Synthesis and separation identification method for aragatroban related substances

A technology of argatroban and related substances, which is applied in the field of synthesis, separation and identification of related substances of argatroban, can solve the problems that have not been seen in the research reports, and achieve reasonable reaction design, simple and easy operation, and easy operation Effect

Inactive Publication Date: 2016-01-27
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] At present, there is no report on related research

Method used

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  • Synthesis and separation identification method for aragatroban related substances
  • Synthesis and separation identification method for aragatroban related substances
  • Synthesis and separation identification method for aragatroban related substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 20ml of fuming nitric acid / 10ml of fuming sulfuric acid into a 100ml three-necked bottle, cool down to below -10°C, slowly add 8.8g of argatroban, after the addition is complete, control the temperature at -10°C to -5°C and stir for 1.5 hours to achieve high efficiency. The liquid phase monitors that the reaction of the raw materials is complete, and the reaction is stopped. Control the low temperature, add 300g of crushed ice to the reaction system, then adjust the pH to 6-7 with concentrated ammonia water, a off-white to light yellow solid precipitates, filter with suction, wash the filter cake with water, and vacuum dry at 40°C for 6h to obtain argatro Class related substance A5.1g, purity 95.6%, yield 53.2%. Product identification: MS (m / z), theoretical value: 553, measured value: 554 [M+H + ].

Embodiment 2

[0034] Add 10ml of fuming nitric acid and 20m of acetic acid into a 100ml three-necked flask, cool down to below -10°C, and slowly add 4.4g of argatroban. After the addition, the temperature was controlled at -10°C to 0°C and the reaction was stirred for 2.5 hours. The high-performance liquid phase was used to monitor the complete reaction of the raw materials, and the reaction was stopped. Control the low temperature, add 200g of crushed ice to the reaction system, adjust the pH to 6-7 with ammonia water, and a off-white to light yellow solid precipitates, filter with suction, wash the filter cake with water, and vacuum-dry at 40°C for 6 hours to obtain related substances of argatroban A1.6g, purity 89.2%, yield 33.4%. Product identification: MS (m / z), theoretical value: 553, measured value: 554 [M+H + ].

Embodiment 3

[0036] Add 3g of argatroban and 90ml of a saturated aqueous solution of barium hydroxide or calcium hydroxide into a 250ml three-necked bottle, stir and heat to reflux, and keep reflux for 12h, and the content of related substance B of argatroban is no longer increased by high performance liquid phase monitoring. Stop responding. Cool to room temperature, add 100ml of ethyl acetate, adjust the pH to neutral with dilute sulfuric acid, and filter with suction to remove insoluble substances. The filtrate was layered, the aqueous phase was extracted with 60ml of ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to obtain 0.4g of oily argatroban related substance B with a purity of 93.6%. Yield 14.5%. Product identification: MS (m / z), theoretical value: 466, measured value: 467 [M+H + ].

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Abstract

The invention discloses a synthesis and separation identification method for aragatroban two related substances. The method comprises taking aragatroban as a raw material, nitrating by fuming nitric acid, and separating to obtain (2R,4R)-1-[NG-nitro-N2-((R,S)-3-methyl-1,2,3,4-tetrahydro-8- quinolylsulfonyl)-L-arginyl]-4-methyl-2-pipecolinic acid (wherein G in NG and 2 in N2 are both superscripts) (aragatroban related substance A); and taking aragatroban as a raw material, hydrolyzing through an aqueous solution of sodium hydroxide, barium hydroxide or other highly-basic reagent, and separating to obtain (2R,4R)-1-[N-((R,S)-3-methyl-1,2,3,4-tetrahydro-8-quinolylsulfonyl)-L-ornithyl]-4-methyl-2-pipecolinic acid (aragatroban related substance B). The provided preparation method for the aragatroban related substances is simple and practicable, and low in cost, avoids a complex tedious operation process for total synthesis of the aragatroban related substances, and is a suitable preparation method for the aragatroban related substances. The aragatroban related substance A and the aragatroban related substance B are both shown in the specification.

Description

technical field [0001] The present invention relates to two argatroban related substances A [(2R, 4R)-1-[N G -Nitro-N 2 -((R,S)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid] Argatroban related substance B [(2R,4R)-1-[N-((R,S)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl) The synthesis, separation and identification of -L-ornithyl]-4-methyl-2-piperidinecarboxylic acid] belongs to the field of pharmaceutical compound synthesis. Background technique [0002] Argatroban is a new type of antithrombin active substance researched and developed by Mitsubishi Chemical Corporation of Japan. It is an intravenous injection and has been marketed in many countries with good prospects for clinical application. The chemical name of argatroban is: (2R,4R)-1-[N 2 -((R,S)-3-Methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methylpiperidine-2-carboxylic acid- Hydrate. The chemical structural formula is as follows: [0003] ...

Claims

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Application Information

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IPC IPC(8): C07K5/068
Inventor 尚德斌
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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