5-azacytosine synthesis method

A technology of azacytosine and a synthesis method, applied in the field of organic synthesis, can solve the problems of increased difficulty in process safety control and waste liquid treatment, large amount of organic waste and waste water, high environmental pollution pressure, etc., and achieves easy biochemical degradation treatment, The effect of reducing production costs and reducing side reactions

Active Publication Date: 2016-08-10
NINGXIA SIKEDA BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

): After directly mixing dicyandiamide and formic acid, reacting in a flask at 130° C. for 3 hours, a large amount of pasty solid was obtained, which was washed with ethanol, and finally 5-azacytosine was obtained (the chemical reaction formula is as follows ), the yield of this method is less than 20%, and a large amount of dicyandiamide copolymers are produced in the reaction process, which is difficult to separate and purify
However, there are many organic wastes and waste water produced in the reaction process, and the environmental pollution pressure is great.
In particular, a large amount of alcohol is used in the refining process of the final product, which increases the difficulty of process safety control and waste liquid treatment

Method used

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Experimental program
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Effect test

Embodiment 1

[0043] (1) Add anhydrous formic acid (99.5%) 1.5Kg, dicyandiamide 2.5Kg and p-toluenesulfonic acid catalyst (0.005Kg) successively in 10L autoclave. Under the condition of sealing and stirring, the reactor was pressurized and the temperature was slowly raised to 110° C. After the reaction was completed, the reaction temperature was slowly lowered to room temperature to obtain a white solid.

[0044] (2) Transfer the white solid to a 50L glass reactor, and add 10L of 5% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, heat the mixed solution through a filter cartridge to a crystallization kettle, add 30% ammonia water to the crystallization kettle to adjust the pH to 6, and precipitate white crystals. After centrifugation, dry in a hot air oven to obtain 5 -Azacytosine 2.8kg (yield is 85% based on dicyandiamide).

[0045] Depend on figure 1 with figure 2 It can be seen that the product prepared by the present invention is 5-azacytosi...

Embodiment 2

[0047] (1) Add anhydrous formic acid (98%) 1.3Kg, dicyandiamide 2.5Kg and p-toluenesulfonic acid catalyst (0.005Kg) successively in 10L autoclave. Under the condition of sealing and stirring, the reactor was pressurized and the temperature was slowly raised to 100° C. After the reaction was completed, the reaction temperature was slowly lowered to room temperature to obtain a white solid.

[0048] (2) Transfer the white solid to a 50L glass reactor, and add 10L of 5% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, heat the mixed solution through a filter cartridge to a crystallization kettle, add 30% ammonia water to the crystallization kettle to adjust the pH to 6, and precipitate white crystals. After centrifugation, dry in a hot air oven to obtain 5 -Azacytosine 2.65kg (yield is 80% based on dicyandiamide).

[0049] Depend on Figure 4 It was found that the purity was higher than 95% as can be seen by high performance liquid chrom...

Embodiment 3

[0051] (1) Add anhydrous formic acid (99.5%) 2.0Kg, dicyandiamide 2.5Kg and p-toluenesulfonic acid catalyst (0.005Kg) successively in 10L autoclave. Under the condition of sealing and stirring, the reactor was pressurized and the temperature was slowly raised to 120° C. After the reaction was completed, the reaction temperature was slowly lowered to room temperature to obtain a white solid.

[0052] (2) Transfer the white solid to a 50L glass reactor, and add 10L of 5% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, heat the mixed solution through a filter cartridge to a crystallization kettle, add 30% ammonia water to the crystallization kettle to adjust the pH to 6, and precipitate white crystals. After centrifugation, dry in a hot air oven to obtain 5 -Azacytosine 2.8kg (yield is 85% based on dicyandiamide).

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Abstract

The invention discloses a 5-azacytosine synthesis method .The method comprises the following steps that 1, dicyandiamide, formic acid and a catalyst p-toluenesulfonic acid are added into an airtight reaction device and heated to react to obtain emulsion matter; 2, the product obtained in the step 1 is refined through hydrochloric acid to obtain the 5-azacytosine .A high-pressure reaction kettle is utilized, under the p-toluenesulfonic acid catalysis condition, the dehydration reaction temperature of guanylurea formate is effectively lowered, anhydrous formic acid in a system is directly utilized as a dehydrating agent, the steps of a synthesis process are simplified, side reactions are reduced, the product quality is ensured, the productivity is improved, and reaction yield is higher than 80% based on dicyandiamide .

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for synthesizing 5-azacytosine. Background technique [0002] 5-azacytosine is the basic raw material for the chemical synthesis of azaglycosides. 5-azacytosine is a therapeutic drug that uses 5-azacytosine as a raw material, and the trade name is Vidaza. There is also 5-aza-2'-deoxycytidine, trade name Decitabine. They all belong to hypomethylation drugs and have a unique therapeutic mechanism of methyltransferase inhibitors. Its clinical efficacy for myelodysplastic syndrome, myeloid leukemia, sickle cell anemia, and some solid tumors has been certified by the US FDA. [0003] In the past clinical practice, the efficacy and safety of 5-azacytidine drugs have been continuously verified, and its indications have also been extended with the development of various applied research, and are gradually used in many different malignant tumors The treatment has achieved goo...

Claims

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Application Information

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IPC IPC(8): C07D251/16
CPCC07D251/16
Inventor 陈红余田永福孙风程王科
Owner NINGXIA SIKEDA BIOTECH CO LTD
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