CN102643208B - Preparation method of agomelatine I crystal form - Google Patents

Abstract

The invention discloses a preparation method of agomelatine I crystal form, comprising the following steps: heating and melting agomelatine at 110-200°C, then rapidly cooling at -20-30°C, and standing until crystallization . The method used in the present invention has simple operation, easy control of reaction conditions, high yield, no need to use any organic solvent, single crystal form, green and environmental protection, and is very suitable for industrial production.

Description

A kind of preparation method of agomelatine I crystal form

technical field

The invention belongs to the field of medicine, and in particular relates to a preparation method of agomelatine I crystal form. the

Background technique

Agomelatine (Agomelatine), the chemical name is N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, and its chemical structure is as follows (1):

阿戈美拉汀商品名为Valdoxan，是法国施维雅公司首次研制，既是首个褪黑素受体激动剂，也是5-羟色胺2C(5HT2c)受体拮抗剂，能有效的治疗抑郁症，抗焦虑及调整睡眠周期循环节律。

The trade name of agomelatine is Valdoxan, which was first developed by the French company Servier. It is not only the first melatonin receptor agonist, but also a 5-hydroxytryptamine 2C (5HT2c) receptor antagonist, which can effectively treat depression. Anti-anxiety and adjust sleep cycle rhythm.

At present, the method for preparing the crystal form of agomelatine is to first dissolve agomelatine in a solvent and then extract it. The biggest difference between the current methods is that the solvents used are different. CN101921205A reports a method for preparing agomelatine type I. The drug is heated and dissolved in a mixed solvent of DMF and water, and the temperature is slowly cooled in an ice bath to obtain a solid. CN101704763A has reported another preparation method of type I, is about to dissolve medicine in the hydrophilic organic solvent, as alcohols, amides, ketones, nitriles or diol derivatives, after the solution is filtered, drip under stirring situation Add water and dry the precipitated solid to obtain type I powder. The above method has some disadvantages and deficiencies, such as cumbersome operation, easy formation of mixed crystal forms, a large amount of organic solvent used in the experiment, which is not economical and environmentally friendly, and the production cost is high, and the yield is less than 90%. ZL200510071611.6 records the new synthesis method, new crystal form and pharmaceutical composition of agomelatine, and adopts the method of ethanol recrystallization to prepare agomelatine II crystal. CN200910160307.7 The preparation of V-type agomelatine by spray drying method requires the introduction of inert gas, high production cost and cumbersome operation. the

Contents of the invention

The object of the present invention is to provide a preparation method of agomelatine I crystal form. the

The technical scheme that the present invention takes is:

A preparation method of agomelatine I crystal form, comprising the following steps: agomelatine is heated and melted at 110-200°C, then rapidly cooled at -20-30°C, and left to stand until crystallization. the

Preferably, it is rapidly cooled to 0-30°C. the

Preferably, the rapid cooling method is: cooling the melted agomelatine in a liquid at -20-30°C. the

Preferably, the rapid cooling method is: cooling the container containing the molten agomelatine in liquid at -20-30°C. the

Preferably, a method for preparing crystal form I of agomelatine comprises the following steps: heat and melt agomelatine at 110-200°C, and then cool it in a liquid at -20-30°C to 0-30°C. °C, let stand until crystallization. the

Preferably, the liquid is at least one of water and ethanol. Except water, ethanol, other liquids that can be used for cooling can be used in the present invention. the

The preparation method of agomelatine I crystal form according to claim 1, characterized in that: the X-ray powder diffraction spectrum of agomelatine I crystal form obtained by the method has a 2θ value of 11.07±02, 11.78±0.2, 14.87±0.2, 17.47±0.2, 18.29±0.2, 19.48±0.2, 20.46±0.2, 21.76±0.2, 22.45±0.2, 23.00±0.2, 24.56±0.2, 26.28±0.2, 26.99±0.2, 30.09 The positions of 0.2, 31.20±02, 31.90±02, and 33.28±02 correspond to characteristic diffraction peaks. the

The beneficial effects of the present invention are:

The method of the invention can obtain relatively pure agomelatine I crystal form, the yield is increased to 100%, and the cost is greatly reduced.

The method used in the invention is simple to operate, the reaction conditions are easy to control, and the obtained crystal form is single, which is very suitable for industrial production.

Description of drawings

Fig. 1 is the X-ray powder diffraction figure of embodiment 1 product;

Fig. 2 is the differential scanning calorimetry (DSC) figure of embodiment 1 product;

Fig. 3 is the infrared spectrum of embodiment 1 product;

Fig. 4 is the X-ray powder diffraction figure of comparative example 1 product;

Fig. 5 is the differential scanning calorimetry (DSC) figure of comparative example 2 product;

Fig. 6 is a differential scanning calorimetry (DSC) diagram of the product of Comparative Example 3.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but it is not limited thereto. the

Example 1

After heating and melting 50mg agomelatine at 110°C, place the container containing the melted agomelatine in a 20°C water bath and quickly cool it to 20°C, then let it stand, and the obtained crystal form is agomelatine Form I, yield 100%.

Example 2

After heating and melting 50mg agomelatine at 120°C, place the container containing the melted agomelatine in a 20°C water bath and quickly cool it down to 20°C, then let it stand, and the obtained crystal form is agomelatine Form I, yield 100%.

Example 3

After heating and melting 50 mg agomelatine at 130°C, place the container containing the melted agomelatine in an ice-water bath to rapidly cool to 4°C, and let it stand still. The obtained crystal form is agomelatine I Crystal form, yield 100%.

Example 4

After heating and melting 50 mg agomelatine at 140°C, place the container containing the melted agomelatine in an ice-water bath and quickly cool it to 3°C, and let it stand still. The obtained crystal form is agomelatine I Crystal form, yield 100%.

Example 5

After heating and melting 50 mg agomelatine at 160°C, place the container containing the melted agomelatine in ethanol at -10°C and quickly cool it to -5°C, and let it stand still. The obtained crystal form is Argo Melatine I crystal form, the yield is 100%.

Example 6

After heating and melting 1 g of agomelatine at 120°C, place the container containing the melted agomelatine in a 30°C water bath and quickly cool it to 30°C, then let it stand, and the obtained crystal form is agomelatine Form I, yield 100%.

Example 7

After heating and melting 1 g of agomelatine at 140°C, place the container containing the melted agomelatine in a water bath at 20°C and quickly cool it to room temperature at 22°C, and let it stand still. The obtained crystal form is agomelat Ting I crystal form, yield 100%.

Example 8

After heating and melting 1 g of agomelatine at 150°C, place the container containing the melted agomelatine in an ice-water bath and quickly cool it down to 5°C, and let it stand still. The obtained crystal form is agomelatine I Crystal form, yield 100%.

Example 9

After heating and melting 1g of agomelatine at 200°C, place the container containing the melted agomelatine in ethanol at -20°C and rapidly cool it to 10°C, then let it stand, and the obtained crystal form is agomelat Ting I crystal form, yield 100%.

Example 10

After heating and melting 3g of agomelatine at 120°C, place the container containing the melted agomelatine in an ice-water bath and quickly cool it to 5°C, then let it stand, and the obtained crystal form is agomelatine Form I, yield 100%.

Example 11

After heating and melting 3g of agomelatine at 150°C, place the container containing the melted agomelatine in an ice-water bath and quickly cool it to 10°C, and let it stand still. The obtained crystal form is agomelatine I Crystal form, yield 100%.

Comparative example 1

After heating and melting 50 mg of agomelatine at 120° C., and then cooling slowly until crystallization, the obtained crystal form is agomelatine III crystal form.

Comparative example 2

After heating and melting 50 mg of agomelatine at 120°C, it was placed indoors to cool naturally to room temperature, and left to stand. The crystal form obtained was a mixed crystal form of agomelatine I crystal form and II crystal form.

Comparative example 3

After heating and melting 50mg agomelatine at 160°C, place the container containing the melted agomelatine in a 35°C water bath and quickly cool it down to 35°C, and let it stand still. The obtained crystal form is agomelatine A mixed crystal form of Form I and Form II.

Adopt Bruker D8 Advance diffractometer to measure the X-ray powder diffraction pattern of the product agomelatine I crystal form of embodiment 1, embodiment 2, embodiment 9, measurement condition is as follows: Cu K α, 40kV, 40mV is light source, The step size is 0.12°, the scanning speed is 10°/min, the scanning range is 5°-40°, and it is carried out at room temperature. The X-ray powder diffraction values obtained in the examples are characterized by Bragg 2θ angle, interplanar distance d and relative intensity I (expressed as a percentage relative to the strongest ray). The X-ray powder diffraction pattern of Example 1 is shown in Figure 1, the characterization data of Example 1 is shown in Table 1, the characterization data of Example 2 is shown in Table 2, and the characterization data of Example 9 is shown in Table 3. From Figure 1 and Tables 1 to 3, it can be clearly obtained that the X-ray powder diffraction patterns of agomelatine I crystal form obtained in each embodiment have characteristic diffraction peaks corresponding to the corresponding positions of the 2θ value. the

The characterization data of the X-ray powder diffraction pattern of table 1 embodiment 1

The characterization data of the X-ray powder diffraction pattern of table 2 embodiment 2

The characterization data of the X-ray powder diffraction pattern of table 3 embodiment 9

The differential scanning thermal analysis (DSC) figure of the agomelatine I crystal form obtained in Example 1 is shown in Figure 2, and a peak is shown on the figure, the endothermic transition of the crystal form agomelatine I crystal form The temperature was at 97.6°C. the

The infrared (IR) spectrum of agomelatine I crystal form obtained in Example 1 is shown in Figure 3, as can be seen from the figure, agomelatine I crystal form has wavelengths of 3248.9, 3078.9, 2935.9, 2872.7, 2835.1 , 1638.6, 1551.3, 1507.7, 1438.4, 1363.2, 1257.8 have absorption peaks. the

The X-ray powder diffraction pattern of the product obtained in Comparative Example 1 is shown in Figure 4, from which it can be seen that the product is agomelatine III crystal form. the

The differential scanning calorimetry (DSC) figure of the product obtained in Comparative Example 2 is shown in Figure 5, and two peaks are shown on the figure, and it can be known that the product obtained in Comparative Example 2 is agomelatine I crystal form and II crystal form. mixed crystals. the

The differential scanning calorimetry (DSC) figure of the product obtained in comparative example 3 is shown in Figure 6, and two peaks are shown on the figure, it can be known that the product obtained in comparative example 3 is agomelatine I crystal form and II crystal form mixed crystals. the

From comparative examples 1 to 3, it can be seen that in the preparation method of the present invention, the heated and melted agomelatine cannot obtain agomelatine I crystal form after slow cooling or rapid cooling at a temperature outside the range of -20 to 30°C. Only at the rapid cooling temperature of the present invention -20-30°C, can the crystal form of agomelatine I be obtained. the

Claims (2)

1. A preparation method of agomelatine I crystal form, comprising the following steps: heating and melting agomelatine at 110-200°C, then rapidly cooling to 0-30°C at -20-30°C, standing Until crystallization, the X-ray powder diffraction pattern of the obtained agomelatine I crystal form was 11.07±0.2, 11.78±0.2, 14.87±0.2, 17.47±0.2, 18.29±0.2, 19.48±0.2, 20.46± The positions of 0.2, 21.76±0.2, 22.45±0.2, 23.00±0.2, 24.56±0.2, 26.28±0.2, 26.99±0.2, 30.09±0.2, 31.20±0.2, 31.90±0.2, 33.28±0.2 correspond to characteristic diffraction peaks. 2. The preparation method of agomelatine I crystal form according to claim 1, characterized in that: the method of rapid cooling is: placing the container containing molten agomelatine at -20 to 30°C cooled in liquid.

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