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CAS No. : | 598-50-5 | MDL No. : | MFCD00007950 |
Formula : | C2H6N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XGEGHDBEHXKFPX-UHFFFAOYSA-N |
M.W : | 74.08 | Pubchem ID : | 11719 |
Synonyms : |
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 17.83 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.75 cm/s |
Log Po/w (iLOGP) : | 0.69 |
Log Po/w (XLOGP3) : | -1.4 |
Log Po/w (WLOGP) : | -0.72 |
Log Po/w (MLOGP) : | -0.96 |
Log Po/w (SILICOS-IT) : | -1.22 |
Consensus Log Po/w : | -0.72 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.65 |
Solubility : | 330.0 mg/ml ; 4.45 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.74 |
Solubility : | 411.0 mg/ml ; 5.55 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.23 |
Solubility : | 124.0 mg/ml ; 1.68 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | 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 |
---|---|---|
65.8% | With acetic anhydride In acetic acid at 90℃; | To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 °C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8percent). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
65.8% | With acetic anhydride In acetic acid at 70 - 90℃; for 3 h; | (a) l-Methylpyrimidine-2,4,6(1H,3H,5H.)-trione To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 0C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8percent). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
65.8% | With acetic anhydride In acetic acid at 70 - 90℃; for 3 h; | To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 0C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8percent). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
64% | at 70 - 90℃; for 3 h; | To a solution of 1-methylurea (14 g, 189 mmol, 1.0 eq.) and malonic acid (23.6 g, 226.8 mmol, 1.2 eq.) in acetic acid (60 mL), acetic anhydride (36 mL, 378 mmol, 2.0 eq.) was added slowly at 70° C. After the completion of the addition, the reaction mixture was stirred at 90° C. for 3 h and then cooled to rt. The reaction mixture was concentrated and the residue was diluted with EtOH (100 mL). The solid was collected and re-crystalized in EtOH to give the title compound (17.0 g, 64percent yield) as a light yellow solid. LC-MS (ES, m/z): [M+H]+=143; 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H), 3.58 (s, 2H), 2.50 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: With sodium In ethanol for 1 h; Stage #2: for 24 h; Reflux |
Methyl urea (97.14 g, 1.31 mol), absolute ethanol 1.2 L, metal sodium (30.4 g, 1.32 mol) was added in portions and stirred for 1 h. Diethyl malonate (273.0 g, 1.70 mol) in 100 mL of absolute ethanol was slowly added dropwise to the reaction solution, heating To reflux, reaction 24h. The solvent was evaporated under reduced pressure, 1 L of water was added, and the pH was adjusted to 3 to 4 with 2N HCl, followed by cooling and crystallization. Filter, wash, dry Drying gave a pale yellow powder, 152.8 g of 1-methylpyrimidine-2,4,6-trione, a yield of 82percent, mp. 129-130°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium In ethanolReflux | General procedure: Compounds 1a, 1b and 1e were prepared according to the reportedmethods26–34 by the addition of urea, methylurea and/or methylthiourea (0.1 mol) to ethyl cyanoacetate (0.1 mol) in absolute ethanol(290 mL) containing sodium (0.2 mol). The mixture was refluxed for10–12 h, allowed to cool to r.t. and acidified with acetic acid (pH 6).The resulting precipitate was washed with distilled water and dried in adesiccator overnight. |
32% | Stage #1: at 25℃; for 0.5 h; Reflux Stage #2: for 3 h; Reflux |
Sodium (7.80 g, 340 mmol) was added in batches to ethanol (180 mL) while stirring at 25 °C, heated to 80°C to reflux for 0.5 hours. Methylurea (12.6 g, 170 mmol) was then added in batches and reflux was continued for 0.5 h. Ethyl cyanoacetate (19.0 g, 170 mmol) was added dropwise to the reaction solution, resulting in a large amount of precipitate. Reflux was continued for 3 hours, ethanol was recovered under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH = 7 with dilute hydrochloric acid (1 N). The product was filtered to give 6-amino-1-methylpyrimidine-2,4-dione (7.60 g, as a white solid) with a yield of 32percent. 1H NMR: (400 MHz, DMSO-d6) δ 10.39(br, 1H), 6.79(br, 2H), 4.54(s, 1H), 3.14(s, 3H). MS-ESI calcd. [M + H]+ 142, found 142. |
32% | Stage #1: With sodium In ethanol at 25℃; for 0.5 h; Reflux Stage #2: for 3 h; Reflux |
At 25° C., metallic sodium (7.80 g, 340 mmol) was added into anhydrous ethanol (180 mL) in batches while stirring, followed by heating to 80° C. and refluxing for 0.5 hour. Methylurea (12.6 g, 170 mmol) was then added in batches, and refluxing was continued for 0.5 hour. Ethyl cyanoacetate (19.0 g, 170 mmol) was added into the reaction solution dropwise, and a large amount of precipitate was produced. Refluxing was continued for 3 hours, and then ethanol was recovered under reduced pressure. The residue was dissolved in water (50 mL), and the pH value was adjusted to pH=7 with diluted hydrochloric acid (1N), followed by filtration to give 6-amino-1-methylpyrimidin-2,4-dione (7.60 g, white solid) with a yield of 32percent. 1H NMR: (400 MHz, DMSO-d6) δ10.39 (s, 1H), 6.79 (s, 2H), 4.54 (s, 1H), 3.14 (s, 3H). MS-ESI calculated value: [M+H]+ 142; measured value: 142. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethylene glycol at 165℃; for 1h; | III. general procedure for the synthesis of 1-substituted 4,5-diphenyl-1H-imidazol-2(3H)-ones 9a-e. General procedure: A mixture of 2-hydroxy-1,2-diphenylethanone (benzoin) 11 (21.2 g, 0.1 mol) and ureas 10a-h (0.5 mol) in ethylene glycol (30 mL) was heated at 165 °C for 1 h with stirring. After cooling to room temperature, reaction mixture was extracted by H2O/CHCl3 (1:1) (50 mL) 3 times. Then CHCl3 layer was evaporated and triturated with MeCN (40 mL) and products 9a-e was filtred off. |
With ethanol at 270 - 280℃; | ||
With acetic acid |
beim Zusammenschmelzen; | ||
at 180℃; Yield given; | ||
In ethylene glycol at 180℃; for 1h; | ||
In ethylene glycol at 180℃; for 1.5h; | ||
In ethylene glycol | 1.A 4,5-Diphenyl-1-methyl-(1H),(3H)-imidazolin-2-one Step A 4,5-Diphenyl-1-methyl-(1H),(3H)-imidazolin-2-one A mixture of benzoin (9.5 g, 45 mmol), N-methylurea (10.0 g, 135 mmol) in ethylene glycol (50 mL) was heated to 180° C. for 1.5 hr. The reaction was allowed to cool and was aged for 16 hr before the precipitate was filtered. The solid was recrystallized from ethanol to afford a white solid. The above filtrate was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and combined with the above mother liquor to give a crude solid after evaporation. Recrystallization from ethanol afforded a second crop of white solid title compound. HPLC/MS: 251 (M+1), 292 (100%, M+1+41 (CH3CN)); Rt=2.59 min 1H-NMR (CD3OD): 3.10 (s, 3H), 7.19 (m, 4H), 7.35 (m, 2H), 7.46 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In acetic anhydride at 60℃; for 5h; | 4.1.3 6-Amino-1-methylpyrimidine-2,4(1H,3H)-dione (5) 1-Methylurea (15.0g, 202.5mmol) and 2-cyanoacetic acid (25.8g, 303.7mmol) in the solvent of acetic anhydride (100mL), were stirred at 60°C for 5h and the solid was formed. The precipitation was collected by filtration and washed with water to afford the important intermediate with a good yield about 65%. Dissolve the white solid (18g, 127.5mmol) with 20% NaOH solution (100mL), refluxing for 2h. After the reaction was completed, cooled down the mixture to room temperature, added the hydrochloric acid liquid to form solid. The white precipitate was collected by filtration, washed with water and ethanol to afford the products 5 without any purification. |
With acetic anhydride | ||
With pyridine dann Abkuehlen und tropfenweise unter stetigem Schuetteln mit Phosphoroxychlorid Versetzen; |
In acetic anhydride | ||
With acetic anhydride for 2h; Heating; | ||
With acetic anhydride at 60℃; for 2.5h; Inert atmosphere; | ||
With acetic anhydride; N,N,N',N'-tetramethylguanidinium acetate In water at 60℃; for 1h; | ||
With propionic acid anhydride | ||
With pyridine dann Abkuehlen und tropfenweise unter stetigem Schuetteln mit Phosphoroxychlorid Versetzen; | ||
Stage #1: cyanoacetic acid With oxalyl dichloride In acetone at 0℃; for 5h; Stage #2: N-Methylurea With sodium hydroxide In acetone at 30℃; for 3h; | 1-3; 1 At 0 °C, 1.5 mol of oxalyl chloride was added dropwise to 1 mol of cyanoacetic acid and 5 mol of acetone for 40 minutes. After the dropwise addition, the reaction was completed for 5 hours, and then the reaction solution was concentrated to remove acetone and excess oxalyl chloride. Then slowly add 1 mol of monomethylurea and acetone at 30 °C and add 1 mol of sodium hydroxide. After reacting for 3 hours, add water, stir, and filter to obtain the product, cyanoacetamide. The purity of the product is 98.5%. The cyanamide was dissolved in water and added with liquid caustic soda to adjust the pH=8, then reacted at 95 °C for half an hour to generate a methyl 4AU. Take 1A 4AU 20 g, completely dissolve it in 80g formic acid, and cool to -10 °C. Add 1.2 molar equivalents of sodium nitrite of methyl 4AU and react at room temperature for 2.5 hours. Then add 0.2g of catalyst (5% palladium on carbon), control the temperature at about 50 °C and continue the reaction for 3 hours. The catalyst is recovered by filtration, and the mother liquor is concentrated to recover formic acid to obtain a FAU. Add 100ml of water to monomethyl FAU, increase the temperature to 70 °C and add liquid caustic soda, adjust the alkalinity to 1.5, increase the temperature to 95 °C and keep for 1 hour, add sulfuric acid to adjust to neutrality, cool down and filter to obtain 3-methylxanthine. The 3-methylxanthine is methylated and refined to obtain theobromine. The total yield is 55.8%.The purity is 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium; In ethanol; for 6h;Reflux; | Add sodium (11.5 g, 0.5 mol) and absolute ethanol (250 ml) to a 1 L reaction flask, stir at room temperature for 1 h, add methylurea (18.6 g, 0.25 mol) and ethyl cyanoacetate (26.5 ml, 0.25 mol) Heated to reflux for 6 h. The reaction solution was cooled to room temperature, and ethanol was recovered under reduced pressure. Add distilled water (50 ml) to dissolve, add 4 mol/L hydrochloric acid dropwise to pH 7, stir in an ice bath for 1 h, and filter to obtain a crude product. After recrystallization from water, white crystals (31.7 g, 90%) |
63% | With sodium; In ethanol;Reflux; | General procedure: Compounds 1a, 1b and 1e were prepared according to the reportedmethods26-34 by the addition of urea, methylurea and/or methylthiourea (0.1 mol) to ethyl cyanoacetate (0.1 mol) in absolute ethanol(290 mL) containing sodium (0.2 mol). The mixture was refluxed for10-12 h, allowed to cool to r.t. and acidified with acetic acid (pH 6).The resulting precipitate was washed with distilled water and dried in adesiccator overnight. |
32% | Sodium (7.80 g, 340 mmol) was added in batches to ethanol (180 mL) while stirring at 25 C, heated to 80C to reflux for 0.5 hours. Methylurea (12.6 g, 170 mmol) was then added in batches and reflux was continued for 0.5 h. Ethyl cyanoacetate (19.0 g, 170 mmol) was added dropwise to the reaction solution, resulting in a large amount of precipitate. Reflux was continued for 3 hours, ethanol was recovered under reduced pressure. The residue was diluted with water (50 mL) and adjusted to pH = 7 with dilute hydrochloric acid (1 N). The product was filtered to give 6-amino-1-methylpyrimidine-2,4-dione (7.60 g, as a white solid) with a yield of 32%. 1H NMR: (400 MHz, DMSO-d6) delta 10.39(br, 1H), 6.79(br, 2H), 4.54(s, 1H), 3.14(s, 3H). MS-ESI calcd. [M + H]+ 142, found 142. |
32% | At 25 C., metallic sodium (7.80 g, 340 mmol) was added into anhydrous ethanol (180 mL) in batches while stirring, followed by heating to 80 C. and refluxing for 0.5 hour. Methylurea (12.6 g, 170 mmol) was then added in batches, and refluxing was continued for 0.5 hour. Ethyl cyanoacetate (19.0 g, 170 mmol) was added into the reaction solution dropwise, and a large amount of precipitate was produced. Refluxing was continued for 3 hours, and then ethanol was recovered under reduced pressure. The residue was dissolved in water (50 mL), and the pH value was adjusted to pH=7 with diluted hydrochloric acid (1N), followed by filtration to give 6-amino-1-methylpyrimidin-2,4-dione (7.60 g, white solid) with a yield of 32%. 1H NMR: (400 MHz, DMSO-d6) delta10.39 (s, 1H), 6.79 (s, 2H), 4.54 (s, 1H), 3.14 (s, 3H). MS-ESI calculated value: [M+H]+ 142; measured value: 142. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic anhydride; acetic acid; at 70 - 90℃; for 3h; | (1) Add 270ml of acetic acid to a three-necked reaction flask with a stirrer; Afterwards, 120 g of malonic acid and 75 g of N-methylurea were added to acetic acid; Heat to 70 C, add 195ml of acetic anhydride dropwise; continue to warm to 90 C after stirring, stir for 3h until the reaction is complete; cool to 55 C,The reaction solution was concentrated under reduced pressure, then 180 ml of ethanol was added, and the mixture was cooled to 0 C and stirred for 2 hours. After filtering, washing, drying, 112.2 g of methylpyrimidinetrione was obtained with an LC purity of 98% or more and a yield of 78%. |
65.8% | With acetic anhydride; In acetic acid; at 90℃; | To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
65.8% | With acetic anhydride; In acetic acid; at 70 - 90℃; for 3h; | (a) l-Methylpyrimidine-2,4,6(1H,3H,5H.)-trione To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 0C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
65.8% | With acetic anhydride; In acetic acid; at 70 - 90℃; for 3h; | To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70 0C, acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90 0C for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p. = 131.2-133.1 0C [Lit.1: m.p. = 130-131.5 0C]. |
64% | With acetic anhydride; acetic acid; at 70 - 90℃; for 3h; | To a solution of 1-methylurea (14 g, 189 mmol, 1.0 eq.) and malonic acid (23.6 g, 226.8 mmol, 1.2 eq.) in acetic acid (60 mL), acetic anhydride (36 mL, 378 mmol, 2.0 eq.) was added slowly at 70 C. After the completion of the addition, the reaction mixture was stirred at 90 C. for 3 h and then cooled to rt. The reaction mixture was concentrated and the residue was diluted with EtOH (100 mL). The solid was collected and re-crystalized in EtOH to give the title compound (17.0 g, 64% yield) as a light yellow solid. LC-MS (ES, m/z): [M+H]+=143; 1H NMR (400 MHz, DMSO-d6): delta 11.32 (s, 1H), 3.58 (s, 2H), 2.50 (s, 3H) ppm. |
With acetic anhydride;Microwave irradiation; | 1-Methylbarbituric acid was prepared from methylurea and malonicacid in acetic anhydride under microwave conditions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride at 225℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With boron trifluoride diethyl etherate In neat (no solvent) at 145℃; for 0.133333h; Microwave irradiation; Sealed tube; Green chemistry; chemoselective reaction; | Representative Procedure for Synthesis of Compound 4 with Lewis Acid Ethyl 3-oxo-3-phenylpropanoate (4a, 2mmol), taken in a reactor vessel with BF3 · Et2O(339mg, 2.4mmol), was mixed thoroughly for 1min with urea (2.6mmol). The vessel was closed immediately and was subjected to microwave irradiation at 145° C for about 8min. Reaction was complete within 8 min, which was verified by thin-layer chromatography (TLC). Compound 4 was further purified by column chromatography (silicagel 60-120 mesh, 60% ethyl acetate in hexane). |
26% | at 135℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Methyl urea (97.14 g, 1.31 mol), absolute ethanol 1.2 L, metal sodium (30.4 g, 1.32 mol) was added in portions and stirred for 1 h. Diethyl malonate (273.0 g, 1.70 mol) in 100 mL of absolute ethanol was slowly added dropwise to the reaction solution, heating To reflux, reaction 24h. The solvent was evaporated under reduced pressure, 1 L of water was added, and the pH was adjusted to 3 to 4 with 2N HCl, followed by cooling and crystallization. Filter, wash, dry Drying gave a pale yellow powder, 152.8 g of 1-methylpyrimidine-2,4,6-trione, a yield of 82%, mp. 129-130C. | |
With sodium; In methanol; for 18h;Reflux; | (A) weigh each raw material according to a molar ratio of methyl urea, diethyl malonate and catalyst: 1:1.2:1; first dissolve methyl urea in methanol, then slowly add sodium metal to obtain a reaction solution. Then, the diethyl malonate is dissolved, and slowly added dropwise to the reaction solution, while the reaction solution is heated to reflux under the conditions of 18 h, and finally purified and dried to obtain 1-methylpyrimidine-2,4,6-trione |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; | 1.3.A To an ice-cold solution of 1-methylurea (200 mg, 2.70 mmol) in dry tetrahydrofuran (6 mL) was added oxalyl chloride (0.26 mL, 2.97 mmol) dropwise, under a nitrogen atmosphere. The reaction mixture was stirred at 0-5° for 2 h and then allowed to warm to room temperature for 1 h before being diluted with water. The product was extracted with ethyl acetate, and the extracts were washed with water, dried and evaporated to give the product as an off-white solid (326 mg, 94%), mp 146-149°C (lit. 145-148°C). |
92% | In benzene at 20℃; | |
88% | In tetrahydrofuran at 0℃; for 2h; |
59% | In diethyl ether for 2h; Inert atmosphere; Reflux; | 2 10: Under argon atmosphere, in a 250 mL round bottom flask, N-methylurea (2.96 g, 0.04 mol) was added, diethyl ether (100 mL) was added, oxalyl chloride (3.3 mL, 0.04 mol) was added, and the mixture was heated under reflux for 2 h.The mixture was desolvated, washed with a small amount of dichloromethane, and suction-filtered to obtain 2.87 g of a white solid. The yield was 59%. |
59% | In diethyl ether for 2h; Reflux; Inert atmosphere; | |
In diethyl ether for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sulfuric acid; lithium bromide In 1-methyl-pyrrolidin-2-one at 80℃; for 12h; | |
20 % Chromat. | With polymer incarcerated Pd(PPh3)4; sulfuric acid; benzyltriethylammonium bromide In 1,4-dioxane at 120℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With polyphosphate ester In tetrahydrofuran for 24h; Heating; | |
88% | With chloro-trimethyl-silane In N,N-dimethyl-formamide at 20℃; for 48h; | |
88% | With cerous p-toluenesulfonate tetrahydrate at 80℃; for 0.833333h; Green chemistry; | General Procedure for the Synthesis of N1-substituted-4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones (a-d') General procedure: An aldehyde (10 mmol), b-dicarbonyl compound (10 mmol), N-substituted urea or thiourea(13 mmol) and CePTS (0.363 g, 0.5 mmol) were added successively to a 25mLdried round-bottom flask. The mixture was stirred at 80 C for an appropriate time. Thecompletion of the reaction was determined on TLC plates using ethyl acetate/petroleumether (V/V3:7) mixture as a mobile phase. After completion, the mixture was cooledto room temperature, then crushed ice was added to precipitate the product. The solidprecipitate was separated by filtration through a Buckner funnel, and washed with coldwater to remove excess N-substituted urea. Then, it was air dried. It was further purifiedby recrystallization from hot ethanol to afford pure DHPM derivatives. The productswere characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. Spectraldata for the novel compounds are given below. |
63% | at 130℃; | |
59.5% | With hydrogenchloride In methanol for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With cerium(III) p-toluenesulfonate tetrahydrate In neat (no solvent) at 80℃; for 0.3h; Green chemistry; | Preparation of C6-phenyl substituted 3,4-dihydropyrimidinones (4) General procedure: A mixture of aromatic aldehyde (10 mmol), ethyl benzoylacetate (10 mmol), urea(10 mmol) and CePTS (0.3 mmol) was stirred at 80 C on an oil bath until the reactionwas determined to be complete by TLC. The reaction mixture was cooled to room temperature,and ice water was added. The crude products were obtained by filtration anddrying and were purified by recrystallization from hot ethanol. All of the products werecharacterized by IR, 1H/13C NMR and elemental analysis. The spectral data of the newproducts are as follows: |
0.57 g | Stage #1: 4-methyl-benzaldehyde; N-Methylurea With 1,2,3-Benzotriazole; Amberlyst(R) 15 for 12h; Heating; Stage #2: ethyl 3-oxo-3-phenylpropionate With zinc dibromide In 1,2-dichloro-ethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With cerium(III) p-toluenesulfonate tetrahydrate In neat (no solvent) at 80℃; for 0.3h; Green chemistry; | Preparation of C6-phenyl substituted 3,4-dihydropyrimidinones (4) General procedure: A mixture of aromatic aldehyde (10 mmol), ethyl benzoylacetate (10 mmol), urea(10 mmol) and CePTS (0.3 mmol) was stirred at 80 C on an oil bath until the reactionwas determined to be complete by TLC. The reaction mixture was cooled to room temperature,and ice water was added. The crude products were obtained by filtration anddrying and were purified by recrystallization from hot ethanol. All of the products werecharacterized by IR, 1H/13C NMR and elemental analysis. The spectral data of the newproducts are as follows: |
0.70 g | Stage #1: 4-chlorobenzaldehyde; N-Methylurea With 1,2,3-Benzotriazole; Amberlyst(R) 15 for 12h; Heating; Stage #2: ethyl 3-oxo-3-phenylpropionate With zinc dibromide In 1,2-dichloro-ethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With cerous p-toluenesulfonate tetrahydrate at 80℃; for 0.5h; Green chemistry; | General Procedure for the Synthesis of N1-substituted-4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones (a-d') General procedure: An aldehyde (10 mmol), b-dicarbonyl compound (10 mmol), N-substituted urea or thiourea(13 mmol) and CePTS (0.363 g, 0.5 mmol) were added successively to a 25mLdried round-bottom flask. The mixture was stirred at 80 C for an appropriate time. Thecompletion of the reaction was determined on TLC plates using ethyl acetate/petroleumether (V/V3:7) mixture as a mobile phase. After completion, the mixture was cooledto room temperature, then crushed ice was added to precipitate the product. The solidprecipitate was separated by filtration through a Buckner funnel, and washed with coldwater to remove excess N-substituted urea. Then, it was air dried. It was further purifiedby recrystallization from hot ethanol to afford pure DHPM derivatives. The productswere characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. Spectraldata for the novel compounds are given below. |
85% | With toluene-4-sulfonic acid In methanol for 16h; Reflux; Inert atmosphere; | |
81% | With myo-inositol 1,2,3,4,5,6-hexakisphosphate In neat (no solvent) at 100℃; for 2h; Green chemistry; |
0.54 g | Stage #1: 4-chlorobenzaldehyde; N-Methylurea With 1,2,3-Benzotriazole; Amberlyst(R) 15 for 12h; Heating; Stage #2: acetoacetic acid methyl ester With zinc dibromide In 1,2-dichloro-ethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With cerium(III) p-toluenesulfonate tetrahydrate In neat (no solvent) at 80℃; for 0.9h; Green chemistry; | Preparation of C6-phenyl substituted 3,4-dihydropyrimidinones (4) General procedure: A mixture of aromatic aldehyde (10 mmol), ethyl benzoylacetate (10 mmol), urea(10 mmol) and CePTS (0.3 mmol) was stirred at 80 C on an oil bath until the reactionwas determined to be complete by TLC. The reaction mixture was cooled to room temperature,and ice water was added. The crude products were obtained by filtration anddrying and were purified by recrystallization from hot ethanol. All of the products werecharacterized by IR, 1H/13C NMR and elemental analysis. The spectral data of the newproducts are as follows: |
0.74 g | Stage #1: 4-nitrobenzaldehdye; N-Methylurea With 1,2,3-Benzotriazole; Amberlyst(R) 15 for 12h; Heating; Stage #2: ethyl 3-oxo-3-phenylpropionate With zinc dibromide In 1,2-dichloro-ethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 125℃; for 5h; | |
91% | With Indion-130 resin at 110℃; for 0.166667h; | |
86% | With silica gel-supported polyphosphoric acid at 120℃; for 0.133333h; |
77% | With barium phosphate In neat (no solvent) at 100℃; for 0.25h; | 2.3 General procedure General procedure: To a mixture of aromatic aldehyde (1 mmol), 2-naphthol/dibenzofuran-2-ol (1 mmol) and acetamide/bezamide/urea (1.3 mmol) was added Ba3(PO4)2 nano-particles (0.1 mmol), and the mixture was heated at 100 °C in an oil bath for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, mass was cooled to 25 °C and the mixture was dissolved in pure acetone. The catalyst was removed by simple filtration. The solvent was evaporated and the solid product was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With silica gel-supported polyphosphoric acid at 120℃; for 0.0833333h; | |
94% | With Indion-130 resin at 110℃; for 0.1h; | |
94% | With sulfanilic acid functionalized silica coated Fe3O4 nanoparticles In neat (no solvent) at 120℃; for 0.166667h; Green chemistry; |
93% | at 125℃; for 4h; | |
93% | With iodine In 1,2-dichloro-ethane at 20℃; for 8h; | |
80% | With barium phosphate In neat (no solvent) at 100℃; for 0.166667h; | 2.3 General procedure General procedure: To a mixture of aromatic aldehyde (1 mmol), 2-naphthol/dibenzofuran-2-ol (1 mmol) and acetamide/bezamide/urea (1.3 mmol) was added Ba3(PO4)2 nano-particles (0.1 mmol), and the mixture was heated at 100 °C in an oil bath for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, mass was cooled to 25 °C and the mixture was dissolved in pure acetone. The catalyst was removed by simple filtration. The solvent was evaporated and the solid product was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With silica gel-supported polyphosphoric acid at 120℃; for 0.0666667h; | |
92% | With sulfanilic acid functionalized silica coated Fe3O4 nanoparticles In neat (no solvent) at 120℃; for 0.2h; Green chemistry; | |
90% | With Indion-130 resin at 110℃; for 0.2h; |
89% | at 125℃; for 6h; | |
82% | With barium phosphate In neat (no solvent) at 100℃; for 0.333333h; | 2.3 General procedure General procedure: To a mixture of aromatic aldehyde (1 mmol), 2-naphthol/dibenzofuran-2-ol (1 mmol) and acetamide/bezamide/urea (1.3 mmol) was added Ba3(PO4)2 nano-particles (0.1 mmol), and the mixture was heated at 100 °C in an oil bath for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, mass was cooled to 25 °C and the mixture was dissolved in pure acetone. The catalyst was removed by simple filtration. The solvent was evaporated and the solid product was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With barium phosphate In neat (no solvent) at 100℃; for 0.416667h; | 2.3 General procedure General procedure: To a mixture of aromatic aldehyde (1 mmol), 2-naphthol/dibenzofuran-2-ol (1 mmol) and acetamide/bezamide/urea (1.3 mmol) was added Ba3(PO4)2 nano-particles (0.1 mmol), and the mixture was heated at 100 °C in an oil bath for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, mass was cooled to 25 °C and the mixture was dissolved in pure acetone. The catalyst was removed by simple filtration. The solvent was evaporated and the solid product was purified by recrystallization from ethanol. |
69% | at 125℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: phenylacetaldehyde; N-Methylurea With iodine In acetonitrile at 20℃; for 0.166667h; Inert atmosphere; Stage #2: phenylacetaldehyde In acetonitrile for 12h; Inert atmosphere; Reflux; | General procedure for the iodine-catalyzed synthesis of DHPMs 4 General procedure: Mono-substituted urea 1 (2.5 mmol), aromatic aldehyde 3 (3.75 mmol) and iodine (0.25 mmol) were dissolved in 3 mL acetonitrile under nitrogen atmosphere. After the mixture was stirred at room temperature for 10 minutes, alkylaldehyde 2 (2.5 mmol) was added, and the resulting mixture was stirred under reflux for 12 hours. Then the reaction mixture was diluted with ethyl acetate, and washed with a solution of sodium thiosulfate followed by water. The organic phase was dried over anhydrous Na2SO4, and evaporation of the solvent followed by purification on silica gel afforded the pure desired DHPM 4. |
59% | With 4 A molecular sieve; boron trifluoride diethyl etherate In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ammonia In water at 65℃; | 13 EXAMPLE 13; Methyl urea A quantity of 30% aqueous ammonia (g 102, moles 1.80) is added, while stirring, to the N,S-dimethyl thiocarbamate (g 15.75, moles 0.15) and the mixture is heated to 65 C., still stirring it. The reaction produces methanthiol, which is absorbed by a sodium hydroxide aqueous solution. The course of the reaction is monitored through thin layer chromatography (SiO2; eluent: CHCl3/CH3OH, 9.8:0.2). The reaction is completed in 3 hours. The water is distilled by means of a rotating evaporator, the solid product is then completely dried by adding chloroform and subsequently distilling it. g 10.99 of product is obtained, which is 97% pure. After washing the raw residue at 0 C. in 4-5 ml of anhydrous dioxane, g 10.66 (yield 96%) of pure (TLC, GC, GC-MS, 1H NMR) methyl urea is obtained: m.p. 101.9-102.1 C.; MS: m/e 74; 1H NMR (DMSO-d6): ?=2.46 (d, J=5.00 Hz, 3H, CH3), 5.49 (enlarged s, 2H, NH2), 5.85 ppm (enlarged s, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 9 STR24 A mixture of alpha-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and methylurea (407 mg; 5.5 mmoles) in DMF (3 ml) was heated at 90 C. with stirring for 4 hours. DMF was evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel to give 118 mg (yield 12%) of 1-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-3), 20 mg (yield: 2%) of 3-methyl-5-trifluoromethyl-5,6-dihydrouracil and 706 mg (yield: 66%) of 1-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)-3-methylurea. 1-(2-Hydroxycarbonyl-3,3,3-trifluoropropyl)-3-methylurea: m.p.: 149.5-150.5 C. Mass spectrum: m/e (relative intensity) M+ 214(9), 30 (100). IR (KBr): 3430, 3400 cm-1 (nuN--H), 3600-2200 cm-1 (nuO--H). 1740, 1725, 1610 cm-1 (nuc=o). 1 H NMR (CD3 COCD3:TMS): delta2.70(s, 3H), 3.3-3.8(m, 3H), 5.9(bs, 1H). 6.1(bs, 1H), 10.7(bs, 1H). 19 F NMR (CD3 COCD3:CFCl3): delta-66.1(m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; | EXAMPLE 8 To a solution of ethyl veratroylacetate (100 g) in toluene (1.0 l) was added N-methylurea (29.4 g) and the mixture was refluxed under azeotropic dehydration by use of Cope apparatus for one day. After cooling, the resultant precipitates were filtered. To the filtrate was added an additional N-methylurea (10.0 g) and the mixture was refluxed under the same condition for one day. After cooling, the resulting precipitates were filtered. The combined precipitates were washed successively with water and diisopropyl ether and dried under reduced pressure. To a suspension of the precipitates obtained above in toluene (250 ml) was added conc.hydrochloric acid (1 ml), and the suspension was refluxed under azeotropic dehydration for 5.5 hours. The mixture was cooled, and the resulting precipitates were collected by filtration and recrystallized from a mixture of chloroform and methanol (9:1) to afford 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)pyrimidinedione (24.9 g). The filtrate was evaporated and the residue was recrystallized from chloroform to afford 6-(3,4-dimethoxyphenyl)-1-methyl-2,4(1H,3H)-pyrimidinedione (1.77 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetralin; ethyl acetate; | EXAMPLE 13 To a solution of ethyl veratroylacetate (8.0 g) in tetralin (24 ml) was added N-methylurea (3.52 g) and the mixture was heated for an hour at 170 C. After being cooled to 95 C., ethyl acetate (33 ml) was added thereto. The precipitate was collected by filtration and washed with ethyl acetate to give 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.35 g). IR (Nujol): 1710, 1640, 1610 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | at 100℃; for 18h;Inert atmosphere; | Step 1 : 1 ,6-dimethylpyrimidine-2,4(l H,3H)-dioneA solution of 1-methylurea (30 g, 0.356 mol) in 4-methyleneoxetan-2-one (26.4 g, 0.356 mol) was heated at 100C for 18 h, cooled to RT then diluted with MeOH (50 mL). The reaction was filtered and the filtered solid was washed with MeOH (20 mL) and dried to give 1,6- dimethylpyrimidine-2,4(lH,3H)-dione (9 g, 8% yield) as a white solid. ]H NMR (CDClj) 6: 8.33 (s, 1H), 5.58 (s, 1H), 3.38 (s, 3H), 2.26 (s, 3H). LCMS: MH+ 141 and TR = 0.368 min. Used without further purification. |
14% | In acetic acid; at 120℃; for 12h; | 4-Methyleneaxetan-2-one (8.0 g, 95 mmol) and N-methylurea (5.0 g, 68 mmol) were dissolved in acetic acid (50 ml), followed by stirring at 120 C. for 12 hours. The solvent was removed under reduced pressure. To the obtained residue, ethyl acetate (50 ml) was added, followed by stirring for 30 minutes. After the precipitated solid was filtered, purification was conducted by reversed-phase HPLC (H2O containing 0.1% FTA/CH3CN system) to obtain the title compound (1.3 g, 14%). [0618] 1H NMR (400 MHz, CD3OD): δ 5.59 (s, 1H), 3.39 (s, 3H), 2.32 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With myo-inositol 1,2,3,4,5,6-hexakisphosphate In neat (no solvent) at 100℃; for 0.5h; Green chemistry; | |
90% | With toluene-4-sulfonic acid In methanol for 16h; Reflux; Inert atmosphere; | |
88% | With cerous p-toluenesulfonate tetrahydrate at 80℃; for 0.0833333h; Green chemistry; | General Procedure for the Synthesis of N1-substituted-4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones (a-d') General procedure: An aldehyde (10 mmol), b-dicarbonyl compound (10 mmol), N-substituted urea or thiourea(13 mmol) and CePTS (0.363 g, 0.5 mmol) were added successively to a 25mLdried round-bottom flask. The mixture was stirred at 80 C for an appropriate time. Thecompletion of the reaction was determined on TLC plates using ethyl acetate/petroleumether (V/V3:7) mixture as a mobile phase. After completion, the mixture was cooledto room temperature, then crushed ice was added to precipitate the product. The solidprecipitate was separated by filtration through a Buckner funnel, and washed with coldwater to remove excess N-substituted urea. Then, it was air dried. It was further purifiedby recrystallization from hot ethanol to afford pure DHPM derivatives. The productswere characterized by IR, 1H NMR, 13C NMR, MS, and elemental analysis. Spectraldata for the novel compounds are given below. |
86% | With yttrium (III) acetate hydrate; acetic acid at 115℃; for 4.5h; | |
With toluene-4-sulfonic acid In ethanol Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.4% | Stage #1: 2-(4-bromophenyl)-7,7-dimethyl-4-morpholino-6,7-dihydrofuro[3,2-d]pyrimidine; N-Methylurea With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 110℃; for 1h; Inert atmosphere; Microwave; Stage #2: trifluoroacetic acid In water; acetonitrile | 2 In a microwave vial 2-(4-bromophenyl)-7,7-dimethyl-4-morpholino-6,7-dihydrofuro[3,2-d]pyrimidine (0.060 g, 0.154 mmol), 1-methylurea (0.171 g, 2.306 mmol), copper(I) iodide (9.96 mg, 0.052 mmol), Xantphos (0.018 g, 0.031 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol), sodium tert-butoxide (0.222 g, 2.306 mmol), and degassed dioxane (2.2 ml) were combined. The reaction vial was flushed with nitrogen for 7 minutes then heated in the microwave at 110° C. for 1 hour. The reaction mixture cooled and purified by preparative HPLC eluting with a gradient 30-70% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as its TFA salt: 0.0415 g, 70.4% yield. MS [M+H] found 384. 1H NMR (400 MHz, MeOD) δ 1.54 (s, 6H), 2.79 (s, 3H), 3.75-3.90 (m, 4H), 4.12-4.25 (m, 4H), 4.49 (s, 2H), 7.55-7.64 (m, J=8.84 Hz, 2H), 7.94-8.06 (m, J=8.84 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With boric acid; acetic acid; at 100℃; for 2h; | General procedure: A solution of compound 7 (1 eq), ethyl acetoacetate (1.5 eq), urea derivatives (1.8 eq) and H3BO3 (0.75 eq), in glacial acetic acid (10 mL) is heated at 100 C, while stirring for 2 h. Then it was cooled to room temperature, and poured into a mixture of ice water (50 mL) and ethanol. The product was collected by filtration and recrystallised from EtOH (95%), to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trifluoroacetic acid In tetrahydrofuran at 95℃; for 0.25h; Microwave irradiation; Sealed tube; chemoselective reaction; | 4.3. General procedure for the synthesis of 6m-6w General procedure: To a mixture of oxalacetic acid (2.6 mmol), aldehyde (2.0 mmol) and N-substituted urea/thiourea (2.6 mmol) in THF (3 mL) was added TFA (0.10 mL). The mixture was heated at 95 °C for 15 min using microwave irradiation in a sealed tube. Thereafter, the mixture was cooled and the solvent was removed under reduced pressure. 0.5 M NaOH (20 mL) was then added to the residue and the resulting solution was extracted with EtOAc (3×15 mL). Subsequently, the aqueous phase was acidified using concd HCl and extracted with 10% iPrOH in CH2Cl2 (3×15 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was washed with Et2O and dried under vacuum to afford the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With trifluoroacetic acid In tetrahydrofuran at 95℃; for 0.25h; Microwave irradiation; Sealed tube; chemoselective reaction; | 4.3. General procedure for the synthesis of 6m-6w General procedure: To a mixture of oxalacetic acid (2.6 mmol), aldehyde (2.0 mmol) and N-substituted urea/thiourea (2.6 mmol) in THF (3 mL) was added TFA (0.10 mL). The mixture was heated at 95 °C for 15 min using microwave irradiation in a sealed tube. Thereafter, the mixture was cooled and the solvent was removed under reduced pressure. 0.5 M NaOH (20 mL) was then added to the residue and the resulting solution was extracted with EtOAc (3×15 mL). Subsequently, the aqueous phase was acidified using concd HCl and extracted with 10% iPrOH in CH2Cl2 (3×15 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was washed with Et2O and dried under vacuum to afford the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With trifluoroacetic acid In tetrahydrofuran at 95℃; for 0.25h; Microwave irradiation; Sealed tube; chemoselective reaction; | 4.3. General procedure for the synthesis of 6m-6w General procedure: To a mixture of oxalacetic acid (2.6 mmol), aldehyde (2.0 mmol) and N-substituted urea/thiourea (2.6 mmol) in THF (3 mL) was added TFA (0.10 mL). The mixture was heated at 95 °C for 15 min using microwave irradiation in a sealed tube. Thereafter, the mixture was cooled and the solvent was removed under reduced pressure. 0.5 M NaOH (20 mL) was then added to the residue and the resulting solution was extracted with EtOAc (3×15 mL). Subsequently, the aqueous phase was acidified using concd HCl and extracted with 10% iPrOH in CH2Cl2 (3×15 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was washed with Et2O and dried under vacuum to afford the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 150℃; for 1h;Inert atmosphere; microwave irradiation; | To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)-lH-imidazo-[4,5-c]pyridine (0.050 g, 0.15 mmol), 1-methylurea (0.031 g, 0.3 mmol), Pd2(dba)3 (0.013 g, 0.015 mmol), XantPhos (0.034 g, 0.030 mmol), Cs2C03 (0.147 g, 0.45 mmol) and dioxane (1.0 mL). The mixture was degassed with N2 for 1 min. The resulting mixture was irradiated in a microwave reactor at 150 C for 1 hour and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated by vacuum. The residue was purified by prep-HPLC (Gilson GX 281 , Shim-pack PRC-ODS 250 mm x 20 mm x 2, gradient: CH3CN / 10 mm/L NH4HCO3, 17 min) to give the desired product (21 mg, 40% yield). ¾ NMR (DMSO-</6, 500 MHz): delta 12.70 (s, 1H), 9.34 (s, 1H), 8.48 (s, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.67 (m, 3H), 7.26 (d, J = 5.5 Hz, 1H), 2.83 (d, J= 5.0 Hz, 3H). LCMS(ESI) m/z: 336.2 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 2h; | Example 14N-hydroxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; Compound I-286 Step 1: methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate Intermediate-5To a solution of <strong>[18643-86-2]dimethyl 2-bromoterephthalate</strong> (0.25 g, 0.92 mmol) and methylurea (88.2 mg, 1.19 mmol) in 1,4-dioxane (7 mL) was added cesium carbonate (0.60 g, 1.83 mmol). 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.0 mg, 0.092 mmol) was then added followed by tris(dibenzylideneacetone)dipalladium (42 mg, 0.046 mmol). The reaction mixture was heated to 100 C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. Water was added and the remaining solid was filtered. The collected solid was then washed with DCM (3×) to afford methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.15 g, 70%). LC-MS: (FA) ES+235; 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.77 (d, J=1.4 Hz, 1H), 7.71 (dd, J=8.2, 1.5 Hz, 1H), 3.89 (s, 3H), 3.26 (s, 3H). |
58.3% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 16h; | To a solution of <strong>[18643-86-2]dimethyl 2-bromoterephthalate</strong> (3.00 g, 10.99 mmol) and 1-methylurea (1.06 g, 14.28 mmol) in 1,4-dioxane (10.0 mL) was added cesium carbonate (7.16 g, 21.97 mmol), xantphos (0.64 g, 1.099 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.00 g, 1.099 mmol). The reaction mixture was heated to 120C for 16 h. The reaction mixture was then cooled to room temperature and concentrated to afford crude solid. To the crude solid add 60.0 mL dichloromethane and stirred it for 5 minutes. Filtered this reaction mixture to get crude solid which was purified by column chromatography using eluent 0-10% of methanol in dichloromethane to afford the titled compound methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate 1.5 g, 58.3 % yield as a light yellow solid. MS (ES+) m/z = 235.27 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.80 - 7.67 (m, 2H), 3.90 (s, 3H), 3.27 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 48h; | 18.1 Example 18N-hydroxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxamide; Compound I-169 Step 1: methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate Intermediate-7To a solution of dimethyl 4-bromoisophthalate (0.25 g, 0.92 mmol) and methylurea (88.2 mg, 1.19 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (0.60 g, 1.83 mmol). 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.0 mg, 0.092 mmol) was then added followed by tris(dibenzylideneacetone)dipalladium (0) (42 mg, 0.046 mmol). The reaction mixture was heated to 100° C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. Water was added and the remaining solid was filtered. The collected solid was then washed with DCM (3×) to afford methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (0.17 g, 80%). LC-MS: (FA) ES+235; 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.16 (dd, J=8.6, 2.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 3.87 (s, 3H), 3.26 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.4% | Stage #1: 2-(4-bromophenyl)-7,7-dimethyl-4-morpholino-6,7-dihydrofuro[3,2-d]pyrimidine; N-Methylurea With copper(l) iodide; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 110℃; for 1h; Inert atmosphere; Microwave irradiation; Stage #2: trifluoroacetic acid In water; acetonitrile | 2 In a microwave vial 2-(4-bromophenyl)-7,7-dimethyl-4-morpholino-6,7- dihydrofuro[3,2-d]pyrimidine (0.060 g, 0.154 mmol), 1-methylurea (0.171 g, 2.306 mmol) , copper(I) iodide (9.96 mg, 0.052 mmol), Xantphos (0.018 g, 0.031 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol), sodium tert-butoxide (0.222 g, 2.306 mmol), and degassed dioxane (2.2 ml) were combined. The reaction vial was flushed with nitrogen for 7 minutes then heated in the microwave at 110°C for 1 hour. The reaction mixture cooled and purified by preparative HPLC eluting with a gradient 30-70% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as its TFA salt:0.0415 g, 70.4 % yield. MS [M+H] found 384. 1H NMR (400 MHz, MeOD) δ 1.54 (s, 6 H), 2.79 (s, 3 H), 3.75 - 3.90 (m, 4 H), 4.12 - 4.25 (m, 4 H), 4.49 (s, 2 H), 7.55 - 7.64 (m, J = 8.84 Hz, 2 H), 7.94 - 8.06 (m, J = 8.84 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.2% | With hydrogenchloride; In ethanol; water; for 72.0h;Reflux; | [00156] A mixture of 1,2-diphenylethanone (400 mg, 2.04 mmol), 3-ethoxy-4- hydroxy- 5 -nitrobenzaldehyde (430 mg, 2.04 mmol), and 1-methylurea (454 mg, 6.12 mmol) in anhydrous EtOH was added concentrated HC1 (204 mg, 2.04 mmol), and the reaction mixture was refluxed for 3 days. When TLC (EtOAc:MeOH=10: l) showed that the starting materials were consumed, the reaction mixture was concentrated, and purified by preparative HPLC to afford Compound 11 as a yellow solid (138 mg, yield: 15.2%). 1H NMR (DMSO- d6 400 MHz TMS): delta 10.25 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.45 (s, 1H), 7.20-7.28 (m, 3H), 7.15-7.20 (m, 3H), 6.85-6.95 (m, 3H), 6.70 (d, J = 6.4 Hz, 1H), 5.00 (d, J = 2.4 Hz, 1H), 4.02 (m, 2H), 2.60 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); MS (ESI): m/z 446.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tin(II) chloride hydrate In acetonitrile Reflux; | |
73% | With tin(II) chloride dihdyrate In acetonitrile at 70 - 75℃; Sonication; | 4.3.1. General method for the synthesis of 3,4-dihydropyrimidine-2-ones and 3,4-dihydropyrimidine-2-thiones General procedure: A mixture of an aldehyde (10 mmol), a diamino compound (12 mmol), a dicarbonyl compound (10 mmol, mL), SnCl2·2H2O (10 mol%) and acetonitrile (10 mL) was mixed in a pyrex tube. The mixture was then irradiated in ultrasonic bath at 70-75 °C. The reaction was monitored by TLC. After the completion of the reaction, the resulting precipitate was filtered and crude product was recrystallized from an appropriate solvent or purified through columnchromatography. |
With tin(II) chloride dihdyrate In acetonitrile Sonication; Heating; | General method for the synthesis of 3,4-dihydropyrimidine-2-ones and 3,4-dihydropyrimidine-2-thiones (1-13) General procedure: A mixture of an aldehyde (10mmol), a diamino compound (12mmol), a dicarbonyl compound (10mmol, mL), SnCl2.2H2O (10mol %) and acetonitrile (10mL) was mixed in a pyrex tube. The mixture was then irradiated in ultrasonic bath at 70-75°C. The reaction was monitored by TLC. After the completion of the reaction, the resulting precipitate was filtered and crude product was recrystallized from an appropriate solvent or purified through column chromatography. |
With toluene-4-sulfonic acid In ethanol Reflux; Inert atmosphere; | ||
With tin(II) chloride dihdyrate In acetonitrile at 70 - 75℃; Sonication; | 4.1. Synthesis of 3,4-dihydropyrimidinones (1a-k) General procedure: In a pyrex tube equimolar quantities of variety of aldehydes and dicarbonylcompounds (10 mmol each) along with urea (12 mmol) were mixed in acetonitrile (10 mL). SnCl2·2H2O (10 mol %) was used as catalyst. The reaction mixture was then sonicated in an ultrasonic bath at 70-75 °C. Progress of the reaction was monitored through TLC. Pure product was obtained through silica gel chromatography. All the products were characterized by their melting points, LC/MS and their spectral data. Compounds (1a-k) were already synthesized and reported earlier by our research group [20,21]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride; sodium methylate In methanol for 18h; Reflux; | 8.1 Step 1. Synthesis of6-amino-i ,5-dimethylpyrimidine-2,4(1H,3H)-dione,hydrochloride salt (C33) Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C33) A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1-methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3*50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for one hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (br s, 1H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H). |
80% | Stage #1: ethyl 2-cyanopropionate; N-Methylurea With sodium methylate In methanol for 18h; Reflux; Stage #2: With hydrogenchloride In water | 216.1 Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C87). 1-Methylurea (98%, 8.26 g, 109 mmol) and ethyl 2-cyanopropanoate (95%, 13.2 mL,99.6 mmol) were dissolved in methanol (75 mL) and treated with sodium methoxide (25 weightpercent solution in methanol, 27 mL, 120 mmol). The resulting mixture was heated at reflux for18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the bulk of the methanol. The solvent was subsequently exchanged by repeated addition of acetonitrile (3 x 50 mL) followed by concentration in vacuo. The resulting solid was dissolved in acetonitrile (100 mL) and water (100 mL), and 6 M aqueous hydrochloric acid was added until the pH reached approximately 2. During this acidification, a white precipitate formed. After the mixture had stirred for an hour, the solid was collected via filtration and washed with tert-butyl methyl ether, providing the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.3 [M+H]. 1H NMR (400 MHz, DMSO-d6) ö 10.37 (br s,1 H), 6.39 (br s, 2H), 3.22 (s, 3H), 1.67 (s, 3H). |
80% | With sodium methylate In methanol for 18h; Reflux; | 1.1; 2.1 Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C1). A solution of sodium methoxide in methanol (4.4 M, 27 mL, 1 19 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1 -methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (br s, 1 H), 6.39 (s, 2H), 3.22 (s, 3H), 1 .67 (s, 3H). |
80% | Stage #1: ethyl 2-cyanopropionate; N-Methylurea With sodium methylate In methanol for 18h; Reflux; Stage #2: With hydrogenchloride In water for 1h; | 15.1 Step 1. Synthesis of 6-amino-i, 5-dimethylpyrimidine-2, 4(1 H, 3H)-dione, hydrochloridesalt(C30). A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1- methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solventin vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]. 1H NMR (400MHz, DMSO-d6) ö 10.38 (brs, 1H), 6.39 (5, 2H), 3.22 (5, 3H), 1.67 (5, 3H). |
80% | Stage #1: ethyl 2-cyanopropionate; N-Methylurea With sodium methylate In methanol for 18h; Reflux; Stage #2: With hydrogenchloride In water for 1h; | 1.1 Synthesis of 6-amino-1 ,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C1). A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1- methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with terf-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]+. 1 H NMR (400 MHz, DMSO-de) δ 10.38 (br s, 1 H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H). |
80% | Stage #1: ethyl 2-cyanopropionate; N-Methylurea With sodium methylate In methanol for 18h; Reflux; Stage #2: With hydrogenchloride In water for 1h; | 1.1; 2.1 Step 1. Synthesis of 6-amino-i, 5-dimet hylpyrimidine-2 , 4(1 H, 3H)-dione, hydrochloridesalt (Cl). A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) wasadded to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1-methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) ö 10.38 (br 5, 1H), 6.39 (5, 2H), 3.22 (5, 3H), 1.67 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 75 - 80℃; for 3.5h;Inert atmosphere; | Procedure for synthesis of 4 1 -methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (Step-1) / A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.202 g, 0.220 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.493 g, 0.826 mmol), potassium carbonate (1.93 g, 13.8 mmol) and methylurea (0.408 g, 5.51 mmol) in 1 ,4-dioxane (30 mL) was treated with 2- chloro-4-(trifluoromethyl)pyridine (commercially available) (1.0 g, 5.51 mmol), The mixture was warmed to 75-80C with stirring under a Nitrogen atmosphere for 3.5 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and filtered through a pad of celite, rinsing through with further small portions of EtOAc and water. The organic phase was separated and the aqueous further extracted with EtOAc (5 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgS04, filtered and the filtrate evaporated giving an orange liquid. This was chromatographed (eluting with an EtOAc/iso-hexane gradient) and fractions containing product were evaporated and triturated with iso-hexane to give the desired product as a light yellow powder (0.669 g, 55%). H NMR (CDCI3): 9.44 (br.s, 1 H), 9.04 (br.s, 1 H), 8.32 (d, 1 H), 7.15 (s, 1 H), 7.06 (d, 1 H), 2.99 (d, 3H). LC-MS: (positive ES MH+ 220). |
55% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 75 - 80℃; for 3.5h;Inert atmosphere; | A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.202 g, 0.220 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.493 g, 0.826 mmol), potassium carbonate (1 .93 g, 13.8 mmol) and methylurea (0.408 g, 5.51 mmol) in 1 ,4-dioxane (30 mL) was treated with 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (1 .0 g, 5.51 mmol), The mixture was warmed to 75- 80C with stirring under a Nitrogen atmosphere for 3.5 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and filtered through a pad of celite, rinsing through with further small portions of EtOAc and water. The organic phase was separated and the aqueous further extracted with EtOAc (5 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgS04, filtered and the filtrate evaporated giving an orange liquid. This was chromatographed (eluting with an EtOAc/iso-hexane gradient) and fractions containing product were evaporated and triturated with iso-hexane to give the desired product as a light yellow powder (0.669 g, 55%). H NMR (CDCI3): 9.44 (br.s, 1 H), 9.04 (br.s, 1 H), 8.32 (d, 1 H), 7.15 (s, 1 H), 7.06 (d, 1 H), 2.99 (d, 3H). LC-MS: (positive ES MH+ 220). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With boron trifluoride diethyl etherate In neat (no solvent) at 145℃; for 0.133333h; Microwave irradiation; Sealed tube; Green chemistry; chemoselective reaction; | Synthesis using BF3*Et2O (1-19): General procedure: A β-ketoester (2 mmol), taken in a reactor vessel with BF3*Et2O (339 mg, 2.4 mmol) was mixed thoroughly for 1 min with urea derivatives (2.6 mmol). The vessel was closed immediately and was subjected to microwave irradiation at 145 °C. The compound (1-18) was further purified by column chromatography. The time of irradiation and observed yield of the compounds are listed in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: ethyl 2-cyanopropionate; N-Methylurea With sodium methylate In methanol for 18h; Reflux; Stage #2: With hydrogenchloride In water; acetonitrile for 1h; | 9.1 Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C27). Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C27). A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1- methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with terf-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]+. 1 H NMR (400 MHz, DMSO-de) δ 10.38 (br s, 1 H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With alumina In neat (no solvent) at 100℃; for 0.15h; Microwave irradiation; Green chemistry; | 2.4. Representative procedure for the Biginelli synthesis of derivatives 4 General procedure: A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol), the corresponding urea derivative 3(3 mmol) and the 3D printed Al2O3 structure (0.350 g) was submitted to microwave irradiation (100 °C) in coated vial. After completion of the reaction, as indicated by TLC, the mixture was cooled and the desired compound solidified. For those 1,2,3,4-tetrahydropyrimidine-5-carboxylates that not solidified, the reaction mixture was poured onto crushed ice and stirred for 5-10 min. The solid obtained was filtered under suction, washed with ice-cold water (20 mL) and then purified by column chro-matography or recrystallization from the appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.65% | With triethylamine; In N,N-dimethyl-formamide; toluene; at 100.0℃; for 3.0h; | To the reactor was added 200 mg (1 mmol) of <strong>[87080-27-1]licorice chalcone A</strong> and 56.92 mg (1.3 mmol) of 1-methylurea,50ml of toluene and 5mL of DMF as the reaction solvent, adding 0.5mL of triethylamine as a catalyst, heating set to 100 , magnetic stirringThe mixture was refluxed for 3 hours.Thin layer chromatography to trace the reaction, after the end of the reaction, under reduced pressure, column chromatography,Drying to give brown powder (113.41mg), the total yield of 48.65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: C9H17NO2S; 3-(2-bromoacetyl)benzonitrile In N,N-dimethyl-formamide at 150℃; for 0.0833333h; Inert atmosphere; Sealed tube; Stage #2: meta-hydroxybenzaldehyde; N-Methylurea In N,N-dimethyl-formamide at 200℃; for 0.166667h; Inert atmosphere; Sealed tube; | 1.13 General procedure for the batch-mode synthesis of DHPMs General procedure: Reaction mixtures of ketal-protected thioamide 3 (50 mg,0.246 mmol, 1 equiv) and a-bromoketones 4 (0.246 mmol) wereprepared in 0.6 mL of DMF and heated to 150 C for 5 min in sealedvials. After cooling, aldehydes 5 (0.295 mmol, 1.2 equiv) and ureas6 (0.295 mmol, 1.2 equiv) were added and the reaction mixturesheated to 200 C for an additional 10 min. Once cooled, the crudereaction mixtures were purified using reverse-phase preparativeHPLC, lyophilized, and tested for anti-HIV activity. When measuringthe efficiency of the process, the crude reaction mixtures wereadsorbed onto silica gel, loaded onto a pre-packed silica gel column(12 g), and chromatographed using either hexanes:EtOAc or CH2-Cl2:MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | With sodium methylate In methanol at 66℃; for 24h; | 1; 3 EXample 1-Process for producing sodium salt of 1-methyl-2,4,6 (1H, 3H, 5H) -pyrimidinetrione 1-methylurea (80.0 g, 1.08 mol) in methanol (1,600 mL),Dimethyl malonate (157.0 g, 1.19 mol) and 28% sodium methoxide in methanol (416.8 g, 2.16 mol) were added, and the mixture was heated to 66 ° C. Then, the mixture was stirred at the same temperature for 24 hours, and the precipitated crystals were cooled to room temperature and then filtered. The filtrate was washed twice with methanol (80 mL) and then dried under reduced pressure at 40 ° C. to give 1-methyl-2,4,6 (1H, 3H, 5H) -pyrimidinetrione sodium salt as a white crystalline powder. 190.9 g was obtained.86,741 ppm of methanol in the crystal (equivalent to 1/2 methanol solvate)Was included.The yield was 98.1% (calculated as a half methanol solvate of sodium salt),The purity was 98.3%.As a result of powder X-ray diffraction measurement of the obtained crystal, its diffraction pattern is shown in FIG.It was a cage. |
91.2% | With sodium hydroxide In propan-1-ol for 8h; Reflux; | 5.1 step one: Add 20.0 g of methylurea to a 500 mL four-necked flask.110g of propanol and 82g of sodium hydroxide, stirred and dissolved,Further, 41.0 g of dimethyl malonate was added, and the reaction was refluxed for 8 hours.Cool to 25 ° C, add acetic acid to adjust the pH of the reaction solution to 6.5,Add 30 mL of water, and keep the reaction solution at 25 ° C for 30 min.The reaction solution was cooled to 11 ° C, and the temperature was maintained for 25 min, and suction filtered.Drying 40.4 g of intermediate 1 in white to off-white loose powder, the yield was 91.2%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 68% 2: 41 %Spectr. 3: 29 %Spectr. | In chloroform at 20℃; for 168h; | Aminolysis of nitropyrimidinone (1) To a solution of nitropyrimidinone (1, 31 mg, 0.2 mmol) in CHCl3 (2 mL), pyrrolidine (80 μL, 1.0 mmol) was added, and the resultant mixture was stood at room temperature for 7 d. After the solvent was removed under reduced pressure, the residue was subjected to column chromatography on silica gel to afford nitroenamine (8, 19 mg, 0.136 mmol, 68%, eluted with EtOAc) as a brown solid, and a mixture of N-formylpyrrolidine (9) and N-methylurea (10) (eluted with MeOH, the yields were determined by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.3% | With sodium ethanolate; In ethanol; at 79℃; for 0.5h; | 1-methylurea (10.0 g, 135 mmol) in ethanol (100 mL),Diethyl malonate (23.8 g, 149 mmol) and 20% sodium ethoxide in ethanol (50.5 g, 149 mmol) were added and the mixture was heated to 79 C. and then stirred for 30 minutes. During the reaction, a gel-like solid was deposited and the stirring property was significantly lowered. Then, it cooled to room temperature and adjusted to pH 3.5 by adding a 6N hydrochloric acid aqueous solution. After adjusting the pH, the mixture was cooled to 2 C., stirred for 1 hour and then filtered. The filtered product was washed twice with ethanol (10 mL) and dried under reduced pressure at 40 C. to give 1-methyl-2,4,6 (1H, 3H, 5H) -pyrimidinetrione as a yellow crystalline powder (6.0 g). Obtained.The yield was 31.3% and the purity was 96.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | With hydrogenchloride In ethanol at 65℃; for 3h; | 4.2. General procedure for the synthesis of tetrahydropyrimidine-5- carboxylates ( 4a-h ) General procedure: To a mixture of the appropriate benzaldehyde (15.00 mmol), (m)ethyl 4-chloroacetoacetate (15.00 mmol) and urea or N- methylurea (45.00 mmol) in 10.0 mL ethanol was added 7 drops of concentrated HCl. The mixture was heated at 65 °C for 3 h. The resulting mixture was cooled to room temperature and fur- ther cooled in crushed ice overnight. The precipitate formed was filtered and recrystallized from hot ethanol to give the pure prod- ucts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.2% | With hydrogenchloride In ethanol at 65℃; for 3h; | 4.2. General procedure for the synthesis of tetrahydropyrimidine-5- carboxylates ( 4a-h ) General procedure: To a mixture of the appropriate benzaldehyde (15.00 mmol), (m)ethyl 4-chloroacetoacetate (15.00 mmol) and urea or N- methylurea (45.00 mmol) in 10.0 mL ethanol was added 7 drops of concentrated HCl. The mixture was heated at 65 °C for 3 h. The resulting mixture was cooled to room temperature and fur- ther cooled in crushed ice overnight. The precipitate formed was filtered and recrystallized from hot ethanol to give the pure prod- ucts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With hydrogenchloride In ethanol at 65℃; for 3h; | 4.2. General procedure for the synthesis of tetrahydropyrimidine-5- carboxylates ( 4a-h ) General procedure: To a mixture of the appropriate benzaldehyde (15.00 mmol), (m)ethyl 4-chloroacetoacetate (15.00 mmol) and urea or N- methylurea (45.00 mmol) in 10.0 mL ethanol was added 7 drops of concentrated HCl. The mixture was heated at 65 °C for 3 h. The resulting mixture was cooled to room temperature and fur- ther cooled in crushed ice overnight. The precipitate formed was filtered and recrystallized from hot ethanol to give the pure prod- ucts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | With hydrogenchloride In ethanol at 65℃; for 3h; | 4.2. General procedure for the synthesis of tetrahydropyrimidine-5- carboxylates ( 4a-h ) General procedure: To a mixture of the appropriate benzaldehyde (15.00 mmol), (m)ethyl 4-chloroacetoacetate (15.00 mmol) and urea or N- methylurea (45.00 mmol) in 10.0 mL ethanol was added 7 drops of concentrated HCl. The mixture was heated at 65 °C for 3 h. The resulting mixture was cooled to room temperature and fur- ther cooled in crushed ice overnight. The precipitate formed was filtered and recrystallized from hot ethanol to give the pure prod- ucts. |
Tags: 598-50-5 synthesis path| 598-50-5 SDS| 598-50-5 COA| 598-50-5 purity| 598-50-5 application| 598-50-5 NMR| 598-50-5 COA| 598-50-5 structure
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P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
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 |
Sorry,this product has been discontinued.
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