Method for preparing fluoro alpha-D-arabinofuranose compound

A technology for furanoses and compounds is applied in the field of preparation of fluoro α-D-arabinofuranoses, and can solve the problems of many by-products, serious environmental pollution, difficulty in industrialized production and the like, and improve the reaction yield. , The effect of high product purity and convenient post-processing

Active Publication Date: 2010-07-14
APELOA PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, HF is highly corrosive. If it encounters high heat, the internal pressure of the container will increase, and there is a risk of cracking and explosion. It requires extremely high equipment, so it is not suitable for industrial production.
Tetrabutylammonium fluoride is expensive, the yield of fluorination reaction is low, only about 20%, the cost is too high, there are many by-products of the reaction, and it is not suitable for industrial production
The fluorinated reagent is liquid, extremely unstable, decomposes with water, and releases a large amount of highly toxic sulfur dioxide and HF gas. The environmental pollution is extremely serious. In the process of production, storage, and transportation, if it encounters collision or high temperature, it is very easy to explode.
Fluorinated reagents are highly corrosive, require high equipment, and are difficult to realize industrial production. Moreover, they are expensive and difficult to produce. There are few manufacturers and difficult to purchase.

Method used

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  • Method for preparing fluoro alpha-D-arabinofuranose compound
  • Method for preparing fluoro alpha-D-arabinofuranose compound
  • Method for preparing fluoro alpha-D-arabinofuranose compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] Under anhydrous and oxygen-free conditions, 4.62g (0.01mol) of 1,3,5-tribenzoyl ribose (compound IIIa) was dissolved in 45mL of dichloromethane, and 4.2g (0.02mol) of 4 - dichloromethane solution of formic acid phenylsulfur trifluoride (compound II-1), after the dropwise addition, rise to room temperature and stir until TLC monitors that the reaction is complete. The reaction solution was poured into ice water, separated, the aqueous layer was extracted twice with dichloromethane, the organic layer was combined, and the organic layer was sequentially washed with saturated NaHCO 3 liquid, water, and saturated brine, and dried over anhydrous sodium sulfate. After filtering and evaporating to dryness, the residue was recrystallized from ethanol to obtain 2.70 g of 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose (Compound Ia), with a yield of 58%.

[0029] 1 HNMR (300Hz, CDCl 3 ): 4.6-4.8 (m, 3H), 5.3-5.4 (d, J=45.6Hz, 1H), 5.65-5.66 (dd, J 1 =2.94Hz,J...

Embodiment 2

[0033]

[0034] Dissolve 5.04g (0.01mol) of 1,3,5-tri-toluoyl ribose (compound IIIb) in 50mL of toluene, and add 3.36g (0.015mol) of 4-methoxycarbonylphenyl trifluoride dropwise under ice-cooling After the toluene solution of sulfur (compound II-7) was added dropwise, it was raised to room temperature and stirred until the reaction was completed as monitored by TLC. The reaction solution was poured into ice water, separated, the water layer was extracted twice with toluene, the organic layer was combined, and the organic layer was sequentially washed with saturated NaHCO 3 liquid, water, and saturated brine, and dried over anhydrous sodium sulfate. Filtered, evaporated to dryness, and the residue was recrystallized with ethyl acetate to obtain 3.22g of 2-deoxy-2-fluoro-1,3,5-tri-p-toluoyl-α-D-arabinofuranose (compound I b). rate of 64%.

[0035] 19 FNMR (282Hz, CDCl 3 ): -184.3.

Embodiment 3

[0037]

[0038] 2.76g (0.01mol) of 1,3,5-triacetyl ribose (compound IIIc) was dissolved in 30mL of acetonitrile, and 3.82g (0.02mol) of 3-cyanophenylsulfur trifluoride (compound II-11) acetonitrile solution, after the dropwise addition is complete, rise to room temperature and stir until the reaction is complete as monitored by TLC. The solvent was evaporated, and the residue was added to ice water and dichloromethane to separate the layers. The aqueous layer was extracted twice with dichloromethane, and the organic layers were combined. The organic layer was sequentially washed with saturated NaHCO 3 , water, saturated brine, and dried over anhydrous sodium sulfate. Filter, evaporate to dryness, and recrystallize the residue with ethyl acetate to obtain 2.09g of 2-deoxy-2-fluoro-1,3,5-triacetyl-α-D-arabinofuranose (Compound Ic), yield 75% .

[0039] 19 FNMR (282Hz, CDCl 3 ): -190.8.

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Abstract

The invention relates to a method for preparing a fluoro alpha-D-arabinofuranose compound. The method comprises the step of carrying out fluorination on substituted alpha-D-arabinofuranose compound (III) by an aryl sulfur fluoride fluoro reagent (II) so as to obtain a 2-deoxidized-2-fluorine substituted alpha-D-arabinofuranose compound (I). Compared with the traditional method, the preparation method has the advantages of simplicity, high product yield, less by-products, easy purification of products and high purity. The fluoro reagent causes less environmental pollution, is easy to store andtransport and is suitable for industrialized production. The reaction process is described in the specification of the invention.

Description

technical field [0001] The invention relates to a preparation method of fluorinated α-D-arabinofuranose compound. Background technique [0002] Fluorinated α-D-arabinofuranose compounds, such as 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose shown in formula (Ia), are the second An important intermediate of the purine nucleotide analogue clofarabine. [0003] Take clofarabine whose structure is shown in formula (IV) as an example, it is a drug specially used for childhood leukemia, and is used as the main drug for treating refractory or relapsed acute lymphoblastic leukemia (ALL) aged 1-21, The cure rate of its treatment is high, the patient's tolerance is good, and there is no unpredictable adverse reaction. [0004] Leukemia, especially acute lymphoblastic leukemia, is the most common malignancy in children and adolescents. Although the cure rate of childhood leukemia is relatively high, if it is treated with adult drugs, it will bring great toxic and side effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H13/08C07H13/06C07H15/18C07H15/04
Inventor 杨勤
Owner APELOA PHARM CO LTD
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