A new method for the synthesis of 5-azacytosine

A technique for the synthesis of azacytosine, which is applied in the field of organic synthesis, can solve the problems of complicated reaction temperature product purification process and low process yield, and achieve the effects of easy biochemical degradation treatment, simple process, and improved conversion efficiency

Active Publication Date: 2022-02-01
SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the overall yield of related processes is low, and the reaction temperature is generally around 150°C, and the product purification process is complicated

Method used

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  • A new method for the synthesis of 5-azacytosine
  • A new method for the synthesis of 5-azacytosine
  • A new method for the synthesis of 5-azacytosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] (1) Weigh 42 g (0.5mol) of dicyandiamide and place it in a dry reactor, measure 76 mL (1.25mol) of methyl formate into the reactor and mix with dicyandiamide, put the reactor into The temperature in the oven was raised to 115°C, kept warm for 120 minutes, then taken out, the liquid in the kettle was evaporated, cooled, and the white solid produced was taken out.

[0044] (2) Transfer the white solid to a 1000 mL three-necked flask, and add 200 mL of 10% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, filter the clear solution while it is hot, add ammonia water to the filtrate to adjust the pH to 6, and white crystals are precipitated, after centrifugation, dry at 120°C in a hot air oven to obtain 40 g of 5-azacytosine ( The yield is 71% based on dicyandiamide).

[0045] Depend on image 3 Infrared spectroscopy can confirm that the synthetic product is 5-azacytosine; Figure 4 It is the high-performance liquid chromatogram of ...

Embodiment 2

[0047] (1) Weigh 42 g (0.5mol) of dicyandiamide and place it in a dry reactor, measure 100 mL (1.25mol) of ethyl formate into the reactor and mix with dicyandiamide, put the reactor into The temperature in the oven was raised to 115°C, kept warm for 120 minutes, then taken out, the liquid in the kettle was evaporated, cooled, and the white solid produced was taken out.

[0048] (2) Transfer the white solid to a 1000 mL three-necked flask, and add 200 mL of 10% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, filter the clear solution while it is hot, add ammonia water to the filtrate to adjust the pH to 6, and white crystals are precipitated, after centrifugation, dry at 120°C in a hot air oven to obtain 42 g of 5-azacytosine ( The yield is 75% based on dicyandiamide).

[0049] Depend on Figure 5 Draw, utilize area normalization method to test purity higher than 98% by high performance liquid chromatography.

Embodiment 3

[0051] (1) Weigh 42 g (0.5mol) of dicyandiamide and place it in a dry reactor, measure 120 mL (1.25mol) of propyl formate into the reactor and mix with dicyandiamide, put the reactor into The temperature in the oven was raised to 115°C, kept warm for 120 minutes, then taken out, the liquid in the kettle was evaporated, cooled, and the white solid produced was taken out.

[0052] (2) Transfer the white solid to a 1000 mL three-necked flask, and add 200 mL of 10% dilute hydrochloric acid. Heat to reflux for 30 minutes until the solution becomes clear, filter the clear solution while it is hot, add ammonia water to the filtrate to adjust the pH to 6, and white crystals are precipitated, after centrifugation, dry in a hot air oven at 120°C to obtain 45g of 5-azacytosine (The yield is 80% based on dicyandiamide).

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Abstract

The invention discloses a method for synthesizing 5-azacytosine, which comprises the following steps: (1) adding dicyandiamide and formate into a closed reaction device, heating and reacting, distilling out unreacted formate and corresponding After alcohol, a white solid was obtained; (2) the product obtained in step (1) was refined with hydrochloric acid and ammonia water to obtain 5‑azacytosine. The present invention uses a high-pressure reactor to directly react formate and dicyandiamide to synthesize 5-azacytosine. Among them, the formate ester is simultaneously used as the reactant, the reaction solvent and the dehydrating agent for the ring closure reaction in the reaction process, so that the hydrolysis of the formate ester, the hydration reaction of dicyandiamide and the dehydration reaction of amidinourea formate can be carried out under hydrothermal conditions. The following can be carried out collaboratively. The synthesis process is simplified, the occurrence of side reactions is avoided, and the product purity is improved. The overall reaction yield is higher than 70% in terms of dicyandiamide, and the purity is higher than 98%.

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, also known as 4-amino-1,3,5-triazin-2-one, is the basic raw material for the synthesis of 5-azacytidine drugs. As a synthetic pyrimidine base, 5-azacytosine can be combined with ribose to form 5-azacytosine, which is a cytosine nucleoside drug, and it can penetrate into tumors as a pseudo-metabolite In the nucleic acid, it interferes with the physiological function of tumor cells to produce anti-tumor effect. The currently developed therapeutic drug using 5-azacytosine as a raw material is 5-azacytidine, trade name Vidaza. There is also 5-aza-2'-deoxycytidine, trade name Decitabine. Such drugs have been clinically proven to be effective in myelodysplastic syndrome, myeloid leukemia, sickle cell anemia, and some solid tumors. [0003] [0004] Based on similar artificially synthesized pyri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D251/16
CPCC07D251/16
Inventor 陈红余李平孙凡荣张熙曼
Owner SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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