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CAS No. : | 615-79-2 | MDL No. : | MFCD00009124 |
Formula : | C7H10O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OYQVQWIASIXXRT-UHFFFAOYSA-N |
M.W : | 158.15 | Pubchem ID : | 69208 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.57 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.45 |
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) : | -7.11 cm/s |
Log Po/w (iLOGP) : | 1.1 |
Log Po/w (XLOGP3) : | 0.22 |
Log Po/w (WLOGP) : | 0.1 |
Log Po/w (MLOGP) : | -0.31 |
Log Po/w (SILICOS-IT) : | 0.77 |
Consensus Log Po/w : | 0.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.63 |
Solubility : | 37.1 mg/ml ; 0.235 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.05 |
Solubility : | 14.1 mg/ml ; 0.0894 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.04 |
Solubility : | 14.5 mg/ml ; 0.0916 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.68 |
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 |
---|---|---|
74% | Stage #1: With hydrazine In acetic acid; ethyl acetate at 0 - 20℃; for 15 h; Stage #2: With sodium hydrogencarbonate In water; acetic acid; ethyl acetate |
Hydrazine monohydrate (5.4 ml_, 110.68 mmol) was added to a 00C cooled solution of ethyl 2,4-dioxopentanoate (11.67 g, 73.79 mmol) in EtOH/AcOH (100/1 ml_). The reaction mixture was stirred at room temperature, for 15 h, poured into H2O (50 ml_) and NaHCO3 (saturated aqueous solution, 5 ml_) and extracted with EtOAc (3x50 ml_). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish ethyl 5-methyl-1 H-pyrazole- 3-carboxylate, which was submitted to next step without further purification (8.41 g, white solid, yield: 74percent). 1H NMR (CDCI3, 250 MHz): δ ppm 6.55 (s, 1 H), 4.34 (c, J = 7.13 Hz, 2H,), 2.35 (s, 3H), 1.33 (t, J = 7.13 Hz, 3H). El MS: m/z = 155 (M+1 ). |
57% | With hydrazine In ethanol; water for 2 h; Heating / reflux | The title compound is commercially available (Maybridge), but has been prepared as follows (J. Med. Chem. 2002, 45, 1035): Hydrazine monohydrate (25.6 g, 162 mmol) was added to a solution of ethyl 2,4-dioxovalerate (7.85 mL, 162 mmol) in absolute EtOH. The mixture was heated at reflux for 2 h and concentrated to give a yellow oil. Crystallisation from EtOH:water (1:3) gave the title compound (14.225 g, 57 percent) as colourless needles. 1NMR (DMSO-de, 400 MHz) 5 13.2 (br. s, 1H), 6.47 (s, 1H), 4.22 (q, 2H), 2.23 (s, 3H), 1.25 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol for 4 h; Reflux Stage #2: With sodium hydroxide In ethanol at 20℃; Stage #3: With hydrogenchloride In water |
Sodium bicarbonate (13.2 g, 0.157 mol), hydroxylamine hydrochloride (10.91 g, 0.157 mol) and ethyl 2,4-dioxopentanoate (25 g, 01.57 mol) were added to 107 mL of ethanol in a 500 mL round bottom flask. The mixture was refluxed for 4 h. The precipitate was filtered and the filtrate concentrated in vacuo to yield the ester. The ester was dissolved in 53.5 mL of EtOH to which was added sodium hydroxide (59 mL, 10percent solution). The solution stirred overnight at r.t.. The solvent was evaporated under reduced pressure. The sodium salt was dissolved in water and acidified with concentrated hydrochloric acid to precipitate the title compound. Recrystallization of the crude product from EtOAc yielded the product, white crystals, mp 172-174 °C (lit. 182 °C (7), 79percent, 1H NMR (DMSO-d6) 2.3 (3H, s, CH3), 6.6 (1H, s, CH), 7.0 (1H, s, COOH). IR spectrum (KBr) 5-methylisoxazole stretch at 3149 cm-1 and CO stretch at 1655.35 cm-1. Anal: (C, H, N, O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium ethanolate In ethanol at -5℃; for 3 h; | Sodium ethylate (30.0 g, 0.45 mol) was added into 300 mL of anhydrous ethanol and stirred evenly in ice-salt baths. Then the mixture solution of acetone (14.7 g, 0.3 mol) and diethyl oxalate (46.7 g, 0.32 mol) was added dropwise into sodium ethoxide–ethanol solution to keep the reaction temperature below -5 °C for 3 h. The mixture was poured into ice water. After using hydrochloric acid (1 mol/L) to keep the pH around 4, the aqueous phase was extracted with ethyl acetate (EA). The organic layer was washed twice with 150 mL water and dried over Na2SO4, filtered,and concentrated under reduced pressure; 46.5 g (94 percentyield, 96 percent purity) yellow liquid (1a) was obtained. Without further purification, compound 1a was used in the next reaction. 1b–h were obtained in analogous procedures. |
71.9% | With sodium In ethanol at 0 - 20℃; | General procedure: A mixture of ketone 15(0.087 mol), diethyl oxalate 16(0.087mol),thinly sliced sodium (0.047mol) in ethanol (55 mL) was first stirred at 0° and then stirred over night at room temperature. After complication, the mixture was acidified(pH3.0,with 20percent H2SO4), filtered and extracted with dichloromethane.The organic phase was dried and concentrated under vacuum to obtainan yellow or orange liquid 17a-e. The 1,3-diketone 17a-e(0.025mol) was dissolved in methanol (10mL),then added dropwise to a cooled solution(0°C) of hydrazinobenzene(0.025 mol) in methanol (30mL). The reaction was stirred for an hour at room temperature, refluxed for 2h,and the solvent was evaporated under reduced pressure. The residual liguid was purified by column chromatography (a5percent gradient of ethyl acetate in hexanes over a column of silica gel) to afford immediate 18a-e.To obtain the acid 19a-e, a solution of 18a-e(0.007 mol) was saponified through adding7ml 6 mol/L NaOH and stirring at 80°Cfor 2 h.The mixture was acidified (pH1–2) with concentrated hydrochloric acid and filtered to afford 19a-e.To a solution of 19a-e(0.010mol) in 15ml DMF, NCS (0.010mol) was added.The reaction mixture was heated at 90°C for 1hand then added to ice water(50ml), and filtered t oobtain 4-chlorosubstituted carboxylic acids 20a-e. The amide derivatives 21-38 were prepared through the acyl chlorides derived from 19 a-e or 20a-e. A solution of 19a-e or 20a-e(0.004mol) in thionyl chloride(10mL) was refluxed for 5 h and then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline (0.004mol) and TEA (0.008mol)in dichloromethane (10mL). The mixture was stirred overnight at room temperature, and then purified on a column of silica using a gradient of ethylacetate in hexanes to afford the pure products.The yields of imtermediate 17a-e, 18a-e, 19a-e and 20a-e are listed intable 1S. |
60% | With sodium In ethanol at 20℃; for 2 h; | Na (25.3 g, 1.1 mol) was added to anhydrous EtOH (600 mL) within 30 min, and the mixture was stirred atroom temparature for 2 h. Then, a mixture of diethyl oxalate (146 g, 1.0 mol) and dry acetone (58 g, 1.0 mol) was addedslowly dropwise within 1 h. The reaction mixture was stirred at room temprature for additional 1 h, and then was filtered.The obtained filter cake was added into a mixture of ice (500 g) and water (1 L), and then concentrated sulfuric acid wasadded to adjust the pH to 1, extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum to give the title compound (95 g, 60 percent). 1H NMR (CDCl3):δ 6.37 (1H, s), 4.35(2H, q, J = 7.2 Hz), 2.26 (3H, s), 1.38 (3H, t, J =7.2 Hz). |
60% | With sodium In ethanol at 20℃; for 4 h; | Na (25.3 g, 1.1 mol) was added to anhydrous EtOH (600 mL) within 30 min, and the mixture was stirred at room temparature for 2 h. Then, a mixture of diethyl oxalate (146 g, 1.0 mol) and dry acetone (58 g, 1.0 mol) was added slowly dropwise within 3 h. The reaction mixture was stirred at room temprature for additional 1 h, and then was filtered. The obtained filter cake was added into a mixture of ice (500 g) and water (1 L), and then concentrated sulfuric acid was added to adjust the pH to 1, extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (95 g, 60percent). 1H NMR (CDCl3):δ6.37 (1H, s), 4.35 (2H, q, J=7.2 Hz), 2.26 (3H, s), 1.38 (3H, t, J=7.2 Hz). |
60% | With sodium ethanolate In ethanol at 10℃; for 4 h; | To an ice bath cooled solution of sodium (0.217 mol) in anhydrous ethanol(125 mL), a solution of acetone 15 (200 mmol) and diethyl oxalate 16 (200 mmol) was slowly added. The reaction mixture was allowed to stir for 4 h keeping the temperature below 10 °C. Subsequently the mixture was filtered, dissolved in cold water and acidified to pH 3 with sulfuric acid (20percent). After the acidification the solution was extracted three times with dichloromethane (each 50 mL), the extracts collected and evaporated under reduced pressure to give the ethyl acetopyruvate 17 (yields 60percent). |
59.2% | at 0 - 20℃; for 1 h; Inert atmosphere | Intermediate 47: Ethyl 2, 4-dioxopentanoateTo a 100 mL two neck RB flask fitted with magnetic stirrer was charged with 25 mL of ethanol. To the stirred solvent was added sodium metal pieces (0.86 g, 37 mmol) slowly at T/IN2011/0004790 °C under nitrogen atmosphere and stirred for 30 minutes at room temperature. After 30 minutes, diethyl oxalate (5 g, 34.2 mmol) in acetone (10 mL) was "added drop wise. During addition, the reaction mixture was changed to yellow color. After addition, thick mass was observed, was added ethanol (10 mL) to the reaction mixture and stirred at room temperature for 1 h. Then, the reaction mixture was filtered; the solids were dissolved in ice-cold water (50 mL), acidified with concentrated sulfuric acid and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure and the solvent traces were removed by triturated with n-hexane. The product was obtained as brown liquid (3.2 g, yield: 59.2percent). 1H NMR (300 MHz, DMSO-d6): δ 5.46(s, 2H), 4.02-4.09(q, 2H), 1.89(s, 3H), 1.18- 1.22(t, 3H). |
33 g | Stage #1: With sodium In ethanol at 0℃; for 1 h; Stage #2: for 1 h; Cooling with ice |
Step A Ethyl 2,4-dioxopentanoate (5a) Sodium metal (8.6 g, 376.6 mmol) was added to ethanol (200 mL) at 0 °C and the mixture was stirred vigorously with mechanical stirrer. Diethyl oxalate (50 g, 342.4 mmol) in acetone (19.86 g, 342.4 mmol) was added to the reaction mixture at 0 °C when a pale yellow solid started separating out. The reaction mixture was stirred for lh. The solids were filtered off, suspended in ice and cooled sulfuric acid (14 mL) was added to the mixture. The mixture was stirred for lh. The product was then extracted with dichloromethane (2x200 mL) and the combined organic layer was evaporated to dryness to yield the product 5a (33 g). 1H NMR (300 MHz, CDCl3): δ 6.35 (s, 1H), 4.32 (q, J=7.10 Hz, 2H), 2.24 (s, 3H), 1.36 (t, J=7.10 Hz, 3H). |
46.5 g | With sodium ethanolate In ethanol at -15 - -5℃; | At -15 to -5 ° C and under stirring conditions, the A mixed solution of acetone (0.30 mol) and diethyl oxalate (0.32 mol) was added dropwise to a solution of 96percent sodium ethoxide (0.45 mol) in ethanol (300 ml). After completion of the dropwise addition, the reaction solution was allowed to stand for 2-4 hours. The reaction solution was poured into ice water, adjusted to pH = 4 with dilute hydrochloric acid, extracted with ethyl acetate, and the resulting organic phase was washed with water, dried over anhydrous sodium sulfate, And concentrated to give ethyl 2 4-dioxovalerate 46. 5 g. 80percent hydrazine hydrate (0.38 mol) was added dropwise to the above mentioned solution of ethyl 2 4-dioxovalerate in ethanol (300 mL) over 1 to 2 hours at -10 to 5 ° C under stirring. After the dropwise addition, the incubation reaction was continued for 1 to 2 hours. After most of the solvent was removed under reduced pressure, ethyl acetate was extracted and the resulting organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 31. 5 g. |
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