Process for the preparation of 5-ethyl-5-isopentylbarbituric acid by acidification crystallization of sodium 5-ethyl-5-isopentylbarbiturate

Abstract

The present application belongs to the technical field of heterocyclic compounds, and particularly relates to a method for preparing 5-ethyl-5-isopentyl malonyl urea by acidifying and crystallizing 5-ethyl-5-isopentyl barbituric acid sodium. Cycloalkane and alicyclic ketone mixed solvents are added to 5-ethyl-5-isopentyl barbituric acid sodium filtrate, hydrochloric acid is added dropwise for acidification and crystallization, centrifugation, ethyl acetate elution, and drying, so as to obtain 5-ethyl-5-isopentyl malonyl urea. The present application adds cycloalkane and alicyclic ketone mixed solvents to 5-ethyl-5-isopentyl barbituric acid sodium filtrate, and controls the pH value of the system to 2.2-2.8 by using hydrochloric acid for acidification and crystallization, so that the crystallization effect is greatly improved. The present application creatively improves the existing acidification and crystallization system, adds cycloalkane and alicyclic ketone to the ethanol aqueous solution, reduces the polarity of the system, controls the pH value of the system, and successfully reduces the twice crystallization process in the prior art to once.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of heterocyclic compounds, and particularly relates to a method for preparing 5-ethyl-5-isopentyl malonyl urea by acidifying and crystallizing 5-ethyl-5-isopentyl barbituric acid sodium. BACKGROUND

[0002] 5-ethyl-5-isopentyl malonyl urea is a hypnotic drug. The method for preparing 5-ethyl-5-isopentyl malonyl urea in the prior art has the defects of complicated operation and low yield.

[0003] Chinese patent CN111606862A discloses a preparation and purification method for preparing 5-ethyl-5-isopentyl malonyl urea. In a methanol solution of sodium methoxide, an appropriate amount of ethyl acetate is added to eliminate free base therein by heating to reflux, then urea and alpha-ethyl-alpha-isopentyl malonic acid diethyl ester are added to react, to obtain a 5-ethyl-5-isopentyl barbituric acid sodium reaction solution. The reaction solution is concentrated, dissolved in water, decolorized, filtered, and the filtrate is acidified to crystallize, centrifuged to obtain wet crude 5-ethyl-5-isopentyl malonyl urea. The wet crude product is recrystallized to obtain fine 5-ethyl-5-isopentyl malonyl urea. The method has the advantages of short reaction time, less waste, good product quality, high yield, effectively reduced impurity content, improved quality of the target product, low production cost, and a yield of about 90%.

[0004] Chinese patent CN101318936A discloses a new process for preparing 5-ethyl-5-isopentyl malonyl urea compound. Alpha-ethyl-alpha-isopentyl malonic acid diethyl ester reacts with urea in the presence of an alcohol solution of sodium alcoholate. The entire reaction is completed in a concentration process. After the concentration is completed, water or mother liquor is added to dissolve the product, and the product is acidified to obtain a crude product. The crude product is recrystallized in an ethanol aqueous solution to prepare 5-ethyl-5-isopentyl malonyl urea compound. The process has the advantages of stability, easy control of reaction conditions, short reaction time, simple operation, high product yield, and suitability for industrial production.

[0005] In the post-treatment stage after the preparation of 5-ethyl-5-isopentyl barbituric acid sodium reaction solution in the above patents, water needs to be added for dissolution, decolorization, pressure filtration, and the filtrate needs to be acidified to crystallize, centrifuged, and recrystallized to obtain fine 5-ethyl-5-isopentyl malonyl urea. Due to the existence of the two steps of acidification crystallization and recrystallization, the yield of 5-ethyl-5-isopentyl malonyl urea is low. The above patents still do not solve the defects of complicated operation and low yield in the method for preparing 5-ethyl-5-isopentyl malonyl urea. SUMMARY

[0006] The application aims to provide a method for preparing 5-ethyl-5-isopentyl malonyl urea by acidifying and crystallizing 5-ethyl-5-isopentyl barbituric acid sodium, which has the characteristics of simple process and high yield.

[0007] The technical scheme adopted by the present application to solve its technical problems is:

[0008] The method for preparing 5-ethyl-5-isopentyl malonyl urea by acidifying and crystallizing 5-ethyl-5-isopentyl barbituric acid sodium according to the present application comprises the following steps: adding a cycloalkane and a cycloalkanone mixed solvent to the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, and adding hydrochloric acid dropwise to perform acidification and crystallization; centrifuging, eluting with ethyl acetate, and drying to obtain 5-ethyl-5-isopentyl malonyl urea.

[0009] Among them:

[0010] The cycloalkane is cyclohexane, 1,2-dimethylcyclohexane or 1,3-dimethylcyclohexane.

[0011] The cycloalkanone is cyclohexanone, 2-methylcyclohexanone, 3-methylcyclohexanone or 4-methylcyclohexanone.

[0012] The mass ratio of the cycloalkane to the cycloalkanone is 1.5-2:1.

[0013] The acidification and crystallization is performed by controlling the pH value of the system to be 2.2-2.8.

[0014] The acidification and crystallization temperature is 5-10℃, and the acidification and crystallization time is 20-30min.

[0015] The elution with ethyl acetate is performed 2-3 times.

[0016] The drying temperature is 30-50℃, and the drying time is 2-3h.

[0017] The preparation of the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium comprises the following steps: reacting urea and diethyl 5-ethyl-5-isopentyl malonate in a sodium methoxide methanol solution to obtain a 5-ethyl-5-isopentyl barbituric acid sodium reaction solution, adding an ethanol aqueous solution after evaporating under reduced pressure, decolorizing with activated carbon, and filtering to obtain the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium.

[0018] The mass of the cycloalkane and the cycloalkanone mixed solvent is 5-10% of the mass of the ethanol aqueous solution.

[0019] The concentration of the ethanol aqueous solution is 10-20wt.%, and the amount of the ethanol aqueous solution is 2-2.5 times of the amount of the sodium methoxide methanol solution.

[0020] If the amount of the cycloalkane and the cycloalkanone mixed solvent is higher than 10% of the mass of the ethanol aqueous solution, the precipitation effect is reduced. If the amount of the cycloalkane and the cycloalkanone mixed solvent is lower than 5% of the mass of the ethanol aqueous solution, the precipitation effect is also not good. In addition, if the concentration of the ethanol aqueous solution is higher than 20wt.%, the precipitation effect is reduced. If the concentration of the ethanol aqueous solution is lower than 10wt.%, the precipitation effect is also not good.

[0021] Specifically, ethyl acetate is added to a methanol solution of sodium methoxide, and the reaction is refluxed at 60-70℃ for 20-25min to eliminate free base, and then urea and diethyl ethylisopentylmalonate are added to prepare a sodium 5-ethyl-5-isopentylbarbiturate reaction solution, which is evaporated under reduced pressure, and then an ethanol aqueous solution is added, activated carbon is used for decolorization, and then filtration is performed to obtain a sodium 5-ethyl-5-isopentylbarbiturate filtrate. In the process, the content of sodium methoxide in the methanol solution of sodium methoxide is 30-35wt.%; the molar ratio of diethyl ethylisopentylmalonate, urea and sodium methoxide is 1:1.1-1.2:1.1-1.5.

[0022] The beneficial effects of the present application are as follows:

[0023] The present application uses urea and diethyl ethylisopentylmalonate to react in a methanol solution of sodium methoxide to prepare a sodium 5-ethyl-5-isopentylbarbiturate reaction solution, which is evaporated under reduced pressure, and then an ethanol aqueous solution is added, activated carbon is used for decolorization, and then filtration is performed to obtain a sodium 5-ethyl-5-isopentylbarbiturate filtrate. Then, a cycloalkane and alicyclic ketone mixed solvent is added to the sodium 5-ethyl-5-isopentylbarbiturate filtrate, hydrochloric acid is added dropwise for acidification and crystallization, centrifugation, ethyl acetate elution and drying are performed to prepare 5-ethyl-5-isopentylmalonylurea.

[0024] In the present application, a cycloalkane and alicyclic ketone mixed solvent is added to the sodium 5-ethyl-5-isopentylbarbiturate filtrate, and at the same time, hydrochloric acid is used to control the pH value of the system to 2.2-2.8 for acidification and crystallization, so that the crystallization effect is greatly improved. The present application creatively improves the existing acidification and crystallization system. By adding a cycloalkane and alicyclic ketone to the ethanol aqueous solution, the polarity of the system is reduced, and by controlling the pH value of the system, the purpose of high yield is achieved. In particular, the cycloalkane and alicyclic ketone are both cyclic skeleton solvents, which are dissolved in the ethanol aqueous solution to form a blending crystallization system with large and small polarity. The cycloalkane and alicyclic ketone act as a crystallization guide agent, so that 5-ethyl-5-isopentylmalonylurea is more easily crystallized.

[0025] By changing the crystallization conditions, the present application can achieve good crystallization effect. After the acidification and crystallization is completed, centrifugation, ethyl acetate elution and drying are performed to obtain the product, without the need for recrystallization. The present application avoids the recrystallization step, shortens the post-treatment process route, simplifies the process, and has higher yield, with a yield of 96.2-97.2%. DETAILED DESCRIPTION

[0026] The present application is further described below in combination with examples.

[0027] Example 1

[0028] To 198.09 g of a methanolic sodium methoxide solution (30 wt.% sodium methoxide in methanol), 25 g of ethyl acetate was added, and the reaction was refluxed at 60°C for 25 min to eliminate the free base. Then, 66.07 g (1.1 mol) of urea and 258.35 g (1 mol) of diethyl ethylisopentylmalonate were added to prepare a reaction solution of sodium 5-ethyl-5-isopentylbarbiturate. After the reaction solution was evaporated under reduced pressure, 495.23 g of a 10 wt.% aqueous ethanol solution was added, and the solution was decolorized with activated carbon. After filtration, a filtrate of sodium 5-ethyl-5-isopentylbarbiturate was obtained.

[0029] To the above filtrate of sodium 5-ethyl-5-isopentylbarbiturate, 24.77 g of a mixed solvent of cyclohexane and cyclohexanone (mass ratio of cyclohexane to cyclohexanone = 1.5:1) was added, and the pH of the system was controlled to 2.2 by dropwise addition of hydrochloric acid to perform acidification. Crystallization was performed at 5°C for 30 min, and the product was separated by centrifugation and eluted twice with ethyl acetate. The product was dried at 30°C for 3 h to obtain 219.67 g of 5-ethyl-5-isopentylmalonylurea at a yield of 97.13% and a purity of 99.93%.

[0030] Example 2

[0031] To 200.65 g of a methanolic sodium methoxide solution (35 wt.% sodium methoxide in methanol), 30 g of ethyl acetate was added, and the reaction was refluxed at 65°C for 23 min to eliminate the free base. Then, 69.07 g (1.15 mol) of urea and 258.35 g (1 mol) of diethyl ethylisopentylmalonate were added to prepare a reaction solution of sodium 5-ethyl-5-isopentylbarbiturate. After the reaction solution was evaporated under reduced pressure, 401.30 g of a 15 wt.% aqueous ethanol solution was added, and the solution was decolorized with activated carbon. After filtration, a filtrate of sodium 5-ethyl-5-isopentylbarbiturate was obtained.

[0032] To the above filtrate of sodium 5-ethyl-5-isopentylbarbiturate, 32.10 g of a mixed solvent of 1,2-dimethylcyclohexane and 2-methylcyclohexanone (mass ratio of 1,2-dimethylcyclohexane to 2-methylcyclohexanone = 1.8:1) was added, and the pH of the system was controlled to 2.5 by dropwise addition of hydrochloric acid to perform acidification. Crystallization was performed at 8°C for 25 min, and the product was separated by centrifugation and eluted three times with ethyl acetate. The product was dried at 40°C for 2.5 h to obtain 217.64 g of 5-ethyl-5-isopentylmalonylurea at a yield of 96.25% and a purity of 99.95%.

[0033] Example 3

[0034] To 245.55 g of a methanolic sodium methoxide solution (33 wt.% sodium methoxide in methanol) was added 40 g of ethyl acetate, and the reaction was refluxed at 70°C for 20 min to eliminate the free base. Then, 72.07 g (1.2 mol) of urea and 258.35 g (1 mol) of diethyl ethylisopentylmalonate were added, and the reaction was carried out to obtain a sodium 5-ethyl-5-isopentylbarbiturate solution. After the solution was evaporated under reduced pressure, 564.77 g of a 20 wt.% aqueous ethanol solution was added, and the solution was decolorized with activated carbon and filtered to obtain a sodium 5-ethyl-5-isopentylbarbiturate solution.

[0035] To the sodium 5-ethyl-5-isopentylbarbiturate solution, 56.48 g of a mixed solvent of 1,3-dimethylcyclohexane and 3-methylcyclohexanone (mass ratio of 1,3-dimethylcyclohexane to 3-methylcyclohexanone = 2:1) was added, and the pH of the system was controlled to 2.8 by dropwise addition of hydrochloric acid to acidify the system. The reaction was carried out at 10°C for 20 min to obtain 5-ethyl-5-isopentylbarbituric acid. The product was centrifuged, washed twice with ethyl acetate, and dried at 50°C for 2 h to obtain 219.19 g of 5-ethyl-5-isopentylbarbituric acid at a yield of 96.95% and a purity of 99.96%.

[0036] Comparative Example 1

[0037] To the sodium 5-ethyl-5-isopentylbarbiturate solution, 24.77 g of cyclohexane was added, and the remaining steps were the same as in Example 1. This resulted in 5-ethyl-5-isopentylbarbituric acid at a yield of 90.43% and a purity of 99.01%.

[0038] Comparative Example 2

[0039] To the sodium 5-ethyl-5-isopentylbarbiturate solution, 24.77 g of cyclohexanone was added, and the remaining steps were the same as in Example 1. This resulted in 5-ethyl-5-isopentylbarbituric acid at a yield of 90.12% and a purity of 99.06%.

[0040] Comparative Example 3

[0041] The pH of the system was controlled to 2.1 by dropwise addition of hydrochloric acid to acidify the system, and the remaining steps were the same as in Example 1. This resulted in 5-ethyl-5-isopentylbarbituric acid at a yield of 90.76% and a purity of 99.14%.

[0042] Comparative Example 4

[0043] The pH of the system was controlled to 2.9 by dropwise addition of hydrochloric acid to acidify the system, and the remaining steps were the same as in Example 1. This resulted in 5-ethyl-5-isopentylbarbituric acid at a yield of 91.05% and a purity of 99.10%.

[0044] Comparative Example 5

[0045] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 19.81 g of cyclohexane and cyclohexanone mixed solvent was added, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 211.26 g was prepared with a yield of 92.76% and a purity of 99.23%.

[0046] Comparative Example 6

[0047] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 54.48 g of cyclohexane and cyclohexanone mixed solvent was added, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 210.01 g was prepared with a yield of 92.31% and a purity of 99.34%.

[0048] Comparative Example 7

[0049] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 9 wt.% of ethanol aqueous solution 495.23 g was added, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 211.34 g was prepared with a yield of 92.84% and a purity of 99.28%.

[0050] Comparative Example 8

[0051] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 21 wt.% of ethanol aqueous solution 495.23 g was added, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 211.68 g was prepared with a yield of 93.01% and a purity of 99.30%.

[0052] Comparative Example 9

[0053] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 24.77 g of cyclohexane and cyclohexanone mixed solvent was added, wherein the mass ratio of cyclohexane to cyclohexanone was 1.4:1, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 212.39 g was prepared with a yield of 93.81% and a purity of 99.82%.

[0054] Comparative Example 10

[0055] To the filtrate of 5-ethyl-5-isopentyl barbituric acid sodium, 24.77 g of cyclohexane and cyclohexanone mixed solvent was added, wherein the mass ratio of cyclohexane to cyclohexanone was 2.1:1, and the remaining steps were the same as in Example 1. 5-ethyl-5-isopentyl malonyl urea 211.98 g was prepared with a yield of 93.66% and a purity of 99.85%.

[0056] As can be seen from Example 1 and Comparative Examples 1-4, when cycloalkane solvent is used alone, or alicyclic ketone solvent is used alone, or the pH value of the system is not within the range of 2.2-2.8, the crystallization effect of 5-ethyl-5-isopentyl malonyl urea is poor, and the yield of 5-ethyl-5-isopentyl malonyl urea is significantly reduced.

[0057] From Example 1 and Comparative Examples 5-8, it can be seen that when the amount of the naphthene and alicyclic ketone mixed solvent is higher than 10% by mass of the aqueous ethanol solution, the precipitation effect is reduced; when the amount of the naphthene and alicyclic ketone mixed solvent is lower than 5% by mass of the aqueous ethanol solution, a good precipitation effect cannot be achieved. In addition, when the concentration of the aqueous ethanol solution is higher than 20 wt.%, the precipitation effect is reduced; when the concentration of the aqueous ethanol solution is lower than 10 wt.%, a good precipitation effect cannot be achieved.

[0058] From Example 1 and Comparative Examples 9-10, it can be seen that when the mass ratio of the naphthene and alicyclic ketone is not within the range of 1.5-2:1, the precipitation effect cannot meet the requirements.

Claims

1. A method for preparing 5-ethyl-5-isopentylmalonylurea by acidification and crystallization of sodium 5-ethyl-5-isopentylbarbiturate, characterized in that: A mixed solvent of cycloalkanes and alicyclic ketones was added to the filtrate of sodium 5-ethyl-5-isopentylbarbiturate, and hydrochloric acid was added dropwise for acidification and crystallization. After centrifugation, ethyl acetate was washed, and the solution was dried to obtain 5-ethyl-5-isopentylmalonylurea. The cycloalkanes were cyclohexane, 1,2-dimethylcyclohexane, or 1,3-dimethylcyclohexane; the alicyclic ketones were cyclohexanone, 2-methylcyclohexanone, 3-methylcyclohexanone, or 4-methylcyclohexanone; the mass ratio of cycloalkanes to alicyclic ketones was 1.5-2:1; hydrochloric acid was added dropwise to control the pH of the system to 2.2-2.8 for acidification and crystallization; the mass of the mixed solvent of cycloalkanes and alicyclic ketones was 5-10% of the mass of the aqueous ethanol solution.

2. The method for preparing 5-ethyl-5-isopentylmalonylurea by acidification and crystallization of sodium 5-ethyl-5-isopentylbarbiturate according to claim 1, characterized in that: The acidification crystallization temperature is 5-10℃, and the acidification crystallization time is 20-30min.

3. The method for preparing 5-ethyl-5-isopentylmalonylurea by acidification and crystallization of sodium 5-ethyl-5-isopentylbarbiturate according to claim 1, characterized in that: Sodium 5-ethyl-5-isopentylbarbiturate reaction solution was prepared by reacting urea and diethyl ethyl isopentyl malonate in a methanol solution of sodium methoxide. After evaporation under reduced pressure, an aqueous ethanol solution was added, activated carbon was used for decolorization, and the solution was filtered to obtain sodium 5-ethyl-5-isopentylbarbiturate filtrate.

4. The method for preparing 5-ethyl-5-isopentylmalonylurea by acidification and crystallization of sodium 5-ethyl-5-isopentylbarbiturate according to claim 3, characterized in that: The concentration of the ethanol-water solution is 10-20 wt.%, and the amount of ethanol-water solution used is 2-2.5 times that of the methanol solution of sodium methoxide.

5. The method for preparing 5-ethyl-5-isopentylmalonylurea by acidification and crystallization of sodium 5-ethyl-5-isopentylbarbiturate according to claim 1, characterized in that: The drying temperature is 30-50℃, and the drying time is 2-3 hours.