and cooled in a freezer for 30 minutes. Even when cold, still no precipitation of product occurred, so the acetone was removed via a stream of nitrogen followed by treatment in a vacuum oven at room temperature. This gave a clear, golden-brown colored, slightly viscous oil in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; acetone; | [0246] 2.922 g (0.02 moles) of alpha-ketoglutaric acid (AKG) was dissolved in 10 mL of dry acetone to give a clear solution. A separate solution was made from 5.206 g (0.04 moles) of l-(2-hydroxyethyl)-2-imidazolidinone (HEI) in 10 mL of dry acetone. Since HEI was supplied as a 75% w/w solution in water, the actual amount of the 75% reagent used was 6.942 g to compensate for the weight of solvent water. The HEI amine solution was added dropwise with stirring over the course of 3 minutes to the AKG solution; no visible indication of reaction was seen, and no warming was noticable. The mixture was shaken briefly but vigorously, and cooled in a freezer for 1 hour. Even when cold, still no precipitation of product occurred, so the acetone solvent was removed via a stream of nitrogen followed by treatment in a vacuum oven at room temperature. This gave clear, water- white, extremely viscous oil in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetone at 35 - 40℃; | 22 Example 22: Formation of an Ammonium Salt via the Reaction of a-Ketoglutaric Acid (CAS 328-50-7) and Ν,Ν-dimethyldodeclyamine (DiMeC12A, CAS 112-18-5) in a 1:1 Molar Ratio (referred to herein as AKG-mono(DiMeC12A)). [0249] 2.922 g (0.02 moles) of a-ketoglutaric acid was dissolved in 12 mL of dry acetone. This solution was added dropwise with stirring over the course of 1-2 minutes to a separate solution of 4.268 g (0.02 moles) of N, N-dimethyldodecylamine in 6 mL of dry acetone. The mixture was shaken, but no visible indication of reaction was seen except that the combined solution warmed up to about 35 - 40° C. The mixture remained clear for a few minutes, but when shaken again, the entire mass instantly solidified into a solid white crystalline block. This solid was warmed up to 30 - 35° C to re-liquify the product so that entrapped acetone could be removed via a stream of nitrogen followed by treatment in a vacuum oven at room temperature. This gave a white, waxy solid in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetone at 35 - 40℃; | 16 Example 16: Formation of a Diammonium Salt via the Reaction of a-Ketoglutaric Acid (CAS 328-50-7) and Ν,Ν-dimethyldodeclyamine (DiMeC12A, CAS 112-18-5) in a 1:2 Molar Ratio. [0233] 1.461 g (0.01 moles) of a-ketoglutaric acid was dissolved in 6 mL of dry acetone. This solution was added dropwise with stirring over the course of 1-2 minutes to a separate solution of 4.268 g (0.02 moles) of N, N dimethyldodecylamine in 6 mL of dry acetone. No visible indication of reaction was seen except that the combined solution warmed up to about 35 - 40° C. The mixture was shaken briefly but vigorously, and cooled in a freezer for 30 minutes. Even when cold, still no precipitation of product occurred, but when the mixture was shaken again, the entire mass almost instantly solidified into a solid, white, waxy substance. This solid was warmed up to 30 - 35° C to re-liquify the product so that entrapped acetone could be removed via a stream of nitrogen followed by treatment in a vacuum oven at room temperature. This gave a white, waxy solid containing the diammonium salt (AKG- DiMeC12A salt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid; for 1h;Reflux; | A suspension of <strong>[6972-82-3]5,6-diamino-1-methyluracil</strong> (1) (1.56 g, 10 mmol) in AcOH (30 ml) was treated with 2-oxopentanedioic acid (1.46 g, 10 mmol). The reaction mixture was heated, giving a clear solution from which a precipitate formed. The reaction mixture was refluxed for 1 h and cooled. The obtained precipitate was filtered off, washed with water, and dried. Yield 1.99 g(75percent), light-yellow powder, mp >300°. IR spectrum,nu, cm?1: 3500, 3056, 2980, 1643, 1556, 1452, 1421, 1325,1181, 834, 791, 750, 693, 669, 630. 1H NMR spectrum,delta, ppm (J, Hz): 2.69 (2H, t, J = 7.2, CH2CH2COOH); 2.93(2H, t, J = 7.1, CH2CH2COOH); 3.44 (3H, s, 1-NCH3);11.42 (1H, s, 3-NH); 11.57?11.98 (2H, m, 8-NH, COOH).13C NMR spectrum, delta, ppm: 26.9 (CH2CH2COOH); 28.5(NCH3); 30.7 (CH2CH2COOH); 118.2 (C-4a); 141.2(C-8a); 148.1 (C-6); 150.6 (C-2); 159.9 (C-4,7); 174.1(COOH). Mass spectrum (EI), m/z (Irel, percent): 248 (29), 246(9), 221 (11), 220 (100), 167 (18), 149 (28), 121 (7), 83(19), 68 (7), 67 (7). Mass spectrum (APCI-ESI), m/z (Irel, percent):267 [M+]+ (100). Found, percent: C 45.15; H 3.82; N 21.09.C10H10N4O5. Calculated, percent: C 45.12; H 3.79; N 21.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With lithium hydroxide In methanol at 50 - 55℃; Large scale; | 15 Example 15. Synthesis of Dilithium Salt of AKG (Lb-AKG). alpha-Ketoglutaric acid (10.0 g, 0.068 mol) was dissolved in 40 mL methanol. Lithium hydroxide (6.0 g, 0.142 mol) was added to the solution. The solution was stirred for 2.0 - 3.0 hours at 50-55°C. The resulted precipitate was isolated, and the cake was washed with 10 mL methanol. The solid was dried at 75- 80°C for 5-6 hours to give 7.56 g (70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium hydroxide In methanol at 25 - 35℃; Large scale; | 16 Example 16. Synthesis of Dipotassium Salt of AKG (K2-AKG). alpha-Ketoglutaric acid (10.0 g, 0.068 mol) was dissolved in 40 mL methanol, and stirred at ambient temperature to a clear solution. Potassium hydroxide (7.54 g, 0.134 mol) was added to the solution. The solution was stirred for 2.0 - 3.0 hours at 25-35°C. The resulted precipitate was isolated, and the cake was washed with 10 mL methanol. The solid was dried at 75 - 85°C for 5-6 hours to give 7.8 g (52 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To obtain derivatized samples, samples (100muL) containing carboxylic acid or amine compounds were mixed with 400muL of 1N NaOH, 66muL of pyridine, and 334muL of ethanol by gently shaking for 30s. Then, 40muL of ECF was added to the mixture, followed by vortexing and repeated addition of ECF with the same volume. To complete the reaction and separate the layers, 800muL of 30mM NaHCO3 and 800muL of chloroform were added, followed by shaking for 10s. Finally, the derivatized samples were filtered using a 0.2mum syringe filter. All reactions were performed at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With acetic acid at 20℃; for 0.5h; | 3-(3-Oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid deriva- tives (4a-d) General procedure: O-Phenylenediamines (0.01 mol), and -ketoglutaric acid (0.01mol) in acetic acid (20 mL) have stirred for 30 min., at room temperature, and then the solid that obtained was collected by fil- tration and recrystallized from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With acetic acid at 20℃; for 0.5h; | 3-(3-Oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid deriva- tives (4a-d) General procedure: O-Phenylenediamines (0.01 mol), and -ketoglutaric acid (0.01mol) in acetic acid (20 mL) have stirred for 30 min., at room temperature, and then the solid that obtained was collected by fil- tration and recrystallized from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With acetic acid at 20℃; for 0.5h; | 3-(3-Oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid deriva- tives (4a-d) General procedure: O-Phenylenediamines (0.01 mol), and -ketoglutaric acid (0.01mol) in acetic acid (20 mL) have stirred for 30 min., at room temperature, and then the solid that obtained was collected by fil- tration and recrystallized from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.57% | In methanol at 20℃; | c. (nicotinamide) 2 : ( α-ketoglutaric acid) 2 : H 2 O [(HL + ) 2 ·(Hkga -) 2 ·H 2 O] (3) A solution of α-ketoglutaric acid (14.6 mg, 0.1 mmol) in 5 mL methanol was added dropwise to a vigorously stirred solution of nicotinamide (12.2 mg, 0.1 mmol) in methanol (4 ml) over a pe- riod of 5 min. The solution was stirred for a few minutes, filtered into a test tube, and left standing at room temperature for sev- eral days. Colorless block crystals were isolated after slow evap- oration of the methanol solution in air. The crystals were col- lected and dried in air to give [(HL + ) 2 ·(Hkga -) 2 ·H 2 O] (3). (Yield: 24 mg, 86.57%). mp 120-122 °C. Elemental analysis: Calc. for C 22 H 26 N 4 O 13 (554.47): C, 47.61; H, 4.69; N, 10.10. Found: C, 47.53; H, 4.62; N, 10.03. Infrared spectrum (cm -1 ): 3717br( ν(H 2 O)), 3579s( ν(HO)), 3461s(multiple, νas (NH)), 3356s( νs (NH)), 3143 m, 2988 m, 2884 m, 2690 m, 2581 w, 1885 m, 1739s( ν(C = O)), 1685s, 1617 m, 1590s( νas (COO -)), 1534 m, 1504 m, 1471 m, 1428 m, 1386s( νs (COO -)), 1342 m, 1286s( ν(C -O)), 1239 m, 1172 m, 1112 m, 1065 m, 1009 m, 956 m, 897 m, 842 m, 797 m, 745 m, 702 m, 654 m, 621 m, 601 m. |
Tags: 328-50-7 synthesis path| 328-50-7 SDS| 328-50-7 COA| 328-50-7 purity| 328-50-7 application| 328-50-7 NMR| 328-50-7 COA| 328-50-7 structure
A613251[ 997-43-3 ]
Potassium 4-carboxy-2-oxobutanoate
Reason: Free-salt
[ 13885-13-7 ]
2-Cyclopropyl-2-oxoacetic acid
Similarity: 0.85
[ 815-17-8 ]
3,3-Dimethyl-2-oxobutanoic acid
Similarity: 0.81
[ 13885-13-7 ]
2-Cyclopropyl-2-oxoacetic acid
Similarity: 0.85
[ 815-17-8 ]
3,3-Dimethyl-2-oxobutanoic acid
Similarity: 0.81
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P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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