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CAS No. : | 603-69-0 | MDL No. : | MFCD00009864 |
Formula : | C8H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YMCDYRGMTRCAPZ-UHFFFAOYSA-N |
M.W : | 172.18 | Pubchem ID : | 79063 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501 | UN#: | N/A |
Hazard Statements: | H227-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 |
---|---|---|
69% | With hydrazine hydrochloride In ethanol for 2 h; Reflux | To a solution of reagent 1 (4.6 mg, 26.7 mmol) in EtOH (50 mL) was added hydrazine hydrochloride (1.8 g, 26.7 mmol). The mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue was washed with EtOAc to give reagent 2 as a colorless solid (3.1 g, 69percent) sufficiently pure for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride; 1,2-dichloro-ethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; copper diacetate 2.) C6H6, 20 deg C, 5 min, 3.) CH2Cl2; Yield given. Multistep reaction; | ||
With <i>tert</i>-amine at 100 - 110℃; | ||
With magnesium at 55℃; |
With selenic acid at 70 - 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: ethyl acetoacetate With ethanol; magnesium In tetrachloromethane; toluene for 1h; Heating; Stage #2: acetyl chloride In tetrachloromethane; toluene at 0 - 20℃; for 1.5h; | |
90% | With pyridine; magnesium chloride In dichloromethane at 0 - 20℃; for 16h; | |
With magnesium; benzene |
Reaktion ueber mehrere Stufen; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With hydrogenchloride In ethanol; water for 2h; Reflux; | |
35% | With hydrogenchloride In ethanol Reflux; | |
Destillation des Reaktionsprodukts unter vermindertem Druck; |
With acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With hydrazine hydrochloride; In ethanol; for 2h;Reflux; | To a solution of reagent 1 (4.6 mg, 26.7 mmol) in EtOH (50 mL) was added hydrazine hydrochloride (1.8 g, 26.7 mmol). The mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue was washed with EtOAc to give reagent 2 as a colorless solid (3.1 g, 69%) sufficiently pure for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 70.3% 2: 22.1% | With sodium; ethyl acetoacetate In ethanol; N,N-dimethyl-formamide at 75℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 20.7% 2: 65.8% | With sodium In ethanol; N,N-dimethyl-formamide at 75℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 22.1% 2: 70.3% | With sodium In ethanol; N,N-dimethyl-formamide at 75℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In diethyl ether at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In diethyl ether at -30 - -25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In ethanol for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 48% 2: 28% | With oxygen; manganese triacetate In acetic acid at 23℃; for 12h; | |
1: 28% 2: 48% | With oxygen; manganese(II) acetate In acetic acid at 23℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In ethanol for 48h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With triethylamine In ethanol for 6h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 13 % Spectr. 2: 87 % Spectr. 3: 87 % Spectr. | With phenylhydrazine In chloroform-d1 at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine In d<SUB>7</SUB>-N,N-dimethylformamide at -20℃; for 0.05h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine In d<SUB>7</SUB>-N,N-dimethylformamide at -20℃; for 0.166667h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In ethanol for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate In acetonitrile at 0 - 20℃; | 23.1 Step 1 Ethyl diacetoacetate (93.4 g), Cs2CO3 (185 g) and CH3CN (550 ml) were mixed together, using an overhead mechanical stirrer. CH3CN (50 ml) was added and the resulting mixture was cooled to 0° C. Methyl trifluoromethane sulfonate (88.6 g) was added dropwise and after addition, the cooling bath was removed. The mixture was stirred for 1 h at RT, filtered, and the salts were washed with Et2O (2×50 ml). The organic extracts were combined and Et2O (300 ml) was added. The resulting mixture was filtered, the filter cake was washed with Et2O (2×100 ml), the Et2O extracts were combined and evaporated to half volume. The solution was cooled in an ice bath and washed once with cooled (0° C.) 2 N NaOH (pH=11). The Et2O layer was dried over MgSO4, filtered and evaporated to give the desired product as a yellow liquid (64.7 g) in 65% yield, which was used directly in the next step. |
65% | With caesium carbonate In acetonitrile at 0 - 20℃; for 1h; | 1 Ethyl diacetoacetate (93.4 g), Cs2CO3 (185 g) and CH3CN (550 ml) were mixed together, using an overhead mechanical stirrer. CH3CN (50 ml) was added and the resulting mixture was cooled to 0°C. Methyl trifluoromethane sulfonate (88.6 g) was added dropwise and after addition, the cooling bath was removed. The mixture was stirred for 1 h at RT, filtered, and the salts were washed with Et2O (2 X 50 ml). The organic extracts were combined and Et2O (300 ml) was added. The resulting mixture was filtered, the filter cake was washed with Et2O (2 X 100 ml), the Et2O extracts were combined and evaporated to half volume. The solution was cooled in an ice bath and washed once with cooled (0°C) 2 N NaOH (pH = 11). The Et2O layer was dried over MgSO4, filtered and evaporated to give the desired product as a yellow liquid (64.7 g) in 65% yield, which was used directly in the next step. |
62% | With caesium carbonate In hexane; acetonitrile at 20℃; for 2h; Inert atmosphere; Cooling with ice; | ethyl 2-acetyl-3-methoxybut-2-enoate (S10) was prepared according to literature precedent.8To an oven-dried 50 mL round bottom flask under argon atmosphere were added Cs2CO3 (3.4 g,11 mmol, 1.05 equiv), ethyl diacetoacetate (1.6 mL, 10 mmol, 1.01 equiv), and acetonitrile (10.5mL). The resulting suspension was cooled in an ice water bath. With vigorous stirring, methyltrifluoromethanesulfonate (1.1 mL, 10 mmol, 1 equiv) was added to the reaction dropwise. Theice water bath was removed and the reaction was stirred vigorously at room temperature for 2S10 S11Me MeCO2EtO OMe MeCO2EtO OMeOTf MeCs2CO3MeCNH2NNHMeNaOEtEtOH, refluxN NMe MeMeCO2EtHCl h. The reaction was filtered and the remaining solids were washed with Et2O. The filtrate wasdiluted with Et2O until no more precipitate formed. The suspension was filtered again to give aclear solution. The filtrate was washed twice with H2O and once with brine. The organic layer wasdried over MgSO4, filtered, and concentrated to dryness. The residue was purified by columnchromatography (SiO2, 20% to 50% EtOAc in hexanes) to give S10 as a mixture of alkene isomers(1.16 g, 6.2 mmol, 62% yield) as a pale yellow oil. |
With CsCO3 In acetonitrile | ||
With caesium carbonate In acetonitrile at 70℃; | 1 ester 88 A mixture of 87 (2.0 g, 11.6 mmoi), cesium carbonate (6.2 g, 19.0 mrnol) in MeCN (20 mL) is stirred at room temperature for 3 hours before methyl trifluoromethanesuifonate (1.4 mL. 12,3 mrnoi) is added. After stirring at 70 O( overnight, the mixture is diluted with water (20 mL) and extracted with EA (20 mL x3). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated to give 88 as a yellow oil (2 g, 93% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: ethyl 2-acetylacetoacetate With caesium carbonate In acetonitrile Stage #2: methyl trifluoromethanesulfonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; magnesium sulfate; at 140℃; for 4 - 6h;Product distribution / selectivity; | Example 6 ethyl-2-(1-ethoxyethylidene)-acetoacetate To ethyl-diacetoacetate (510 mg, 2.96 mmol) were added <strong>[24964-76-9]triethyl orthobutyrate</strong> (845 mg, 4.39 mmol), magnesium sulfate (200 mg) and sulfuric acid (5 μl), and the mixture was heated at 140C for 6 hr. MTBE was added, and the precipitate was filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give an oil containing ethyl-2-(1-ethoxyethylidene)-acetoacetate (449 mg, 2.24 mmol). Example 11: ethyl 4,6-methyl-2-methylthiopyrimidine-5-carboxylate ; To ethyl diacetoacetate (510 mg, 2.96 mmol) were added trimethyl orthobutyrate (845 mg, 4.39 mmol), magnesium sulfate (200 mg) and sulfuric acid (5 µl), and the mixture was stirred at 140C for 4 hr in an oil bath. The reaction mixture was concentrated under reduced pressure. The residue was added to a suspension of methylisothiourea sulfate (412 mg, 1.48 mmol) and sodium carbonate (320 mg, 3.01 mmol) in ethyl acetate, and the mixture was stirred at 80C overnight. After cooling, the mixture was washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (365 mg, 1.61 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Cs2CO3 / acetonitrile 1.2: 58 percent / acetonitrile 2.1: NaOEt / 80 °C | ||
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile; hexane / 2 h / 20 °C / Inert atmosphere; Cooling with ice 2: sodium ethanolate; sodium / ethanol / 12 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CsCO3 / acetonitrile 2: NaOEt / ethanol / Heating | ||
Multi-step reaction with 2 steps 1.1: Cs2CO3 / acetonitrile 1.2: 58 percent / acetonitrile 2.1: NaOEt / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Cs2CO3 / acetonitrile 1.2: 58 percent / acetonitrile 2.1: NaOEt / 80 °C | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran; methanol / 2 h / 40 °C 2: potassium carbonate / ethanol / 20 - 80 °C | ||
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile / 70 °C 2: sodium methylate / ethanol / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) potassium carbonate / 1) THF, rt, 5 min; 2) THF, rt, 2 h 2: 93 percent / C6H5CH2N(1+)(CH3)3*3Br(1-) on Amberlyst A-26 / CH2Cl2 / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) potassium carbonate / 1) THF, rt, 5 min; 2) THF, rt, 2 h 2: 93 percent / C6H5CH2N(1+)(CH3)3*3Br(1-) on Amberlyst A-26 / CH2Cl2 / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) potassium carbonate / 1) THF, rt, 5 min; 2) THF, rt, 2 h 2: 93 percent / C6H5CH2N(1+)(CH3)3*3Br(1-) on Amberlyst A-26 / CH2Cl2 / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature 6: 60 percent / diphenyl ether / 2 h / 180 - 185 °C 7: 52 percent / conc. HCl / methanol / 4 h / Heating 8: HBr / dioxane / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature 6: 60 percent / diphenyl ether / 2 h / 180 - 185 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature 6: 60 percent / diphenyl ether / 2 h / 180 - 185 °C 7: 52 percent / conc. HCl / methanol / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature 6: 60 percent / diphenyl ether / 2 h / 180 - 185 °C 7: 52 percent / conc. HCl / methanol / 4 h / Heating 8: HBr / dioxane / Ambient temperature 9: N,N-dimethylacetamide / 72 h / Ambient temperature 10: 42 percent / 1N NaOH / methanol / 72 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 78 percent / DBU / ethanol / 48 h / Ambient temperature 2: 89 percent / K2CO3 / dimethylformamide / Ambient temperature 3: 56 percent / LiAlH4 / diethyl ether / 3 h / -10 °C 4: 88 percent / N,N-dimethylaniline / CHCl3 / 5 h / Ambient temperature 5: 89 percent / m-CPBA / ethanol / 1 h / Ambient temperature 6: 60 percent / diphenyl ether / 2 h / 180 - 185 °C 7: 52 percent / conc. HCl / methanol / 4 h / Heating 8: HBr / dioxane / Ambient temperature 9: N,N-dimethylacetamide / 72 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid at 120℃; for 3h; | 19 3-Amino-5-phenylpyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5.0 ml) and stirred for 3 hours at 120°C. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N sodium hydroxide solution (3 ml) were added to the residue and then stirred for 1 hour at 70°C. The mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (2.1 g, Y. : 78%) as white crystals.1H NMR; (DMSO-d6) δ (ppm): 2.6 (3H, s), 2.9 (3H, s), 7.2 (1H, s), 7.4 (1H, t), 7.5 (2H, t), 8.1 (1H, d), 13.9 (1H, brs). ESI/MS (m/z): 266 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 3-methyl-5-aminopyrazole; ethyl 2-acetylacetoacetate With acetic acid at 120℃; for 3h; Stage #2: With sodium hydroxide In ethanol; water at 70℃; for 1h; | 17 (Intermediate Example 17) 2,5,7-Trimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 3-Amino-5-methylpyrazole (970 mg) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred at 120°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (5 ml) and 5 N sodium hydroxide solution (2 ml) were added to the residue and stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (1.6 g, Y.: 80%) as white crystals. 1H NMR; (DMSO-d6) δ (ppm): 2.4 (3H, s), 2.5 (3H, s), 2.8 (3H, s), 6.5 (1H, s), 13.8 (1H, brs). ESI/MS (m/z): 206 (M-H)-. |
80% | Stage #1: 3-methyl-5-aminopyrazole; ethyl 2-acetylacetoacetate With acetic acid at 120℃; for 3h; Stage #2: With sodium hydroxide In ethanol; water at 70℃; for 1h; Stage #3: With hydrogenchloride In ethanol; water at 20℃; | 2,5,7-Trimethylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid (3i) 3-Amino-5-methylpyrazole (970 mg) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred at 120°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (5 ml) and 5 N aqueous sodium hydroxide solution (2 ml) were added to the residues and then stirred at 70°C for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the mixture. 2 N hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected and washed with water and n-hexane to give 3h (1.6 g, Y.: 80%) as white crystals.1H NMR: d 2.4 (3H, s), 2.5 (3H, s), 2.8 (3H, s), 6.5 (1H, s), 13.8 (1H, brs); MS (m/z): 206 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid at 120℃; for 3h; | 21 3-Amino-5-t-butylpyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred for 3 hours at 120°C. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N sodium hydroxide solution (3 ml) were added to the residue and then stirred for 1 hour at 70°C. The mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (2.1 g, Y.: 78%) as white crystals.1H NMR; (DMSO-d6) δ (ppm): 2.6 (3H, s), 2.9 (3H, s), 7.2 (1H, s), 7.4 (1H, t), 7.5 (2H, t), 8.1 (1H, d), 13.9 (1H, brs). ESI/MS (m/z): 246 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In methanol; water at 20℃; for 18h; | 30.1 step 1 - Ethyl diacetoacetate (2.3 mL, 14.7 mmol) was added at RT to a solution of cyclohexylhydrazine hydrochloride (2.0 g, 13.3 mmol) in a 8:5 mixture of MeOH/water (65 mL). The resulting mixture was vigorously stirred at RT for 18 h and then evaporated. The residue was purified via SiU2 chromatography (hexane/EtOAc) to afford 1.6 g (48%) of 112a. |
With pyridine In ethanol | 19 Preparation of 1-Cyclohexyl-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 19 Preparation of 1-Cyclohexyl-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of cyclohexyl hydrazine hydrochloride and 2-acetyl-3-oxobutyric Acid Ethyl Ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 66° C.-67° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In ethanol; | EXAMPLE 23 Preparation of 1-(3-Fluorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong> and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that resulting solid was the named product (m.p. 55 C.-56.1 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In ethanol; | EXAMPLE 22 Preparation of 3,5-Dimethyl-1-m-tolyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of m-tolylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of a 50percent pyridine in ethanol. The resulting oil was purified by flash chromatography to yield the named product as a solid (m.p. 46.5° C.-47.5° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 8 Preparation of 3,5-Dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 8 Preparation of 3,5-Dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, 2-pyridylhydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol, then heated under reflux. The solvents were removed under vacuum and the residue purified over silica. The named product crystallized upon standing (m.p. 49° C.-50° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol; chloroform | 3 Preparation of 3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 3 Preparation of 3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, phenyl hydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum and the oil resuspended in chloroform. The resulting suspension was washed with 5% sodium bicarbonate, 5% hydrochloric acid, and then brine. The organic layer was dried over NaSO4, the solids filtered, and the solvents removed under vacuum. The crude material was purified over silica gel to yield the named product as an oil. 1H-NMR (CDCl3, ppm): 1.37 t (3H); 2.51 s (6H); 4.32 q (2H); 7.42 bs (5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 4 Preparation of 3,5-Dimethyl-1-p-tolyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 4 Preparation of 3,5-Dimethyl-1-p-tolyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.-49° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 20 Preparation of 1-Benzyl-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 20 Preparation of 1-Benzyl-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of benzylhydrazine dihydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. The resulting oil was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.35 t (3H); 2.44 s (3H); 2.45 s (3H); 4.38 a (2H); 5.25 s (2H); 7.08 d (2H); 7.29 m (3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In ethanol; | EXAMPLE 2 Preparation of 3,5-Dimethyl-1-(3-nitrophenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, <strong>[51516-96-2]m-nitrophenylhydrazine hydrochloride</strong> (10 mmol, 1.9 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a 50% solution of pyridine in ethanol. A precipitate was formed in the-reaction medium, and was collected by filtration. Analysis confirmed synthesis of the named product, m.p., 107.7 C.-109.2 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In ethanol; hexane; chloroform; | EXAMPLE 5 Preparation of 3,5-Dimethyl-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, o-nitrophenylhydrazine (20 mmol, 3.4 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (20 mmol, 3.4 g) were mixed in a solution of 50% pyridine in ethanol and heated under reflux. The solvents then were removed under vacuum, and the residue was resuspended in chloroform. The resulting mixture was washed with water and dried over NaSO4. The solids then were filtered, and the solvents removed under vacuum. A precipitate formed when the oily solid was dissolved in a solution of 20% hexane in chloroform. The solid was collected and discarded, and the filtrate was purified over silica gel. The named product was contaminated, then was further purified by recrystallization from ethanol to yield a solid having a melting point of 128 C.-130 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 1 Preparation of 1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 1 Preparation of 1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester p-Bromophenylhydrazine hydrochloride (10 mmol, 2.5 g) was added to 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) in ethanol (10 mL) and pyridine (10 mL). The mixture was stirred overnight at room temperature. Thin layer chromatographic (TLC) analysis using chloroform indicated the reaction was complete. The solvents were removed under vacuum. The residue was dissolved in 150 mL ether, then washed with 50 mL water to remove the pyridine. The ether, was dried over sodium sulfate (NaSO4), the solids filtered, then the solvents were removed under vacuum. The resulting oil was purified on a silica column. The named product crystallized upon standing in the column effluent, m.p. 71° C.-73° C. Analysis by 1H-NMR and 13C-NMR verified synthesis the named product. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; In ethanol; | EXAMPLE 24 Preparation of 1-(3-Methoxyphenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of <strong>[39232-91-2]3-methoxyphenylhydrazine hydrochloride</strong> and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a Solution of 50% pyridine in ethanol. The resulting solid was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.38 t (3H); 2.50 s (3H); 2.52 s (3H); 3.84 s (3H); 4.32 q (2H); 6.96 m (3H); 7.3 st (1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 21 Preparation of 1-(3-Chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 21 Preparation of 1-(3-Chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of 3-chlorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed that the resulting solid was determined to be the named product (m.p. 56° C.-57° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In ethanol | 17 Preparation of 3,5-Dimethyl-1-(5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester EXAMPLE 17 Preparation of 3,5-Dimethyl-1-(5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, equimolar amounts of (5-nitropyridin-2-yl)hydrazine and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 117° C.-119° C.). |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid In water | 3 Example 3 Example 3 Synthesis of 6,7-dihydroxy-3-acetyl-4-methylcoumarin 1,2,4-triacetoxybenzene (6.3g, 25mmol) and ethyl diacetoacetate (4.3g, 25mmol) were heated together as described previously and treated with 75% sulphuric acid (35ml). After 16 hours the crude product was isolated by pouring into ice/water. The air dried material was crystallized from hot ethanol with addition of hot water to the point of crystallisation. On cooling, pale yellow needles formed (3.5g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23 Example 23 Example 23 End product: Ethyl 1-amidino-3,5-dimethyl-1H-pyrazole-4-carboxylate hydrochloride Starting compound: Ethyl 2-acetylacetoacetate Physico-chemical properties: Melting point: 174° to 176° C. Mass: 210 (M-HCl)+ Nuclear magnetic resonance spectrum (DMSO-d6, TMS internal standard): δ: 1.31 (3H, t, J=7 Hz), 2.40 (3H, s), 2.72 (3H, s), 4.28 (2H, q, J=7 Hz), 9.74 (4H, brs) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid; In methanol; at 20℃; for 1h; | step 1 - Ethyl diacetoacetate (2 mL, 12.8 mmol) was added at RT to a mixture of 3- chloro-6-hydrazinopyridazine (1.5 g, 10.4 mmol) and HOAc (1 mL) in MeOH (30 mL). The resulting mixture was stirred at RT for 1 h. The resulting precipitate was filtered and rinsed with EtOH. The process was repeated twice as more product precipitated form the filtrate. The combined solids afforded 1.75 g (60%) of 106a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: pyrid-2-ylhydrazine; ethyl 2-acetylacetoacetate With acetic acid for 18h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 11 Preparation 11 : 3,5-Dimethyl-l-pyridin-2-yl-lH-pyrazole-4-carbaldehyde3,5-Dimethyl-l-pyridin-2-yl-lH-pyrazole-4-carboxylic acid ethyl ester Dissolve 2-acetyl-3-oxobutyric acid ethyl ester (20.74 g, 0.120 mol) and 2- pyridylhydrazine (14.5 mL, 0.133 mol) in acetic acid (160 mL) and stir the mixture for 18 hr. Concentrate, dilute with DCM, wash with saturated sodium bicarbonate, dry (sodium sulfate), filter and concentrate to give 3,5-dimethyl-l-pyridin-2-yl-lH-pyrazole-4- carboxylic acid ethyl ester as an oil (28.6 g, 97%). MS (m/z): 246 (M+l). |
97% | Stage #1: pyrid-2-ylhydrazine; ethyl 2-acetylacetoacetate With acetic acid for 18h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane | 45 Dissolve 2-acetyl-3-oxobutyric acid ethyl ester (20.74 g, 0.120 mol) and 2- pyridylhydrazine (14.5 mL, 0.133 mol) in acetic acid (160 mL) and stir the mixture for 18 hr. Concentrate, dilute with DCM, wash with saturated sodium bicarbonate, dry (sodium sulfate), filter and concentrate to give 3,5-dimethyl-l-pyridin-2-yl-lH-pyrazole-4- carboxylic acid ethyl ester as an oil (28.6 g, 97%). MS (APCI): m/z = 246 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With hydrogenchloride In ethanol at 90℃; for 12h; | 6.1 Step 1. Synthesis of ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate. 6a A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to -20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With acetic acid; In water; at 0℃; for 20h; | Following the procedure described in Helvetica Chimica Acta (1952), 35, 478-85, 5.00 g (26.37 mmmol) of <strong>[51516-96-2]3-nitrophenylhydrazine hydrochloride</strong> suspended in 46 ml of 55% aqueous AcOH were dissolved by careful heating and treated (without further heating) with 4.13 ml (26.37 mmol) of ethyl diacetoacetate. The reaction was immediately cooled and kept 20 h at 0 C. The precipitate was diluted with 28 ml of water and after 6 h filtered and washed with 2×5 ml of water to give after drying under reduced pressure 4.66 g (61%) of the title compound as a light yellow solid. MS: 289.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 14h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 3(5)-phenylpyrazol-5(3)-amine; ethyl 2-acetylacetoacetate With acetic acid at 120℃; for 3h; Stage #2: With sodium hydroxide In ethanol; water at 70℃; for 1h; Stage #3: With hydrogenchloride In ethanol; water at 20℃; | 5,7-Dimethyl-2-phenylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid (3h) 3-Amino-5-phenyl pyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5.0 ml) and stirred at 120°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N aqueous sodium hydroxide solution (3 ml) were added to the residues and then stirred at 70°C for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the mixture. 2 N hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected and washed with water and n-hexane to give 3h (2.1 g, Y.: 78%) as white crystals.1H NMR: d 2.6 (3H, s), 2.9 (3H, s), 7.2 (1H, s), 7.4 (1H, t), 7.5 (2H, t), 8.1 (1H, d), 13.9 (1H, brs); MS (m/z): 266 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 5-(tert-butyl)-1H-pyrazol-3-amine; ethyl 2-acetylacetoacetate With acetic acid at 120℃; for 3h; Stage #2: With sodium hydroxide In ethanol; water at 70℃; for 1h; Stage #3: With hydrogenchloride In ethanol; water at 20℃; | 2-t-Butyl-5,7-dimethylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid (3g) 3-Amino-5-t-butyl pyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred at 120°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N aqueous sodium hydroxide solution (3 ml) were added to the residues and then stirred at 70°C for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the mixture. 2 N hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected and washed with water and n-hexane to give 3g (2.1 g, Y.: 78%) as white crystals.1H NMR: d 2.6 (3H, s), 2.9 (3H, s), 7.2 (1H, s), 7.4 (1H, t), 7.5 (2H, t), 8.1 (1H, d), 13.9 (1H, brs); MS (m/z): 246 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus trichloride at 50℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 52% 2: 26% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In toluene at 20℃; regioselective reaction; | General procedure I with PyBrOP reagent. General procedure: To a solution of PyBrOP (318 mg, 0.68 mmol, 1.3eq), Pyridine N-oxide (50 mg, 0.53 mmol, 1 eq) and nucleophile (0.66 mmol, 1.25eq) in appropriate solvent (1mL, 0.53 M), iPr2EtN(300 µL, 1.97 mmol, 3.75 eq) was added. The reaction was stirred at r.t.overnight. The reaction medium was concentrated in vacuo and the residue purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; for 5.5h;Reflux; | 2-Acetyl-3-oxo-butyric acid ethyl ester (2.4 mL) is added to ethyl 4-hydrazino- benzoate hydrochloride (3.4 g) in ethanol (130 mL) and triethylamine (3.4 mL) and the mixture is refluxed for 5.5 h. After concentration in vacuo, the residue is purified by HPLC to yield the intermediate, 1 -(4-ethoxycarbonyl-phenyl)-3,5-dimethyl-1 H- pyrazole-4-carboxylic acid ethyl ester. The intermediate (3.35 g) is added to 1 M aqueous NaOH solution (10.6 mL) in ethanol (250 mL) and the mixture is stirred at room temperature for 3 d. 1 M aqueous hydrochloric acid (10.6 mL) is added and the mixture is concentrated in vacuo. Water is added and the precipitate is collected and dried to yield the title compound. Mass spectrum (ESI+): m/z = 289 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With 1,2-bis(benzylsulfinyl)ethane palladium acetate; 2,6-dimethyl-1,4-benzoquinone In 1,4-dioxane; dimethyl sulfoxide at 45℃; for 24h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: ethyl 2-acetylacetoacetate With boron trioxide In ethyl acetate at 60℃; for 0.666667h; Inert atmosphere; Stage #2: 4-hydroxy-3-(trifluoromethoxy)benzaldehyde With boric acid tributyl ester In ethyl acetate at 60℃; for 0.5h; Inert atmosphere; Stage #3: With N-butylamine In ethyl acetate at 60℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 mg | With acetic acid In ethanol for 18h; Reflux; | 52 Production of ethyl 1-[2-(dimethylamino)-4-methoxy-quinazolin-7-yl]-3,5-dimethyl-1H-pyrazole-4-carboxylate 7-Hydrazinyl-4-methoxy -N, N-dimethyl-quinazolinamine-2-amine dihydrochlorideSalt (20mg) of ethanol (1mL) solution in acetic acid (0.3mL) and diEthyl acetoacetate (14 mg) was added,18 hours was heated to reflux.The reaction solution was cooled to 20-25 ,After the solvent was evaporated under reduced pressure,Residue in ammonia water (0.2mL) and airAdding ethanol (1 mL), and basified. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent;Hexane / ethyl acetate = 40 / 60-0 / 100) to give,The title compound was obtained 8mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In tetrahydrofuran; methanol at 40℃; for 2h; | 8 Ethyl (2E)-2-acetyl-3 -methoxybut-2-enoate To a solution of ethyl 2-acetyl-3-oxobutanoate (4.53 mL, 29.04 mmol) in MeOH (0455) (20 mL) and THF (30 mL) was added 2M (diazomethyl)(trimethyl)silane (36.3 mL) at r.t. (0456) The reaction mixture was stirred at 40°C for 2 h, then quenched with acetic acid (5 mL). (0457) The solvent was removed in vacuo. The residue was dissolved in DCM (30 mL) and washed sequentially with saturated aqueous NaHC03 (20 mL) and brine (20 mL), then dried over Na2S04. The crude material was purified by column chromatography, with a gradient of 0-70%> EtOAc in heptane, to afford the title compound (3 g, 55%>) as a clear oil. Method B HPLC-MS: MH+ mlz 187, RT 1.40 minutes (90%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.333 % de | With silver hexafluoroantimonate; bis(1,5-cyclooctadiene)diiridium(I) dichloride In 1,2-dichloro-ethane at 25℃; for 2h; Inert atmosphere; Overall yield = 41 %; Overall yield = 32 mg; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
326 mg | Stage #1: amino-4 hydroxy-2 toluene With hydrogenchloride; isopentyl nitrite In ethanol; water at 0 - 5℃; for 0.5h; Stage #2: With tin(ll) chloride In ethanol; water at 0 - 5℃; for 1h; Stage #3: ethyl 2-acetylacetoacetate With triethylamine In ethanol; water at 70℃; for 1h; | 5.a a) Synthesis of ethyl 1- (3-hydroxy-4-methylphenyl) -3,5-dimethyl-1 H-pyrazole-3-carboxylate To 2.46 g of 5-amino-2-methylphenol were added 20 mL of ethanol and 1.8 mL of concentrated hydrochloric acid to dissolve them,While cooling to 0 ° C. and stirring,2.80 mL of isoamyl nitrite was added dropwise over 15 minutes so that the internal temperature did not exceed 5 ° C.,The reaction solution A was stirred as it was at 0 to 5 ° C. for 15 minutes.To 9.05 g of tin (II) chloride, 4 mL of ethanol and 1.8 mL of concentrated hydrochloric acid were added and dissolved, and then the solution was cooled with ice.3 mL of the reaction solution A prepared above was added dropwise at an internal temperature of 5 ° C. or lower,The mixture was stirred as it was at 0 to 5 ° C. for 1 hour,32.0 g of Reaction Solution B was prepared.To 8.0 g of Reaction Solution B was added ethyl diacetoacetate0.939 mL was added and stirred,3.5 mL of triethylamine was added,And the mixture was stirred at 70 ° C. for 1 hour.After distilling off the solvent,After adding 1N hydrochloric acid to pH 1,The mixture was extracted with ethyl acetate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (326 mg) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: boron trifluoride diethyl etherate; ethyl 2-acetylacetoacetate In ethyl acetate at 50 - 60℃; for 0.5h; Stage #2: 4-[bis(4-methoxyphenyl)amino]benzaldehyde With boric acid tributyl ester In ethyl acetate at 50 - 60℃; for 0.5h; Stage #3: With N-butylamine In ethyl acetate at 50 - 60℃; | 7 (Synthesis Example 7) Synthesis of Compound 7 In a 50 mL flask, the mixture of Ethyl diacetoacetate (228 μΙ_, 1.463 mmol, 1 eq) and BF3 Et20 (199 μΙ_, 1.609 mmol, 1.1 eq) in 3ml_ ethyl acetate was heated for 30min at 50-60°C in air. Dissolved 4-[Bis(4-methoxyphenyl)amino]benzaldehyde (1 g, 3.000 mmol, 2.05 eq) and B(n-OBu)3 (0.987 mL, 3.658 mmol, 2.5 eq) into 12mL ethyl acetate, then the solution was injected into the first mixture. Kept the reaction at 50-60°C for another 30 min. First portion of morpholine (51 μΙ_, 0.585mmol, 0.4eq) was added dropwise into the reaction. After 6 h heating, second portion of morpholine (51 μΙ_, 0.585mmol, 0.4eq) was added, and the reaction was kept heating at 50-60°C overnight. All the solvents were evaporated. The crude product could be obtained by flash column chromatography (silica, CH2CI2). Further purification was done by many times' precipitation in CH2CI2/petroleum ether, giving dark green powder (318 mg, 26% yield). (0326) 1H NMR (400 MHz, CD2CI2, ppm): (58.04 (d, 3J= 15.2 Hz, 2H), 7.44 (d, 3J= 8.9 Hz, 4H), 7.13 (d, 3J= 8.9 Hz, 8H), 7.07 (d, 3J= 14.8 Hz, 2H), 6.90 (d, 3J= 9.1 Hz, 8H), 6.80 (d, 3J= 9.1 Hz, 4H), 4.40 (q, 3J= 7.0 Hz, 2H), 3.80 (s, 12H), 1 .40 (t, 3J= 7.1 Hz, 2H). (0327) 13C NMR (400 MHz, CDCI3, ppm): Not soluble enough. (0328) HRMS (ESI+) [M + Na]+ calcd for C5oH45N208BF2Na+ m/z= 873.3135, found m/z= 873.3136. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: boron trifluoride diethyl etherate; ethyl 2-acetylacetoacetate In ethyl acetate at 50 - 60℃; for 0.5h; Stage #2: 4-(diphenylamino)benzaldehyde With boric acid tributyl ester In ethyl acetate at 50 - 60℃; for 0.5h; Stage #3: With N-butylamine In ethyl acetate at 50 - 60℃; | 1 (Synthesis Example 1 ) Synthesis of Compound 1 In a 50 mL flask, the mixture of Ethyl diacetoacetate (228 μ, 1.463 mmol, 1 eq) and BF3 Et20 (199 μ, 1.609 mmol, 1 .1 eq) in 3mL ethyl acetate was heated for 30min at 50-60°C in air. Dissolved 4-(N,N-Diphenylamino)-benzaldehyde (1 g, 3.658 mmol, 2.5 eq) and B(n-OBu)3 (0.987 mL, 3.658 mmol, 2.5 eq) into 12mL ethyl acetate, then the solution was injected into the first mixture. Kept the reaction at 50-60°C for another 30 min. First portion of BuNH2 (58 μΙ_, 0.585mmol, 0.4eq) was added dropwise into the reaction. After 6 h heating, second portion of BuNH2 (29 μΙ_, 0.293mmol, 0.2eq) was added, and the reaction was kept heating at 50-60°C overnight. All the solvents were evaporated. The crude product could be obtained by flash column chromatography (silica, CH2CI2) mixed with few ligand and aldehyde. The further purification was done by many times' precipitation in CH2CI2/petroleum ether, giving dark green powder (730 mg, 68% yield). (0293) 1H NMR (400 MHz, CDCI3, ppm): 58.10 (d, 3J= 15.1 Hz, 2H), 7.45 (d, 3J= 8.8 Hz, 4H), 7.34 (m, 8H), 7.17 (m, 14H), 6.97 (d, 3J= 8.7 Hz, 4H), 4.40 (m, 2H), 1.42 (t, 3J= 7.4 Hz, 3H). (0294) 13C NMR (400 MHz, CDCI3, ppm): 5 178.4, 165.7, 151.7, 149.0, 146.1 , 131.3, 129.7, 126.8, 126.1 , 125.0, 120.2, 115.5, 108.5, 61.7, 14.5. (0295) HRMS (ESI+) [M + Na]+ calcd for C46H37N204BF2Na+ m/z= 753.2712, found m/z= 753.2716. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: acetic acid / methanol / 1 h / 20 °C 2.1: hydrogen / palladium 10% on activated carbon / 1,4-dioxane; methanol / 72 h / 20 °C 3.1: potassium hydroxide / water / 24 h / 40 °C 3.2: pH 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetic acid / methanol / 1 h / 20 °C 2: hydrogen / palladium 10% on activated carbon / 1,4-dioxane; methanol / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 mg | With acetic acid at 80℃; for 12h; | 111.2 A solution of ethyl 2-acetyl-3-oxobutanoate (600 mg, 3.48 mmol) in AcOH (6 mL) and MeOH (6 mL) was added li/-imidazol-4-amine (434.33 mg, 5.23 mmol). The mixture was stirred at 80 °C for 12 hrs and monitored by TLC (petroleum ether/EtOAc = 0/1). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc (20 mL), filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2) using a gradient of 0-100% EtOAc/petroleum ether to afford the title compound (50 mg, 228.06 umol, 7% yield) as ayellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: boron trifluoride diethyl etherate; ethyl 2-acetylacetoacetate In ethyl acetate at 50 - 60℃; for 0.5h; Stage #2: 4-(diphenylamino)benzaldehyde With boric acid tributyl ester In ethyl acetate at 50 - 60℃; for 0.5h; Stage #3: With N-butylamine In ethyl acetate at 50 - 60℃; |
Tags: 603-69-0 synthesis path| 603-69-0 SDS| 603-69-0 COA| 603-69-0 purity| 603-69-0 application| 603-69-0 NMR| 603-69-0 COA| 603-69-0 structure
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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 |
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