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Preparation method of safinamide mesilate A1 crystal form

A technology of safinamide methanesulfonate and safinamide, which is applied in the preparation of sulfonate, carboxylic acid amide, preparation of organic compounds, etc., can solve the impurities of methanesulfonic acid safinamide A1 crystal form and optical difference. Problems such as high structure content and insufficient support

Active Publication Date: 2016-03-16
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Second, safinamide mesylate better meets a critical unmet need in the market. Current MAO-B inhibitors, especially rasagiline, have also been proposed to have neuroprotective effects, however their Clinical data do not fully support this claim
[0005] In the prior art, the prepared methanesulfonic acid safinamide A1 crystal form has problems of high content of impurities and optical isomers

Method used

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  • Preparation method of safinamide mesilate A1 crystal form
  • Preparation method of safinamide mesilate A1 crystal form
  • Preparation method of safinamide mesilate A1 crystal form

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Embodiment 1

[0026] The preparation method of the safinamide methanesulfonate A1 crystal form of the present embodiment comprises the following steps:

[0027] (1) in N 2 Under protection, add 45mL of acetone to a 50mL three-neck flask, then cool down to 10°C, add 3.85g of methanesulfonic acid under stirring, transfer to a 100mL constant pressure dropping funnel for dropwise addition after stirring for 10min;

[0028] (2) in N 2 Under protection, add 11g of safinamide (BaseSAF-4) and 175mL of acetone to a 250mL four-neck flask at room temperature, then raise the temperature to 50°C under stirring, and stir for 30min until completely dissolved;

[0029] (3) Control the temperature at 50°C, add the solution of step (1) dropwise to the solution of step (2), and the dropwise addition time is about 1 to 2 hours. Crystallization at ℃ for 1h;

[0030] (4) After crystallization, filter, rinse the filter cake with 35 mL of acetone, and filter to dryness; take out the filter cake and dry it in va...

Embodiment 2

[0032] The preparation method of the safinamide methanesulfonate A1 crystal form of the present embodiment comprises the following steps:

[0033] (1) in N 2 Under protection, add 96mL of butanone into a 50mL three-necked flask, then cool down to 20°C, start adding 3.85g of methanesulfonic acid under stirring, transfer to a 100mL constant pressure dropping funnel for dropwise addition after stirring for 10min;

[0034] (2) in N 2 Under protection, add 11g of safinamide (BaseSAF-4) and 175mL of butanone to a 250mL four-neck flask at room temperature, then raise the temperature to 40°C under stirring, and stir for 30min until completely dissolved;

[0035] (3) Control the temperature at 40°C, add the solution of step (1) dropwise to the solution of step (2), and the dropwise addition time is about 1 to 2 hours. After the dropwise addition, keep stirring at the same temperature for 1.5 hours, and cool down to 20 Crystallization at ℃ for 1h;

[0036] (4) After crystallization, ...

Embodiment 3

[0038] The preparation method of the safinamide methanesulfonate A1 crystal form of the present embodiment comprises the following steps:

[0039] (1) in N 2 Under protection, add 45mL of methyl isobutyl ketone into a 50mL three-necked flask, then cool down to 15°C, add 4.12g of methanesulfonic acid under stirring, transfer to a 100mL constant pressure dropping funnel after stirring for 10min add;

[0040] (2) in N 2 Under protection, add 11g of safinamide (BaseSAF-4) and 330mL of methyl isobutyl ketone to a 250mL four-necked flask in sequence at room temperature, then raise the temperature to 45°C under stirring, and stir for 30min until completely dissolved;

[0041] (3) Control the temperature at 45°C, add the solution of step (1) dropwise to the solution of step (2), and the dropwise addition time is about 1 to 2 hours. After the dropwise addition, keep stirring at the same temperature for 1.5 hours, and cool down to 25 Crystallization at ℃ for 1h;

[0042] (4) After c...

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Abstract

The invention relates to a preparation method of safinamide mesilate A1 crystal form. The preparation method comprises following steps: methane sulfonic acid is reacted with safinamide at a certain temperature, cooling is carried out, and an obtained reaction liquid is subjected to crystallization at 10 to 30 DEG C, wherein one ingredient selected from acetone, butanone, methyl isobutyl ketone, methyl isopropyl ketone, cyclohexanone, and acetic acid isopropyl ester is taken as a reaction and crystallization solvent, and unexpected crystallization effect is achieved. The maximum yield of the prepared safinamide mesilate A1 crystal form can be higher than 99%, purity is 99.9% or higher in HPLC, impurity content is less than 0.01%, and optical isomer content is less than 0.05%.

Description

technical field [0001] The invention relates to a preparation method of the A1 crystal form of safinamide methanesulfonate. Background technique [0002] Safinamide Mesilate (trade name Xadago) is an adjuvant treatment drug for Parkinson's disease jointly developed by Newron and Zambon. This MAO-B and dopamine reuptake inhibitor was approved for marketing in the European Union in February 2015. It is used for early and middle-advanced PD patients who are ineffective in treatment. Safinamide mesylate is a selective monoamine oxidase B (MAO-B) inhibitor, which can reversibly mimic MAO-B in the striatum with high selectivity, block the degradation of dopamine, and improve the symptoms of Parkinson's disease. At the same time, Safinamide can also inhibit the release of glutamate in basal neuron synapses and reduce the excitability of central nervous system. Safinamide mesylate has two advantages over its competitors: [0003] First, safinamide mesylate is highly specific to M...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C231/24C07C237/06C07C303/32C07C303/44C07C309/04
CPCC07B2200/13C07C231/12C07C231/24C07C303/32C07C303/44C07C237/06C07C309/04
Inventor 林祖峰贾江南刘涛颜峰峰姚成志陈为人
Owner ZHEJIANG MENOVO PHARMA
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