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CAS No. : | 13395-36-3 |
Formula : | C10H16O4 |
M.W : | 200.23 |
SMILES Code : | CCOC(=O)C(=O)CC(=O)C(C)(C)C |
MDL No. : | MFCD00052319 |
InChI Key : | NIMKIMUBJFWPTD-UHFFFAOYSA-N |
Pubchem ID : | 83403 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.7 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 51.61 |
TPSA ? Topological Polar Surface Area: Calculated from | 60.44 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.78 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.62 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.12 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.69 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.37 |
Log S (ESOL):? ESOL: Topological method implemented from | -1.71 |
Solubility | 3.94 mg/ml ; 0.0197 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.5 |
Solubility | 0.631 mg/ml ; 0.00315 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -1.88 |
Solubility | 2.65 mg/ml ; 0.0132 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.37 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 2.06 |
* 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 |
---|---|---|
65% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 16h;Reflux; | The title compound is prepared by those skilled in the art according to a literature procedure (Lepage et al, Eur. J. Med. Chem., 1992, 27, 6, 581-93).To a solution of sodium hydrogen carbonate (2.10 g, 25 mmol) and hydroxylamine hydrochloride (1.73 g, 25 mmol) in ethanol (25 mL) is added ethyl trimethyl acetopyruvate (5.00 g, 25 mmol). The mixture is heated at reflux for 16 h. After this time the sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with 8/2 cyclohexane/ethyl acetate to provide the title compound as a yellow oil (3.2 g, 65%), m/z 198 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.38 (9 H, s), 1.42 (3 H, t, /=7.15 Hz), 4.44 (2 H, q, /=7.15 Hz), 6.38 (1 H, s). |
65% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 16h;Reflux; | Step 1: Synthesis of 5-tert-butyl-isoxazole-3-carboxylic acid ethyl ester The title compound is prepared by those skilled in the art according to a literature procedure (Lepage et al, Eur. J. Med. Chem., 1992, 27, 6, 581-93). To a solution of sodium hydrogen carbonate (2.10 g, 25 mmol) and hydroxylamine hydrochloride (1.73 g, 25 mmol) in ethanol (25 mL) is added ethyl trimethyl acetopyruvate (5.00 g, 25 mmol). The mixture is heated at reflux for 16 h. After this time the sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with 8/2 cyclohexane/ethyl acetate to provide the title compound as a yellow oil (3.2 g, 65%), m/z 198 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.3 8 (9 H, s), 1.42 (3 H, t, J=7.15 Hz), 4.44 (2 H, q, J=7.15 Hz), 6.38 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | To a solution of sodium ethoxide (740mmol of sodium in 45OmL ethanol), a mixture of methyl tert-bxAy ketone (740mmol) and diethyl oxalate (820mmol) are added dropwise at room temperature and stirred for Ih at 78C. On complete reaction, the mixture is allowed to cool to room temperature and it is poured onto cold aqueous hydrochloric acid (5M, 800 mL). Following extraction with methyl tert-butyl ether (300 mL x 3), the combined organic phases are washed with saturated aqueous sodium chloride (500 mL) and dried over anhydrous sodium sulfate. After filtration, removal of the solvent under reduced pressure affords the product as a red liquid. Compound wt: 14Og, Yield: 93.3%.[00292] MS (ES+): 199 (M+l). NMR (1H, CDCl3): 6.5 (IH, s, CH); 4.3 (2H, q, OCH2); 1.35 (3H, t, CH3); 1.15 (9H, s, 3xCH3). | |
74.6% | 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 20% 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(0C) 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 (a5% 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 80Cfor 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 90C 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(0C) 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. |
74.6% | With sodium; In ethanol; at 0 - 20℃; | Pinacolone 1 (0.087 mol) and diethyl oxalate 2 (0.087 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol) at 0 C. The mixture was stirred overnight at room temperature. Next morning, the mixture was acidified (pH 3.0, with 20% H2SO4) and filtered to remove the formed solid. The filtrate was extracted with dichloromethane, dried, and concentrated under vacuum to yield an orange red viscous liquid 3 (12.98 g; 74.6% y). A solution of the 1,3-diketone 3 (0.025 mol) in methanol (10 mL) was added dropwise to a cooled solution (0 C) of hydrazinobenzene (0.025 mol) in methanol (30 mL). The mixture was warmed to room temperature by stirring for an hour and then refluxed for 2 h. The resulting cooled mixture was concentrated under vacumm and the pyrazole ester 4 was obtained after purification by column chromatography (a 5% gradient of ethyl acetate in hexanes over a column of silica gel). To saponify the ester, a solution of 4 (0.007 mol) was combined with an aliquot of 6 mol/L NaOH (aq) (7 mL) and the mixture was stirred at 80 C. Ice water (50 mL) was added at the end of 2 h and the mixture was acidified (pH 1-2) with concentrated HCl. The formed solid was collected by filtration and the filter-cake was dried. The carboxylic acid was purified by recrystallization (methanol:water, 1:1) to afford 5 (3.57 g; 83.2% yield). The amide derivatives 6a-p were prepared through the acylchlorides derived from 5. A solution of 5 (0.004 mol) in thionyl chloride (10 mL) was refluxed for 5 h [11] and then concentrated under vacuum. The formed crude acyl chloride was added dropwise to a cooled solution (0 C) of substituted aniline (0.004 mol) and TEA (0.008 mol) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature to produce the crude product, which was purified on a column of silica using a gradient of ethyl acetate in hexanes to afford the pure products 6a-p. |
70% | A mixture of tert-butyl ketone (499 mmol) and diethyl oxalate (548 mmol) in ethanol(550 mL) is added slowly to the solution of sodium (499 mmol) in ethanol (250 mL) at room temperature. After addition, the reaction mixture is heated to 600C for 2 h. On complete reaction, the ethanol is removed under reduced pressure and aqueous hydrochloric acid (2M, 200 mL) is added to the residue. The aqueous phase is extracted with ethyl acetate (500 mL x 3), washed with water (300 mL), saturated aqueous sodium chloride (300 mL) and it is then dried over anhydrous sodium sulfate. The solvent is then removed under reduced pressure to afford 5,5-dimethyl-2,4-dioxo-hexanoic acid ethyl ester as orange colored liquid (72.5g, 70%).[0205] 1H NMR (400 MHz, CDCl3) delta: 1.20 (s, 9H), 1.35 (t, 3H), 4.34 (q, 2H), 6.53 (s, IH), 14.75(bs, IH). Mass (m/z): 201 (M+H). | |
With sodium hydride; In toluene; mineral oil; at 50℃; for 1.5h;Reflux; | General procedure: To a stirred solution of appropriate methyl ketone (0.1 mol) in dry toluene (200 mL)was added a suspension of NaH in mineral oil (60%; 0.2 mol) in portions and the mixture was warmed to50 C. At this temperature a solution of diethyl oxalate (0.15 mol) in dry toluene (60 mL) was addeddropwise under stirring. The reaction mixture was refluxed for 1.5 h. Upon cooling to room temperatureacetic acid (0.25 mol) was added dropwise. The reaction mixture was washed with water (200 mL), organicphase was dried over MgSO4 and evaporated to dryness. The obtained crude diketone was dissolved inethanol (250 mL), hydrazine dihydrochloride (0.11 mol) was added and the mixture was refluxed for 3 h.After evaporation of solvent the residue was treated with water (200 mL) and kept under ice-cooling for 1 h.Crystals were filtered off and dried in air to afford the corresponding pyrazole. In some cases thus obtainedsubstance was purified by recrystallization from aqueous ethanol. | |
With sodium ethanolate; at 0 - 78℃; for 1h; | To a solution of sodium ethoxide (740 mmol of sodium in 450 mL ethanol), a mixture of methyl tert-butyl ketone (740 mmol) and diethyl oxalate (820 mmol) were added dropwise at room temperature and stirred for 1 h at 78 C. On completion of the reaction, the mixture was allowed to cool to room temperature and poured onto cold aqueous hydrochloric acid (5M, 800 mL). Following extraction with methyl tert-butyl ether (300 mL*3), the combined organic phases were washed with saturated aqueous sodium chloride (500 mL) and dried over anhydrous sodium sulfate. After filtration, removal of the solvent under reduced pressure afforded the product as a red liquid. Compound wt: 140 g, Yield: 93.3%. MS (ES+): 199 (M+1). NMR (1H, CDCl3): 6.5 (1H, s, CH); 4.3 (2H, q, OCH2); 1.35 (3H, t, CH3); 1.15 (9H, s, 3*CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol; at 20℃; for 15h;Molecular sieve; | To a solution of <strong>[13395-36-3]ethyl trimethylacetopyruvate</strong> (205 mg, 1.02 mmol) in dry EtOH (1 mL) was added O-methylhydroxylamine hydrochloride (90 mg, 1.07 mmol) and 3A mol. sieves. The reaction was stirred at RT for 15 h, then was filtered and washed with EtOH. The filtrated was concentrated in vacuo, and the residue was partitioned between Et2O and sat. aqueous NaHCO3. The Et2O layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to give Part A compound (176 mg, 75%) as a red-orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 g | With hydrogenchloride; In ethanol; at 80℃; | A solution of N-benzhydrylidene-N'-quinolin-6-yl-hydrazine (32 g, 0.099 mol) in EtOH (500 mL) was treated with cone. HC1 (80 ml, 0.96 mmol). After stirring for 10 min, <strong>[13395-36-3]5,5-dimethyl-2,4-dioxo-hexanoic acid ethyl ester</strong> (26 g, 0.15 mol) was added, and the mixture was heated to 80C overnight. The reaction was concentrated in vacuo to give a residue which was washed with Et20 to afford ethyl 5- tert-butyl-l-(quinolin-6-yl)-lH-pyrazole-3-carboxylate hydrochloride (40 g, 0.1 1 mol, 1 12 % yield). MS (ESI) m/z: 324.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrazine; In ethanol; at 20℃; | Hydrazine hydrate (446 mmol) is added dropwise to solution of 5,5-dimethyl-2,4-dioxo- hexanoic acid ethyl ester (360 mmol) in ethanol at room temperature. After addition, the reaction mixture is stirred overnight at room temperature. On completion, the solvent is removed under reduced pressure and the residue obtained is diluted with water (250 mL) and extracted with dichloromethane (250 mL x are3). The combined organic phases are washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 5-tert-butyl-2H- pyrazole-3-carboxylic acid ethyl ester as a white crystalline solid (70%).[0207] 1H NMR (400 MHz, DMSO-d6) delta: 13.21 (bs, IH), 6.45 (s, IH), 4.23 (q, 2H), 1.27 (s,9H,)1.25 (t, 3H). Mass (m/z): 197 (M+H). |
11 g | With hydrazine dihydrochloride; In ethanol; for 3h;Reflux; | General procedure: To a stirred solution of appropriate methyl ketone (0.1 mol) in dry toluene (200 mL)was added a suspension of NaH in mineral oil (60%; 0.2 mol) in portions and the mixture was warmed to50 C. At this temperature a solution of diethyl oxalate (0.15 mol) in dry toluene (60 mL) was addeddropwise under stirring. The reaction mixture was refluxed for 1.5 h. Upon cooling to room temperatureacetic acid (0.25 mol) was added dropwise. The reaction mixture was washed with water (200 mL), organicphase was dried over MgSO4 and evaporated to dryness. The obtained crude diketone was dissolved inethanol (250 mL), hydrazine dihydrochloride (0.11 mol) was added and the mixture was refluxed for 3 h.After evaporation of solvent the residue was treated with water (200 mL) and kept under ice-cooling for 1 h.Crystals were filtered off and dried in air to afford the corresponding pyrazole. In some cases thus obtainedsubstance was purified by recrystallization from aqueous ethanol. |
Tags: 13395-36-3 synthesis path| 13395-36-3 SDS| 13395-36-3 COA| 13395-36-3 purity| 13395-36-3 application| 13395-36-3 NMR| 13395-36-3 COA| 13395-36-3 structure
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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 |
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