WO2009079940A1 - Method for transformation of crystal form of zopiclone - Google Patents

Abstract

The invention discloses a method for transformation of crystal form of zopiclone. The method comprises transforming crystal form C of zopiclone as a raw material in isopropanol at the temperature from 20°C to b.p. of the solvent system, cooling to 0°C after the reaction completed, filtering, and drying to obtain crystal form A of zopiclone. The method of the invention has the advantages of good safety and reliability of production, high yield, and good quality.

Description

 Method for crystal transformation of zopiclone

 The present invention relates to a crystal form conversion of a compound, and in particular to a method for crystal phase conversion of zopiclone. Background technique

 Zopiclone, chemical name (5RS) 6 - (5-chloro-2-pyridyl)-7-oxo- 6. 7-dihydro-5H pyrrolo[3,4-b]pyrazine -5-Methyl 4-methylpiperazine-1-carboxylate, developed by the company Chole-Cou-PouIent Rorer, France. It is a pyrrole ketone compound and is a new non-benzodiazepine sedative hypnotic drug that has been used in clinical practice for the treatment of insomnia, especially for patients who cannot tolerate the residual effects of the morning.

 The 3⁄4 third-generation non-benzodiazepine hypnotics can selectively act on the sputum receptors, resulting in a relatively small residual effect, and rarely produce a "sleep" phenomenon in the morning, which does not affect the mental activity and movement of the morning. The sensitivity, and the smaller dose, S complex application is also very little accumulation, so it is safer.

 In 2000, RJ Terblanche ^ [Characterization of Zopiclone Crystal Forms Found Among Generic Raw Materials. Drug Development and Industrial Phamacy, 26 (5), 531-537, 2000] reported: zopiclone drug substance has a polymorphic phenomenon, a total of Three crystal forms: Form A (anhydrous compound), Form B (containing two water of crystallization) and Form C (a mixture of Form A and Nie B).

 The X-ray powder diffraction (XRPD) curves of these three crystals (see Figure 1) have different characteristic peaks (the 2 Θ angles are shown in Table 1), which indicates that the three crystals are three different crystal forms.

 Table

 The three crystals were analyzed by thermogravimetric analysis (TGA), and the three crystals contained different amounts of crystal water:

 Type A: The curve is a straight line, without weight loss, indicating that Form A does not contain crystal water;

 1

Replacement page (Article 28) The crystal form β: TGA curve has weight loss phenomenon, indicating that the crystal form B contains 8. 0%~8. 8%, and the theoretical value is 8.47%; crystal form C: TGA curve has weight loss phenomenon, indicating crystal form C contains water of crystallization (the water content varies depending on the proportion of crystal form A and form B).

 According to differential scanning calorimetry (DSC) analysis, the three crystals have different melting points:

Form A: The DSC curve has only one distinct endothermic peak, and its maximum endothermic value is about 177 'C _;

 Form B: The DSC curve has a desolvation endothermic peak at 97 ° C, an endothermic peak at 146 ° C, then an exothermic peak upon recrystallization, and finally a maximum at approximately 173 ° C. Endothermic peak

 Form C: The DSC curve is similar to the DSC curve for Form B, but finally has a maximum endothermic peak at approximately 176 Å. According to the requirements of the European Pharmacopoeia, zopiclone is an anhydrous compound, crystal form A, which has a melting point of about 177 ° C and decomposes simultaneously upon melting. The zopiclone produced by the conventional method is the crystalline form C.

 US Patent US 3862149 and US 4220646, Chen Hengchang, etc. [Journal of Zhengzhou University (Natural Science Edition), 1993, 25,

73~76], etc., were recrystallized from a mixture of acetonitrile and diisopropyl ether (1:1, by volume) to give a melting point of about 177.

'C's zopiclone. This method is difficult to produce zopiclone which meets the requirements, and the isopropyl ether used in the method is a flammable and explosive substance, mass production is safe and difficult to secure, and the yield is low.

Summary of the invention

 The object of the present invention is to provide a novel zopiclone crystal form conversion method, which has the characteristics of safe and reliable production, high yield and good product quality.

 The technical scheme of the present invention is as follows - a method for crystal transformation of zopiclone, which uses a zopiclone of crystal form C as a raw material, and performs a crystal form conversion reaction in isopropanol at a reaction temperature of 20 ° C to the boiling point of the solvent system. The reaction time is 0. 5~4. 5 hours, the temperature is lowered to O'C, 'filtered, dried, and the zopiclone of the crystal form A is obtained.

 The zopiclone of the resulting product Form A has:

 (1) The X-ray powder diffraction method (XRPD) curve is consistent with the curve of Form A in Figure 1.

 (2) Thermogravimetric analysis (TGA) The curve is a straight line with no weight change (before 130 )).

 (3) The differential scanning calorimetry (DSC) curve has only one endothermic peak, and the maximum endothermic peak is 177 °C.

 Preferably, the above reaction temperature is from 35 'C to the boiling point of the solvent system;

 Preferably, the amount of isopropanol is from 2 to 20 times the weight of the crystalline form C zopiclone.

 More preferably, the amount of isopropanol is 4 to 10 times the weight of the crystalline form C zopiclone.

 By comparing the X-ray powder diffraction (XRPD) curve, the thermogravimetric analysis (TGA) curve and the differential scanning calorimetry (DSC) curve of the zopiclone crystal of Form C with the zopiclone crystal of Form A , can get the following conclusions:

 (1) The X-ray powder diffraction (XRPD) curves of the two crystals have different characteristic peaks, and the 2 Θ angle values are shown in the table, indicating that the two crystals are crystals of two different crystal forms;

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Table 2

 (2) The thermogravimetric analysis (TGA) curve indicates that the crystal before the conversion of the zopiclone crystal of the crystal form C contains crystal water, and the zopiclone crystal of the crystal form A obtained does not contain crystals after being treated with isopropyl alcohol. Water

 ' ( 3 ) Differential Scanning Calorimetry (DSC) curves indicate that the melting points of the two crystals are not the same, but relatively close. .

 The excellent effects of the present invention are as follows:

 The zopiclone crystal form conversion method of the invention has the characteristics of safe and reliable production, high yield and good product quality.

2, the process is operability, large-scale industrial production, has a great 'implementation value.

 3. The yield of zopiclone crystal of Form A is over 90%.

DRAWINGS

 Figure 1 is a standard diagram of three crystal X-ray powder diffraction (XRPD) curves of zopiclone, where 1 is a crystal C curve, 2 is a crystal form A curve, and 6 is a crystal form B curve;

 Figure 2 X-ray powder diffraction (XRPD) curve of the zopiclone raw material of Form C;

 Figure 3 is a thermogravimetric analysis (TGA) curve of the zopiclone starting material of Form C;

 Figure 4 is a differential scanning calorimetry (DSC) curve of the zopiclone raw material of Form C;

 Figure 5 crystal form A zopiclone product X-ray powder diffraction method (XRPD) curve;

Figure 6 Thermogravimetric analysis (TGA) curve of crystal form A zopiclone product; page change (Article 26) Figure 7. Differential Scanning Calorimetry (DSC) curve for Form A Azopiclone product.

 detailed description

 The present invention will be further described below in conjunction with the embodiments, but is not limited thereto. The zopiclone raw material of Form C used therein has the following properties:

1. The X-ray powder diffraction method (XRPD) curve is shown in Fig. 2, which is consistent with the curve of Form C in Figure 1.

 2. The thermogravimetric analysis (TGA) curve shows weight loss as shown in Figure 3, indicating that Form C contains crystallization water 1.937% (before 130'C).

 3. The differential scanning calorimetry (DSC) curve has a desolvation endothermic peak as shown in Figure 4, and finally has a maximum endothermic peak at approximately 176 °C.

 Example 1

 The granules of 18.5g were obtained. The granules were added to the granules of the granules of the granules of the granules. The zopiclone of Form A has a yield of 92.5% and a melting point of about 177'C (decomposed simultaneously upon melting).

 The resulting crystalline form A zopiclone has the following properties -

(1) The X-ray powder diffraction method (XRPD) (see Figure 5) is consistent with the curve of Form A in Figure 1.

 (2) The thermogravimetric analysis (TGA) curve (see Figure 6) is a straight line with no change in weight (before 130 °C).

 (3) The differential scanning calorimetry (DSC) curve (see Figure 7) has only one endothermic peak with a maximum endothermic peak of approximately 177'C.

 Example 2:

 The granules of 18.2g are obtained. The crystals of the crystals of the crystal form C are added to a 500 ml three-necked flask, and the mixture is heated to reflux. The zopiclone of the type A has a yield of 91.0%, a melting point of about 177 ° C (decomposes simultaneously upon melting). The zopiclone starting material of Form C used and the resulting crystalline form A zopiclone were of the same nature as in Example 1.

 Example 3:

 The crystallization of 18.4g of crystals is obtained. The crystals of the crystals of the crystal form C are added to the 500 ml of the three-necked flask, and the mixture is heated to a refluxing temperature, and the temperature is lowered to 0 ° C, filtered, and dried to obtain 18.4 g of crystals. The zopiclone of type A has a yield of 92.0%, a melting point of about 177 Ό (decomposes simultaneously upon melting). The zopiclone starting material of Form C used and the resulting crystalline form A zopiclone were of the same nature as in Example 1.

Example 4 _:

 The granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules of the granules Zopiclone, yield 93.0%, melting point about 177 ° C (decomposed simultaneously upon melting). The zopiclone starting material of Form C used and the resulting crystalline form A zopiclone were of the same nature as in Example 1.

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Claims

A method for crystal transformation of zopiclone, characterized in that a zopiclone of crystal form c is used as a raw material, and a crystal form conversion reaction is carried out in isopropanol at a reaction temperature of 20 Torr to the boiling point of the solvent system, and the reaction time is 0. 5~4. 5 hours, cooled to 0 ° C, filtered, dried to obtain zopiclone of Form A.  The above-described zopiclone crystal form conversion method according to claim 1, wherein the reaction temperature is 35 Torr to the boiling point of the solvent system.  The above-described method for converting a crystal form of a succinimide according to claim 1, wherein the amount of isopropyl alcohol is 2 to 20 times the weight of the crystalline form C zopiclone. Wo'  The above-described zopiclone crystal form conversion method according to claim 1, wherein the amount of isopropyl alcohol is 4 to 10 times the weight of the crystalline form C zopiclone. ' begging