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Method for preparing azacitidine by high-purity and low-calcination residue

A technology of azacitidine and azacytosine, which is applied in the field of azacitidine synthesis technology, can solve the problems of easy residual metal tin, difficulty in large-scale production, low yield of crude product, etc., to achieve easy quality control and reduce emulsification Phenomenon, the effect of high product purity

Inactive Publication Date: 2019-08-06
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the synthetic routes that have been reported, there are mainly the following problems: 1) tin tetrachloride is used as a catalyst in the condensation step, which is highly toxic and easily leaves tin metal in the final product (WO2004082619); 2) silyl ether Benzene is used as a solvent, the yield is low, and large-scale production is relatively difficult (US3350388); 3) bromosugar is used as a reaction intermediate, because bromo is often a mixture of epimers, which leads to stereoselection of the resulting product (J Org Chem, 1970, (35): 491-495); 4) 5-azacytosine silylating reagents are used more, and the molar ratio of 5-azacytosine to HMDS is as high as 1: 3 or more (US7038038); 5) Intermediate 1 was not purified by filtration, resulting in difficulty in stratification after the coupling reaction, the target product was hydrolyzed with many impurities, and it was difficult to purify the final product once to meet the standard requirements; 6) The amount of tetraacetyl ribose used was large, lead to low yield of crude product

Method used

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  • Method for preparing azacitidine by high-purity and low-calcination residue
  • Method for preparing azacitidine by high-purity and low-calcination residue
  • Method for preparing azacitidine by high-purity and low-calcination residue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of Intermediate 1: Add 5-azacytosine (224g, 2.0mol), HMDS (646g, 4.0mol) and ammonium sulfate (24g, 0.18mol) in a dry 2L round bottom flask, start mechanical stirring and mix, Gradually raise the temperature to 145-150°C to reflux, and the system begins to become clear in about 5 hours. After the reflux reaction was continued for 15 hours, the heating was stopped. When the temperature dropped to 40-50° C., a large amount of white crystals were precipitated. After cooling down to room temperature, suction filtration was performed. The crystals were soaked with 50 ml of HMDS, drained and dried to obtain 492 g of intermediate 1. Yield 96.0%, mp: 136-138°C.

[0045] Preparation of Intermediate 2: Take Intermediate 1 (164g, 0.64mol) prepared by the above method, add tetraacetyl ribose (221.3g, 0.69mol), dissolve in 1250ml of anhydrous dichloromethane, stir well and slowly add TMSOTf (195g, 0.87mol), the reaction system gradually became clear during the dropwise ...

Embodiment 2

[0049] Preparation of Intermediate 1: Same as Example 1.

[0050] Preparation of Intermediate 2: Take Intermediate 1 (164g, 0.64mol) prepared by the above method, add tetraacetyl ribose (221g, 0.69mol), dissolve in 1200ml of anhydrous dichloromethane, stir slowly and drop TMSOTf ( 195g, 0.87mol), the reaction system gradually became clear during the dropwise addition, and reacted overnight at room temperature. Prepare 1000ml of 0.24N dilute hydrochloric acid solution in cold water, add it to the reaction system, and the color of the reaction solution becomes lighter with stirring. After reacting for 45 minutes, slowly add 1700 ml of ice-cold 10% sodium carbonate solution, stir well until the pH is 8-9, and let stand to separate the organic phase and the aqueous phase. The organic phase was washed with ice water, dried over anhydrous sodium sulfate overnight, and concentrated to give Intermediate 2 253 g as a fluffy white solid with a moisture content of 1.8%.

[0051] Prepar...

Embodiment 3

[0053] Embodiment 3 (comparative example)

[0054] Preparation of Intermediate 1: Same as Example 1.

[0055] Preparation of Intermediate 2: Take Intermediate 1 (164g, 0.64mol) prepared by the above method, add tetraacetyl ribose (256g, 0.80mol), dissolve in 1200ml of anhydrous dichloromethane, stir slowly and drop TMSOTf ( 195g, 0.87mol), the reaction system gradually became clear during the dropwise addition, and reacted overnight at room temperature. Take 70g of sodium carbonate, 56g of sodium bicarbonate, 750g of ice and 500g of purified water, mix and stir evenly, pour the reaction solution into the mixture, stir vigorously until no more bubbles are generated, separate the water phase and the organic phase, and use 200ml of distilled water for the water phase. Extract with methyl chloride, combine the organic phases and wash with cold 10% sodium bicarbonate solution and cold saturated brine, and dry over anhydrous sodium sulfate overnight. After concentration and evapor...

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Abstract

The invention relates to the field of a pharmaceutical synthesis technology, and discloses a method for synthesizing azacitidine. The method improves the quality and product purity of azacitidine, andthe reaction conditions are easy to control and reduce the production cost, and the method is suitable for industrial preparation.

Description

technical field [0001] The invention relates to azacitidine synthesis technology. The biggest feature of the technology product is high purity, low burning residue and high yield, and is especially suitable for industrial production. Background technique [0002] Azacitidine (5-Azacytidine), the chemical name is 1-(β-D-ribofuranosyl)-4-amino-1,3,5-triazin-2(1H)-one, also known as 5-nitrogen Azacytidine, 5-azacytidine, azacytidine or azacytidine having the following structural formula: [0003] [0004] Azacitidine is a DNA methyltransferase inhibitor developed by Pharmion Corporation of the United States, which was first launched in the United States in July 2004; it is a cell cycle-specific drug that acts on the S phase, and can quickly phosphorylate and penetrate into RNA (ribonucleic acid) ) and DNA (deoxyribonucleic acid) can inhibit the synthesis of protein by destroying the smooth translation of nucleic acid into protein, and can also affect the synthesis of pyrimi...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00
CPCC07H1/00C07H19/12
Inventor 潘显道林菁菁杜国华沈珑瑛
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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