Pralatrexate degradation impurity and preparation method thereof

An impurity, pteridine-based technology, applied in the field of pralatrexate degrading impurities, can solve the problems of limited reaction degree, structural stability, difficult to degrade, separate, no compound synthesis report, etc.

Active Publication Date: 2014-02-19
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the limitations of the degree of reaction and the stability of its own structure, it is difficult to obtain
And there is no synthetic report of this compound in the literature

Method used

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  • Pralatrexate degradation impurity and preparation method thereof
  • Pralatrexate degradation impurity and preparation method thereof
  • Pralatrexate degradation impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add compound (II) (3.5g), sodium hydroxide (1.2g), water (30ml), and DMSO (30ml) into a 250ml reaction bottle, heat up to 60-65°C for reaction, HPLC detects that the reaction is complete, add isopropyl Alcohol (150ml), adjust the pH to 5-6 with glacial acetic acid, the solid precipitates, stir and beat for 1 hour, filter, wash the filter cake with water, and dry in vacuum for 16 hours to obtain 2.6g of compound (III) as a yellow solid, yield 74.1 %. TLC plate detection is single point, TLC conditions (developing solvent is dichloromethane:methanol:acetic acid=10:1:1, Rf=0.2).

Embodiment 2

[0029] Compound (III) (2.6g) and DMSO (14ml) were added into a 50ml reaction flask, and the temperature was raised to 25°C. Add L-glutamate dimethyl hydrochloride (1.9g), HOBt (1.5g), EDC (2.1g), add triethylamine (4ml), TLC monitors the completion of the reaction, pour the reaction solution into water (200ml ), the solid precipitated, stirred and beaten for 1 hour, filtered, the filter cake was washed with water, dried in vacuum for 16 hours, and purified by column chromatography (dichloromethane:methanol=30:1) to obtain 2.2g of compound (IV), which was light red Solid, yield 58.4%. The purity was 97% as detected by HPLC.

Embodiment 3

[0031] Add compound (IV) (2.2g), methanol (7ml), water (7ml) into a 25ml reaction flask. Add sodium hydroxide (0.5g), monitor the completion of the reaction by TLC, filter, adjust the pH of the filtrate to 5-6 with glacial acetic acid, solid precipitates, stir and beat for 1 hour, filter, wash the filter cake with water, and dry in vacuum for 16 hours to obtain the target compound 1.8g, as a light red solid, yield 86.6%. Through HPLC detection, the product purity is 96%.

[0032] a. MS-ESI (m / z): 477.23[M-H]-;

[0033] b. 1 H-NMR (DMSO-d 6 )δ:12.07(br,2H),8.49(d,J=7.6Hz,1H),8.35(d,J=2.4Hz,1H),7.77(d,J=8.0Hz,2H),7.37(d, J=7.6Hz,2H),6.98(s,2H),4.40-4.35(m,1H),3.45-3.42(m,1H),3.32-3.27(m,1H),3.20-3.14(m,1H) ,2.77(s,1H),2.61(d,J=5.6Hz,2H),2.35(t,J=7.4Hz,2H),2.10-2.07(m,1H),1.97-1.92(m,1H).

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Abstract

The invention relates to a pralatrexate degradation impurity and a preparation method thereof. Specifically, the formula (I) of the pralatrexate degradation impurity is N-[4-1- [(2-amino-4-hydrox-6-pteridine) methyl]-3-butine-1-group] benzoyl]-L-glutamate. An N-[4-1- [(2-amino-4-diamido-6-pteridine) methyl]-3-butine-1-group] benzoic acid compound is subjected to substitution, condensation and hydrolysis, and a target compound is obtained, so that the pralatrexate degradation impurity is synthesized. According to the method, the compound of the formula (I) is chemically synthesized for the first time, and the obtained target compound can be separated efficiently and rapidly.

Description

technical field [0001] The present invention relates to a kind of N-[4-[1-[(2-amino-4-hydroxyl-6-pteridyl)methyl]-3-butyn-1-yl]benzoyl]-L-glucose Amino acid and its preparation method, the compound is the degradation impurity of pralatrexate. Background technique [0002] Pralatrexate (Pralatrexate, the structure shown below) was first synthesized by SRI, and its preclinical and clinical research was carried out in cooperation with Memorial Sloan-Kettering (MSKCC). In 2003, Allos Therapeutics Inc. acquired its global development rights from SRI and MSKCC. In September 2009, the FDA approved the new drug application for pralatrexate as an orphan drug for peripheral T-cell lymphoma, and it was launched in the United States in October 2009. [0003] [0004] Pralatrexate is the first drug approved by the FDA for the treatment of peripheral T-cell lymphoma. Clinical studies have found that it can reduce tumor volume and prolong the survival of cancer patients. [0005] In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/04
CPCC07D475/04
Inventor 乔智涛董淑求周炳城
Owner 连云港恒运药业有限公司
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