A kind of synthetic method of 5-azacytosine

An azacytosine and a synthesis method technology, 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: 2018-07-20
NINGXIA SIKEDA BIOTECH CO LTD
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  • Summary
  • 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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  • A kind of synthetic method of 5-azacytosine
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  • A kind of synthetic method of 5-azacytosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] (1) Into a 10L autoclave, 1.5Kg of anhydrous formic acid (99.5%), 2.5Kg of dicyandiamide and p-toluenesulfonic acid catalyst (0.005Kg) were sequentially added. Under the state of sealing and stirring, pressurize the reactor and slowly raise the temperature to 110°C. After the reaction is completed, slowly lower the reaction temperature to room temperature to obtain a white solid.

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

[0045] by figure 1 with figure 2 It can be seen that the product prepared by the present invention is 5-azacytosine, which...

Embodiment 2

[0047] (1) Into a 10L autoclave were sequentially added 1.3Kg of anhydrous formic acid (98%), 2.5Kg of dicyandiamide and p-toluenesulfonic acid catalyst (0.005Kg). Under the state of sealing and stirring, pressurize the reactor and slowly raise the temperature to 100°C. After the reaction is completed, slowly lower the reaction temperature to room temperature to obtain a white solid.

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

[0049] by Figure 4 It can be seen from the high performance liquid chromatogram that the purity is higher than 95%.

Embodiment 3

[0051] (1) Add anhydrous formic acid (99.5%) 2.0Kg, dicyandiamide 2.5Kg and p-toluenesulfonic acid catalyst (0.005Kg) into a 10L autoclave. Under the state of sealing and stirring, pressurize the reactor and slowly raise the temperature to 120°C. After the reaction is completed, slowly lower the reaction temperature to room temperature to obtain a white solid.

[0052] (2) Transfer the white solid to a 50L glass reactor, and add 10L of dilute hydrochloric acid with a mass concentration of 5%. Heat at reflux for 30 minutes until the solution becomes clear. Filter the mixed liquid through a filter cartridge to a crystallization kettle. Add 30% ammonia to the filtrate to adjust the pH to 6 and precipitate white crystals. After centrifugation, dry in a hot air oven to obtain 5 -Azacytosine 2.8 kg (yield of 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, and particularly relates to a method for synthesizing 5-azacytosine. Background technique [0002] 5-Azacytosine is the basic raw material for chemical synthesis of azaglycoside drugs. The therapeutic drugs that use 5-azacytidine as the raw material are 5-azacytidine, the trade name Vidaza. There is also 5-aza-2'-deoxycytidine, trade name Decitabine. They all belong to demethylation drugs with unique therapeutic mechanism of methyltransferase inhibitors. Its clinical effect on 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 their indications have also been extended with the development of various application studies, and they have gradually been used in a variety of different malignant tumors. The treatment...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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