CN113045447A - 2-amino malonamide and synthetic method thereof - Google Patents

2-amino malonamide and synthetic method thereof Download PDF

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CN113045447A
CN113045447A CN202110280439.4A CN202110280439A CN113045447A CN 113045447 A CN113045447 A CN 113045447A CN 202110280439 A CN202110280439 A CN 202110280439A CN 113045447 A CN113045447 A CN 113045447A
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reaction
aminomalonamide
ammonium carbonate
synthesizing
temperature
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吴法浩
李钢
高仰哲
陈红玉
王志航
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Nanjing Redwood Fine Chemical Co ltd
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Nanjing Redwood Fine Chemical Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/14Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups

Abstract

The invention relates to the technical field of organic synthesis, in particular to 2-amino malonamide and a synthesis method thereof. The synthesis method comprises the following steps: the reaction of 2-chloromalonic ester and ammonium carbonate is favorable to lowering production cost, simplifying reaction process, benefiting industrial production and ensuring the yield and purity of 2-amino malonamide.

Description

2-amino malonamide and synthetic method thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to 2-amino malonamide and a synthesis method thereof.
Background
2-amino malonamide is an important intermediate for producing 5-hydroxy-1H-imidazole-4-formamide, therefore, the dosage is large, and mass production is needed, while the prior art basically adopts diethyl 2-amino malonate or hydrochloride thereof to prepare 2-amino malonamide, the diethyl 2-amino malonate needs to be synthesized by 2-chloromalonate, and the cost of diethyl 2-amino malonate is high, so that the raw materials are not easy to be used, and the production cost is high. Meanwhile, the synthesis of 2-amino malonamide in the prior art has the defects of complex reaction process, long period and high requirement on equipment, for example, the equipment is required to be corrosion-resistant, so that the synthesis of 2-amino malonamide is not beneficial to industrialization. For example:
method 1: a5 liter 4-necked round-bottomed flask equipped with an overhead stirrer was charged with commercially available aminomalonic acid diethylamine hydrochloride (338g, 1.596 mol). 7N ammonia in MeOH (2L) was removed from the freezer and added cold in portions. All air inlets are covered with a plastic cover. Within 1 hour, the reaction mixture became clear yellow. The flask was vented once and there was no observable pressure increase. The mixture was stirred overnight. A precipitate formed which was isolated by filtration. The powder was washed with MeOH (500 mL). The pale yellow powder was dried under vacuum overnight to give diamide 2(170g, 1.45mol, 91% yield).
Method 2: to a solution of diethylaminomalonate hydrochloride (25g, 0.12mol) in water (20mL) was added solid sodium bicarbonate until pH > 7. After extraction with ethyl acetate, the organic phase is separated and evaporated under reduced pressure. The residue was dissolved in methanolic ammonia solution (6M, 300mL) and the reaction mixture was heated in a high pressure reactor at 80 ℃ overnight. The resulting mixture was concentrated under reduced pressure, and the residue was washed successively with methanol and ether to give aminomalonamide (10g, 73%).
Method 3: a solution of diethyl aminomalonate hydrochloride (50.0g, 0.237mol) in methanolic ammonia (75.0mL, 7N, 5.25mol) was stirred in a closed flask for 7 days. Filtration and washing of the solid with MeOH will afford 2-amino-malonamide as a pale yellow product (25g, 69%).
Method 4: 17.5g of 2-aminomalonate and 22g of 50% aqueous ammonium chloride solution were weighed and heated at 100 ℃ under reflux for 2 hours. After completion of the reaction, the mixture was filtered and dried by hot air at 60 ℃ for 8 hours. 10.2g 2-aminomalonamide were obtained in 87% yield as a white color.
Method 5: diethyl 2-aminomalonate (8.16 g; 46.6mmol) was added to a 2M solution of ammonia in methanol (233 ml; 466mmol) and heated at 60 ℃ under argon for 19 hours. The reaction solvent was removed under reduced pressure to give crude 2-aminomalondiamide as a pale yellow powder. Yellow impurities were removed by solid-liquid extraction with methanol (100ml) at 90 ℃ under argon atmosphere using a Soxhlet extractor. The almost colorless residue in the extraction cartridge was recrystallized from water to give colorless 2-aminomalonamide (2.65 g; 22.6 mmol; yield, 49%).
The methods 1 to 5 all adopt 2-amino diethyl malonate, so that the production cost is high, the reaction processes of the methods 1 to 3 and 5 are complex and have long period, and the method 4 has high requirements on equipment.
Therefore, the invention is provided in view of the problems of high cost, complicated flow, long period, high equipment and the like which are not beneficial to industrial production in the synthesis of 2-amino malonamide in the prior art.
Disclosure of Invention
The invention aims to provide 2-amino malonamide and a synthesis method thereof. The invention provides a new synthesis method, which is not only beneficial to reducing the production cost, simplifying the reaction process and being beneficial to industrial production, but also ensures the yield and the purity of the produced 2-amino malonamide.
The invention is realized by the following steps:
in a first aspect, the present invention provides a method for synthesizing 2-aminomalonamide, comprising: 2-chloromalonate will be reacted with ammonium carbonate.
In an alternative embodiment, the method comprises the following steps: mixing the 2-chloromalonate with a solvent containing water, and then mixing with the ammonium carbonate for reaction.
In an alternative embodiment, the method comprises the following steps: mixing the 2-chloromalonate with water, and then mixing with the ammonium carbonate to react for 6-8 hours at the temperature of 50-60 ℃.
In an alternative embodiment, the mass ratio of the 2-chloromalonate to the water is from 1:3 to 5.
In alternative embodiments, the molar ratio of the 2-chloromalonate to the ammonium carbonate is from 1:3 to 5.
In an alternative embodiment, the 2-chloropropionate is methyl 2-chloropropionate or ethyl 2-chloropropionate.
In an alternative embodiment, the method comprises the following steps: after the reaction is finished, post-treatment is carried out.
In an alternative embodiment, the post-processing comprises: heating to decompose unreacted ammonium carbonate;
preferably, the temperature is increased after the reaction is finished, and the temperature after the temperature increase is higher than the reaction temperature and lower than 70 ℃;
preferably, the temperature is raised to 65-70 ℃ after the reaction is finished, and the heating time is 2-8 hours.
In an alternative embodiment, the post-processing comprises: heating to decompose unreacted ammonium carbonate, concentrating, cooling, filtering and drying.
In a second aspect, the present invention provides a 2-aminomalonamide produced by the method for synthesizing a 2-aminomalonamide according to any one of the preceding embodiments.
The invention has the following beneficial effects: the embodiment of the invention provides a novel synthesis method, which can efficiently synthesize 2-amino malonamide by using 2-chloromalonate and ammonium carbonate for reaction, and ensures the yield and purity of the synthesized 2-amino malonamide. Meanwhile, the synthesis method has the advantages of easily available raw materials and low cost, so that the synthesis cost is reduced, the method is simple and convenient to operate, special requirements on equipment are not required, and the industrial production is facilitated.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a schematic diagram of a process for synthesizing 2-aminomalondiamide according to an embodiment of the present invention;
FIG. 2 is a diagram showing the results of HPLC analysis of 2-aminomalondiamide provided in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides a method for synthesizing 2-amino malonamide, which comprises the following steps:
referring to fig. 1, 2-chloromalonate and ammonium carbonate are reacted, and the embodiment of the invention provides a new synthesis path, which adopts 2-chloromalonate and ammonium carbonate as reaction raw materials, can not only synthesize 2-amino malonamide with high efficiency, but also ensure the yield and purity of 2-amino malonamide. Meanwhile, the reaction operation is simple, no special requirement is required for reaction equipment, and the industrial production is facilitated.
Specifically, the 2-chloromalonate is mixed with a solvent containing water, and then mixed with the ammonium carbonate to react. The aqueous solvent may be water or a mixed solvent of water and another solvent, but the water content in the mixed solvent is larger. The other solvent may be an alcohol such as methanol or ethanol, or a solvent such as DMF, but the most preferable aqueous solvent is water because it costs more than water and easily remains, and further the purity of 2-aminomalonamide is lowered, so that it is most preferable to form a reaction system using water as the reaction solution.
Specifically, the 2-chloromalonate is mixed with water and then mixed with the ammonium carbonate to react for 6 to 8 hours at the temperature of 50 to 60 ℃. For example, the temperature is 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃ and 60 ℃, etc., and the reaction time can be 6 hours, 6.5 hours, 7 hours, 7.5 hours and 8 hours, etc., of any value between 50 ℃ and 60 ℃. The synthesis temperature is favorable for reaction, ensures the formation of 2-amino malonamide and is favorable for improving the purity and yield of the 2-amino malonamide.
The mass ratio of the 2-chloromalonate to the water is 1:3 to 5, and may be any value between 1:3 and 5, such as 1:3, 1:3.1, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.6, 1:4.7, 1:4.9, and 1: 5. The molar ratio of the 2-chloromalonate to the ammonium carbonate is 1:3 to 5, and may be any value between 1:3 and 5, such as 1:3, 1:3.1, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.6, 1:4.7, 1:4.9, and 1: 5. The adoption of the proportion is beneficial to improving the purity and the yield of the 2-amino malonamide, the yield in the range can reach more than 85 percent, and the purity can reach more than 99.0 percent.
The 2-chloropropanedioic acid ester is 2-chloropropanedioic acid methyl ester or 2-chloropropanedioic acid ethyl ester, the formation of 2-amino malonamide can be ensured by adopting the two 2-chloromalonic acid esters, and the 2-amino malonamide cannot be formed if the 2-chloromalonic acid ester is replaced by other 2-chloromalonic acid ester.
Further, after the reaction is completed, post-treatment is performed, and a large amount of ammonium carbonate remains in the reaction system after the reaction is completed, which affects the purity and physiological activity of 2-aminomalondiamide, and thus, it is necessary to remove ammonium carbonate. Specifically, after the reaction is finished, further heating the reaction system to decompose unreacted ammonium carbonate, wherein the temperature after heating is higher than the reaction temperature and lower than 70 ℃; the heating temperature cannot be higher than 70 ℃, and if the heating temperature is higher than 70 ℃, a side reaction may occur to cause 2-amino malonamide, and then the purity and yield of the 2-amino malonamide are reduced. Preferably, the temperature is raised to 65-70 ℃ after the reaction is completed, the heating time is 2-8 hours, for example, the temperature is any value between 65-70 ℃ such as 65 ℃, 66 ℃, 67 ℃, 68 ℃, 69 ℃ and 70 ℃, and the time is 2-8 hours such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours and 8 hours.
Then sequentially carrying out concentration, cooling filtration and drying to obtain the high-purity 2-amino malonamide.
The embodiment of the invention also provides 2-amino malonamide which is prepared by the synthesis method of the 2-amino malonamide.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example provides a method for synthesizing 2-aminomalonamide, which includes:
adding 2-dimethyl chloropropionate 100g into 400ml of water, adding ammonium carbonate 57.6g, heating the reaction system to 50 ℃ for reaction for 6 hours, controlling the temperature of the liquid phase, continuing to heat to 65 ℃ for reaction for 2 hours after the reaction is finished, concentrating the reaction liquid to 1/3 volume after the reaction is finished, cooling, crystallizing, filtering, and drying to obtain 60.8g of 2-amino malonamide with the purity of 99.2% and the yield of 86.6%. The high performance liquid phase analysis was performed, and the detection result is shown in fig. 1, and it can be seen from fig. 1 that 2-amino malonamide was synthesized in this example, and the purity was 99.2%.
Example 2
This example provides a method for synthesizing 2-aminomalonamide, which includes:
adding 117g of 2-ethyl chloropropionate into 450ml of water, adding 57.6g of ammonium carbonate, heating a reaction system to 50 ℃ for reacting for 6 hours, controlling the temperature of a liquid phase, continuously heating to 65 ℃ for reacting for 2 hours after the reaction is finished, concentrating a reaction solution to 1/3 volume after the reaction is finished, cooling, crystallizing, filtering, and drying to obtain 61.3g of 2-amino malonamide with the purity of 99.2% and the yield of 87.2%.
Examples 3 to 6
2-Aminomalonamide was prepared with reference to the synthesis of 2-aminomalonamide provided in example 1, except that: 2-Chloropropanedioic acid dimethyl ester: the molar ratio of ammonium carbonate was varied and the remaining conditions and procedure were the same as in example 1, specifically, dimethyl 2-chloropropionate: the molar ratio of ammonium carbonate is shown in table 1.
TABLE 1
Figure BDA0002978084620000061
According to the table, when the using amount of ammonium carbonate is kept above 3mol times, the yield can reach above 85%, but when the using amount is continuously increased above 5 times, the yield has no obvious change, and the problems of cost and the like are comprehensively considered, namely, the 2-chloropropanedioic acid dimethyl ester: molar ratio of ammonium carbonate 1:3 to 5 is suitable.
Examples 7 and 8
2-Aminomalonamide was prepared with reference to the synthesis of 2-aminomalonamide provided in example 1, except that: the reaction temperatures of dimethyl 2-chloropropionate and ammonium carbonate were varied, the remaining conditions and procedures were the same as in example 1, and specifically, the reaction temperatures of dimethyl 2-chloropropionate and ammonium carbonate are shown in Table 2.
TABLE 2
Examples 9 to 10
2-Aminomalonamide was prepared with reference to the synthesis of 2-aminomalonamide provided in example 1, except that: the temperature was raised after the completion of the reaction under the same conditions and in the same manner as in example 1, and specifically, the temperature was raised after the completion of the reaction, as shown in Table 3.
TABLE 3
Comparative example 7: 2-Aminomalonamide was prepared with reference to the synthesis of 2-aminomalonamide provided in example 1, except that: using dipropyl 2-chloropropanedioate and the same conditions and procedures as in example 1, 2-aminomalonamide was obtained in a purity of 72.7% and a yield of 47%.
In summary, the embodiments of the present invention provide a novel synthesis method, which can efficiently synthesize 2-aminomalonamide by reacting 2-chloromalonate with ammonium carbonate, and ensure the yield and purity of the synthesized 2-aminomalonamide. Meanwhile, the synthesis method has the advantages of easily available raw materials and low cost, so that the synthesis cost is reduced, the method is simple and convenient to operate, special requirements on equipment are not required, and the industrial production is facilitated.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A method for synthesizing 2-amino malonamide is characterized by comprising the following steps: 2-chloromalonate will be reacted with ammonium carbonate.
2. The method of synthesizing 2-aminomalonamide according to claim 1, which comprises: mixing the 2-chloromalonate with a solvent containing water, and then mixing with the ammonium carbonate for reaction.
3. The method of synthesizing 2-aminomalonamide according to claim 1, which comprises: mixing the 2-chloromalonate with water, and then mixing with the ammonium carbonate to react for 6-8 hours at the temperature of 50-60 ℃.
4. The method according to claim 3, wherein the mass ratio of the 2-chloromalonate to the water is 1: 3-5.
5. The method for synthesizing 2-aminomalonamide according to claim 1, wherein the molar ratio of the 2-chloromalonate to the ammonium carbonate is 1:3 to 5.
6. The method for synthesizing 2-aminomalonamide according to any one of claims 1 to 5, wherein the 2-chloropropionate is methyl 2-chloropropionate or ethyl 2-chloropropionate.
7. The method of synthesizing 2-aminomalonamide according to claim 1, which comprises: after the reaction is finished, post-treatment is carried out.
8. The method of synthesizing 2-aminomalonamide according to claim 7, wherein the post-treatment comprises: heating to decompose unreacted ammonium carbonate;
preferably, the temperature is increased after the reaction is finished, and the temperature after the temperature increase is higher than the reaction temperature and lower than 70 ℃;
preferably, the temperature is raised to 65-70 ℃ after the reaction is finished, and the heating time is 2-8 hours.
9. The method of synthesizing 2-aminomalonamide according to claim 8, wherein the post-treatment comprises: heating to decompose unreacted ammonium carbonate, concentrating, cooling, filtering and drying.
10. A 2-aminomalonamide produced by the method for synthesizing a 2-aminomalonamide according to any one of claims 1 to 9.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113429310A (en) * 2021-08-02 2021-09-24 大连理工大学 Continuous preparation method of 2-amino malonamide
CN113831255A (en) * 2021-11-25 2021-12-24 山东诚创蓝海医药科技有限公司 Preparation method of 2-amino malonamide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113429310A (en) * 2021-08-02 2021-09-24 大连理工大学 Continuous preparation method of 2-amino malonamide
CN113831255A (en) * 2021-11-25 2021-12-24 山东诚创蓝海医药科技有限公司 Preparation method of 2-amino malonamide
CN113831255B (en) * 2021-11-25 2022-03-11 山东诚创蓝海医药科技有限公司 Preparation method of 2-amino malonamide

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