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Impurity preparation and analysis method of rasagiline mesylate

A technology of rasagiline mesylate and a detection method, applied in the fields of analytical chemistry and pharmaceutical analytical chemistry, to achieve the effects of high purity, high yield and mild reaction conditions

Active Publication Date: 2016-08-24
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above method is easy to generate genotoxic substance 2-C1-AAI due to the use of reagents containing halide ions, especially chloride ions, such as 3-chloropropyne, see documents US7598420, US7572834 and US7619117, etc.

Method used

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  • Impurity preparation and analysis method of rasagiline mesylate
  • Impurity preparation and analysis method of rasagiline mesylate
  • Impurity preparation and analysis method of rasagiline mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Embodiment 1: the preparation of rasagiline mesylate

[0115] ① Dissolve 133g of R-aminoindane in a reaction flask with dimethylformamide, stir evenly, add 138g of potassium carbonate, stir, and add dropwise a DMF solution of 96.1g of propargyl methanesulfonate. Process control temperature 25-35°C, stirring and reacting for more than 20 hours; cooling, adding water, extracting the water phase twice with dichloromethane, combining dichloromethane, washing with acid water, separating the water phase, adding ethyl acetate and oxidizing with hydroxide Wash with sodium solution, extract twice with ethyl acetate, dry, filter, and concentrate under reduced pressure to obtain about 112 g of viscous liquid (crude rasagiline).

[0116] ②Dissolve the viscous liquid obtained above in 560mL of isopropanol, heat above 60°C, add methanesulfonic acid to adjust the pH under stirring, the pH is ≤4 after the addition, reflux for about 20 minutes, cool to crystallize, filter, and dry under...

Embodiment 2

[0117] Embodiment 2: the separation of impurity A, impurity B

[0118] Concentrate the dichloromethane solution after washing with acid water in Step ① of Example 1 to dryness to obtain a solid, which can be purified and treated by high-pressure liquid phase preparation to obtain a high-purity impurity reference substance. The specific operations are as follows:

[0119] Purification conditions:

[0120]

[0121] Gradient elution ratio:

[0122] time (minutes)

A％

B％

0

80

20

30

50

50

60

50

50

[0123] Specific steps:

[0124] Concentrate the dichloromethane solution washed with acid water in Example 1 to dryness to obtain a solid, take 1g, dissolve it with 50% acetonitrile / water, filter, put it on the column, and elute it with a gradient program. According to the peak situation, collect it in sections For the eluate, the eluate containing impurity A and impurity B with a purity >98% were collected and combined respec...

Embodiment 3

[0148] Embodiment 3: the separation of impurity C

[0149] Concentrate and dry the isopropanol filtrate obtained in step ② of Example 1 to obtain a solid, which can be purified and treated by high-pressure liquid phase preparation to obtain a high-purity impurity C reference substance. The specific operations are as follows:

[0150] Purification conditions:

[0151]

[0152] Gradient elution ratio:

[0153] time (minutes)

A％

B％

0

80

20

30

50

50

60

50

50

[0154] Specific steps:

[0155] Take the isopropanol filtrate obtained in step ② of Example 1 and concentrate to dry 1g of the solid obtained, dissolve it with 20% acetonitrile / water, put it on the column, and gradient elution, according to the peak situation, collect the eluent in sections, with a purity of >95% The eluents were combined. Concentrate and evaporate to dryness to obtain a white or off-white solid (impurity C), add 3 times the amount of ethanol to ...

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Abstract

The invention provides a preparation method of an impurity A, an impurity B and an impurity C of rasagiline mesylate and provides a raw medicine for applying a prepared impurity standard product to a rasagiline mesylate product and a quality analysis method of a preparation thereof. Structures of the impurities A, B and C are as shown in the specification.

Description

technical field [0001] The invention relates to the field of analytical chemistry, in particular to the field of pharmaceutical analytical chemistry, in particular to an impurity analysis and preparation method of rasagiline mesylate. Background technique [0002] Rasagiline is a second-generation selective and irreversible monoamine oxidase-B (MAO-B) inhibitor jointly developed by Teva and Lundbeck for the treatment of Parkinson's disease (PD). The drug was approved for marketing in Israel for the first time in January 2005 as a first-line drug for the early treatment of Parkinson's disease (PD), or in combination with levodopa (levodopa) for the treatment of moderate to severe Parkinson's disease. Azilect, then the drug was approved by the European Union in February 2005 to be marketed in Europe, and has obtained an approval letter from the FDA. In addition, the drug is currently undergoing clinical research for the treatment of Alzheimer's disease (AD), depression, and A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/24C07C211/42C07C209/16C07C309/04C07C303/32G01N30/02
Inventor 孙永强严益民屠永锐冯晓晖蒋伟钱明霞王菊香祁琪曹月华
Owner CHANGZHOU NO 4 PHARMA FACTORY
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