Process for the synthesis of azacitidine and decitabine

A technology of azacitidine and decitabine, applied in the field of synthesis of azacitidine-ketone) and decitabine-ketone), achieving the effect of high simplicity and avoiding the steps of handling and separation

Active Publication Date: 2011-10-05
CHEMI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Thus, it is evident that the currently available processes for the synthesis of nucleosides derived from azacytosine still present unresolved problems related to their possible use at an industrial level

Method used

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  • Process for the synthesis of azacitidine and decitabine
  • Process for the synthesis of azacitidine and decitabine
  • Process for the synthesis of azacitidine and decitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1. Preparation of Azacitidine

[0059] 34.7 mL of BSTFA was added to a suspension of 6.3 g of azacytosine in 126 mL of dichloromethane. The mixture was brought to reflux temperature and stirred for 90 minutes. In about 10 minutes, 11.35 mL of trimethylsilyl triflate was added to the clear solution, followed by 16.7 g of 1,2,3,5-tetra-O-acetyl-D-ribofuranose A solution in 33 mL of dichloromethane was added to the clear solution. Reflux and stirring are maintained for 2 hours, it is cooled to room temperature and it is poured into a solution of 9.5 g of sodium bicarbonate in 330 ml of water. It was stirred for 10 minutes and the pH was adjusted to pH=4.5 using acetic acid. Allowed to settle, the phases were separated and the aqueous phase was washed twice with 125 ml of dichloromethane per wash. The organic phases anhydrated by treating them with anhydrous calcium chloride were combined. Concentration was carried out under reduced pressure until a viscous re...

Embodiment 2

[0061] Example 2. Preparation of Azacitidine

[0062] 34.7 mL of BSTFA was added to a suspension of 6.3 g of azacytosine in 126 mL of acetonitrile. The mixture was brought to 50°C and stirred for 90 minutes. In about 10 minutes, 11.35 mL of trimethylsilyl triflate was added to the clear solution, followed by 16.7 g of 1,2,3,5-tetra-O-acetyl-D-ribofuranose A solution in 33 mL of acetonitrile was added to the clear solution. Stirring was maintained for 75 minutes, it was cooled to room temperature and it was poured slowly into a mixture of 500 ml of dichloromethane and 330 ml of water into which 9.5 g of sodium bicarbonate had previously been dissolved. Stirring was carried out for 15 minutes and the pH was adjusted to pH=4.5 using acetic acid. The mixture was allowed to settle and the phases were separated. The aqueous phase was washed twice with 125 ml of dichloromethane for each wash. The organic phases, which were dehydrated by treating them with anhydrous calcium chl...

Embodiment 3

[0064] Example 3. Preparation of Azacitidine

[0065]34.7 mL of BSTFA was added to a suspension of 6.3 g of azacytosine in 126 mL of dichloromethane. The mixture was brought to reflux temperature and stirred for 90 minutes. In about 10 minutes, 62 mL of 1M tin tetrachloride in dichloromethane was added to this clear solution, followed by 16.7 g of 1,2,3,5-tetra-O-acetyl-D-ribofuranose in 33 mL The solution in dichloromethane was added to the clear solution. Reflux and stirring are maintained for 75 minutes, it is cooled to room temperature and it is poured into a solution of 9.5 g of sodium bicarbonate in 330 ml of water. It was stirred for 10 minutes and the pH was adjusted to pH=4.5 using 30% aqueous sodium hydroxide solution. Allowed to settle, it was filtered on an earth filter and the phases were separated, the aqueous phase was washed twice with 125 ml of dichloromethane for each wash. The organic phases, which were dehydrated by treating them with anhydrous calciu...

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Abstract

Described herein is a process for the synthesis of azacitidine or decitabine, comprising the silylation of azacytosine in the presence of N,O-bis-trimethylsilyl)-trifluoroacetamide. Such reaction is performed in an organic solvent, preferably aprotic, even more preferably selected from among dichloromethane, dichloroethane and/or acetonitrile. According to a further aspect of the process, 2 to 3 moles of N,O-bis-trimethylsilyl-trifluoroacetamide are used per mole of azacytosine, preferably from 2.2 to 2.5.

Description

technical field [0001] The present invention relates to azacitidine (also known as amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) and decitabine (also known as Synthesis of 4-amino-1-(2-deoxy-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one). Background technique [0002] Various drugs having chemical structures similar to those of natural nucleosides are used in the fields of antiviral drugs and antitumor drugs. [0003] Azacitidine, whose structural formula is shown below, is an antineoplastic drug effective for the treatment of myelodysplastic syndrome (MDS), and it is the first drug approved by the FDA for this disease. [0004] [0005] In Collect.Czech.Chem.Commun. 29 , 2060 (1964) first reported the synthesis of azacitidine based on the construction of an s-triazine ring starting from an appropriately substituted sugar and was also reported in US3350388. A synthetic scheme providing silylation of azacytosine and subsequent coupling to a ribose derivative allows the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/00C07F7/18
CPCC07H19/12C07D405/04C07H1/00
Inventor 洛伦佐·德费拉毛里齐奥·泽诺尼斯特凡诺·图尔凯塔莫罗·阿尼巴尔迪埃托雷·阿米拉蒂保罗·布兰迪乔治·贝拉尔迪
Owner CHEMI SPA
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