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Method for separating and determining raltitrexed and its impurities by high performance liquid chromatography

A technology for raltitrexed and impurities, applied in the field of separation and determination of raltitrexed and its impurities by high performance liquid chromatography, to achieve the effect of ensuring quality controllability

Active Publication Date: 2019-08-06
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] There is no literature report about the separation and determination method of raltitrexed and the above seven impurities

Method used

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  • Method for separating and determining raltitrexed and its impurities by high performance liquid chromatography
  • Method for separating and determining raltitrexed and its impurities by high performance liquid chromatography
  • Method for separating and determining raltitrexed and its impurities by high performance liquid chromatography

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of embodiment 1 impurity C

[0038] (1) Preparation of 5-nitro-2-thiophenoyl chloride

[0039] Put 30g of 5-nitro-2-thiophenecarboxylic acid and 50ml of thionyl chloride into a 100ml three-neck flask, raise the temperature, control the inner temperature to 75℃~80℃ and stir for 2 hours, take about 1ml of the reaction solution, add 2ml of anhydrous Methanol derivatization, using 5-nitro-2-thiophenecarboxylic acid as a control, TLC detection (ethyl acetate: n-hexane = 1:1) to the end of the reaction. The reaction solution was transferred to a 250ml single-necked bottle, concentrated to dryness, and then dried under reduced pressure by adding 30ml of toluene to obtain green needle crystals.

[0040] (2) Preparation of N-(5-nitro-2-thiophenoyl)-L-glutamic acid diethyl ester

[0041] Put 35.0g of L-diethyl glutamate, 150ml of dichloromethane and 12.5ml of diisopropylethylamine into a 250ml three-necked bottle, lower the temperature, and slowly add 50ml of di...

Embodiment 2

[0048] The preparation of embodiment 2 impurity F

[0049] (1) Preparation of N-(5-amino-2-thiophenoyl)-L-glutamic acid diethyl ester

[0050] Prepare with reference to steps (1), (2), and (3) of Example 1.

[0051] (2) Diethyl N-(5-methylamino-2-thienyl)-L-glutamate

[0052] Add 100ml of DMF, 2.0g of 2,6-lutidine, 10g of diethyl N-(5-amino-2-thiophenoyl)-L-glutamate, and 4.5g of methyl iodide into a 250ml three-necked flask, Stir evenly, heat up, and control the feed liquid temperature to 50-60°C for 6 hours. The completion of the reaction was monitored by HPLC, the temperature was lowered to 10-30° C., quenched by adding 80 ml of 15% saline, extracted with 200 ml of ethyl acetate in 3 times on average, and allowed to stand for liquid separation. Combine the organic phases, add anhydrous magnesium sulfate, stir and dehydrate for 2 hours, and filter with suction until no liquid flows out. The filtrate was transferred to a rotary evaporator and concentrated until no liquid ...

Embodiment 3

[0058] Embodiment 3 specificity test

[0059] Instrument: Agilent 1260 high performance liquid chromatograph

[0060] Detector: DAD

[0061] Workstation: Agilent OpenLAB CDS (EZChrom Edition)

[0062] Chromatographic column: Agilent Extend-C18 (4.6mm×250mm, 5μm)

[0063] Detection wavelength: 226nm

[0064] Flow rate: 1.0mL / min

[0065] Column temperature: 30°C

[0066] Injection volume: 10μL

[0067] Mobile phase: buffer-methanol (70:30), where the buffer is 0.005mol / L tetrabutylammonium bromide aqueous solution (adjust the pH to 8.5 with phosphoric acid)

[0068] Blank solution preparation: Precisely measure 0.4mL of 0.1mol / L sodium hydroxide aqueous solution, put it in a 10mL measuring bottle, add mobile phase to dilute to the mark, and shake well.

[0069] Positioning solution preparation: Accurately weigh about 10.0 mg of each impurity, put them in a 20 mL volumetric bottle, add 0.4 mL of 0.1 mol / L sodium hydroxide aqueous solution and ultrasonically dissolve them,...

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Abstract

The invention discloses a method for separation and determination of Raltitrexed and impurities of the Raltitrexed by high performance liquid chromatography. Chromatographic conditions of the method are that octadecylsilane chemically bonded silica is taken as a filler, 0.005 mol / L tetrabutylammonium bromide aqueous solution-methanol is taken as a mobile phase, detection wavelength is 210-310 nm,column temperature is 25-40 DEG C, and mobile phase velocity is 0.5-2.0 mL / min, wherein the tetrabutylammonium bromide aqueous solution is adjusted to a pH of 8.0-9.0 with phosphoric acid. Sample solution preparation is to prepare solutions containing the Raltitrexed and the purities of the Raltitrexed of 0.1-1.0 mg / mL by using a polar solvent. The determination is to inject the solutions into high performance liquid chromatograph, record chromatograms and analyze the chromatograms. The method of the invention can be used to rapidly and accurately perform quantitative analysis on related substances of Raltitrexed bulk medicine and preparations of the Raltitrexed, thereby ensuring the quality controllability of the Raltitrexed.

Description

technical field [0001] The invention belongs to the field of drug analysis, in particular to a method for separating and measuring raltitrexed and its impurities through high-performance liquid chromatography. Background technique [0002] Raltitrexed was developed by the Cancer Research Unit at the Royal Marsden Hospital in the UK in collaboration with Zeneca. It is a thymonucleotide synthase inhibitor, a derivative of folic acid, used in the treatment of patients with advanced colorectal cancer. It was launched in the UK for the first time in 1996 under the trade name Tomudex, and it was launched in France and other countries in the same year. As a first-line treatment drug for advanced colorectal cancer, it has the advantages of less toxic and side effects, convenient administration, and low price, and is in great demand in China. [0003] The structural formula of raltitrexed is as follows: [0004] [0005] The main adverse reactions of raltitrexed include reversi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02
CPCG01N30/02
Inventor 柴雨柱许建良储雪原王足兵宋洁梅兰公剑王华萍徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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