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Method for synthesizing cytosine

A technology of cytosine and aminoacrylonitrile, applied in the field of synthesizing cytosine, can solve the problems of unreproducible reaction yield, difficult stirring, complicated operation and the like in small test, avoid product quality risks, simplify production operation, process operation simple effect

Active Publication Date: 2018-02-02
TUOXIN GROUP +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In these two synthetic methods, the solubility of cytosine sulfate is similar to that of cytosine, and the cytosine separated by recrystallization contains a significant amount of cytosine sulfate impurities, and repeated recrystallization is required to obtain cytosine with high purity. The operation is too cumbersome
[0009] 2.3 Peeters et al. used a mixture of 3-ethoxyacrylonitrile and 3,3-diethoxyacrylonitrile and urea in a solution of potassium tert-butoxide in tert-butanol to obtain cytosine directly, with a yield of no more than 62%. , if the alcoholic solution of sodium alkoxide is used, the yield is even lower
[0014] Sodium salt, the sodium salt of cytosine formed during the reaction is precipitated from the solvent and adheres to the stirrer, making stirring difficult
This process is more serious when the process is enlarged, and the yield fluctuates differently with the scale of the enlargement, and the reaction yield in the small test cannot be reproduced.

Method used

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  • Method for synthesizing cytosine
  • Method for synthesizing cytosine
  • Method for synthesizing cytosine

Examples

Experimental program
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Effect test

Embodiment 1

[0035]

[0036] Step 1: Add 200mL of 10% ammonia-methanol solution into the three-neck flask, cool down to 0°C, then slowly add 38.2g (70% content) (0.25mol) of 3-hydroxyacrylonitrile potassium salt, and then slowly add concentrated Sulfuric acid 12g (0.122mol), control the internal temperature not to exceed 10°C, continue to stir for 1 hour after the dropwise addition, then raise the temperature to 60°C, continue to stir for 5 hours, cool down and suction filter the solid, and concentrate the filtrate under reduced pressure to obtain the residue 3- Aminoacrylonitrile 13g.

[0037] Step 2: In a 1-liter high-pressure reactor, add 500ml of toluene, 35g (0.389mol) of dimethyl carbonate, and then add 13g (0.191mol) of 3-aminoacrylonitrile, the product of the previous step, react at 150°C for 10h, and monitor the reaction by HPLC After completion, it was then lowered to room temperature and used directly in the next reaction.

[0038] Step 3: Add 1.7g (0.011mol) DBU to the auto...

Embodiment 2

[0040]

[0041] Step 1: Add 200mL of 10% ammonia-methanol solution into the three-neck flask, cool down to 0°C, then slowly add 26.8g (70% content) (0.25mol) of 3-hydroxyacrylonitrile lithium salt, and then slowly add concentrated Sulfuric acid 12g (0.122mol), control the internal temperature not to exceed 10°C, continue to stir for 1 hour after the dropwise addition, then raise the temperature to 60°C, continue to stir for 5 hours, cool down and suction filter the solid, and concentrate the filtrate under reduced pressure to obtain the residue 3- Aminoacrylonitrile 13g.

[0042]Step 2: Add 500mL of toluene and 35g (0.389mol) of dimethyl carbonate into a 1-liter high-pressure reactor, then add 13g (0.191mol) of 3-aminoacrylonitrile, the product of the previous step, react at 130°C for 10h, and monitor the reaction by HPLC After completion, it was then lowered to room temperature and used directly in the next reaction.

[0043] The third step: add the product of the previou...

Embodiment 3

[0045]

[0046] Step 1: Add 200mL of 10% ammonia-methanol solution into the three-necked flask, cool down to 0°C, then slowly add 32.5g (70% content) (0.25mol) of 3-hydroxyacrylonitrile sodium salt, and then slowly add concentrated Sulfuric acid 12g (0.122mol), control the internal temperature not to exceed 10°C, continue to stir for 1 hour after the dropwise addition, then raise the temperature to 60°C, continue to stir for 5 hours, cool down and suction filter the solid, and concentrate the filtrate under reduced pressure to obtain the residue 3- Aminoacrylonitrile 13g.

[0047] Step 2: In a 1-liter high-pressure reactor, add 500 mL of xylene, 35 g (0.389 mol) of dimethyl carbonate, and then add 13 g (0.191 mol) of the product from the previous step, react at 140 ° C for 10 h, and monitor by HPLC After the reaction was completed, it was cooled to room temperature and used directly in the next reaction.

[0048] Step 3: Add the product of the previous step and 1.7g (0.011...

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Abstract

The invention discloses a method for synthesizing cytosine, and belongs to the field of nucleoside synthesis in organic chemistry. The method comprises the following reaction steps: reacting a raw material 3-hydroxyacrylonitrile sodium salt with ammonia to generate aminoacrylonitrile, reacting the aminoacrylonitrile with carbonate ester to obtain an intermediate, and reacting the intermediate withammonia in the presence of DBU or DBN to generate cytosine. Only a three-step reaction is carried out in the whole process, so the use of urea is avoided, and the process conditions are suitable forindustrial amplification.

Description

technical field [0001] The invention belongs to the field of organic chemistry and relates to the synthesis of pyrimidine bases, in particular to a method for synthesizing cytosine. Background technique [0002] Cytosine, chemical name: 2-carbonyl-4-aminopyrimidine, CAS number: 71-30-7, molecular formula C4H5N3O, is the main base component in nucleic acid (DNA and RNA), as a very important pharmaceutical intermediate , can be used to prepare antiviral and antitumor 5-fluorocytosine and lamivudine and other drugs. The methods currently reported in the literature are as follows: [0003] The first category: using pyrimidine as raw material [0004] 1.1 Davidson et al. chlorinated uracil to generate 2,4-dichloropyrimidine, then ammonolyzed to obtain a mixture of 2-amino-6-chloropyrimidine (40%) and 2-chloro-6-aminopyrimidine (60%), separated 2-Chloro-6-aminopyrimidine was obtained, and cytosine was obtained after hydrolysis with a yield of 20%. Hilbert et al. simplified the...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 杨西宁李涛卫涛靳海燕蔡玉英王秀强
Owner TUOXIN GROUP
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