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Method for preparing taltirelin tetrahydrate alpha crystal form crystal by using beater

A technology of tatirelin and tetrahydrate, which is applied in a new field of preparation, can solve the problems of troublesome storage, difficult process drying, low yield, etc., and achieves the advantages of reduced control difficulty, good process stability and strong operability Effect

Inactive Publication Date: 2015-06-24
重庆莱美隆宇药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, tatirelin is a tripeptide product synthesized by the condensation of three amino acids. It is very polar and easily soluble in water. It is difficult to obtain a higher yield by crystallization with a single solvent.
Based on the above-mentioned prior art, to prepare α crystal form from a single solvent water, not only the conditions for crystallization are relatively harsh (low speed, slow cooling, but high efficiency in production), but also because α crystal form itself is a metastable crystal form , it is very easy to convert into a stable β crystal form. In order to obtain the α crystal form, only a solvent with high water content can be selected for crystallization. However, due to the low melting point of the α crystal form (65-70°C), this brings certain difficulties to the drying process. Difficult, if the temperature is too high, the product will easily lose crystal water, if the temperature is too low, the product moisture will not be easy to dry, which will directly lead to a lower melting point of the crystallized product, which will bring great harm to further preparation processing, transportation and storage trouble
[0008] In view of the fact that the crystallization of the existing listed crystal forms is not easy to control in industrial production, it is very easy to prepare mixed crystal forms, and the yield of the preparation is low, and the drying in industrial production needs to be controlled by special equipment and complicated process control conditions

Method used

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  • Method for preparing taltirelin tetrahydrate alpha crystal form crystal by using beater
  • Method for preparing taltirelin tetrahydrate alpha crystal form crystal by using beater
  • Method for preparing taltirelin tetrahydrate alpha crystal form crystal by using beater

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add 5.0 g of tatirelin amorphous powder and 25.0 ml of tetrahydrofuran into the reaction flask, control the temperature at 25±2°C, and stir and beat for 6 hours at a speed of 320 / min with a beater. Then cool down to 3±2°C and keep stirring at 3±2°C for 9h. Filter and dry under reduced pressure at 30°C. 4.4 g of white solid was obtained, the yield was 88.0%, the melting point was 67-69°C, and the moisture content was 15.2%. Through X-ray powder diffraction detection, it is obvious that the generated crystals are in α crystal form. See attached figure 1 .

Embodiment 2

[0052] Add 4.0 g of tatirelin amorphous powder and 28.0 ml of ethyl acetate into the reaction flask, control the temperature at 40±2°C, and stir and beat for 10 hours at a speed of 400 / min with a beater. Then cool down to 5±2°C and keep stirring at 5±2°C for 8h. Filter and dry under reduced pressure at 35°C. 3.7 g of white solid was obtained, the yield was 92.5%, the melting point was 68-70°C, and the moisture content was 14.8%. Through X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis, it is obvious that the generated crystals are in the α crystal form, see attached figure 2 And attached image 3 .

Embodiment 3

[0054] Add 4.0 g of tatirelin amorphous powder and 44.0 ml of ethyl acetate into the reaction flask, control the temperature at 40±2°C, and stir and beat for 10 hours at a speed of 480 / min with a beater. Then lower the temperature to 5±2°C, keep the temperature at 5±2°C and stir for 8h. Filter and dry under reduced pressure at 35°C. 3.6 g of white solid was obtained, the yield was 90.0%, the melting point was 69-70°C, and the moisture content was 14.6%. Through X-ray powder diffraction detection, it is obvious that the generated crystals are in α crystal form. See attached Figure 4 .

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Abstract

The present invention provides a taltirelin (formula I) tetrahydrate alpha crystal form crystal preparation method, particularly to a method for preparing a taltirelin tetrahydrate alpha crystal form crystal by using a beater. The method specifically comprises: adding taltirelin to a non-protonic solvent, stirring, and using crystallization of the temperature difference method, solid-liquid separation, and drying to obtain the taltirelin alpha crystal form crystal. The method is characterized in that the stirring is specifically the complete stirring at a temperature of 20-60 DEG C by using a beater, the stirring speed is controlled to 300-500 r / min, and the non-protonic solvent is tetrahydrofuran, ethyl acetate, acetone, and acetonitrile. According to the present invention, the method has characteristics of good process stability, strong operability, high yield, and the like; and the obtained product has characteristics of low free water content, melting point close to the upper limit of the standard value, easy formulation processing, storage, and transportation, and the like. The formula I is defined in the instruction.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new preparation method of tatirelin α crystal form. Background technique [0002] Tatirelin (Taltirelin), chemical name (4S)-N-[(2S)-2-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-(1H-imidazole- 4-yl)-1-oxopropan-2-yl]-1-methyl-2,6-dioxo-1,3-diazepine-4-carboxamide (as shown in formula Ⅰ) . [0003] [0004] Tatirelin is a synthetic TRH (thyrotropin-releasing hormone) analog that is clinically used to improve ataxia in patients with spinocerebellar degeneration. Spinocerebellar ataxias (spinocerebellar ataxias, SCAs), formerly known as autosomal dominant ataxias, are a group of chronic degenerative diseases of the central nervous system with the main clinical manifestations of ataxia and dysmetria. Since the disease is genetic, there is no effective treatment so far. The only approved drug for ataxia is TRH. However, clinical studies have shown that due to the rapid metaboli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/097C07K1/30
Inventor 黄文峰李胜伟杨威蔡明君王宇
Owner 重庆莱美隆宇药业有限公司
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