New synthesis method of 5-aza-cytosine

A technology of azacytosine and a synthesis method, applied in the field of organic synthesis, can solve the problems of complicated reaction temperature product purification process, low process yield and the like, so as to improve the reaction yield and product purity, improve the conversion yield, and increase the atomic economical effect

Active Publication Date: 2018-12-18
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 temperat

Method used

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  • New synthesis method of 5-aza-cytosine
  • New synthesis method of 5-aza-cytosine
  • New synthesis method of 5-aza-cytosine

Examples

Experimental program
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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 new synthesis method of 5-aza-cytosine, which includes the steps of: (1) adding dicyandiamide and formate into a sealed reaction device, performing a heating reaction and distilling out non-reacted formate and corresponding alcohol to obtain a white solid; (2) purifying the white solid with hydrochloric acid and ammonia water to obtain the 5-aza-cytosine. In the method, the 5-aza-cytosine is directly synthesized through a reaction on the dicyandiamide and formate in a high-pressure reaction kettle, wherein the formate serves as a reactant, a reaction solvent, and a dehydrator in a ring-closing reaction in the process, so that processes of hydrolysis of the formate, hydration of the dicyandiamide and dehydration of dicyandiamidine formate can be carried out simultaneously under a hydrothermal condition, thus simplifying the synthesis route, avoiding side reactions and increasing purity of product. The total reaction yield is higher than 70% on the basis of dicyandiamide, and product 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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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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