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CAS No. : | 759-65-9 | MDL No. : | MFCD00009163 |
Formula : | C9H14O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OQOCQBJWOCRPQY-UHFFFAOYSA-N |
M.W : | 202.20 | Pubchem ID : | 97750 |
Synonyms : |
|
Chemical Name : | Diethyl 2-methyl-3-oxosuccinate |
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.15 |
TPSA : | 69.67 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.6 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 1.32 |
Log Po/w (WLOGP) : | 0.32 |
Log Po/w (MLOGP) : | 0.32 |
Log Po/w (SILICOS-IT) : | 1.04 |
Consensus Log Po/w : | 1.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.46 |
Solubility : | 6.96 mg/ml ; 0.0344 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.38 |
Solubility : | 0.835 mg/ml ; 0.00413 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.23 |
Solubility : | 11.8 mg/ml ; 0.0585 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.68 |
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 |
---|---|---|
67% | With sodium ethanolate In ethanol at 20℃; Inert atmosphere | [0238] To a solution of 38 (300 g, 2.94 mol) and ethylpropionate (429.4 g, 2.94 mol) in 1.8 L of anhydrous EtOHwas addedNaOEt (300 g, 4.41 mol) at room temperature. Themixture was stirred overnight. After cooling, the mixture wasadjusted to pH=7 with 6N HCI. The mixture was concentratedin vacuum. The residue was diluted with water, and thenextracted with EtOAc. The combined EtOAc layers weredried over Na2S04 and concentrated in vacuo to furnish theproduct 3 9 ( 400 g, 67percent) as a red liquid without further purificationfor the next step. 1 H NMR: ( 400 MHz, CDC13 ) o ppm4.103-4.386 (m, 5H); 1.246-1.439 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl ether; aluminium amalgam | ||
With copper chromite; ethanol at 200℃; Hydrogenation; | ||
With platinum(IV) oxide Hydrogenation.unter geringem Ueberdruck; |
With sodium amalgam; sulfuric acid; water ueber mehrere Stufen; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate | ||
3.40 g | With 18-crown-6 ether; potassium <i>tert</i>-butylate In diethyl ether; toluene for 4h; Reflux; | 30A Diethyl 2-ethyl-2-methyl-3-oxobutanedioate General procedure: 624 mg (5.564 mmol) of potassium tert-butoxide were initially charged in toluene (40 ml), and 0.932 mg (4.945 mmol) of diethyl 2-methyl-3-oxobutanedioate were added. 3.073 ml (32.457 mmol) of methyl bromoacetate and 122 mg (0.465 mmol) of 18-crown-6 were then added, and the mixture was heated at reflux for 4 h. The reaction mixture was then cooled to 5° C. and added to diethyl ether and 7% strength hydrochloric acid. The phases were separated and the organic phase was extracted once more with 7% strength hydrochloric acid and twice with water. The organic phase was then dried over sodium sulphate, filtered and concentrated. The residue was dried under high vacuum overnight and then used without further purification. This gave 1.45 g of the title compound which were reacted further without further purification. LC-MS (Method 2): Rt=0.96 min; MS (ESIpos): m/z=275 (M+H)+ j1049] 7.788 ml (97.370 mmol) of iodoethane were added to 2.796 ml (14.836 mmol) of diethyl 2-methyl-3-oxobutane- dioate analogously to the procedure of Example 12A. This gave 3.40 g of the title compound which was reacted in the next steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium ethanolate In ethanol at 20℃; Inert atmosphere; | |
67% | With sodium ethanolate In ethanol at 20℃; Inert atmosphere; | 39 [0237] Intermediate 39: [0238] To a solution of 38 (300 g, 2.94 mol) and ethylpropionate (429.4 g, 2.94 mol) in 1.8 L of anhydrous EtOHwas addedNaOEt (300 g, 4.41 mol) at room temperature. Themixture was stirred overnight. After cooling, the mixture wasadjusted to pH=7 with 6N HCI. The mixture was concentratedin vacuum. The residue was diluted with water, and thenextracted with EtOAc. The combined EtOAc layers weredried over Na2S04 and concentrated in vacuo to furnish theproduct 3 9 ( 400 g, 67%) as a red liquid without further purificationfor the next step. 1 H NMR: ( 400 MHz, CDC13 ) o ppm4.103-4.386 (m, 5H); 1.246-1.439 (m, 9H). |
With diethyl ether; sodium |
With alkali ethylate solution | ||
With diethyl ether; sodium ethanolate | ||
With sodium ethanolate | ||
With sodium ethanolate In diethyl ether Heating; | ||
3.5 g | With ethanol; sodium hydride In diethyl ether; Petroleum ether for 48h; | |
With C2H6O*Na(1+) In diethyl ether Heating; overnight; | ||
3.6 g | With ethanol; sodium hydride In diethyl ether; Petroleum ether for 48h; | |
With sodium ethanolate In ethanol at 20℃; | 1.IB.1 Step 1: diethyl 2-methyl-3-oxosuccinate To a solution of diethyl oxalate (100 g, 684 mmol) and ethyl propionate (69.9 g, 684 mmol) in 600 ml of anhydrous EtOH was added NaOEt (69.8 g, 1026 mmol) at room temperature. The mixture was stirred overnight. After cooling, the mixture was adjusted to pH = 7 with 6N HC1. The residue was diluted with water, and then extracted with DCM. The combined organic layers were dried over NaoSCT and concentrated under vacuum to get the title product as a red liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Erhitzen des Reaktionsprodukts in Mineraloel; | ||
Stage #1: diethyl oxalpropionate; 4-Ethoxyaniline With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Erhitzen des Reaktionsprodukts in Mineraloel auf 255grad; | ||
Stage #1: diethyl oxalpropionate; 4-fluoroaniline With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 18-crown-6 ether; potassium <i>tert</i>-butylate In toluene at 20℃; | |
1.21 g | With potassium <i>tert</i>-butylate In benzene for 20h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: diethyl oxalpropionate at 20℃; Electrolysis; Stage #2: 4-penten-3-one at 20℃; for 1h; | |
With triethylamine In ethanol; benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In acetic acid at 50℃; for 24h; Reflux; Inert atmosphere; | |
61% | With acetic acid at 50℃; for 24h; | |
With acetic acid at 20 - 50℃; for 60h; | Preparation of intermediate A1 To a mixture of diethyl oxalpropionate (CAS [759-65-9], 50.0 g, 247 mmol) and acetic acid (150 mL) was added aniline (CAS [62-53-3], 22.5 mL, 247 mmol) at room temperature. The resulting mixture was stirred at 50°C for 24 h and at room temperature for 1.5 days. The reaction mixture was concentrated under reduced pressure and portioned between DCM (500 mL) and water (500 mL) and the aqueous 10 layer was extracted with DCM (2 x 250 mL). The combined organic layers were dried over Na2S04, filtered and concentrated to dryness under reduced pressure affording 68.3 g as an orange liquid. It was purified by flash chromatography over silica gel (cyclohexane/EtOAc 100/0 for 5 min, then 100/0 to 7/3 over 60 min) affording two fractions: 47.8 g (70% as a yellow liquid and 8.94 g (13%) as a yellow solid of 15 intermediate A1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide In water at 0℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With water for 24h; | |
acid hydrolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrazine hydrate In ethanol for 0.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With toluene-4-sulfonic acid In benzene for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With potassium <i>tert</i>-butylate In benzene for 6h; Heating; | |
26% | With 18-crown-6 ether; potassium <i>tert</i>-butylate In benzene for 6h; Heating; | |
26% | With sodium hydride In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 68h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 48% 2: 24% | Stage #1: diethyl oxalpropionate; 6,7-diamino-8-chloroquinoline With sulfuric acid In water at 60℃; for 1h; Stage #2: With sodium hydroxide In water | 5.1.11. General procedure for preparation of pyrido[2,3-g]quinoxalines 3e-f, 4g-j and 5k-o General procedure: A solution (15 mL) of the 6,7-diamino-8-chloroquinoline (6b) (3 mmol) in 1 M H2SO4 was added of 4.0 mmol 2-oxo-2-phenylacetaldehyde, benzyl, sodium 2-oxobutanoate or sodium 2-oxo-3-phenylpropanoate and heated at 60 °C under stirring for 1 h. After cooling the resulting precipitate was filtered, while the acid mothers were neutralized by 2 N NaOH, the solids obtained were gathered together, washed, dried and crystallized by ethanol to give the pyrido[2,3-g]quinoxalines 3e-f, 4g and 5n, respectively. In the same condition condensation of 6,7-diamino-8-chloroquinolin-4(1H)-one (6c) with 2-oxo-2-phenylacetic acid afforded the pyrido[2,3-g]quinoxaline 5o. On the contrary, the reaction of 6b with ethyl 3-methyl-2-oxobutanoate, diethyl 2-methyl-3-oxosuccinate or 2-oxo-2-phenylacetic acid, gave the mixture 4h/5k; 4i/5l; 4j/5m, respectively, that were resolved by chromatography on silica gel column eluting with a mixture of diethyl ether/acetone in the ratio of 8:2. |
1: 35% 2: 17% | In ethanol for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With magnesium sulfate | |
67% | With acetic acid In toluene Reflux; Dean-Stark; | |
With toluene-4-sulfonic acid In toluene Heating; |
In dichloromethane Heating / reflux; | 26 Example 26: Synthesis of 1- [4- (5-FLUORO-2-METHOXYPHENYL)-2-HYDROXY-4-METHYL-2- TRIFLUOROMETHYLPENTYL]-3-METHYL-LH-QUINOLIN-4-ONE Example 26: Synthesis of 1- [4- (5-FLUORO-2-METHOXYPHENYL)-2-HYDROXY-4-METHYL-2- TRIFLUOROMETHYLPENTYL]-3-METHYL-LH-QUINOLIN-4-ONE A mixture of aniline (10.7 g) and diethyl OXALPROPIONATE (21. 7 mL) in 75 mL of methylene chloride was heated at reflux overnight, cooled to room temperature, washed with IN HC1, water, brine, and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue (2-methyl-3- (phenylimino) succinic acid diethyl ester) was taken forward without additional purification. A mixture of 2-methyl-3- (phenylimino) succinic acid diethyl ester (2.42 g) in silicon oil (7 ML) was heated at 240°C-245°C for 20 minutes with removal of ethanol by distillation, cooled to room temperature, diluted with hexanes, and filtered. The solid (3-METHYL-4-OXO-1, 4- dihydroquinoline-2-carboxylic acid ethyl ester) was dried in vacuo. Yield: 0.91 g. A mixture OF 3-METHYL-4-OXO-1, 4-dihydroquinoline-2-carboxylic acid ethyl ester (1.42 g) and aqueous NAOH (18.4 mL of a IN solution) was heated at reflux for 3 hours, cooled to room temperature, acidified with concentrated HC1, filtered, and the solid dried in vacuo. The solid (1.1 g) was suspended in 10 mL of silicon oil and heated at 260°C-265°C for 10 minutes, cooled to room temperature, diluted with hexanes, and filtered. The solid (3-METHYL-LH-QUINOLIN-4- one) was dried in vacuo. A mixture of 3-methyl-lH-quinolin-4-one (0.76 g), 2- [2- (5-FLUORO-2-METHOXYPHENYL)-2- methylpropyl] -2-trifluoromethyloxirane (0.089 g) and sodium ethoxide in ethanol (0.18 mL of a 21 wt. % solution) in 2 mL of anhydrous ethanol was heated at 85°C for 12 hours, cooled to room temperature, and most of the volatiles removed in vacuo. The residue was diluted with diethyl ether and methanol and washed with water and brine, and dried over magnesium sulfate. The residue was purified by flash silica gel chromatography using ethyl acetate as the eluent. The product-rich fractions were concentrated in vacuo and dried to afford 1- [4- (5-FLUORO-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-lH-quinolin-4-one, m. p. >225°C. | |
With toluene-4-sulfonic acid In cyclohexane at 120℃; for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With ethanol; sodium for 24h; Heating / reflux; | 85.a Example 85 2-Cyclohexyl-6-(4-guanidino-phenyl)-5-methyl-pyrimidine-4-carboxylic acid benzylamide Step a 2-Cyclohexyl-6-hydroxy-5-methyl-pyrimidine-4-carboxylic acid ethyl esterClean sodium metal (0.4g, 18.4mmol) was dissolved in dry EtOH (8mL) under argon and added drop-wise to a solution of cyclohexylamidine.HCl (3.Og, 18.4mmol) in EtOH (13mL). The precipitate formed was removed by filtration. Diethyloxalpropionate (3.5mL, 18.4mmol) was added to the filtrate and the mixture refluxed for 24 h. On cooling, concentration of the solution afforded the product as yellow crystals (1.92g, 40%). 1H NMR (CDCl3) 11.69 (IH, s), 4.43 (2H, q), 2.65 (IH, m), 2.20 (3H, s), 1.99-1.57 (7H, m), 1.44 (3H, t), 1.40-1.25 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: p-TsOH*H2O / toluene / Heating 2: 2.42 g / diphenyl ether / 1 h / 250 °C 3: aq. NaOH / 2.5 h / Heating | ||
Multi-step reaction with 2 steps 1: aniline / Erhitzen des Reaktionsprodukts in Mineraloel auf 255grad 2: aqueous NaOH | ||
Multi-step reaction with 2 steps 1.1: acetic acid / toluene / 110 °C / Dean-Stark 1.2: 250 °C 2.1: lithium hydroxide; water / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 32 g / 4 A sieves / ethanol / 240 h / Heating 2: H2 / 10percent Pd/C / ethanol / 14 h / 2585.7 Torr 3: aq. NaOH / methanol / 14 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 32 g / 4 A sieves / ethanol / 240 h / Heating 2: H2 / 10percent Pd/C / ethanol / 14 h / 2585.7 Torr 3: aq. NaOH / methanol / 14 h / Ambient temperature 4: 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 32 g / 4 A sieves / ethanol / 240 h / Heating 2: H2 / 10percent Pd/C / ethanol / 14 h / 2585.7 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 32 g / 4 A sieves / ethanol / 240 h / Heating 2: H2 / 10percent Pd/C / ethanol / 14 h / 2585.7 Torr 3: aq. NaOH / methanol / 14 h / Ambient temperature 4: 2 h / 80 °C 5: 30 percent / AlCl3 / 0.33 h / 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 32 g / 4 A sieves / ethanol / 240 h / Heating 2: H2 / 10percent Pd/C / ethanol / 14 h / 2585.7 Torr 3: aq. NaOH / methanol / 14 h / Ambient temperature 4: 2 h / 80 °C 5: 17 percent / AlCl3 / 0.33 h / 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 26 percent / NaH / tetrahydrofuran / Heating 2: 76 percent / tri-n-butyltin hydride, AIBN / benzene / Heating | ||
Multi-step reaction with 2 steps 1: 26 percent / potassium t-butoxide, 18-crown-6 / benzene / 6 h / Heating 2: 76 percent / tri-n-butyltin hydride, AIBN / benzene / 10 h / Heating | ||
Multi-step reaction with 2 steps 1: 26 percent / KO-t-Bu / 18-crown-6 / benzene / 6 h / Heating 2: 71 percent / vitamin B12s / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 87 percent / p-toluenesulfonic acid / benzene / 48 h / Heating 2: 77 percent / t-BuOK / 18-crown-6 / benzene / 24 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 87 percent / p-toluenesulfonic acid / benzene / 48 h / Heating 2: 77 percent / t-BuOK / 18-crown-6 / benzene / 24 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 2.) POCl3 2: activated molecular sieve / acetonitrile / 22 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 98 percent / conc. H2SO4, SOCl2 / 72 h / Heating 4: 83 percent / POCl3 / 0.5 h / Heating 5: 99 percent / Sodium azide / dimethylformamide / 18 h / Ambient temperature 6: 97 percent / H2 / 5percent Pd/C / ethanol / 10 h / 1520 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 98 percent / conc. H2SO4, SOCl2 / 72 h / Heating 4: 92 percent / Sodium acetate, Bromine / acetic acid / 0.25 h / Heating 5: 77 percent / H2 / 5percent Pt/C / ethyl acetate / 20 h / 1551.4 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 70 percent / hydrazine hydrate / ethanol / 0.5 h / Heating 2: 90 percent / Cl2 / CH2Cl2 3: 4 percent / N,N-diisopropylethylamine / CH2Cl2 / 0 °C 4: 15 percent / K2CO3, H2, acetic acid / 10percent Pd/C / 0.33 h / 70 °C / 760 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 13 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: 79 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 12: 80 percent / NaBH3CN, 2 N HCl / methanol; tetrahydrofuran / 0.5 h / Ambient temperature 13: 12 percent / H2 / 10percent Pd/C / ethanol; ethyl acetate / 4 h / 3040 Torr | ||
Multi-step reaction with 13 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: Sodium azide / methanol / 6 h / 50 °C 12: 80 percent / NaBH3CN, 2 N HCl / methanol; tetrahydrofuran / 0.5 h / Ambient temperature 13: 12 percent / H2 / 10percent Pd/C / ethanol; ethyl acetate / 4 h / 3040 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 70 percent / hydrazine hydrate / ethanol / 0.5 h / Heating 2: 90 percent / Cl2 / CH2Cl2 3: 4 percent / N,N-diisopropylethylamine / CH2Cl2 / 0 °C 4: 15 percent / K2CO3, H2, acetic acid / 10percent Pd/C / 0.33 h / 70 °C / 760 Torr 5: 80 percent / ICl / CH2Cl2 / 24 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 93 percent / Bromine, Sodium acetate / acetic acid / 40 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: 79 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 12: 80 percent / NaBH3CN, 2 N HCl / methanol; tetrahydrofuran / 0.5 h / Ambient temperature | ||
Multi-step reaction with 12 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: Sodium azide / methanol / 6 h / 50 °C 12: 80 percent / NaBH3CN, 2 N HCl / methanol; tetrahydrofuran / 0.5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: 79 percent / Sodium azide / dimethylformamide / 18 h / 25 °C | ||
Multi-step reaction with 11 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 96 percent / Phosphorous oxychloride / 0.5 h / Heating 9: 86 percent / Sodium azide / dimethylformamide / 18 h / 25 °C 10: 100 percent / Dioxane dibromide / CCl4 / 1 h / Heating 11: Sodium azide / methanol / 6 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 93 percent / Bromine, Sodium acetate / acetic acid / 40 h / Ambient temperature 9: Sodium carbonate / ethanol / 40 h / Ambient temperature 10: 90percent H2SO4 / 2 h / 0 °C | ||
Multi-step reaction with 9 steps 1: 43 percent / KOH / ethanol / Heating 2: 65 percent / conc. HCl / H2O 3: 67 percent / pyridine / 44 h / 85 °C 4: Ac2O / pyridine / Ambient temperature 5: 95percent H2SO4 / 18 h / 70 °C 6: 92 percent / 5.5 h / Heating 7: 100 percent / H2 / 1percent Pd/C / ethyl acetate; ethanol / 12 h / 1551.4 Torr 8: 93 percent / Bromine, Sodium acetate / acetic acid / 40 h / Ambient temperature 9: Sodium carbonate / ethanol / 40 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: diethyl oxalpropionate; aniline With acetic acid In benzene Heating / reflux; Stage #2: In diphenylether at 250℃; for 0.5h; | 1 REFERENTIAL EXAMPLE 1; Ethyl 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (1) Aniline (51.1 g) and 21.4 g of Diethyl oxalpropionate were dissolved in 200 mL of benzene, to which was then added 4 mL of acetic acid, and the mixture was refluxed upon heating overnight by a Dean-Stark condenser. The solvent was distilled off to obtain a yellow oily substance. [0076] (2) The compound obtained in (1) was dissolved in 200 mL of diphenyl ether, and the solution was heated at 250° C. for 30 minutes. After allowing to stand for cooling, the reaction mixture was poured into 600 mL of hexane, and precipitates were filtered out. The crystals were rinsed with diethyl ether and dried to obtain 36.7 g (63%) of the titled compound. MS: 232 (M+ +1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid In ethanol for 72h; Reflux; | 19 Ester 19-72 (10 g, 49 mmol), glacial AcOH (10 mL), and methylhydrazine (2.96 g, 64.0 mmol) are combined in absolute EtOH (50 mL) at room temperature. The mixture is heated to reflux for 3 days, then cooled to room temperature and concentrated in vacuo. A 1: 1 mixture of heptanes:EtOAc is added and the product crystallizes out of solution. The solid is collected by filtration, then washed with heptanes and dried in vacuo to give 8.9 g of 19-73. | |
Microwave irradiation; | ||
In ethanol; acetic acid for 48h; Heating / reflux; | A STEP A : To a magnetically stirred solution of diethyl oxalpropionate (3-1) (10.04 g, 49.65 mmol) in ethanol (50 mL) and acetic acid (10 ML) under a nitrogen atmosphere was added methylhydrazine (3.4 ML, 1.3 eq). The mixture was heated to reflux for two days. After this time the solvent was removed under reduced pressure and hexane with some ethyl acetate was added. The product 3-2 crystallized and the solid was filtered, washed and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In water | 5 7-Amino-3-(1-ethoxycarbonylethyl)-1-methylpyrimido(4,5-c)-pyridazine-4,5(1H, 6H)-dione EXAMPLE 5 7-Amino-3-(1-ethoxycarbonylethyl)-1-methylpyrimido(4,5-c)-pyridazine-4,5(1H, 6H)-dione To a stirred, refluxing solution of 6-(1-methylhydrazino)isocytosine hemihydrate (1.86 g) in water (120 ml) was added diethyl 3-methyl-2-oxo-succinate (4.59 g). After refluxing for a further 3 hours, the solid formed during the course of the reaction was collected by filtration of the hot reaction mixture, washed with two portions of water (20 ml each) and dried under vacuum at 70° C. to yield 7-amino-3-(1-ethoxycarbonylethyl)-1-methylpyrimido(4,5-c)pyridazine-4,5(1H, 6H)-dione (1.93 g; 58% theoretical yield; m.p.>280° C.). Elemental analysis: Calcd. for C12 H15 N5 O4: C,49.14%; H,5.16%; N,23.88%. Found: C,49.10%; H,5.18%; N,23.62%. nmr (TFA) δ 1.38 (t, 3H), 1.77(d, 3H), 4.28 (s, 3H), 4.41(q, 3H), 7.17(br s, 2H). uv λ max (CH3 OH) 257 nm (ε 41,100), 299.5(7,400), 310 sh (5,600). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid In toluene at 55℃; for 4.5h; | 1.A Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-dichlorophenylhydrazine hydrochloride(12.6 g) is dissolved in 100 ml of toluene and this solution is placed under nitrogen; after stirring, 10 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 5 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 30 ml of water. The mixture is separated by settling out, the aqueous phase is discarded and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 10 ml of toluene and the expected product then crystallizes, m=10.2 g. ES-: [M-H]-=313.0. NMR (DMSO-d6 1H at 300 MHz): 1.26 ppm: t: 3H; 2.11 ppm: s: 3H; | |
102 g | With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Reflux; | 1.A A) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Reflux; | 1.A A) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride In toluene; trifluoroacetic acid at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene; trifluoroacetic acid at 20 - 75℃; | Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride In toluene; trifluoroacetic acid at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene; trifluoroacetic acid at 20 - 75℃; | Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic acid at 20 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: diethyl oxalpropionate; diguanidine carbonate With sodium hydroxide In water at 100℃; for 18h; Stage #2: methanol With sulfuric acid for 12h; Reflux; Stage #3: With ammonia In water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; 4-bromo-aniline With acetic acid In toluene at 110℃; Stage #2: With diphenylether at 250℃; | ||
With acetic acid In benzene at 20℃; Reflux; | 1 To a solution of 4-bromoaniline (25 g) and diethyl 2-methyl-3-oxo succinate (30 mL) in benzene (300 mL) was added dropwise acetic acid (3.3 mL) at room temperature, followed by refluxing using a Dean-Stark reflux apparatus for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was gradually added dropwise to 100 mL of diphenyl ether which had been previously heated to 270°C, followed by stirring at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature, and hexane was added thereto. The precipitated solid was collected by filtration to obtain ethyl 6-bromo-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (19 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | Intermediate IaPotassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. | |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | 1a Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and commercially available diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. | |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | Intermediate 1; Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | Intermediate 1; Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. | |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | Intermediate 1a Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and commercially available diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. | |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In diethyl ether; ethanol; water | Intermediate 17aPotassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and commercially available diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml methanol. The insoluble inorganic salts were filtered off. The solution was concentrated to give the desired compound. | |
Stage #1: diethyl oxalpropionate; formamidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In ethanol; water | Intermediate 17a Intermediate 17a [0387] [0388] Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and commercially available diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml methanol. The insoluble inorganic salts were filtered off. The solution was concentrated to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; o-methylisourea hydrochloride With sodium t-butanolate In ethanol for 18h; Reflux; Stage #2: With hydrogenchloride In water | Intermediate IdA suspension of sodium tert-butoxide (3.9 g, 40.5 mmol) in 25 ml dry ethanol was added to a solution of diethyl oxalpropionate (3.0 ml, 16.2 mmol) and O-methylisourea hydrochloride (2.15 g, 19.5 mmol) in 25 ml dry ethanol and the reaction mixture was refluxed for 18h. The reaction mixture was allowed to cool to room temperature and the precipitate removed by filtration. The filtrate was concentrated in vacuum, and the residue was purified by reversed phase HPLC to give the desired product (752 mg, 3.5 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol; at 20℃; for 18h; | A suspension of sodium ethoxide (940 mg, 13.8 mmol) in ethanol (4.5 ml) was added to a solution of <strong>[38980-96-0]4-(trifluoromethyl)benzamidine hydrochloride</strong> dihydrate (2.79 g, 12.4 mmol) and diethyl oxalpropiolate (2.6 ml, 13.8 mmol) in ethanol (30ml) and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then dichloromethane was added and the solution dried over magnesium sulphate, filtered and evaporated under redcued pressure. The crude product was purified by chromatography on silica using hexane/ethyl acetate (3:2) as eluent to provide a mixture of 6-ethoxycarbonyl-4-hydroxy- 5-methyl-2-(4-trifluoromethylphenyl)-pyrimidine and 4,6-dihydroxy-6-ethoxycarbonyl-5- methyl-2-(4-trifluoromethylphenyl)-3,4-dihydropyrimidine as a pale brown solid (2.21 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In ethanol for 4h; Reflux; | Intermediate lb; Commercially available cyclopropancarboxyamidine (10 g, 83 mmol), diethyloxalpropionate (15.63 ml, 83 mmol) and potassium carbonate (26.6 g, 207 mmol) were suspended in 160 ml of ethanol and the reaction mixture was stirred under reflux for 4h. The reaction mixture was filtered over a celite pad and the filtrate solution was evaporated. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: SNAP lOOg; eluent: dichloromethane) to give the desired compound (4.6 g, 18.6 mmol). | |
With potassium carbonate In ethanol for 4h; Reflux; | Intermediate lb; Commercially available cyclopropancarboxyamidine (10 g, 83 mmol), diethyloxalpropionate (15.63 ml, 83 mmol) and potassium carbonate (26.6 g, 207 mmol) were suspended in 160 ml of ethanol and the reaction mixture was stirred under reflux for 4h. The reaction mixture was filtered over a celite pad and the filtrate solution was evaporated. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: SNAP lOOg; eluent: dichloromethane) to give the desired compound (4.6 g, 18.6 mmol). | |
With potassium carbonate In ethanol for 4h; Reflux; | Commercially available cyclopropancarboxyamidme (10 g, 83 mmol), diethyloxalpropionate (15.63 ml, 83 mmol) and potassium carbonate (26.6 g, 207 mmol) were suspended in 160 ml ethanol and the reaction mixture was stirred under reflux for 4h. The reaction mixture was filtered over a celite pad and the filtrate solution was evaporated. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: SNAP lOOg; eluent: dichloromethane) to give the desired compound. |
With potassium carbonate In ethanol for 4h; Reflux; | Intermediate 17d Intermediate 17d [0392] [0393] Commercially available cyclopropancarboxyamidine (10 g, 83 mmol), diethyloxalpropionate (15.63 ml, 83 mmol) and potassium carbonate (26.6 g, 207 mmol) were suspended in 160 ml ethanol and the reaction mixture was stirred under reflux for 4 h. The reaction mixture was filtered over a celite pad and the filtrate solution was evaporated. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: SNAP 100 g; eluent: dichloromethane) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; guanidine hydrochloride With potassium carbonate In ethanol for 3h; Reflux; Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane | 1a Intermediate laDiethyl-oxalpropionate (50 ml, 265.3 mmol), formamidine hydrochloride (42.7 g, 530.6 mmol) and potassium carbonate (91.68 g, 663.3 mmol) were dissolved in 350 ml of ethanol and the reaction mixture was refluxed for 3h. The reaction mixture was cooled to room temperature, the solid was filtered off, the organic phase was concentrated under vacuum and the crude product obtained was suspended and stirred in 600 ml of dichloromethane and 100 ml of a 4M solution of hydrochloric acid in 1,4-dioxane. The solid was filtered off and the organic phase was concentrated under vacuum. 28g of the desired product were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium hydroxide / ethanol / Reflux 1.2: pH 2 2.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / Reflux 3.1: potassium carbonate / dichloromethane / 1 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: sodium ethanolate / ethanol / 12 h / Reflux; Inert atmosphere 2: trichlorophosphate / 4 h / Reflux; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium ethanolate / ethanol / 12 h / Reflux 2: trichlorophosphate / 4 h / Reflux |
Multi-step reaction with 2 steps 1: sodium ethanolate / ethanol / 16 h / 90 °C / Inert atmosphere 2: oxalyl dichloride; N,N-dimethyl-formamide / ethyl acetate / 2 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 3 h / 90 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / chloroform / 2 h / 70 °C | ||
Multi-step reaction with 2 steps 1.1: potassium hydroxide / ethanol / Reflux; Inert atmosphere 2.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / 90 °C / Inert atmosphere 2.2: 1 h / 20 - 25 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; guanidine acetic acid With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In water | 1 Intermediate 1Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With polyphosphoric acid at 130℃; for 2h; | Preparation of intermediate B1 To a mixture of diethyl oxalpropionate (CAS [759-65-9], 2.00 g, 9.89 mmol) and polyphosphoric acid (4.00 g) was added 4-fluoroaniline (CAS [371-40-4], 0.949 mL, 0.989 mmol) at room temperature. The resulting mixture was stirred at 130°C for 2 h. The reaction mixture was poured onto ice water (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (50 mL), a saturated aqueous NaHCCb solution (50 mL), dried over sodium sulfate, filtered and concentrated to dryness to afford a brownish sticky solid. It was triturated with diethyl ether (3 x 5 mL) and dried under reduced pressure to afford intermediate B1 as a pale-yellow solid, 0.565 g (23%). |
Stage #1: diethyl oxalpropionate; 4-fluoroaniline With acetic acid In toluene at 110℃; Stage #2: With diphenylether at 250℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane at 95℃; for 72h; | 5 Intermediate 2 Intermediate 1 (52 mCi, 60 mCi/mmol, 0.867 mmol) was dissolved in 1,2-dimethoxyethane (5 ml). To this was added diethyl oxalpropionate (183 μl, 0.969 mmol) and the solution was refluxed at 95° C. for 72 hours.The product was purified by HPLC on a Gemini C18 column eluting with a 20 mM ammonium hydroxide: methanol gradient system then rotary evaporated to a solid (21.2 mCi, 60 mCi/mmol, 0.353 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxylamine hydrochloride In ethanol at 78℃; for 14h; Inert atmosphere; | Ethyl 4-Methyl-5-oxo-2H-isoxazole-3-carboxylate (30) To a solution of diethyl 2-methyl-3-oxobutanedioate (29; 3 g, 0.014mol) in EtOH (30 mL) was added NH2OH·HCl (1.74 g, 0.025 mol). The reaction mass was heated at 78 °C for 14 h. After completion of the reaction (TLC monitoring), the mixture was directly concentrated under reduced pressure. The residue was triturated 3 times with petroleum ether to obtain the desired product 30 as a white solid; yield: 2.5 g (quant); mp 68-70 °C.IR (KBr): 3610, 3116, 1728, 1398, 1238 cm-1.1H NMR (400 MHz, DMSO-d6): δ = 1.30 (t, J = 7.09 Hz, 3 H), 1.91 (s, 3H), 4.32 (q, J = 7.09 Hz, 2 H).13C NMR (100 MHz, CDCl3): δ = 172.2, 159.9, 153.5, 153.2, 62.0, 14.3,7.0.MS (ESI): m/z = 169.8 (M - H). |
94.7% | With hydroxylamine hydrochloride In ethanol at 78℃; for 14h; | 1 Synthesis of INT 7-b To a solution of 1 ,4-diethyl 2-methyl-3-oxobutanedioate (5 g, 24.7 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3 g, 43.1 mmol). The reaction was heated at 78 °C for 14 hours. The reaction mixture was directly concentrated under reduced pressure. The residue was triturated with petroleum ether to give ethyl 4-methyl-5-oxo-2,5-dihydro-l,2- oxazole-3-carboxylate as a solid (4.00 g, 94.7%).m/z: [M + H]+ Calcd for C7H9NO4 172.1; Found 172.1. NMR (400MHz, DMSO-d6) d = 4.32 (q, J=7.2 Hz, 2H), 1.92 (s, 3H), 1.29 (t, J=7.2 Hz, 3H). |
74.3% | With hydroxylamine hydrochloride In ethanol for 12h; Reflux; | 27.A Synthesis of Compound 27BA solution of compound 27 A (100 g, 0.50 mol) and hydroxylamine hydrochloride (42 g, 0.60 mol) in EtOH (1000 mL) was heated to reflux for 12 hours. The reaction mixture was concentratred in vacuo and the residue obtained was triturated with petroleum ether (100 mL) to provide compound 27B (63 g, 74.3% yield). MS (ESI) m/z: 172.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In ethanol Inert atmosphere; Reflux; | Intermediate IdCommercially available tetrahydropyran-4-carboxamidine (3.5 g, 17 mmol), diethyl- oxalpropionate (3.2 ml, 17 mmol) and potassium carbonate (5.88 g, 42.5 mmol) were suspended under nitrogen atmosphere in 60 ml ethanol and stirrred under reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum. The crude product was loaded on a SCX cartridge and eluted with a 7M solution of ammonia in methanol. The crude product was purified by flash chromatography (eluent:dichlorometane/methano 1=90/10) to give the desired product. | |
With potassium carbonate In ethanol for 4h; Reflux; Inert atmosphere; | Intermediate 1d Intermediate 1d [0322] [0323] Commercially available tetrahydropyran-4-carboxamidine (3.5 g, 17 mmol), diethyl-oxalpropionate (3.2 ml, 17 mmol) and potassium carbonate (5.88 g, 42.5 mmol) were suspended under nitrogen atmosphere in 60 ml ethanol and stirred under reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum. The crude product was loaded on a SCX cartridge and eluted with a 7M solution of ammonia in methanol. The crude product was purified by flash chromatography (eluent: dichlorometane/methanol=90/10) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With acetic acid In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; | 1-1-1 Preparation of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1H- py razo le-3-ca rboxy late 4.65 g of diethyl 2-methyl-3-oxobutanedioate (23.0 mmol, 1.00 eq.) were dissolved in 100 ml_ of dry dioxane under argon atmosphere. 2.1 ml_ of glacial acetic acid and 6,32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred for 16 hours at 90 °C bath temperature. The reaction mixture was evapo rated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried in vacuo at 40 . The filtrate was concentrated in vacuo and purified by flash chromatography (hexane/ ethyl acetate - gradient with hexane 0 - 100%). The filter cake and the received purified compound of the flash chromatography were stirred together in ethyl acetate, filtered off and provided 3.95 g (11.3 mmol, 49 %) of the analytically pure target compound. 1H-NMR (300MHz, DMSO-d6): δ [ppm]= 1.13 - 1.36 (m, 6H), 1.97 (s, 3H), 4.01 (q, 2H), 4.14 (q, 2H), 5.04 (s, 2H), 6.65 - 6.73 (m, 2H), 10.60 (br. s., 1 H). |
49% | With acetic acid In 1,4-dioxane at 90℃; for 16h; Inert atmosphere; | Preparation of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1H-pyrazole-3-carboxylate 4.65 g of diethyl 2-methyl-3-oxobutanedioate (23.0 mmol, 1.00 eq.) were dissolved in 100 mL of dry dioxane under argon atmosphere. 2.1 mL of glacial acetic acid and 6.32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred for 16 hours at 90° C. bath temperature. The reaction mixture was evapo rated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried in vacuo at 40° C. The filtrate was concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate-gradient with hexane 0-100%). The filter cake and the received purified compound of the flash chromatography were stirred together in ethyl acetate, filtered off and provided 3.95 g (11.3 mmol, 49%) of the analytically pure target compound. 1H-NMR (300 MHz, DMSO-d6): δ [ppm]=1.13-1.36 (m, 6H), 1.97 (s, 3H), 4.01 (q, 2H), 4.14 (q, 2H), 5.04 (s, 2H), 6.65-6.73 (m, 2H), 10.60 (br. s., 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium ethanolate In ethanol for 12h; Inert atmosphere; Reflux; | |
30% | With sodium ethanolate In ethanol for 12h; Reflux; Inert atmosphere; | 40 [0239] Intermediate 40: [0240] A mixture of39 (300 g, 1.485 mol), formimidamideacetate (225 g, 2.12 mol) and NaOEt (160 g, 2.36 mol) inEtOH (2000 mL) was heated to reflux for 12 hours. Aftercooling, the mixture was adjusted to pH=7 with 6N HCI. Themixture was concentrated in vacuum. The residue was dilutedwith water, and then extracted with DCM. The combinedDCM layers were washed with water, brine and concentratedin vacuo. The crude product was purified by chromatographyon silica gel (PE: EtOAc= 1: 1-pure EtOAc) to afford the productas a white solid (80 g, 30% yield). ES+MS m/z: 183.0(M+l). 1H NMR: (400 MHz, CDC13 ) o ppm 8.126 (s, lH);4.345-4.399 (m, 2H); 2.242 (s, 3H); 1.337-1.373 (t, 3H). |
29.6% | With potassium carbonate In ethanol at 90℃; for 3h; | 1 Synthesis of INT 1-b A mixture of 1 ,4-diethyl 2-methyl-3-oxobutanedioate (5 g, 24.7 mmol) , acetic acid; methanimidamide (3.85 g, 37.0 mmol), K2CO3 (6.82 g, 49.4 mmol) in EtOH (50 mL) was stirred at 90 °C for 3 h, then cooled to 25 °C. The reaction was concentrated under reduced pressure to removed ethanol, diluted with water (50 mL), acidified with 1 M HC1 to pH =7 and extracted with EtOAc (50 mL c 3). The combined organic layers were washed with brine (50 mL c 2), dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/1) to give ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate (1.33 g, 29.6% yield) as a solid. NMR (400 MHz, CDCh) d = 13.07 (br s, 1H), 8.19 (s, 1H), 4.44 (q, J= 7.2 Hz, 2H), 2.31 (s, 3H), 1.42 (t, J = 12 Hz, 3H). |
19.5% | With sodium ethanolate In ethanol at 90℃; for 16h; Inert atmosphere; | 2.1 Step 1. ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate (2) To a mixture of diethyl 2-methyl-3-oxo-butanedioate (1, 30 g, 148.4 mmol) in EtOH (350 mL) was added EtONa (16.15 g, 237.4 mmol) and formimidamide acetate (21.6 g, 207.7 mmol) at 20 . Then the mixture was stirred at 90 for 16 h under N2. The mixture was added 2 N HCl to adjust pH = 7, then the mixture was added water (200 mL) and extracted with EtOAc (3 x 200 mL) . The organic layer was collected and washed with brine (200 mL) , dried over Na2SO4, filtered and concentrated in vacuum to give a residue as brown oil. The residue was purified by column chromatography on silica gel eluted with (Petroleum ether: EtOAc =1: 3) to afford ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate (2, 6.0 g, 19.5%yield) as yellow solid.[0346]1H NMR (400 MHz, CD3OD) δ: 8.09 (s, 1H) , 4.40 (q, J = 7.2 Hz, 2H) , 2.20 (s, 3H) , 1.39 (t, J = 7.2 Hz, 3H) . LC-MS: (ESI) m/z: 182.9 [M+H] . |
With sodium ethanolate In ethanol for 12h; Reflux; | 1.IB.2 Step 2: ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate To a stirring solution of product of step 1 (92 g, 455 mmol) and formamidine acetate (71.1 g, 682 mmol) in EtOH (700 mL) was added NaOEt (46.40 g, 682 mmol) and reaction mixture was heated to reflux for 12 h. After cooling, the reaction mixture was adjusted to pH = 7 with 6N HC1. The mixture was concentrated under vacuum. The residue was diluted with water, and then extracted with DCM. The combined DCM layers were washed with water, and evaporated to get crude product. The crude product was stirred with 200 ml n- Hexane for 30 min and filtered to get yellowish solid as a product. ESI-MS (m/z): 183.05 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; <i>p</i>-toluidine With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; 4-aminoethylbenzene With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; 4-methoxy-aniline With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; 4-(trifluoromethoxy)aniline With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-trifluoromethylphenylamine; diethyl oxalpropionate With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate; aniline With acetic acid In toluene at 110℃; Dean-Stark; Stage #2: In diphenylether at 250℃; | General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.15 g | With 18-crown-6 ether; potassium <i>tert</i>-butylate In diethyl ether; toluene for 4h; Reflux; | 28A Diethyl2-[(benzyloxy)methyl] -2-methyl-3-oxobutanedioate General procedure: 624 mg (5.564 mmol) of potassium tert-butoxide were initially charged in toluene (40 ml), and 0.932 mg (4.945 mmol) of diethyl 2-methyl-3-oxobutanedioate were added. 3.073 ml (32.457 mmol) of methyl bromoacetate and 122 mg (0.465 mmol) of 18-crown-6 were then added, and the mixture was heated at reflux for 4 h. The reaction mixture was then cooled to 5° C. and added to diethyl ether and 7% strength hydrochloric acid. The phases were separated and the organic phase was extracted once more with 7% strength hydrochloric acid and twice with water. The organic phase was then dried over sodium sulphate, filtered and concentrated. The residue was dried under high vacuum overnight and then used without further purification. This gave 1.45 g of the title compound which were reacted further without further purification. LC-MS (Method 2): Rt=0.96 min; MS (ESIpos): m/z=275 (M+H)+ 11043] 13.495 ml (97.370 mmol) of benzyl chloromethyl ether were added to 2.796 ml (14.836 mmol) of diethyl 2-me- thyl-3-oxobutanedioate analogously to the procedure of Example 12A. This gave, after filtration, 2.15 g of the title compound which were reacted in the next steps without further purification.11044] MS (Method 6): MS mlz=323 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.45 g | With 18-crown-6 ether; potassium <i>tert</i>-butylate In diethyl ether; toluene for 4h; Reflux; | 12A 1,2-Diethyl 3-methyl 2-methyl-1-oxopropane-1,2,3-tricarboxylate 624 mg (5.564 mmol) of potassium tert-butoxide were initially charged in toluene (40 ml), and 0.932 mg (4.945 mmol) of diethyl 2-methyl-3-oxobutanedioate were added. 3.073 ml (32.457 mmol) of methyl bromoacetate and 122 mg (0.465 mmol) of 18-crown-6 were then added, and the mixture was heated at reflux for 4 h. The reaction mixture was then cooled to 5° C. and added to diethyl ether and 7% strength hydrochloric acid. The phases were separated and the organic phase was extracted once more with 7% strength hydrochloric acid and twice with water. The organic phase was then dried over sodium sulphate, filtered and concentrated. The residue was dried under high vacuum overnight and then used without further purification. This gave 1.45 g of the title compound which were reacted further without further purification. LC-MS (Method 2): Rt=0.96 min; MS (ESIpos): m/z=275 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With hydrazine hydrate at 55 - 67℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl oxalpropionate With caesium carbonate In acetone at 20 - 34℃; for 0.0833333h; Stage #2: diethyl sulfate In acetone at 20 - 33℃; for 27h; | 3.1 Cesium carbonate (20.43g, 62.71 mM) was suspended in acetone (50ml) with stirring at room temperature, then diethyl 2-methyl-3-oxo-butanedioate (12.68g, 62.71 mM) was added all at once, washing in with acetone (5ml).The reaction exothermed to 34°C, and there was very mild effervescence and a yellow colour developed. The reaction was stirred for 5 minutes, and reaction was now at 33°C. Diethyl sulfate (9.669g, 62.71 mM) was added over 1 minute, resulting in no exotherm. The reaction was stirred and allowed to cool slowly to room temperature. The reaction was stirred at room temperature for 27 hours. Most of the acetone was evaporated, then water (100ml) and dichloromethane (100ml) were added, shaken, and the layers separated. The aqueous layer was extracted a further 2x50ml dichloromethane, and the combined dichloromethane extracts were dried with Na2S04 and filtered to give an amber oil (18.1g) which was chromatographed to give a colourless oil (12.50g, 93% pure so 80% yield) H NMR (CDCI3) 4.33 (q, 2H), 4.17 (q, 2H), 3.95 (q, 2H), 1.84(s, 3H), 1 .36(t, 3H), 1 .33 (t, 3H), 1.27 (t, 3H) | |
12.50 g | Stage #1: diethyl oxalpropionate With caesium carbonate In acetone at 20 - 34℃; for 0.0833333h; Stage #2: diethyl sulfate In acetone at 20 - 33℃; for 27h; | 14.1 Cesium carbonate (20.43g, 62.71 mM) was suspended in acetone (50m1) with stirring at room temperature, then diethyl 2-methyl-3-oxo-butanedioate (12.68g, 62.71 mM) was added all at once, washing in with acetone (5m1).The reaction exothermed to 34°C, and there was very mildeffervescence and a yellow colour developed. The reaction was stirred for 5 minutes, and reaction was now at 33°C. Diethyl sulfate (9.669g, 62.71 mM) was added over 1 minute, resulting in no exotherm. The reaction was stirred and allowed to cool slowly to room temperature. The reaction was stirred at room temperature for 27 hours. Most of the acetone was evaporated, then water (lOOmI) and dichloromethane (lOOmI) were added, shaken, and the layers separated. Theaqueous layer was extracted a further 2x50m1 dichloromethane, and the combineddichloromethane extracts were dried with Na2SO4 and filtered to give an amber oil (18.lg) whichwas chromatographed to give a colourless oil (12.50g, 93% pure so 80% yield)1H NMR (CDCI3) 4.33 (q, 2H), 4.17(q, 2H), 3.95(q, 2H), 1.84(s, 3H), 1.36(t, 3H), 1.33 (t, 3H),1.27 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With bismuth(III) chloride at 100℃; for 3h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium acetate In benzene at 90℃; | 1 Synthesis of ethyl 1 -(2-fluorobenzyl)-5-hydroxy-4-methyl- 1 H-pyrazole-3 -carboxylate A mixture containing (2-fluorobenzyl) hydrazine hydrochloride (1 equiv.), diethyl2-methyl-3-oxosuccinate (1 equiv.) and sodium acetate (1 equiv.) in benzene was stirred at 90 °C overnight. After cooling, the mixture was diluted with ethyl acetate and water. Phases were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (80 g ISCO, 30 % to 100 % ethyl acetate in hexane over 35 mins) to give ethyll-(2-fluorobenzyl)-5-hydroxy-4-methyl-lH-pyrazole-3-carboxylate (2.9 g, 49 % yield) as an offwhite solid. MR (500 MHz, DMSO-i δ ppm 10.73 (s, 1 H) 7.35 (q, 1 H) 7.21 (t, 1 H) 7.16 (t, 1 H) 7.01 (t, 1 H) 5.22 (s, 2 H) 4.20 (q, 2 H) 2.05 (s, 3 H) 1.25 (t, 3 H). m/z = 279.1 (M+H) |
29% | With sodium acetate In benzene at 90℃; for 1h; | 1.1 Step 1: Synthesis of ethyl 1 -(2-fluorobenzyl)-5 -hydroxy-4-methyl- 1 H-pyrazole-3 -carboxylate. Step 1: Synthesis of ethyl 1 -(2-fluorobenzyl)-5 -hydroxy-4-methyl- 1 H-pyrazole-3 -carboxylate. A mixture containing sodium acetate (1 equiv.), diethyl oxalpropionate (1 equiv.), and (2-fluorobenzyl)hydrazine hydrochloride (1 equiv.) in benzene was heated to 90 °C for 1 h. The mixture was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered and evaporated to give a solid. The solid was purified via silica gel chromatography (0 to 100% ethyl acetate in hexanes) to deliver the desired intermediate, ethyl 1-(2-fluorobenzyl)-5-hydroxy-4-methyl-1H-pyrazole-3-carboxylate (800 mg, 29% yield) as a white solid.‘H NMR (500 MHz, CD3OD) ppm 7.29 (tdd, 1 H), 7.06 - 7.12 (m, 2 H), 6.94 - 6.99 (m, 1 H), 5.26 (s, 2 H), 4.28 -4.34 (m, 2 H), 2.13 (s, 3 H), 1.35 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride In ethanol at 80℃; for 3h; | A.1 Step 1: Ethyl 4-methyl-5-oxo-4,5-dihydroisoxazole-3-carboxylate To diethyl oxalyl propionate (300 g, 1.48 mol) in Ethanol (2 l) was added hydroxylamine hydrochloride (124 g, 1.78 mol) and the reaction mixture was heated at 80° C. for 3 hours. The resulting mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was treated with water and DCM and the aqueous extracted with DCM. The combined organics were dried and the solvent removed under reduced pressure to afford the title compound; (0777) 1H NMR (400 MHz, CDCl3) δ 4.40 (2H, q), 2.09 (3H, s), 1.38 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.6% | In ethanol at 100℃; for 30h; Inert atmosphere; | 81.a Preparation of 7-bromo-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid 5-bromopyridin-2-amine (6g, 0.035mol) diethyl 2-methyl-3-oxosuccinate (7g, 0.035mol) and ethanol (165 mL of) was added to a250mL round bottom flask the reaction was stirred for 30 hours at 100 degrees. The reaction was cooled to room temperature,the solid was washed with cold ethanol to give the product as a white solid shape (3g, 30.6%). |
30.6% | In ethanol for 30h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.16 g | With Eaton′s Reagent at 80℃; for 5h; | 63.A A) ethyl 2-(dimethylamino)-5-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate A mixture of 1,1-dimethylguanidinium sulfate (1.0 g), diethyl 3-methyloxaloacetate (1.36 mL) and Eaton reagent (7.0 g) was stirred at 80°C for 5 hr. Ice water was added to the reaction mixture, 8 M aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.16 g). MS: [M+H]+ 226.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With acetic acid In ethanol for 48h; Reflux; | 4.1.6. Procedure for synthesis of compound12 (diethyl 3-((4-chlorophenyl)imino)-2-methyl pentanedioate) To a solution of 4-chloroaniline (2 g, 15.68 mmol) and diethyloxalpropionate(3.8 g, 18.81 mmol) in ethanol (30 mL), acetic acid(10 drops) was added and the reaction mixture heated under refluxunder for 48 h. After completion of the reaction, ethanol wasremoved by vacuo and the residue was extracted with ethyl acetateand washed with saturated sodium bicarbonate solution and brine.Organic layer was dried over MgSO4 and evaporated to give crudeproduct which purified by column chromatography on silica usingEtOAc/hexanes (1:10) to give pure imine 12 as an oil in yield of 84%;1H NMR (250 MHz, CDCl3) δ 7.19 (d, J 8.50 Hz, 2H, Ar-H), 6.88 (d,J 8.50 Hz, 2H, Ar-H), 4.75 (q, J 7.2 Hz, 1H, CHCH3), 4.35-4.00 (m,4H, 2 CH2CH3), 1.82 (d, J 7.2 Hz, 3H, CHCH3), 1.29 (t, J 7.0 Hz,3H, CH2CH3), 1.12 (t, J 7.25 Hz, 3H, CH2CH3); 13C NMR (62.5 MHz,CDCl3) δ 170.63, 164.73, 146.56, 139.20, 129.22, 129.05, 122.04, 97.17,61.95, 60.34, 14.37, 13.78, 13.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
166 mg | Stage #1: pyrazolo[5,1-b][1,3]thiazole-7-carbonitrile With sodium methylate In methanol at 20℃; for 1h; Stage #2: With ammonium chloride In methanol at 70℃; for 2h; Stage #3: diethyl oxalpropionate With water; sodium hydroxide at 90℃; for 0.75h; | 4 Reference Example 4: 6-Hydroxy-5-methyl-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidine-4-carboxylic acid To a solution of pyrazolo[5,1-b][1,3]thiazole-7-carbonitrile obtained in Reference Example 1 (300 mg) in methanol (6 mL) was added a solution of 28 % sodium methoxide in methanol (0.41 mL), and the mixture was stirred at room temperature for 1 h. Then, ammonium chloride (215 mg) was added thereto, and the mixture was stirred at 70 °C for 2 h. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in 5 M aqueous sodium hydroxide solution (1.2 mL) and water (7 mL), methyloxalacetic acid diethyl ester (611 mg) was added to the solution, and the mixture was stirred at 90 °C for 45 min. To the reaction mixture was added conc. hydrochloric acid to make the solution acidic, and the precipitated solid was collected on a filter, and dried to obtain the title compound (166 mg). MS (m/z): 277 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.9% | With triethylamine In ethanol for 2.5h; Inert atmosphere; Reflux; | Ethyl 6-hydroxy-2-[(4-methoxyphenoxy)methyl]-5-methylpyrimidine-4-carboxylate(9). Diethyl oxalpropionate (0.932 mL, 4.95 mmol) was added to a solution of 2-(4-methoxyphenoxy)acetamidine hydrochloride (1.18 g, 5.44 mmol, 1.1 equiv) in ethanol (20 mL) andtriethylamine (1.52 mL, 10.9 mmol, 2.2 equiv) and refluxed for 2.5 h under argon atmosphere.The yellow solution turned brown approaching the reflux point. The solvent was evaporatedunder reduced pressure at 40 C. The residue was taken up with EtOAc, water (15 mL) wasadded and the mixture was extracted with EtOAc (3×25 mL). The combined organic layerswere washed with brine (3×25 mL) and the solvent was evaporated under reduced pressure at40 C. The residue was purified by flash column chromatography [cyclohexane (A), EtOAc(B); gradient: 25%40% B×7 CV + 40%100% B×7 CV] to give 9 (488 mg, 1.53 mmol,30.9% yield) as a yellow solid. Rf 0.45 (cyclohexane/EtOAc 1:1). 1H NMR (400 MHz, CDCl3)δppm 11.05 (br s, 1H), 6.98±6.89 (m, 2H), 6.89±6.79 (m, 2H), 4.98 (s, 2H), 4.43 (q, J = 7.1 Hz,2H), 3.76 (s, 3H), 2.25 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δppm165.5, 163.5, 155.1, 154.7, 151.1, 150.0, 125.3, 115.9 (sym, 2C), 115.0 (sym, 2C), 67.3, 62.4, 55.8,14.3, 11.8. MS-APCI (m/z): [M+H]+ 319.3. HRMS-ESI (m/z): [M+H]+ calcd for C16H19N2O5319.1294; found 319.1296. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.6% | With potassium hydroxide In ethanol Reflux; Inert atmosphere; | 26.1 Example 26: (R)-1-((7-cyano-2-(6-(3-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-tolyl)-5-methylpyrimidin-4-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid (Z-1157- 1) Step 1: Suspend potassium hydroxide (42g, 0.75mol) in 200ml of dry ethanol, add formamidine acetate (26g, 0.25mol) and diethyl oxalate propionate 1157-1a (50g, 0.25mol) slowly, under reflux Stir overnight.The reaction mixture was cooled to room temperature, and the formed precipitate was filtered, washed with ethanol, the filter cake was dissolved in 200 ml of water, and the resulting solution was acidified to pH=2 with 37% aqueous hydrochloric acid.The acidic aqueous solution was concentrated under vacuum, the resulting residue was suspended and stirred in 100 ml of methanol, and the insoluble inorganic salt was filtered out.The solution was concentrated to obtain the product 1157-1b (20 g, light brown oil), yield: 52.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). | ||
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene at 20 - 75℃; | Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene at 20 - 75℃; | Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
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