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CAS No. : | 80370-42-9 | MDL No. : | MFCD11112084 |
Formula : | C6H8O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HMFLBGNCDZYITR-UHFFFAOYSA-N |
M.W : | 144.13 | Pubchem ID : | 11029955 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 32.64 |
TPSA : | 60.44 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) : | -7.29 cm/s |
Log Po/w (iLOGP) : | 0.89 |
Log Po/w (XLOGP3) : | -0.15 |
Log Po/w (WLOGP) : | -0.44 |
Log Po/w (MLOGP) : | -0.66 |
Log Po/w (SILICOS-IT) : | 0.52 |
Consensus Log Po/w : | 0.03 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.31 |
Solubility : | 70.7 mg/ml ; 0.491 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.66 |
Solubility : | 31.2 mg/ml ; 0.216 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.28 |
Solubility : | 74.9 mg/ml ; 0.52 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
72.4% | With hydrazine In ethanol at 0 - 20℃; for 17 h; | 6.2 g (193 mmoles) of hydrazine was added, with ice-cooling, to a solution of 27.6 g (192 mmoles) of (ethoxycarbonyl)malondialdehyde dissolved in 150 ml of ethanol. The mixture was stirred at room temperature for 17 hours to give rise to a reaction. The reaction mixture was subjected to vacuum distillation to remove the ethanol contained therein. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate mixed solvent) to obtain 19.4 g (72.4percent) of ethyl 1H-pyrazole-4-carboxylate as yellow crystals. 1H-NMR [CDCl3/TMS, δ (ppm)]: 8.08 (2H,s), 5.30 (1H,s) 4.31 (2H,q), 1.36 (3H,t) |
72.4% | With hydrazine In ethanol at 20℃; for 17 h; | REFERENCE EXAMPLE 29 Production of ethyl 1H-pyrazole-4-carboxylate; 6.2 g (193 mmoles) of hydrazine was added, with ice-cooling, to a solution of 27.6 g (192 mmoles) of (ethoxycarbonyl)malondialdehyde dissolved in 150 ml of ethanol. The mixture was stirred at room temperature for 17 hours to give rise to a reaction. The reaction mixture was subjected to vacuum distillation to remove the ethanol contained therein. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate mixed solvent) to obtain 19.4 g (72.4percent) of ethyl 1H-pyrazole-4-carboxylate as yellow crystals. 1H-NMR [CDCl3/TMS, δ (ppm)]: 8.08 (2H,s), 5.30 (1H,s), 4.31 (2H,q), 1.36 (3H,t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | at 5 - 20℃; | j00324J Step A: ethyl l-methyl-1H-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) to obtain a clear yellowish solution. The reaction was cooled in an ice bath to 5 °C, and then methyihydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated on a rotary evaporator to a crude orange oil. The crude was taken up in DCM and re-concentrated, then on high vacuum for 2 days to yield tan orange oil. LC/MS and ‘H NMR showed essentially pure ethyl 1-methyl- 1 H-pyrazole-4-carboxylate (106 g, 99.1percent). |
99% | at 5 - 20℃; for 16 h; | [00352] Step A: ethyl 1 -methyl- 1 H-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue dissolved in DCM and re-concentrated, then dried for 2 days to yield ethyl 1 -methyl- lH-pyrazole-4-carboxylate (106 g, 99percent yield) as a tan orange oil. MS (apci) m/z = 155.1 (M+H). |
99.1% | at 5 - 20℃; | 1006631 Step A: ethyl 1-methyl-1H-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mE) to obtain a clear yellowish solution. The reaction was cooled in an ice bath to 5 °C, and then methyihydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated on a rotary evaporator to a crude orange oil. The crude was taken up in DCM and re-concentrated, then on high vacuum for 2 days to yield tan orange oil. LC/MS and ‘H NMR showed essentially pure ethyl 1-methyl-1H- pyrazole-4-carboxylate (106 g, 99.1percent). |
99% | at 5 - 20℃; for 16 h; | Intermediate 24 1 ',4-dimethyl- 1 -phenyl- 1 H, 1 -3 ,4'-bipyrazol-5-amine [00463] Step A: ethyl 1 -methyl- 1 H-pyrazole-4-carboxylate: To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction was concentrated under vacuum and the residue dissolved in DCM and re-concentrated, then dried for 2 days to yield ethyl 1 -methyl- lH-pyrazole-4-carboxylate (106 g, 99percent yield) as a tan orange oil. MS (apci) m/z = 155.1 (M+H). |
99% | at 5 - 20℃; | To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction was concentrated under vacuum and the residue dissolved in DCM and re-concentrated, then dried for 2 days to yield ethyl 1 -methyl- lH-pyrazole-4-carboxy late (106 g, 99percent yield) as a tan orange oil. MS (apci) m/z = 155.1 (M+H). |
99% | at 12 - 20℃; for 16 h; | 1006621 Step A: ethyl 1-methyl-1H-pyrazole-4-carboxylate: To a 3000-mL three- necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL). The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue dissolved in DCM and re-concentrated, then dried for 2 days to yield ethyl 1-methyl-i H-pyrazole-4-carboxylate (106 g, 99percent yield) as a tan orange oil. MS (apci) m/z = 155.1 (M+H). |
99.1% | at 5 - 20℃; | To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate (100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) to obtain a clear yellowish solution. The reaction was cooled in an ice bath to 5 °C, and then methylhydrazine (35.8 mL, 680 mmol) was added dropwise. A vigorous exotherm was observed during hydrazine addition and the temperature was kept below 12 °C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated on a rotary evaporator to a crude orange oil. The crude was taken up in DCM and re-concentrated, then on high vacuum for 2 days to yield the title compound as a tan orange oil (106 g, 99.1percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In diethyl ether at 0 - 20℃; for 15 h; | 12.6 g of sodium hydride (purity: 60percent, 525.0 mmoles) was washed with diethyl ether by decantation several times and then made into a solution in 500 ml of diethyl ether. Thereto were added, in a nitrogen current at 0 to 10°C, 194 g (2.6 moles) of ethyl formate and 50 g (262.0 mmoles) of ethyl 3,3-diethoxy-propionate. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by washing with diethyl ether. The resulting aqueous layer was allowed to have a pH of 1 with hydrochloric acid, followed by extraction with dichloromethane. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.6 g (yield: 100percent) of crude (ethoxycarbonyl)malondialdehyde as a dark red oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]: 9.09 (2H,s), 5.26 (1H,s), 4.27 (2H,q), 1.28 (3H,t) |
100% | With sodium hydride In diethyl ether at 0 - 20℃; for 15 h; | REFERENCE EXAMPLE 28 Production of (ethoxycarbonyl)malondialdehyde; 12.6 g of sodium hydride (purity: 60percent, 525.0 mmoles) was washed with diethyl ether by decantation several times and then made into a solution in 500 ml of diethyl ether. Thereto were added, in a nitrogen current at 0 to 10° C., 194 g (2.6 moles) of ethyl formate and 50 g (262.0 mmoles) of ethyl 3,3-diethoxy-propionate. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by washing with diethyl ether. The resulting aqueous layer was allowed to have a pH of 1 with hydrochloric acid, followed by extraction with dichloromethane. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.6 g (yield: 100percent) of crude (ethoxycarbonyl)malondialdehyde as a dark red oily substance. 1H-NMR [CDCl3/TMS, δ (ppm)]: 9.09 (2H,s), 5.26 (1H,s), 4.27 (2H,q), 1.28 (3H,t) |
99.7% | With sodium hydride In tetrahydrofuran at 0 - 20℃; | [00442] To a stirred suspension of sodium hydride (60percent, 1.68 g, 42.1 mmol) in THF (20 mL) was added ethyl formate (8.5 mL, 105.7 mmol). The solution was cooled to 0 °C and a solution of ethyl 3,3-diethoxypropanoate (4 g, 21.0 mmol) in THF (10 mL) was added dropwise over 30 mins and the reaction mixture stirred at r.t. overnight. 2M aq HCl (30 mL) was added under whilst cooling with ice and the reaction stirred at r.t. for 30 mins. The reaction mixture was extracted with diethyl ether (2 x 50 mL) and the combined organic extracts were dried over MgS04 and concentrated in vacuo to afford the title compound (3.02 g, 99.7percent) as an amber liquid. [00443] 1H NMR (250 MHz, Chloroform-d) δ 9.13 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.37 - 1.28 (m, 3H). |
74.2% | With sodium hydride In diethyl ether; hexane at 20℃; for 15 h; Cooling with ice | Weighed out sodium hydride (2.46 g, 61.5 mmol) in a dry 100-mL pear flask. Washed with hexanes then with diethyl ether. Suspended in ether (100 mL), cooled in ice bath then ethyl formate (24.84 ml, 308 mmol) was added then ethyl 3,3-diethoxypropanoate (5.98 ml, 30.8 mmol). The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by washing with diethyl ether. The resulting aqueous layer was allowed to have a pH of 1 with hydrochloric acid, followed by extraction with dichloromethane. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl 2-formyl-3-oxopropanoate (3.29 g, 22.83 mmol, 74.2 percent yield) as a golden syrup |
70% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: With hydrogenchloride In water |
EXAMPLE 1Preparation of Ethyl-2-formyl-3-oxopropionate[0059] A three- or four-neck round bottom flask equipped with magnetic stir bar, thermocouple, digital thermometer, gas inlet and outlet and addition funnel was flushed <n="19"/>with argon. Ethyl 3,3-diethoxypropionate (64.5 g) in tetrahydrofuran were charged to the addition funnel. Sodium hydride (21.2 g of a 60percent dispersion) was charged to the reaction flask followed by tetrahydrofuran. The contents of the flask were cooled to 0- 5°C in an ice-bath, and ethyl formate (257 g) was added. The mixture was cooled to 0- 50C and the contents of the addition funnel added drop wise, maintaining an internal temperature of less than 5°C. The ice-bath was removed and the contents allowed to warm to ambient temperature. Consumption of ethyl 3,3-diethoxypropionate was monitored by TLC analysis. The reaction was quenched by addition of ice-water (10.6 vol), and extracted three times with methyl t-butyl ether (5.4 vol each), and the organic layers discarded. The aqueous phase was acidified with cone, hydrochloric acid to a pH of 1 to 1.5. The acidified aqueous layer was extracted three times with dichloromethane and the combined organic layers dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue distilled under vacuum, to provide ethyl 2-formyl-3-oxopropionate, 27.92 g, 70percent yield. |
70% | With sodium hydride In tetrahydrofuran at 0 - 20℃; | [0066] A three- or four-neck round bottom flask equipped with magnetic stir bar, thermocouple, digital thermometer, gas inlet and outlet and addition funnel was flushed with argon. Ethyl 3,3- diethoxypropionate (64.5 g) in tetrahydrofuran were charged to the addition funnel. Sodium hydride (21.2 g of a 60percent dispersion) was charged to the reaction flask followed by tetrahydrofuran. The contents of the flask were cooled to 0-50C in an ice-bath, and ethyl formate (257 g) was added. The mixture was cooled to 0-50C and the contents of the addition funnel added dropwise, maintaining an internal temperature of less than 5°C. The ice-bath was removed and the contents allowed to warm to ambient temperature. Consumption of ethyl 3,3- diethoxypropionate was monitored by TLC analysis. The reaction was quenched by addition of ice-water (10.6 vol), and extracted three times with methyl t-butyl ether (5.4 vol each), and the organic layers discarded. The aqueous phase was acidified with cone, hydrochloric acid to a pH of 1 to 1.5. The acidified aqueous layer was extracted three times with dichloromethane and the combined organic layers dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue distilled under vacuum, to provide ethyl 2-formyl-3 -oxopropionate, 27.92 g, 70percent yield. |
59% | With sodium hydride In tetrahydrofuran at 0 - 30℃; for 24 h; | 4) In a 500 ml four-necked flask equipped with magnetic stirring, 160 ml of tetrahydrofuran and9.84g NaH, mass fraction of NaH in tetrahydrofuran solution is 60percent, the solution is cooled in an ice bath to 0 °C to 5 °C, and then 119g of ethyl formate is added to slowly increase the temperature, when the temperature stabilizes to 0 °C At 5 °C, 80 ml of a tetrahydrofuran solution containing D was continuously added dropwise into a 500 ml four-necked flask, wherein the mass fraction of D was 5percent. After the dropwise addition, the water bath was removed and heated to room temperature. At this time, a large amount of hydrogen was evolved. It will first rise to 30 °C and then gradually decrease to 25 °C. After 24 hours of reaction, the reaction solution was poured into ice water and quenched. 5) The resulting product is first extracted with 500 ml of tert-butyl methyl ether three times to remove the organic phase, and then with concentrated hydrochloric acid to adjust the pH of the aqueous phase to 1~1.5; then extract the aqueous phase with 300 ml of dichloromethane, twice The combined organic phases were combined; the combined organic phases were then dried over anhydrous sodium sulfate and evaporated to give a brown-red liquid which was evaporated in vacuo. GC yield was 99.3percent. The yield was 85.9percent. Finally, the 9 mm Hg diaphragm was distilled under reduced pressure. The colorless transparent liquid E, ethyl 2-formyl-3-oxopropanoate, was obtained in a yield of 59percent. |
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