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1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and application

A technology of fluorenylmethoxycarbonyl and acetoxy, which is applied in the field of medicinal chemistry, can solve the problems of being unsuitable for large-scale industrial production, difficult operation, low yield, etc., to reduce one column chromatography operation and make the process easy to operate , the effect of improving the synthesis yield

Active Publication Date: 2011-05-25
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are generally two shortcomings in these methods: 1, harsh deprotection conditions, poor reaction repeatability, low yield, and low product purity; 2, the preparation of chlorine-substituted 2-deoxy-D-ribose derivatives needs to use a large amount of hydrochloric acid gas , Corrosion equipment, difficult operation, not suitable for large-scale industrial production
In the preparation method of WO2009086687A1, the synthesis strategy of Fmoc-(fluorenylmethyloxycarbonyl) as the protecting group is adopted, which can remove the protecting group conveniently, but the process adopts methoxyl substitution on the reaction site, and is used in the preparation of α , β-swirl decitabine precursor 1-(2-deoxy-3,5-di-O-acyl-D-ribose)-4-amino-1,3,5-s-triazin-2-one When α:β>3:2 disclosed in this process, the proportion of the target product β-isomer is relatively small, and the yield is low, which cannot meet the needs of modern industrial production.

Method used

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  • 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and application

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1 Preparation of 1-acetoxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose, and using this as an intermediate to prepare decitabine

[0029] Proceed as follows:

[0030] 14kg 1-methoxy-2-deoxy-3,5-di-o-fluorenylmethoxycarbonyl-D-ribofuranose and 7.8L acetic anhydride were dissolved in a mixed solution of 1.9L ethyl acetate and 32L acetic acid, Slowly add 4L of sulfuric acid in acetic acid solution (sulfuric acid: acetic acid solution, 14:1, V / V) dropwise at 0°C, stir at 0°C for 15 min after the addition, after TLC detects that the reaction is complete, add 30L of dichloromethane to the reaction solution and 50L saturated sodium chloride solution, after standing to separate layers, the organic phase was washed with saturated sodium bicarbonate solution until weakly alkaline, and then washed with a large amount of saline until neutral, the organic phase was separated, dried with sodium sulfate, and evaporated to dryness. That is, 8.435 kg of 1-acetoxy-2...

Embodiment 2

[0035] Example 2 Preparation of 1-acetoxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose, and using this as an intermediate to prepare decitabine

[0036] Proceed as follows:

[0037] Dissolve 1300g of 1-methoxy-2-deoxy-3,5-two-o-fluorenylmethoxycarbonyl-D-ribofuranose and 840mL of acetic anhydride in a mixed solution of 250mL of ethyl acetate and 2.6L of acetic acid, 10 Slowly add 400 mL of acetic acid solution of sulfuric acid (sulfuric acid: acetic acid solution, 14:1, V / V) dropwise at ℃, stir at 10 ℃ for 1 h after the addition, after TLC detects that the reaction is complete, add 3 L of dichloromethane and 5L saturated sodium chloride solution, after stirring and stratifying, the organic phase was washed with saturated sodium bicarbonate solution to weak alkalinity, and after stratification, the organic phase was washed with a large amount of salt water until neutral, the organic phase was separated, dried with sodium sulfate, and evaporated to dryness The solv...

Embodiment 3

[0040] Example 3 Preparation of 1-acetoxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose, and using this as an intermediate to prepare decitabine

[0041] Proceed as follows:

[0042] Dissolve 300g of 1-methoxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose and 840mL of acetic anhydride in a mixed solution of 250mL of ethyl acetate and 2.6L of acetic acid,- Slowly add 170 mL of sulfuric acid in acetic acid solution (sulfuric acid: acetic acid solution, 14:1, V / V) dropwise at 10°C, stir at -10°C for 4 hours after addition, after the reaction is detected by TLC, add 1L of dichloro Methane and 1L saturated sodium chloride solution were stirred and separated, and the organic phase was washed with saturated sodium bicarbonate solution until it was slightly alkaline. After the layers were separated, the organic phase was washed with a large amount of salt water until it was neutral, and the organic phase was separated and dried with sodium sulfate. The solvent ...

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Abstract

The invention discloses 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose, which has a following structural formula as the accompanying drawing. A method for preparing the 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose comprises the following steps: adding 1-methoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and acetic anhydride into solvents; and then, adding catalysts to carry out nucleophilic substitution reaction under the acid catalysis to obtain the 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose, wherein the solvents are acetic acid and ethyl acetate, the catalysts are sulphuric acid, the reaction temperature is between -30 DEG C and 30 DEG C, and the reaction time t is higher than 0 and lower than or equal to 4 hours. The 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose disclosed by the invention can be used as a midbody to synthesize 2-deoxy-5-azacytidine.

Description

technical field [0001] The invention relates to a key intermediate 1-acetoxy-2-deoxy-3,5-di-O-fluorenylmethoxycarbonyl-D-ribofuranose for synthesizing the ribose antitumor drug decitabine, and The preparation method and the application in the preparation of decitabine belong to the field of medicinal chemistry. Background technique [0002] 2-deoxy-5-azacytidine, the common name is decitabine, and its structure is shown in formula I below: [0003] [0004] Formula I [0005] Decitabine is a DNA methyltransferase inhibitor with clinical utility in the treatment of myelodysplastic syndromes. In 2006, it was approved by the FDA for the treatment of myelodysplastic syndrome (MDS). Others such as acute and chronic myelogenous leukemia, colorectal cancer, head and neck cancer, and non-small cell lung cancer are also in various phases of clinical research. [0006] At present, there are many documents disclosing the preparation method of decitabine, such as CN 101311184, CN ...

Claims

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Application Information

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IPC IPC(8): C07H13/12C07H19/12C07H1/00
Inventor 王晶翼张照珍房玺范传文张明会
Owner QILU PHARMA HAINAN
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