* 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.
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[ 1462-12-0 ]
[ 594-19-4 ]
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[ 133-13-1 ]
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[5] Patent: US2376837, 1942, ,
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42
[ 50-01-1 ]
[ 133-13-1 ]
[ 30201-72-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With sodium In ethanol at 20℃; for 4 h; Inert atmosphere Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200–300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
88%
With sodium In ethanolInert atmosphere
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200–300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 °C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
E Method E--Preparation of 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone
Method E--Preparation of 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1 H-NMR (d6-DMSO) δ1.05(3H,t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m).
31.89 g (51%)
With sodium methylate In methanol; water
E Method E--Preparation of 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone
Method E--Preparation of 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1 H-NMR (d6-DMSO) δ 1.05(3H,t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m).
e Compound Embodiments
A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1 H-NMR (d6 -DMSO)δ1.05(3H, t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m). Method F--General Description Method F is similar to Method D except that a 3-alkoxyacrylate ester is used instead of a beta-keto ester: R2 C(=NH)NH2 +RO(R6)C=C(R5)C(=O)OR→FIG. I with R3 =H
Stage #1: ethyl diethyl malonate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: 1-bromo-4-(2-iodoethyl)benzene In N,N-dimethyl-formamide at 0 - 40℃; for 2.83333h;
Stage #3: With hydrogenchloride; potassium hydroxide; water more than 3 stages;
30 4-(4-bromophenyl)-2-ethoxycarbonyl-2-ethylbutyric acid
To a solution of diethyl ethylmalonate (42.6 g) in N,N-dimethylformamide (350 mL) was added sodium hydride (60%, 9.96 g) in two portions under ice-cooling. After stirring for 30 min under ice-cooling, a solution of 2-(4-bromophenyl)ethyl iodide (77.4 g) obtained in the same manner as in Reference Example 2 in N,N-dimethylformamide (50 mL) was added, and the mixture was stirred for 20 min under ice-cooling and further stirred at 40°C for 2.5 hr. The reaction mixture was poured into water. After extraction with ethyl acetate, the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in ethanol (300 mL) was added potassium hydroxide (85%, 15.2 g), and the mixture was stirred at 65°C for 10 hr. The solvent was evaporated under reduced pressure, water was added, and the aqueous layer was washed with ether. The aqueous layer was acidified with hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (71.0 g) as a yellow oil. 1H-NMR(CDCl3)δ(ppm):0.89(3H, t, J=7.5Hz), 1.32(3H, t, J=7.2Hz), 1.90-2.00(1H, m), 2.02-2.18(2H, m), 2.22-2.31(1H, m), 2.37-2.44(1H, m), 2.52-2.60(1H, m), 4.18-4.31(2H, m), 7.03(2H, d, J=8.4Hz), 7.39(2H, d, J=8.4Hz).
Stage #1: ethyl diethyl malonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1.5h; Inert atmosphere;
Stage #2: 1-bromo-6-benzyloxyhexane In N,N-dimethyl-formamide; mineral oil at 20℃; for 3.5h; Inert atmosphere;
91%
Stage #1: ethyl diethyl malonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1.5h; Inert atmosphere;
Stage #2: 1-bromo-6-benzyloxyhexane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3.5h; Inert atmosphere;
1 Synthesis 1Diethyl 2-(6-(benzyloxy)hexyl)-2-ethylmalonate
Synthesis 1Diethyl 2-(6-(benzyloxy)hexyl)-2-ethylmalonate (1 )To a solution of diethyl 2-ethylmalonate (99%, 1 .9 ml_, 10.0 mmol, 1 eq) in dry DMF (15 ml_), sodium hydride (60% dispersion in mineral oil, 490 mg, 12.3 mmol, 1 .2 eq) was added at 0°C. The suspension was stirred under nitrogen atmosphere at 0°C for 1.5 hours. Then ((6-bromohexyloxy)methyl)benzene (97%, 2.9 ml_, 12.5 mmol, 1.2 eq) was added. The solution was stirred at room temperature under nitrogen atmosphere for 3.5 hours. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with small portions of diethyl ether. The collected organic phases were dried over anhydrous Na2S04, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (CH2CI2) to give 3.444 g of the title compound (91 %) as a yellow oil.Rf = 0.34 (CH2CI2). 1 H NMR (400 MHz, CDCI3) δ: 7.30 - 7.18 (m, 5H), 4.42 (s, 2H), 4.10 (q, J = 7.1 Hz, 4H), 3.38 (t, J = 6.6 Hz, 2H), 1.89 - 1.74 (m, 4H), 1.59 - 1.48 (m, 2H), 1.38 - 1 .25 (m, 4H), 1 .20 (t, J = 7.1 Hz, 6H), 1 .16 - 1 .06 (m, 2H), 0.74 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCI3) δ: 172.2, 139.0, 128.7, 127.9, 127.8, 73.2, 70.7, 61.2, 58.2, 31.9, 30.1 , 30.0, 26.3, 25.5, 24.2, 14.5, 8.8. ESI MS m/z: calcd. for C22H3505 [/W+H]+ 379.2, [M+UaY C22H3405 Na 401.2, found: 379.2, 401 .2.
Synthesis 27Diethyl 2-((6-chloropyridin-3-yl)methyl)-2-ethylmalonate (27)To a solution of diethyl 2-ethylmalonate (99%, 880 muIota_, 4.6 mmol, 1.2 eq) in dry DMF (10 ml_), sodium hydride (60% dispersion in mineral oil, 222 mg, 5.5 mmol, 1 .4 eq) was added at 0C. The suspension was stirred under nitrogen atmosphere at 0C for 1 hour. Then 26 (800 mg, 3.9 mmol, 1 eq) was added. The solution was stirred at room temperature under nitrogen atmosphere for 4.5 hours. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with small portions of diethyl ether. The collected organic phases were dried over anhydrous Na2S04, filtered and the solvent was removed in vacuo. The residue was purified by flashchromatography on silica gel (gradient: from n-Hex/EtOAc 9:1 to n-Hex/EtOAc 8.5:1 .5) to give 1.087 g of 27 (89%) as a pale yellow oil.Rf = 0.25 (n-Hex/EtOAc 9:1 ). 1 H NMR (400 MHz, CDCI3) delta 8.1 1 (d, J = 2.1 Hz, 1 H), 7.40 (dd, J = 8.2, 2.5 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1 H), 4.22 - 4.06 (m, 4H), 3.15 (s, 2H), 1 .82 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.1 Hz, 6H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCI3) 5 170.9, 151 .1 , 150.4, 140.4, 131 .4, 124.0, 61.7, 59.4, 34.6, 25.8, 14.3, 8.8; ESI MS m/z: calcd. for Ci5H2iCIN04 [/W+H]+ 314.1 , Ci5H20CINNaO4 [/W+Na]+ 336.1 , found: 314.1 , 316.1 , 336.1 , 338.1 .
Synthesis 35Diethyl 2-(6-(te/t-butyldimethylsilyloxy)hexyl)-2-ethylmalonate (35)To a solution of diethyl 2-ethylmalonate (99%, 1 .9 mL, 10.0 mmol, 1 eq) in dry DMF (20 mL), sodium hydride (60% dispersion in mineral oil, 515 mg, 12.9 mmol, 1 .2 eq) was added at 0C. The suspension was stirred under nitrogen atmosphere at 0C for 1 hour. Then (6-bromohexyloxy)(te/?-butyl)dimethylsilane (99%, 3.4 mL, 12.0 mmol, 1 .3 eq) was added. The solution was stirred at room temperature under nitrogen atmosphere for one night. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with small portions of diethyl ether. The collected organic phases were dried over anhydrous Na2S04, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (gradient: from n-Hex/EtOAc 9.5:0.5 to n-Hex/EtOAc 9:1 ) to give 3.024 g of 35 (75%) as a pale yellow oil. Rf = 0.29 (n-Hex/EtOAc 9.5:0.5). 1H NMR (400 MHz, CDCI3) 5 4.16 (q, J = 7.1 Hz, 4H), 3.57 (t, J = 6.6 Hz, 2H), 1.91 (q, J = 7.6 Hz, 2H), 1 .87 - 1 .81 (m, 2H), 1 .52 - 1.44 (m, 2H), 1.34 - 1 .27 (m, 4H), 1.23 (t, J = 7.1 Hz, 6H), 1.19 - 1 .09 (m, 2H), 0.88 (s, 9H), 0.80 (t, J = 7.6 Hz, 3H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCI3) δ 172.0, 63.3, 61.0, 58.0, 32.9, 31 .6, 29.8, 26.1 , 25.7, 25.3, 24.0, 18.5, 14.2, 8.5, -5.2; ES/ MS m/z: calcd. for C2iH4305Si [/W+H]+ 403.3, C2iH42Na05Si [/W+Na]+ 425.3, found: 403.3, 425.3.
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200-300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
88%
With sodium; In ethanol;Inert atmosphere;
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200-300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
80%
With sodium carbonate; In water; at 60.0℃; for 0.5h;Sonication;
General procedure: Into the round-bottom reaction vessels having an appropriate thickness for the sonochemicalreactions; guanidine hydrochloride (0.052 mol) and corresponding beta-diketone compound (0.052 mol) were placed in water (15 mL) and Na2CO3 (0.052 mol). The reaction vessel has been put in a hot water bath at 60C, and the flask content was exposed to ultrasonic waves for 30 min. The solid product obtained at the end of the experiment was treated with a small quantity of water and filtered through the Nuche funnel.
Stage #1: ethyl diethyl malonate With sodium ethanolate In ethanol; ethyl acetate at 125℃; for 2h;
Stage #2: pentan-2-yl methanesulfonate In ethyl acetate; toluene at 40 - 135℃; for 5h;
1.1
A solution containing 453.3g of sodium ethoxide in ethanol solution (content 15%) and an appropriate amount of ethyl acetate were added to the reaction flask and stirred at temperature 60-70 deg.] C, for 30 minutes.Added 188.2g ethyl malonate, after the addition was completed, ethanol was distilled off during the reaction heated to an internal temperature of around 125 , stop heating, then evaporated under reduced pressure until no alcohol effluent, the internal temperature was 105 , stop Save pressure, holding the bottle (kettle) vacuum, toluene was added 564.6g, 182.2g dropwise addition of methanesulfonic acid (2-pentyl), was added dropwise while residual ethanol fractionation steamed, the maximum temperature does not exceed 78 , the internal temperature was gradually increased, not exceeding 110 , about 3h addition was completed, after the addition was complete, the reaction held at reflux for 2h, then steamed until no toluene until the internal temperature is about 135 , stop heating, cooling to 40 , 200ml of water was added with 50% sulfuric acid aqueous solution adjusted PH6.5-7.0, standing layered reservoir for the compound () crude, then by vacuum distillation was 236.5g compound ().
diethyl 2-((4-bromophenyl)thio)-2-ethylmalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 6h;
12 Example 12 Synthesis of diethyl 2-((4-bromophenyl)thio)-2-ethylmalonate
Take 15mL pressure resistant reaction tube,130 mg of cesium carbonate, 75 mg of diethyl 2-ethylmalonate, 151 mg of 4-bromothiophenol and 2 mL of N,N-dimethylformamide were added, and the mixture was reacted with an open atmosphere and stirred at room temperature for 6 h.After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and 10 mL of brine was added to wash, and the organic phase was separated.The aqueous phase was extracted 3 times with ethyl acetate.The organic phases are combined and separated by column chromatography.Diethyl 2-((4-bromophenyl)thio)-2-ethylmalonatePure product 139mg, yield 94%.
89%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure: To a stirred solution of 2-methyl-2-thiopseudourea sulfate (8.35 g, 60 mmol) in ethanol 120 mL was added 1,3-dicarbonyl derivatives (50 mmol) and sodium hydroxide (2.4 g, 60mmol) at room temperature, and then heated at refluxed for 4 h. After this time, the reaction mixture was cooled to room temperature, the residue was precipitated and filtered, yielding compounds 3 as white solid. The solid was dried in vacuum and used directly to react with POCl3 (40 mL) in the presence of NEt3 (5.05 g, 50 mmol) heated at reflux for 3 h. The solvent was evaporated under reduced pressure, the residue was dissolved in 100 mL ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure. The desired products 4-chloro-2-(methylthio)pyrimidines 4a-4f were obtained by recrystallization from the mixed solvent of EtOAc-petroleum ether. Yields, melting points and spectroscopic data for selected 2-(methylsulfonyl)pyrimidines are listed as follows.
With sodium ethanolate In ethanol; ethyl acetate at 75 - 125℃; for 5h;
1.B; 2.B; 3.B; 4.B Step B:
In a 1000 ml four-neck reaction flask equipped with a stirrer, a thermometer and a reflux condenser, 362 g of a sodium ethanolate solution containing 18.99% (W / W) of ethanol was added.And 5 g of ethyl acetate, and evaporate the ethanol with stirring to a concentration of sodium ethoxide to reach 40% (W / W),Reduce the temperature to 100 ° C and add 188.2g of diethyl ethyl malonate. Evaporate the ethanol during the temperature rise reaction until the internal temperature reaches about 125 ° C and stop heating.The alcohol was distilled under reduced pressure to an internal temperature of 75 ° C.Start to dropwise add 176.5 g of the 2-bromopentane and 2-pentanol mixture prepared in Step A, and fractionally distill off the alcohol during the dropwise addition,The highest temperature does not exceed 76 ° C.With the continuous separation of alcohol, the internal temperature gradually rises,The highest temperature does not exceed 118 , and it takes about 3h to finish.After the addition was completed, the reaction was refluxed for 2 h.Then steam the alcohol to an internal temperature of 135 ° C and lower the temperature to below 40 ° C.Add 200ml water to dissolve,Adjust pH 6.7 7.0 with 50% sulfuric acid, leave it to separate layers,Fractionation of the organic phase under reduced pressureEthyl- (1-methylbutyl) malonic acidDiethyl ester217.3g, content 98.73%.
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