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Detection and analysis method for quality control of raltitrexed synthesis

A technology of raltitrexed and analysis method, which is applied in the detection and analysis field of raltitrexed synthetic quality control, to achieve the effects of comprehensive quality control, convenient operation and strong specificity

Active Publication Date: 2019-01-29
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is no literature report on the detection of its enantiomers by high performance liquid chromatography

Method used

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  • Detection and analysis method for quality control of raltitrexed synthesis
  • Detection and analysis method for quality control of raltitrexed synthesis
  • Detection and analysis method for quality control of raltitrexed synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 High performance liquid chromatography determines the purity of starting material 6-bromomethyl-3,4-dihydro-2-methyl-quinazolin-4-one

[0044] 1.1 Chromatographic conditions

[0045] Instrument: Agilent 1260 high performance liquid chromatography;

[0046] Detector: VWD;

[0047] Chromatographic column: Agilent Extend-C18 chromatographic column (4.6mm×250mm, 5μm);

[0048] Mobile phase: water: acetonitrile = 80:20;

[0049] Column temperature: 35°C;

[0050] Flow rate: 1.0mL / min;

[0051] Detection wavelength: 230nm;

[0052] Injection volume: 10μL

[0053] 1.2 Sample preparation

[0054] Blank solution: 50% acetonitrile in water

[0055] Preparation of positioning solution: Accurately weigh about 10 mg of impurity E and impurity X, add appropriate amount of 50% acetonitrile aqueous solution to dissolve, and dilute to make a solution containing 0.1 mg per 1 mL, respectively as impurity positioning solution.

[0056] Preparation of system suitabilit...

Embodiment 2

[0074] Embodiment 2 HPLC measures the purity of starting material 5-nitro-2-thiophenecarboxylic acid

[0075] 2.1 Chromatographic conditions

[0076] Instrument: Agilent 1260 high performance liquid chromatograph

[0077] Detector: VWD

[0078] Workstation: Agilent OpenLAB CDS (EZChrom Edition)

[0079] Chromatographic column: Agilent Extend-C18 (4.6mm×250mm, 5μm)

[0080] Detection wavelength: 226nm

[0081] Flow rate: 1.0mL / min

[0082] Column temperature: 30°C

[0083] Injection volume: 10μL

[0084] Mobile phase: 0.1% trifluoroacetic acid in water: methanol (55:45)

[0085] 2.2 Sample preparation

[0086] Blank: 45% methanol in water

[0087] 5-Nitro-2-thiophene formaldehyde stock solution: Accurately weigh about 10.0mg of 5-nitro-2-thiophene formaldehyde, put it in a 20mL measuring bottle, add a blank solvent to dissolve and dilute to the mark, shake well to get ready. (about 0.5mg / mL)

[0088] 4-Nitro-2-thiophenecarboxylic acid stock solution: Accurately weigh...

Embodiment 3

[0107] Embodiment 3 high performance liquid chromatography is determined the content of raltitrexed

[0108] 3.1 Chromatographic conditions

[0109] Instrument: Agilent 1260 high performance liquid chromatograph

[0110] Detector: DAD

[0111] Workstation: Agilent OpenLAB CDS (EZChrom Edition)

[0112] Chromatographic column: Agilent Extend-C18 (4.6mm×250mm, 5μm)

[0113] Detection wavelength: 226nm

[0114] Flow rate: 1.0mL / min

[0115] Column temperature: 30°C

[0116]Injection volume: 10μL

[0117] 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)

[0118] 3.2 Solution preparation

[0119] Reference substance solution: take a certain amount of raltitrexed reference substance, and prepare a solution with a concentration of about 1.0 mg / mL with 0.1 mol / L sodium hydroxide aqueous solution.

[0120] Test product solution: take a certain amount of raltitrexed test...

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Abstract

The invention discloses a detection and analysis method for quality control of raltitrexed synthesis. The method includes purity detection of a starting material 6-bromomethyl-3,4-dihydro-2-methyl-quinazoline-4-one, purity detection of a starting material 5-nitro-2-thiophenecarboxylic acid, raltitrexed content determination, content detection of the 6-bromomethyl-3,4-dihydro-2-methyl-quinazoline-4-one, 6-hydroxymethyl-3,4-dihydro-2-methyl-quinazoline-4-one and the 5-nitro-2-thiophenecarboxylic acid in raltitrexed, and raltitrexed enantiomer detection. The method of the invention has the characteristics of high sensitivity and strong specificity, and can rapidly and accurately perform quality control on a synthesis process of the raltitrexed, thereby ensuring the quality of raltitrexed bulk medicine.

Description

technical field [0001] The invention belongs to the field of drug analysis, in particular to a detection and analysis method for quality control of raltitrexed synthesis. 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] [0004] There are multiple synthetic methods for raltitrexed, and the commonly used synthetic routes are as follows: [0005] [0006] In this route, using 5-nitro...

Claims

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Application Information

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