JP2021535218A - New crystalline form of DPP-IV inhibitor hypoglycemic agent and its preparation method - Google Patents

Abstract

DPP-IV inhibitor hypoglycemic agent (8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4) -Methylquinazoline-2-yl) Methyl] -1H-Purin-2,6-dione) is disclosed as a new crystalline form F and a method for preparing the same. The X-ray powder diffraction patterns of the crystalline form F are 12.8 ± 0.2 °, 14.6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 ° and 18. The differential scanning calorimetry spectra of the crystalline form F include three or more or more 2θ values selected from the group consisting of 1 ± 0.2 °, and the differential scanning calorimetry spectra are 80 to 110 ° C, 120 to 135 ° C, 167 to 172. Having heat absorption peaks at ° C. and 203-209 ° C., the crystalline form F has the advantages of stable physical and chemical properties, high purity, simple preparation method, and suitability for large-scale industrial production. ..

Description

The present invention belongs to the field of drug synthesis, and specifically, a hypoglycemic agent for a DPP-IV inhibitor (8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl)). A new crystal form of -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione), and a method for preparing the new crystal form. Regarding.

8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl) methyl] -1H-purine-2,6-dione (8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4) -methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione) is a dipeptidyl peptidase-IV (DPP-IV) developed by the German company Boehringer Ingelheim for the treatment of type 2 diabetes. It is an inhibitor and was approved for sale by the US FDA in May 2011. Unlike other DPP-4 inhibitors, 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[((3R) -3,7-dihydro-3-methyl-1-[() 4-Methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione is excreted mainly through bile and intestine in a non-metabolized form, and is excreted mainly in bile, which is a non-kidney removal pathway. It is the first DPP-4 inhibitor to be used and has the characteristics of high activity, selectivity, long-term efficacy and oral administration, and has a good market outlook.

特許ＷＯ２００７１２８７２１は、８−［（３Ｒ）−３−アミノピペリジン−１−イル］−７−（２−ブチニル）−３，７−ジヒドロ−３−メチル−１−［（４−メチルキナゾリン−２−イル）メチル］−１Ｈ−プリン−２，６−ジオンのフォーム（Form）Ａ〜Ｅの五つの結晶形を発表し、ここで、フォームＣの水和物結晶形のＸ線粉末回折パターンの２θ値は、６．８５、７．１８、７．５２、７．９６、１３．３０、１３．７５、１４．３８、１８．７５、２２．５９、２３．７６、２６．９３および２７．２２に特徴ピークを有し、テスト誤差は、±０．２°である。特許は、その熱重量分析スペクトルを同時に開示し、約３０〜１００℃で水分を損失し、約１５０℃および１７０℃の付近でさらなる熱効果を有する。

Patent WO2007128721 is based on 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-]. Il) Methyl] -1H-purine-2,6-dione forms (Form) A to E Five crystal forms were announced, where 2θ of the X-ray powder diffraction pattern of the hydrate crystal form of Form C. Values are 6.85, 7.18, 7.52, 7.96, 13.30, 13.75, 14.38, 18.75, 22.59, 23.76, 26.93 and 27.22. It has a characteristic peak at, and the test error is ± 0.2 °. The patent simultaneously discloses its thermogravimetric analysis spectrum, which loses moisture at about 30-100 ° C and has additional thermal effects near about 150 ° C and 170 ° C.

Patent US201301123282 describes a series of 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-). 2-Il) Methyl] -1H-Purin-2,6-dione crystallographic features are disclosed, wherein the 2θ value of the crystalline X-ray powder diffraction pattern of Form XIX is 13.6, 14.0. , 14.7, 22.3 and 26.5 with characteristic peaks, with a test error of ± 0.2 °. This patent also did not disclose other characteristic data of this crystalline form.

If they have the same molecular structure but different crystalline forms, they may have different bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density and fluidity. Some polymorphies are difficult to formulate due to their shape or hygroscopicity. The X-ray powder diffraction pattern is a necessary method for identifying crystalline forms, but it is not the only method.

Due to the different binding methods of water and compounds, the crystalline form of the hydrate may resemble its X-ray powder diffraction pattern, but other methods such as DSC, or infrared, or nuclear magnetism identification methods, etc. The characteristic data of is different.
The same drug, different crystalline or different hydrates, and different stability, fluidity, hygroscopicity, compressibility have a significant impact on the application of the drug, thereby significantly affecting the bioavailability of the drug.

8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) methyl] Given the wide range of uses of -1H-purine-2,6-dione, there is an urgent need to develop new crystalline forms of the product in this area, to enrich or develop more suitable pharmaceutical forms. It is very important for that.

An object of the present invention is high purity, stable physical and chemical properties, good reproducibility, simple manufacturing process, and suitable for industrial production 8-[(3R) -3-aminopiperidine-1. -Il] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl) methyl] -1H-purine-2,6-dione new crystals To provide shape.

The first aspect of the present invention is 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-4-methyl-1-yl]. Methyl quinazoline-2-yl) methyl] -1H-purine-2,6-dione crystal form F is provided, and the X-ray powder diffraction pattern of the crystal form F is 12.8 ± 0.2 °, 14. Three or more 2θ values selected from the group consisting of 6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 ° and 18.1 ± 0.2 °. include.

In another preferred example, the X-ray powder diffraction pattern of crystalline form F is 12.8 ± 0.2 °, 14.6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0. Includes all 2θ values of .2 ° and 18.1 ± 0.2 °.
In another preferred example, the X-ray powder diffraction pattern of the crystalline form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 15.0 ± 0. It further includes one, two, three, four or five 2θ values selected from the group consisting of .2 °, 16.8 ± 0.2 ° and 19.0 ± 0.2 °.

In another preferred example, the X-ray powder diffraction pattern of the crystalline form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 12.8 ± 0. .2 °, 14.6 ± 0.2 °, 15.0 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.1 ± 0.2 ° and 19 Includes six or more than six 2θ values selected from the group consisting of 0.0 ± 0.2 °.
In another preferred example, the X-ray powder diffraction pattern of the crystalline form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 12.8 ± 0. .2 °, 14.6 ± 0.2 °, 15.0 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.1 ± 0.2 ° and 19 Includes all 2θ values of 0.0 ± 0.2 °.

In another preferred example, the crystalline form F has an X-ray powder diffraction pattern as shown in FIG.
In another preferred example, the differential scanning calorimetry spectra of the crystalline form F have endothermic peaks at 80-110 ° C, 120-135 ° C, 167-172 ° C and 203-209 ° C.

In another preferred example, under the test conditions of the differential scanning calorimetry method 2, the differential scanning calorimetry spectrum of the crystalline form F is 144.6 ± 0.5 ° C. (preferably 144.6 ± 0.2 ° C.). ) Has no exothermic peak.
In another preferred example, the crystalline form F has a differential scanning calorimetry spectrum as shown in FIG.
In another preferred example, the crystalline form F has a differential scanning calorimetry spectrum as shown in FIG.
In another preferred example, the crystalline form F is a hydrate, where the water content is 0-5%, preferably the water content is 1.0% to 2.0%. ..

A second aspect of the present invention provides a method for preparing the crystalline form F, wherein the preparation method is described.
(1) 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) ) Methyl] -1H-purine-2,6-dione raw material is suspended in a mixed solvent, and the obtained system is heated to completely dissolve it.
(2) The step of lowering the temperature of the system obtained in step (1) to -5 to 35 ° C. and stirring for 1 to 5 hours while keeping the temperature warm, and (3) filtering to collect the solid and solid. Is further dried to 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-). 2-Il) Methyl] -1H-purine-2,6-dione including the step of obtaining crystalline form F.

In another preferred example, in the step (1), the mixed solvent is a mixed solvent of an organic solvent and water, wherein the water content is 0 to 10%, preferably 0.3 to 10. It is 5%, more preferably 0.5 to 3%, and the organic solvent is methanol (methanol), ethanol (ethanol), isopropanol (isopropanol), acetonitrile (acetonitrile) or tetrahydrofuran (tetrahydrofuran).
In another preferred example, when the temperature of the system obtained in step (1) is lowered in step (2), the cooling rate is 1-20 ° C / min, preferably 2-15 ° C / min. Is.

In another preferred example, the operation of lowering the temperature of the system obtained in step (1) in step (2) completes the system obtained in step (1) at a cooling rate of 1-20 ° C./min. It comprises a step of cooling from the melting temperature to <35 ° C., stirring, then further cooling to −5 to 5 ° C., and stirring for 1 to 5 hours while keeping warm.
In another preferred example, in step (3), the step of drying the material is to first dry the material at 0-40 ° C for 5-20 hours and then dry the material at 45-65 ° C for 5-20 hours. Including the stage of further drying.
In another preferred example, in step (1), heating to 50-60 ° C.

The present invention relates to 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-]. Il) Methyl] -1H-Purin-2,6-dione provides a new crystalline form F, the crystalline form of which is highly pure, stable in crystalline form, good in reproducibility, large-scale industry. Has the advantage of adapting to production.
Within the scope of the invention, new or preferred technical features may be combined between the above technical features of the invention and the technical features specifically described below (eg, Examples). It should be understood that the solution can be constructed. Space is limited, so I won't repeat it here.

The X-ray powder diffraction pattern (XRPD) of the crystalline form F is shown. The differential scanning calorimetry spectrum (DSC) of the crystal form F is shown. The thermogravimetric analysis data (TGA) of the crystal form F is shown. The X-ray powder diffraction pattern (XRPD) of the crystal form C is shown. The differential scanning calorimetry spectrum (DSC) of the crystal form C is shown. The differential scanning calorimetry spectrum (DSC) of the crystalline XIX is shown. The X-ray powder diffraction pattern (XRPD) of the solid G which is an intermediate in Examples 1 to 3 is shown. The differential scanning calorimetry spectra (DSC) of the crystal form C and the crystal form F in Example 4 are shown. Here, FIGS. 2, 5 and 6 are detected by the differential scanning calorimetry method 1, and FIG. 8 is detected by the differential scanning calorimetry method 2.

Through in-depth research, the present invention presents 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-4-methyl-1-yl]. Methyl quinazoline-2-yl) methyl] -1H-purine-2,6-dione was obtained in a new crystalline form, which has high purity, stable crystalline form, good reproducibility, and large scale. Has the advantage of being suitable for industrial production.

Crystal form F of the present invention
The X-ray powder diffraction pattern of the crystalline form F of the present invention is 12.8 ± 0.2 °, 14.6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 ° and Includes three or more 2θ values selected from the group consisting of 18.1 ± 0.2 °.
Preferably, the X-ray powder diffraction pattern of the crystalline form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 12.8 ± 0.2 °. , 14.6 ± 0.2 °, 15.0 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.1 ± 0.2 ° and 19.0 ± Contains six or more than six 2θ values selected from the group consisting of 0.2 °.
Preferably, the X-ray powder diffraction pattern of crystalline form F has the 2θ values and relative intensities shown in Table 1.

Preferably, the crystalline form F has an X-ray powder diffraction pattern as shown in FIG.
Preferably, the differential scanning calorimetry spectrum of the crystalline form F has endothermic peaks at 80-110 ° C, 120-135 ° C, 167-172 ° C and 203-209 ° C.
Preferably, the crystalline form F has a differential scanning calorimetry spectrum as shown in FIG.

Preparation Method The present invention provides a method for preparing crystalline form F, wherein the preparation method is as follows.
(1) 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) ) Methyl] -1H-purine-2,6-dione raw material is suspended in a mixed solvent, and the obtained system is heated to completely dissolve it.
(2) The step of lowering the temperature of the system obtained in step (1) to -5 to 35 ° C. and stirring for 1 to 5 hours while keeping the temperature warm, and (3) filtering to collect the solid and solid. Is further dried to 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-). 2-Il) Methyl] -1H-purine-2,6-dione including the step of obtaining crystalline form F.

In the step (1), the mixed solvent is a mixed solvent of an organic solvent and water, and the water content is 0 to 10%, preferably 0 to 5%, and the organic solvent is used. Is methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran.
The operation of lowering the temperature of the system obtained in step (1) in step (2) is to cool the system obtained in step (1) at a cooling rate of 1 to 20 ° C./min from the complete melting temperature to <35 ° C. Including a step of further cooling to −5 to 5 ° C. and stirring for 1 to 5 hours while keeping warm after cooling and stirring.
In the step (3), the step of drying the material includes first drying the material at 0 to 40 ° C. for 5 to 20 hours, and then further drying the material at 45 to 65 ° C. for 5 to 20 hours. ..
In the step (1), it is heated to 50-60 ° C.

Those skilled in the art can use the crystal form F prepared by the above preparation method as a seed crystal to prepare the crystal form F by the following steps.
(1) 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) ) Methyl] -1H-purine-2,6-dione raw material is suspended in a mixed solvent, and the obtained system is heated to completely dissolve it.
(2) The step of lowering the temperature of the system obtained in step (1) to -5 to 35 ° C. and stirring for 1 to 5 hours while keeping the temperature warm, and (3) filtering to collect the solid and solid. Is further dried to 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-). 2-Il) Methyl] -1H-Purin-2,6-dione Crystal form F is obtained.

In the step (1), the mixed solvent is a mixed solvent of an organic solvent and water, and the water content is 0 to 10%, preferably 0 to 5%, and the organic solvent is used. Is methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran.
The operation of lowering the temperature of the system obtained in step (1) in step (2) is to cool the system obtained in step (1) at a cooling rate of 1 to 20 ° C / min to 35 ° C or less from the complete melting temperature. After cooling to, the seed crystal of crystalline form F is added, and after crystallization, the temperature is further cooled to 0 to 10 ° C., and the mixture is stirred for 1 to 5 hours while keeping the temperature warm.
In the step (3), the step of drying the material includes first drying the material at 0 to 40 ° C. for 5 to 20 hours, and then further drying the material at 45 to 65 ° C. for 5 to 20 hours. ..
In the step (1), it is heated to 50-60 ° C.

Hereinafter, the present invention will be further described together with specific examples. It should be understood that these examples are used only to illustrate the invention and do not limit the scope of the invention. In the following examples, experimental methods that do not indicate specific conditions usually follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise stated, percentages and copies are calculated as weight percentages and copies by weight.
Experimental materials and reagents used in the following examples are available from commercial channels unless otherwise stated.

X-ray powder diffraction (XRPD):
X-ray powder diffraction equipment: Brucker D8 advance X-ray powder diffractometer, parameters of X-ray powder diffraction are as follows. Scan under copper target (α = 1.540600A), room temperature conditions.
Voltage: 40kV
Current: 40mA
Scan mode: Continuous scan range: 2.0 to 35.0 degrees Step size: 0.020 °
Measurement time per step: 12.6 seconds

Differential Scanning Calorimetry (DSC) Method 1:
Differential scanning calorimetry (DSC) equipment: TA Q2000 type. The parameters of the differential scanning calorimetry (DSC) analysis method 1 are as follows.
Sample tray: T-Zero aluminum tray,
Detection procedure:
(1) Temperature range: 25 to 250 ° C
(2) Scan speed: 10 ° C / min (3) Shield gas: nitrogen, 50 ml / min

Differential Scanning Calorimetry (DSC) Method 2:
Differential scanning calorimetry (DSC) equipment: TA Q2000 type, the parameters of the differential scanning calorimetry (DSC) analysis method 2 are as follows.
Sample tray: T-Zero sealed aluminum tray,
Detection procedure:
(1) Temperature range: 25 to 250 ° C
(2) Shield gas: nitrogen, 50 ml / min (3) Heating rate: 10 ° C / min

Thermogravimetric analysis data (TGA):
Thermogravimetric analysis (TGA) equipment: TATGA55 type. The parameters of the thermogravimetric analysis (TGA) method are:
Temperature range: 25-300 ° C
Scan speed: 10 ° C / min Shield gas: Nitrogen, 60 ml / min

Example 1
20 g of Form A 8-[(3R) -3-aminopiperidin-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2) -Il) Methyl] -1H-Prince-2,6-dione (preparation method is the same as in Example 1 of patent US200759900A1) Suspended in 80 ml of 95% methanol and heated to 50-55 ° C. to complete the system. Melt, lower the temperature of the reaction system to room temperature at a cooling rate of 15 ° C / min, further cool the temperature to about -5-5 ° C, gradually precipitate the solid, and keep it warm for 1-2 hours. Stirring and filtering to give solid G, dried at room temperature for 5 hours and further dried in a hot air oven at 60 ° C. for 8 hours to give 19.5 g of solid, yield 97.5%.
The resulting solid X-ray powder diffraction pattern is as shown in FIG. 1, the differential scanning calorimetry spectrum is shown in FIG. 2, and the thermogravimetric analysis spectrum is as shown in FIG. , Crystal form F.
Further, the intermediate solid G is a wet product and its X-ray powder diffraction pattern is as shown in FIG.

Example 2
20 g of amorphous 8-[(3R) -3-aminopiperidin-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline) -2-yl) Methyl] -1H-purine-2,6-dione (preparation method is the same as in Example 1 of patent CN104418857A) was suspended in 100 ml of 98% ethanol and heated to 52-58 ° C. Completely melt the system, reduce the temperature of the reaction system to about 0-10 ° C at a cooling rate of 10 ° C / min, add 0.5 g of crystalline F seed crystal, and maintain the temperature at 0-10 ° C. While stirring for 1 to 2 hours, the mixture was filtered to obtain solid G, dried at room temperature for 10 hours, and further dried in a hot air oven at 60 ° C. for 12 hours to obtain 18.9 g of solid, and the yield was , 94.5%.
The resulting solid X-ray powder diffraction pattern is as shown in FIG. 1, the differential scanning calorimetry spectrum is as shown in FIG. 2, and the thermogravimetric analysis spectrum is as shown in FIG. Yes, that is, the crystalline form F.

Example 3
20 g of 8-[(3R) -3-aminopiperidin-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl)) Methyl] -1H-purine-2,6-dione XXII form (preparation method is the same as in Example 29 of patent US201301123282A) was suspended in 100 ml of methanol and heated to 52-58 ° C to completely dissolve the system. The temperature of the reaction system was lowered to about 10 to 20 ° C. at a cooling rate of 2 ° C./min, stirred for 1 to 2 hours while maintaining the temperature of 10 to 20 ° C., and filtered to obtain solid G, 35. Dry in a hot air oven at ° C. for 5 hours and further dry in a hot air oven at 60 ° C. for 12 hours to give 18.9 g of solid, yielding 94.5%.
The resulting solid X-ray powder diffraction pattern is as shown in FIG. 1, the differential scanning calorimetry spectrum is as shown in FIG. 2, and the thermogravimetric analysis spectrum is as shown in FIG. Yes, that is, the crystalline form F.

Comparative Example 1
8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-with reference to the method of Example 3 of Japanese Patent US20027259900A1. [(4-Methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione crystal form C was prepared, the XRD spectrum of which is as shown in FIG. 4, and the DSC spectrum is shown in FIG. It seems to be shown in 5.

Comparative Example 2
8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-with reference to the method of Example 26 of patent US201301123282A1. [(4-Methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione crystal form XIX is prepared. Its XRD spectrum is the same as FIG. 22 of US201301123282A, and the DSC spectrum is as shown in FIG.

Example 4
The crystal form F prepared in Example 1 or Example 2 or Example 3 and the crystal form C obtained in Comparative Example 1 were tested according to the differential scanning calorimetry (DSC) method 2, and the obtained DSC spectrum was obtained. , As shown in FIG. From FIG. 8, it can be seen that the crystalline form F of the present invention does not have an exothermic peak at 144.6 ± 0.5 ° C.

Example 5
The comparison between the crystal form F of the present invention and the crystal form C and the crystal form XIX is as follows.
(1) Influential factor experiment Crystal form F, crystal form C and crystal form XIX are placed under high temperature, high humidity and sunshine conditions, respectively, and the stability of their crystal forms is compared. (Crystal form XIX does not test for influencing factors, but the crystalline form changes in 1 hour under high temperature conditions)

＊：結晶形ＸＩＸを６０℃の高温に１時間置くと、結晶形の変化が検出され、高湿および日照に置かない。

*: When the crystalline XIX is placed at a high temperature of 60 ° C. for 1 hour, a change in the crystalline form is detected, and the crystalline XIX is not placed in high humidity and sunlight.

(2) Sample purity stability test (observation temperature: 60 ° C)

All documents referred to in the present invention are cited as references in this application as if each document was cited individually as a reference. In addition, after reading the above teachings of the invention, one of ordinary skill in the art may make various changes or modifications to the invention, the equivalent of which is also within the scope defined by the scope of the attachment of this application. Please understand that it is included in.

Claims (12)

8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) methyl] -1H-purine-2,6-dione crystal form F,
The X-ray powder diffraction patterns of the crystalline form F are 12.8 ± 0.2 °, 14.6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 ° and 18. The crystalline form F, characterized in that it comprises three or more or more 2θ values selected from the group consisting of 1 ± 0.2 °. The X-ray powder diffraction patterns of the crystalline form F are 12.8 ± 0.2 °, 14.6 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 ° and 18. The crystalline form F according to claim 1, wherein the crystalline form F comprises all 2θ values of 1 ± 0.2 °. The X-ray powder diffraction pattern of the crystal form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 12.8 ± 0.2 °, 14. 6 ± 0.2 °, 15.0 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.1 ± 0.2 °, 19.0 ± 0.2 The crystalline form F according to claim 1, wherein the crystal form F comprises six or more than six 2θ values selected from the group consisting of °. The X-ray powder diffraction pattern of the crystal form F is 6.8 ± 0.2 °, 8.0 ± 0.2 °, 10.1 ± 0.2 °, 12.8 ± 0.2 °, 14. 6 ± 0.2 °, 15.0 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.1 ± 0.2 ° and 19.0 ± 0.2 The crystalline form F according to claim 1, wherein the crystalline form F comprises all 2θ values of °. The crystal form F according to claim 1, wherein the crystal form F has an X-ray powder diffraction pattern shown in FIG. The crystal form F according to claim 1, wherein the differential scanning calorimetry spectrum of the crystal form F has endothermic peaks at 80 to 110 ° C., 120 to 135 ° C., 167 to 172 ° C. and 203 to 209 ° C. .. The crystal form F according to claim 1, wherein the crystal form F has a differential scanning calorimetry spectrum shown in FIG. The crystal form F according to claim 1, wherein the crystal form F is a hydrate, wherein the water content is 0 to 5%. The method for preparing the crystalline form F according to claim 1.
The preparation method is
(1) 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl) ) Methyl] -1H-purine-2,6-dione raw material is suspended in a mixed solvent, and the obtained system is heated to completely dissolve it.
(2) The step of lowering the temperature of the system obtained in step (1) to -5 to 35 ° C. and stirring for 1 to 5 hours while keeping the temperature warm, and (3) filtering to collect the solid and solid. Is further dried to 8-[(3R) -3-aminopiperidine-1-yl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methylquinazoline-). 2-Il) Methyl] -1H-Purin-2,6-dione The preparation method comprising the step of obtaining the crystalline form F. In the step (1), the mixed solvent is a mixed solvent of an organic solvent and water, wherein the water content is 0 to 10%, and the organic solvent is methanol, ethanol, isopropanol, acetonitrile or. The preparation method according to claim 9, wherein the solvent is tetrahydrofuran. The preparation method according to claim 9, wherein the cooling rate in the step (2) is 1 to 20 ° C./min. In the step (3), the drying step comprises first drying the material at 0 to 40 ° C. for 5 to 20 hours, and then further drying the material at 45 to 65 ° C. for 5 to 20 hours. The preparation method according to claim 9.

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