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Nelarabine N-9 site alpha isomer, and preparation method and application thereof

A technology of N-9, isomers, applied in the field of medicinal chemistry

Inactive Publication Date: 2011-05-18
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the N-9 alpha isomer of nelarabine has never been independently prepared and separated from nelarabine

Method used

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  • Nelarabine N-9 site alpha isomer, and preparation method and application thereof
  • Nelarabine N-9 site alpha isomer, and preparation method and application thereof
  • Nelarabine N-9 site alpha isomer, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Quantitative analysis of the N-9 alpha isomer in nelarabine

[0050] A. HPLC chromatography

[0051] Chromatographic column: Agilent Zorbax Bonus-Rp 4.6×150mm;

[0052] Mobile phase: 0.01mol / L disodium hydrogen phosphate solution (containing 0.6% triethylamine, adjust the pH value to 7.0 with phosphoric acid)-acetonitrile (95:5);

[0053] Detection wavelength: 249nm;

[0054] Flow rate: 1.0mL / min;

[0055] Column temperature: 40°C

[0056] Injection volume: 20μl

[0057] B. Prepare the standard solution positioning map for identifying the N-9 alpha isomer of nelarabine:

[0058] Prepare the solution of nelarabine N-9 α-isomer standard in the mobile phase, identify the N-9 α-isomer peak at the relative retention time RRT of 0.9, see the chromatogram Figure 1 .

[0059] C. Preparation of a marker solution for identifying the N-9 alpha isomer of nelarabine:

[0060] Prepare a nelarabine marker solution containing the N-9 alpha isomer of nelarabine at a ...

Embodiment 2

[0066] Example 2 Preparation of 2-amino-6-chloro-9-D-(2,3,5-tri-O-benzyl-arabinofuryl)-9H-purine (intermediate A)

[0067] Add 152.6 g (0.9 mol) of 2-amino-6-chloropurine and 2300 g of hexamethyldisilazane into the reaction flask, stir for 10 minutes, then add 147 g (1.35 mol) of trimethylchlorosilane, heat to 120°C, The reaction was kept for 9 hours, the solid basically dissolved to form a solution, and concentrated under reduced pressure to dryness to obtain the silylated product of 2-amino-6-chloropurine, which was directly used in the next reaction.

[0068] The 2-amino-6-chloropurine silylated product obtained in the previous step was placed in a 20L reaction flask, and then 355g (0.81 mol) and 9,000 g of 1,2-dichloroethane, add 200 g (0.9 mol) of trimethylsilyl trifluoromethanesulfonate (TMSOTf) dropwise at 20-30°C under controlled internal temperature, and React for 12 hours, after TLC monitors that the raw material point disappears, pour the reaction solution into 500...

Embodiment 3

[0069] Example 3 Preparation of 2-amino-6-methoxy-9-α-D-(2,3,5-tri-O-benzyl-arabinofuranosyl)-9H-purine (intermediate B)

[0070] Put 11.4g of intermediate A (0.02mol) prepared according to Example 2 into a reaction flask, add 114mL of methanol, under magnetic stirring, add 3.6g (0.067mol) of sodium methoxide, heat up to 60°C and keep it warm for 30 minutes, The reaction at the raw material point was detected by TLC, and the reaction solution was concentrated and evaporated to dryness to obtain an oily substance; 200mL of dichloromethane and 200mL of purified water were added to dissolve, and the water layer was separated, and the water layer was extracted twice with 100mL of dichloromethane, and the organic layer was combined, saturated with chlorine Sodium chloride solution 100mL × 2 washes, the organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and evaporated to dryness to obtain a light yellow oil;

[0071] Dissolve the sample with dichloromethan...

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Abstract

The invention provides a nelarabine N-9 site alpha isomer, a preparation method thereof, and application of the nelarabine N-9 site alpha isomer as a reference compound for qualitative analysis and quantitative analysis on N-9 site alpha isomer impurities in a nelarabine sample.

Description

technical field [0001] The invention relates to a nelarabine N-9 α-type isomer, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Background technique [0002] The chemical name of Nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine, and its structural formula is: [0003] [0004] Nelarabine was developed by GlaxoSmithKline and was approved by the US FDA in October 2005. It has become a treatment for acute T-cell lymphoblastic leukemia (T-ALL) that does not respond to at least two chemotherapy regimens or relapses after treatment. ) and T-cell lymphocytic lymphoma (T-LBL) drugs, which were officially launched in the United States in 2006. Nelarabine is a T-lymphocyte selective nucleoside analogue and a 6-methoxy derivative of the water-soluble deoxyguanosine analogue ara-G. Nucleoside analogues have been shown to be effective as cytotoxic agents in the treatment of hematological malignancies. Nelarabi...

Claims

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Application Information

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IPC IPC(8): C07H19/19C07H1/00G01N21/31G01N30/02G01N30/90
Inventor 赵俊宗在伟杜有国
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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