Green production process of uracil
阅读说明：本技术 一种尿嘧啶绿色生产工艺 (Green production process of uracil ) 是由 吴政杰 顾海宁 欧阳凯 于 2021-01-29 设计创作，主要内容包括：本发明涉及化学领域,具体提供了一种尿嘧啶的绿色生产工艺,本发明将3-烷氧基(氨基)丙烯酸酯(酰胺)和尿素碱金属盐环合,再经酸化后转化为尿嘧啶,收率达到95％以上。(The invention relates to the field of chemistry, and particularly provides a green production process of uracil, wherein 3-alkoxy (amino) acrylate (amide) and urea alkali metal salt are cyclized and then are converted into uracil after acidification, and the yield is over 95%.)
1. A process for preparing uracil from compound of formula II and compound of formula I through cyclization in the presence of organic solvent,
wherein:
m is alkali metal such as Na, Mg, K, Ca and the like, preferably Na;
R1and R2Each independently is C1-C4Alkoxy, amino, dimethylamino.
2. The process according to claim 1, wherein R is1Or R2Each independently selected from OC (CH)3)3,OCH2CH(CH3)2,OCHCH3CH2CH3,OCH2CH2CH2CH3,OCH2CH2CH3,OCH(CH3)2,OCH2CH3,OCH3,NH2,N(CH3)2。
3. The process according to claim 2, wherein R is1Or R2Independently of one another, are amino, methoxy and ethoxy.
4. The production process according to claim 1, wherein a catalyst is present in the reaction system.
5. The production process according to claim 1, wherein the catalyst is a phase transfer catalyst and is subjected to an acidification treatment after the completion of the reaction,
wherein:
M、R1、R2is as defined in any one of claims 1 to 3.
6. The production process according to claim 5, wherein the phase transfer catalyst is selected from one or more of Tween 60, Tween 80, polydimethylsiloxane, polytrifluoropropylmethylsiloxane, polyethylene glycol siloxane, OP-3, polyoxyethylene alkylphenyl ether phosphate triethanolamine salt, polyoxyethylene lauryl ether phosphate sodium salt, preferably polyoxyethylene lauryl ether phosphate sodium salt. The amount of the phase transfer catalyst is 0.9-2%, preferably 4-7% of the compound of formula II.
7. The process according to claim 5, wherein the reaction solvent is selected from one or more of toluene, xylene, chlorobenzene, dichlorobenzene, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane, and isooctane, preferably toluene and xylene; the mass ratio of the solvent to the compound shown in the formula II is (20-5) to 1, preferably (15-10): 1; the process according to claim 5, wherein the temperature in the first stage of the reaction is 40 to 120 ℃ and the reaction is characterized by the cyclization to form an alkali metal uracil salt. The second stage is 110-140 ℃, and is characterized in that alcohol substances or ammonia substances generated by the reaction are evaporated; the molar mass ratio of the reaction compound shown in the formula I to the compound shown in the formula II is 1:1-3: 1. Preferably 1:1 to 1.5:1, more preferably 1.1: 1.
8. The process according to claim 5, wherein the acid is an organic or inorganic acid, preferably hydrochloric acid.
9. The production process according to claim 5, further comprising the steps of: wherein the compound of formula I is prepared by reacting a compound of formula 1 with a compound of formula 2:
wherein:
m is alkali metal such as Na, Mg, K, Ca and the like;
R3is H radical, NH2The base group is a group of a compound,OH group, C1-C4Alkoxy group of (a);
preferably, said M (R)3)nIs sodium hydride, potassium hydride, sodium amide, potassium amide, and C1-C4Sodium or potassium alkoxides of (a), more preferably sodium methoxide.
10. The production process according to claim 1, comprising: adding a compound shown in formula I and a compound shown in formula II into a solvent, adding a catalyst, heating to react completely, adding water, removing an upper layer, and adjusting the pH value of a lower layer by using an acid; after the preparation is finished, the compound shown in the formula III is separated out, filtered, washed and dried to obtain the uracil.
Technical Field
The invention relates to the field of chemistry, and particularly relates to a green production process of uracil.
Background
Uracil is a base specific to RNA and is one of four constituent bases constituting RNA. The compound is an important intermediate for synthesizing 5-fluorouracil serving as an antitumor drug, an antiviral drug, a drug for treating AIDS, uridine serving as a drug for treating hepatitis B and iodoglycoside, and is an important raw material for synthesizing medical intermediates such as 2-chloro-4-amino-5-nitropyrimidine, 2, 4-dichloropyrimidine, 2, 4-dibromopyrimidine, 5-hydroxymethyl uracil and the like, and the compound is wide in application and large in demand.
Current methods for synthesizing uracil have several routes. A route for synthesizing uracil from malic acid, urea and oleum is provided in patent application publication No. CN 107793366A. The method has serious pollution, complicated post-treatment and yield of about 50 percent, and does not meet the requirement of current sustainable development.
In patent application publication No. CN106674135A, a route for synthesizing uracil from charcoal, carbon dioxide, ethyl acetate and urea as raw materials under the action of alkali is provided. The reaction temperature of the route is higher than 200 ℃, wherein the reaction of charcoal and carbon dioxide is involved, and the equipment requirement is high.
In patent application publication No. CN110437160A, 3-dimethoxy-propionate is prepared from trimethyl orthoformate and acetate, and 3-dimethoxy-propionate is cyclized with urea under the action of alkali to prepare uracil. Trimethyl orthoformate in the route is expensive, a large amount of byproducts are generated in the reaction, the post-treatment is complicated, and the method is not suitable for the industrial development of uracil.
Meanwhile, in the above patents, the inevitable material caking phenomenon of the raw materials and urea in the solvent during the reaction process is ignored, so that the mass transfer and heat transfer are seriously hindered, the consumption of urea and alkali is greatly increased, and the post-treatment cost and the environmental protection cost are increased.
In addition, patent application publication No. CN106928152A discloses that 3-ethoxy-3-oxoprop-1-en-1-oic acid sodium is obtained by using ethyl acetate and ethyl formate as raw materials under the action of sodium methoxide, and thiouracil is obtained by cyclization of the intermediate and thiourea. Thiouropyrimidine is oxidized by hydrogen peroxide to prepare uracil. In the route, thiourea is used as a cyclic compound, then uracil is obtained through oxidation synthesis, the process is repeated, a large amount of sulfur-containing substances are generated in the post-treatment, and the pollution is great. And thiourea is relatively expensive compared to urea. The production cost is higher, and the environmental pollution is serious, so the route is not preferable.
Disclosure of Invention
In order to overcome the problems, the invention innovatively uses a compound with higher reaction activity and selectivity as a formula II, and the compound as a formula I is used as a raw material to be cyclized in an organic solvent to obtain the uracil.
Wherein:
m is alkali metal such as Na, Mg, K, Ca and the like, preferably Na;
R1is C1-C4Alkoxy, amino, dimethylamino;
R2is C1-C4Alkoxy, amino, dimethylamino.
Wherein R is1And R2Each independently, i.e., may be the same group or different groups at the same time.
Specific R1Or R2Selected from OC (CH)3)3,OCH2CH(CH3)2,OCHCH3CH2CH3,OCH2CH2CH2CH3,OCH2CH2CH3,OCH(CH3)2,OCH2CH3,OCH3,NH2,N(CH3)2。
Preferably, R1Or R2Independently of one another, are amino, methoxy and ethoxy.
Preferably, a catalyst is present in the reaction system.
Preferably, in order to overcome the series of problems of excessive usage of the urea alkali metal salt, reduced yield and increased post-treatment cost caused by material caking in the reaction process, the method carries out the reaction in the presence of a phase transfer catalyst, and the selection can ensure that the raw materials are uniformly dispersed in an organic solvent, effectively reduce the usage of the urea alkali metal salt and improve the yield of the uracil.
The specific technical scheme is as follows:
wherein:
m is alkali metal such as Na, Mg, K, Ca and the like, preferably Na;
R1is C1-C4Alkoxy, amino, dimethylamino;
R2is C1-C4Alkoxy, amino, dimethylamino.
Wherein R is1And R2Each independently, i.e., may be the same group or different groups at the same time.
Specific R1Or R2Selected from OC (CH)3)3,OCH2CH(CH3)2,OCHCH3CH2CH3,OCH2CH2CH2CH3,OCH2CH2CH3,OCH(CH3)2,OCH2CH3,OCH3,NH2,N(CH3)2。
Preferably, R1Or R2Independently of one another, are amino, methoxy and ethoxy.
The phase transfer catalyst is selected from one or more of Tween 60, Tween 80, polydimethylsiloxane, polytrifluoropropylmethylsiloxane, polyethylene glycol siloxane, OP-3, polyoxyethylene alkyl phenyl ether phosphate triethanolamine salt and polyoxyethylene dodecyl ether phosphate sodium salt, and is preferably polyoxyethylene dodecyl ether phosphate sodium salt. The amount of the phase transfer catalyst is 0.9-2%, preferably 4-7% of the compound of formula II.
The reaction solvent is selected from one or more of toluene, xylene, chlorobenzene, dichlorobenzene, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane and isooctane, and toluene and xylene are preferred; the mass ratio of the solvent to the compound shown in the formula II is (20-5) to 1, preferably (15-10): 1.
the first stage of the reaction temperature is 40-120 ℃, preferably 80-90 ℃, and is characterized in that the uracil alkali metal salt is generated by cyclization. The second stage is 110-140 deg.c, preferably 110 deg.c, and features the distilling off of alcohol or ammonia produced in the reaction.
The molar mass ratio of the reaction compound shown in the formula I to the compound shown in the formula II is (1-3): 1. Preferably (1-1.5):1, more preferably 1.1: 1.
The acid used in the reaction is hydrochloric acid. But is not limited to hydrochloric acid and may be other organic acid or inorganic acid.
According to the technical scheme, further, the compound of formula i, wherein is prepared by the following reaction:
wherein:
m is alkali metal such as Na, Mg, K, Ca and the like;
R3is H radical, NH2Radical, OH radical, C1-C4Alkoxy group of (2).
Preferably, said M (R)3)nIs sodium hydride, potassium hydride, sodium amide, potassium amide, and C1-C4Sodium or potassium alkoxides of (a), more preferably sodium methoxide.
Further, the reaction temperature is 40 to 135 ℃, preferably 60 to 120 ℃. More preferably 60-80 deg.c. The reaction time is 1-6h, preferably 2-4h, more preferably 4 h.
Further, the reaction solvent is xylene, toluene, dichlorobenzene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, preferably toluene or xylene.
Further, the amount of the reaction solvent is calculated in a manner of 2 to 20 times, preferably 5 times, the mass of urea.
Detailed Description
Synthesis of Compounds of formula I:
example 1
12.0g (0.2mol) of urea, the same R3Different alkaline substances with different molar weights are added into 60g of dimethylbenzene, and the temperature is raised to 60 ℃ by stirring for reaction for 4 hours. Evaporating xylene and low boiling point compounds, and vacuum drying to obtain urea alkali metal salt.
Example 2
12.0g (0.2mol) of urea and 10.8g (0.2mol) of sodium methoxide were added to 60g of xylene, and the mixture was stirred and heated to different temperatures for 4 hours of reaction. Evaporating xylene and methanol, and vacuum drying to obtain urea sodium salt.
Example 3
12.0g (0.2mol) of urea and 10.8g (0.2mol) of sodium methoxide were added to 60g of xylene, and the mixture was stirred and heated to 60 ℃ for reaction for various times. Evaporating xylene and methanol, and vacuum drying to obtain urea sodium salt.
Example 4
12.0g (0.2mol) of urea and 10.8g (0.2mol) of sodium methoxide were added to 60g of different solvents, and the mixture was stirred and heated to 60 ℃ to react for 4 hours. Evaporating the solvent and methanol, and drying in vacuum to obtain the urea sodium salt.
Example 5
12.0g (0.2mol) of urea and 10.8g (0.2mol) of sodium methoxide are added into different amounts of dimethylbenzene, and the mixture is stirred and heated to 60 ℃ for reaction for 4 hours. After the reaction, xylene and methanol are evaporated, and the urea sodium salt is obtained by vacuum drying.
And (3) synthesis of uracil:
example 6
9.02g (0.11mol) of urea sodium salt, 120g of compound formula II and 120g of dimethylbenzene are added into a 500ml three-necked bottle, 0.05g of polyoxyethylene dodecyl ether phosphate sodium salt is added, the temperature is increased to 80 ℃, the reaction is carried out for 4 hours under stirring, the temperature is increased to 110 ℃, the reaction is carried out for 2 hours, and alcohol substances or ammonia substances are evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 7
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate, 120g of xylene and 0.05g of different phase transfer catalysts are added into a 500ml three-necked flask, the temperature is increased to 80 ℃, the mixture is stirred and reacted for 4 hours, the temperature is increased to 110 ℃, the reaction is carried out for 2 hours, and methanol is distilled out. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 8
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate and 120g of xylene are added into a 500ml three-necked bottle, polyoxyethylene dodecyl ether phosphate sodium salt with different amounts is added, the temperature is increased to 80 ℃, the reaction is carried out for 4 hours under stirring, the temperature is increased to 110 ℃, the reaction is carried out for 2 hours, and methanol is evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table. For convenience of weighing and calculation, we optimized here the amount of catalyst to be 0.01(0.9 ‰),0.03(2.6 ‰),0.05(4.3 ‰), 0.07(6.0 ‰), 0.15 (1.3%), 0.20 (1.7%), 0.23 (2.0%)
Example 9
In a 500ml three-necked bottle, different amounts of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate, 120g of xylene and 0.05g of sodium polyoxyethylene lauryl ether phosphate are added according to different proportions, the temperature is increased to 80 ℃, the mixture is stirred and reacted for 4 hours, the temperature is increased to 110 ℃, the reaction is carried out for 2 hours, and methanol is distilled out. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 10
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate and 120g of xylene are added into a 500ml three-necked bottle, 0.05g of polyoxyethylene dodecyl ether phosphate sodium salt is added, the temperature is increased to different temperatures, the mixture is stirred and reacted for 4 hours, the temperature is increased to 110 ℃, the reaction is carried out for 2 hours, and methanol is evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 11
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate and 120g of xylene are added into a 500ml three-necked bottle, 0.05g of polyoxyethylene dodecyl ether phosphate sodium salt is added, the temperature is raised to 80 ℃, the mixture is stirred and reacted for 4 hours, the temperature is raised to different temperatures of 110-140 ℃, the reaction is carried out for 2 hours, and the methanol is evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 12
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate and 120g of different organic solvents are added into a 500ml three-necked bottle, 0.05g of polyoxyethylene dodecyl ether phosphate sodium salt is added, the temperature is increased to 80 ℃, the mixture is stirred and reacts for 4 hours, the temperature is increased to 110 ℃, the reaction lasts for 2 hours, and methanol is evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolving, recovering the upper organic solvent, adding hydrochloric acid into the lower water layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, totaling 50ml of water, and drying to obtain the uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table.
Example 13
9.02g (0.11mol) of urea sodium salt, 11.6g (0.10mol) of methyl 3-methoxyacrylate, different amounts of xylene and 0.05g of polyoxyethylene dodecyl ether phosphate sodium salt are added into a 500ml three-necked bottle, the mixture is stirred and reacted for 4 hours when the temperature is raised to 80 ℃, the temperature is raised to 110 ℃, the reaction is carried out for 2 hours, and methanol is evaporated. After the reaction is finished, cooling to 50 ℃, adding 100ml of water, separating liquid after dissolution, recovering xylene at the upper layer, adding hydrochloric acid into the water layer at the lower layer for acidification, standing for 4 hours at normal temperature, separating out a large amount of crystals, filtering, washing a filter cake for three times by using cold water, adding 50ml of water in total, and drying to obtain uracil. The purity of uracil by HPLC was 99.1%, and the yield of uracil was calculated as shown in the following table. For ease of weighing and calculation, we here optimize the amount of xylene to be 60, 80, 100, 120, 140, 160, 180, 200, 230.
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