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Preparation method of 6-chloro-1,3-dimethyluracil

A technology of dimethyl uracil and dimethyl barbituric acid is applied in the field of preparation of 6-chloro-1,3-dimethyl uracil, and can solve the problem of large dosage of phosphorus oxychloride and high requirements for reaction equipment , increase the difficulty of operation and other problems, to achieve the effect of simplifying post-processing, easy operation, and reducing the generation of waste acid

Active Publication Date: 2013-04-03
SHENGQUAN HEALTANG
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Problems solved by technology

[0009] However, in the above two processes for preparing 6-chloro-1,3-dimethyluracil, the amount of phosphorus oxychloride used in the chlorination process is relatively large, generally 1,3-dimethylbarbital 10 to 15 times the weight of the acid, not only the cost is high, but also the excess phosphorus oxychloride needs to be removed by vacuum distillation after the reaction is completed, which requires high requirements for the reaction equipment and increases the difficulty of operation; at the same time, a large amount of water needs to be added to quench the reaction, A large amount of spent acid solution is produced, which still needs further treatment

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  • Preparation method of 6-chloro-1,3-dimethyluracil

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[0036] The invention provides a preparation method of 6-chloro-1,3-dimethyluracil, comprising the following steps:

[0037] A) The 1,3-dimethylbarbituric acid and the chlorinating agent are refluxed in a water-immiscible organic solvent to obtain a reaction mixture; the chlorinating agent includes phosphorus oxychloride;

[0038] B) After adding water to the reaction mixture to quench the reaction, 6-chloro-1,3-dimethyluracil is obtained.

[0039] The present invention uses 1,3-dimethylbarbituric acid and a chlorinating agent including phosphorus oxychloride as raw materials, reacts in an organic solvent immiscible with water, and can obtain 6-chlorobarbiturate after quenching the reaction -1,3-Dimethyluracil. Further, in the process of reacting 1,3-dimethylbarbituric acid and a chlorinating agent comprising phosphorus oxychloride, the present invention uses a water-immiscible organic solvent as the reaction medium, which can greatly reduce the three The consumption of phosp...

Embodiment 1

[0061] In a 1000L dry reactor, add 440kg of methanol, 44kg of 1,3-dimethylurea and 26kg of sodium methoxide, and start stirring. After 0.5 hours, slowly add 66kg of dimethyl malonate. After the addition is complete, the temperature is raised for reflux reaction , after reacting for 6 hours, down to room temperature, centrifuged to obtain 88kg1,3-dimethyl barbituric acid sodium salt; in the obtained 1,3-dimethyl barbituric acid sodium salt, add 100kg water, and then use 30% concentrated hydrochloric acid to adjust the pH value of the mixture of 1,3-dimethylbarbituric acid sodium salt and water to 1~2, and finally centrifuged to obtain 58.5kg of 1,3-dimethylbarbituric acid product , and the yield was 75%.

[0062] NMR analysis of 1,3-dimethylbarbituric acid, see figure 1 and figure 2 , figure 1 It is the 1,3-dimethylbarbituric acid hydrogen nuclear magnetic resonance spectrogram prepared in the embodiment 1 of the present invention, figure 2 It is the carbon nuclear magnet...

Embodiment 2

[0064] In a 100L dry reaction kettle, add 50kg of xylene, 10kg of 1,3-dimethylbarbituric acid prepared in Example 1 and 12kg of phosphorus oxychloride, start stirring, and cool the above mixture to -5~0 ℃, under the condition of less than 10℃, slowly add 5kg of methanol dropwise, after the dropwise addition, slowly raise the temperature for reflux reaction, after 5 hours of reaction, stop heating, lower to room temperature, and slowly add 12kg of methanol to it under the temperature below 40℃ After adding water, continue to stir for 0.5 hours, cool down to room temperature, centrifuge to obtain solid crude product and centrifuged mother liquor, add 35kg methanol and 0.5kg activated carbon to the crude product, decolorize through reflux, filter, cool and crystallize, centrifuge, and dry to obtain 10.06 kg fine 6-chloro-1,3-dimethyluracil; the centrifuged mother liquor was layered, washed three times with 30kg of water, and then dried with 0.5kg of anhydrous sodium sulfate,

[0...

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Abstract

The invention provides a preparation method of 6-chloro-1,3-dimethyluracil, which comprises the following steps: carry out reflux reaction on 1,3-dimethylbarbituric acid and a chlorinating agent in a water-insoluble organic solvent to obtain a reaction mixture; and adding water to quench the reaction to obtain the 6-chloro-1,3-dimethyluracil, wherein the chlorinating agent comprises phosphorus oxychloride. The preparation method provided by the invention reduces the consumption of phosphorus oxychloride, and does not need to perform vacuum distillation on the phosphorus oxychloride. Furthermore, additives can be added in the reaction process to enhance the yield of the 6-chloro-1,3-dimethyluracil. The invention also provides a method for synthesizing 1,3-dimethylbarbituric acid, which is implemented by reacting 1,3-dimethylurea, dimethyl malonate and a condensing agent in an organic solvent. The method avoids using abundant malonic acid and acetic anhydride.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of 6-chloro-1,3-dimethyluracil. Background technique [0002] 6-Chloro-1,3-dimethyluracil, also known as 6-chloro-1,3-dimethyluracil, has the structure of formula I and is a synthetic antihypertensive drug urapidil and antiarrhythmic drug nifi An important intermediate of Karan. [0003] [0004] The prior art discloses a variety of synthetic methods for 6-chloro-1,3-dimethyluracil. For example, in US Patent No. 4,659,651A, the synthesis steps of 6-chloro-1,3-dimethyluracil are as follows: [0005] First, dissolve dimethylurea and malonic acid in acetic acid at 60-70°C, add acetic anhydride, and keep the temperature constant to 90°C, react for 6 hours and then acidify to obtain 1,3 with the structure of formula II - Dimethylbarbituric acid; [0006] [0007] Then add a small amount of water to 1,3-dimethylbarbituric acid, then d...

Claims

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Application Information

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IPC IPC(8): C07D239/553
Inventor 江成真张恩选宁述光夏松程经纬
Owner SHENGQUAN HEALTANG
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