KR102494848B1 - Crystal form I of teneligliptin ditosylate dihydrate and preparation process thereof - Google Patents

Abstract

The present invention provides a new crystalline form of teneligliptin ditosylate dihydrate and a method for preparing the new crystalline form. Form I, a new crystalline form according to the present invention, is easy to manufacture, has high purity, and has excellent properties such as high stability and low hygroscopicity.

Description

Crystal form I of teneligliptin ditosylate dihydrate dihydrate and its preparation method {Crystal form I of teneligliptin ditosylate dihydrate and preparation process thereof}

The present invention relates to a novel crystalline form of teneligliptin ditosylate dihydrate and a process for preparing such a crystalline form.

[Formula A]

Teneligliptin represented by Formula A (3-{(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl] Pyrrolidin-2-ylcarbonyl} thiazolidine) is a DPP-IV inhibitor that inhibits DPP-4, an enzyme that degrades glucagon-like peptide-1 (hereinafter referred to as GLP-1), which lowers blood sugar in plasma, thereby inhibiting GLP-4. It is a drug that treats diabetes by sustaining the activation of -1. Korean Patent No. 10-0817378 describes a method for preparing proline derivatives including teneligliptin and teneligliptin trihydrochloride. However, in the case of teneligliptin trihydrochloride, there are problems such as moisture absorption stability and manufacturing reproducibility.

Meanwhile, Korean Patent No. 10-1352650 describes an improved method for preparing teneligliptin 2.5 hydrobromide. However, the strong acidity and strong fugitiveness of hydrobromic acid cause a risk of acid exposure to workplaces and workers, and the risk reduces the ease of manufacturing. Therefore, research on new salts to improve the risk is active.

Korean Patent No. 10-1352650 describes pharmaceutically possible salts, and among them, teneligliptin ditosylate is introduced. Compared to hydrobromic acid, tosylic acid hydrate has significantly lower risks mentioned above and ease of manufacture is guaranteed. In addition, crystal forms A, B, and C of teneligliptin ditosylate are introduced, and the 2θ value of XRD crystal analysis for each crystal form and its preparation method are described.

However, there are no reports or literature on a raw material of teneligliptin tosylate, which is non-hygroscopic and has useful physical properties in terms of drug production, and a method for easily producing such a useful raw material and useful raw material in high yield. The demand for is steady.

Republic of Korea Patent Registration No. 10-0817378 Republic of Korea Patent Registration No. 10-1352650

Therefore, the problem to be solved by the present invention is teneligliptin 2, which is easier to manufacture than conventional teneligliptin 2.5 hydrobromide, has high yield and purity, and has excellent physical properties in various aspects for use as a raw material for pharmaceuticals. It is to provide a new crystalline form of tosylate and a method for preparing the same.

In order to solve the above problems, the present invention provides a crystalline form I of teneligliptin ditosylate dihydrate represented by the following Chemical Formula 1 and a method for preparing the same.

[Formula 1]

Crystalline Form I of teneligliptin ditosylate dihydrate according to the present invention showed 2θ diffraction angles of 4.4±0.2°, 13.3±0.2°, 18.8±0.2°, and 20.4±0.2° in powder X-ray diffraction (XRD) analysis. , 24.3±0.2°, 27.9±0.2°, and 33.7±0.2°, preferably 4.4±0.2°, 6.1±0.2°, 13.3±0.2°, 18.0±0.2°, 18.3±0.2°, 18.8±0.2° , 20.4±0.2°, 21.8±0.2°, 22.9±0.2°, 24.3±0.2°, 25.6±0.2°, 27.9±0.2°, 33.7±0.2° [I/I ₀ (I: peaks at each diffraction angle intensity, I ₀ : the intensity of the largest peak) has a diffraction pattern of 2θ] of 10% or more.

While studying the crystallization of teneligliptin 2tosylate, the present inventors discovered that a new crystalline form of teneligliptin 2tosylate dihydrate exists and that this new crystalline form has very desirable physical properties in terms of hygroscopicity and stability. The present invention was completed by optimizing the manufacturing method for preparing this crystalline form.

Preferably, the crystalline form I of teneligliptin ditosylate dihydrate according to the present invention comprises the steps of: 1) crystallizing by introducing tosylic acid hydrate into an organic solvent mixed with water to which teneligliptin free base is added; 2) It can be made by a manufacturing method comprising the step of aging the crystals obtained in the above process.

1) Step of crystallizing by adding tosylic acid to an organic solvent mixed with water to which teneligliptin free base is added

[Formula 2]

[Formula 3]

More specifically, after dissolving the teneligliptin free base represented by Chemical Formula 2 in an organic solvent mixed with water, tosyl acid (preferably tosylic acid hydrate) represented by Chemical Formula 3 is dissolved in a mixture of 20 It is added at a temperature of -25℃. The use of tosylic acid ensures a lower risk than conventional hydrobromic acid and ease of manufacture. At this time, the amount of the tosylic acid (hydrate) is 2-3 equivalents, more preferably 2-2.1 equivalents, based on teneligliptin free base. If the amount of tosylic acid (hydrate) is less than 2 equivalents, the yield of teneligliptin ditosylate dihydrate may decrease, and if it is more than 3 equivalents, crystallization may not occur due to the use of excessive amount of tosylic acid (hydrate). However, it can lead to a decrease in content and an increase in cost.

Alcohols or ketones that are mixed with water may be used as the organic solvent, and preferably, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, or a mixture thereof is used. More preferably, acetone and methyl ethyl ketone are used. If an organic solvent immiscible with water is used, crystallization does not occur because it does not mix with water, or anhydride is precipitated. Alcohols can also be used, but drying in vacuum does not work well, and residual solvents may cause problems. The mixing ratio with water is 30:1 - 10:1 (organic solvent: water) (volume ratio) based on the organic solvent, and more preferably 30:1 - 15:1. The amount of reaction solvent used is 5 to 30 times (volume ratio), preferably 10 to 15 times the amount of teneligliptin free base. At this time, if the amount of the solvent used is less than 5 times, it is not easy to stir in the crystallization step, so homogeneous crystallization does not occur, and if it exceeds 30 times, the yield decreases.

2) Crystal ripening stage

Next, the solution of teneligliptin 2tosylate dihydrate obtained in step 1) is cooled to a temperature of 0 to 5° C., aged for 1 to 2 hours, and then the precipitated crystals are filtered to obtain teneligliptin 2tosylate 2 The crystalline form I of the hydrate is obtained.

In another aspect, the present invention also provides a pharmaceutical composition comprising the novel crystalline form according to the present invention and a pharmaceutically acceptable carrier. Methods for preparing pharmaceutical compositions are well known to those skilled in the art. For example, Handbook of Pharmaceutical Excipients (7 ^th ed.), Remington: The Science and Practice of Pharmacy (20 ^th ed.), Encyclopedia of Pharmaceutical Technology (3 ^rd ed.), Sustained and Controlled Release Drug Delivery Systems (1978 ), etc., a pharmaceutical composition for the purpose of the present invention can be prepared by appropriately mixing a pharmaceutically acceptable carrier, carrier, additives, etc. with the compound according to the present invention.

Crystalline form I of teneligliptin ditosylate dihydrate according to the present invention is easier to manufacture than other salts and other crystal forms, such as teneligliptin 2.5 hydrobromide, has high purity, high stability, low hygroscopicity, etc. exhibits excellent properties. In addition, the manufacturing method according to the present invention has a high yield and has the effect of lowering the production cost.

1 is an X-ray diffraction spectrum of teneligliptin ditosylate dihydrate crystalline Form I according to the present invention.
2 is a hydrogen nuclear magnetic resonance spectrum of crystalline form I of teneligliptin ditosylate dihydrate according to the present invention.
3 is a graph of the change in water content over time for Form I crystals of teneligliptin ditosylate dihydrate according to this study.
4 is an HPLC graph of crystalline form I of teneligliptin ditosylate dihydrate according to the present invention.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Reference example 1

3-{(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thia Zolidine

3-{(2S, 4S)-1-[1,1-dimethylethyloxycarbonyl-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5yl)piperazin-1-yl 25.00 g of ]pyrrolidin-2-ylcarbonyl} thiazolidine was dissolved in 200 ml of dichloromethane, 50 ml of trifluoroacetic acid was added at room temperature, and the mixture was stirred for 19 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, followed by extraction with dichloromethane. After the extract was washed with saturated brine and dehydrated using anhydrous sodium sulfate, it was filtered and the solvent was removed under reduced pressure, and the concentrated residue was used.

Comparative Example 1

10.0 g of the concentrated teneligliptin free base residue prepared in Reference Example 1 was dissolved in 100 ml of ethanol, and 9.88 g (2.5 eq) of 48% hydrobromic acid was added at reflux temperature. It was cooled to room temperature over about 1 hour and stirred at room temperature for another 1 hour. The precipitate was collected by filtration, washed with 10 ml of ethanol, and dried under reduced pressure to obtain crystals of teneligliptin hydrobromide. (Yield: 88%, Purity: 99.73%)

Example 1

3-{(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thia Zolidine·2tosylate dihydrate

10.0 g of the concentrated teneligliptin free base residue prepared in Reference Example 1 was dissolved in 150 ml of acetone:water (30:1), and 8.91 g (2.0 eq) of tosylic acid hydrate was added and stirred for 3 hours. The precipitate was cooled and stirred for 2 hours to mature the crystal, then filtered and dried under reduced pressure to obtain crystalline Form I of the title compound. (Yield: 94.2%, Purity: 99.95%)

Example 2

3-{(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thia Zolidine·2tosylate dihydrate

10.0 g of the concentrated residue of teneligliptin free base prepared in Reference Example 1 was dissolved in 150 ml of methanol:water (30:1), and 8.91 g (2.0 eq) of tosylic acid hydrate was added and stirred for 3 hours. The precipitate was cooled and stirred for 2 hours to mature the crystal, then filtered and dried under reduced pressure to obtain crystalline Form I of the title compound. (Yield: 93.2%, Purity: 99.94%)

Powder X-ray diffraction (XRD) analysis

Powder X-ray diffraction analysis was performed on crystalline form I of teneligliptin ditosylate dihydrate obtained in Example 1, and the results are shown in FIG. 1 . As shown in FIG. 1, the 2θ diffraction angles are 4.4°, 6.1°, 13.3°, 18.0°, 18.3°, 18.8°, 20.4°, 21.8°, 22.9°, 24.3°, 25.6°, 27.9°, and 33.7°. peaks were observed, respectively. At this time, the measurement conditions of the powder X-ray diffraction (XRD) spectrum are as follows.

1) Device: Rigaku's MiniFlex 600 / X-ray source: Cu

2) Tube voltage: 40 kV / Tube current: 15mA

3) Diverging slit: 1° / Scattering slit: 1° / Light-receiving slit: 0.15mm

4) Scan range: 3 to 40° 2θ / sampling interval 0.04°C

5) Scan speed: 10°/min

On the other hand, according to Korean Patent No. 10-1352650, the 2θ diffraction angles of teneligliptin ditosylate type A crystals are 5.3°, 6.0°, 14.8°, 16.4°, 20.8°, and the 2θ diffraction angles of type B crystals are is 5.7°, 11.4°, 14.0°, 18.2°, 19.7°, and the 2θ diffraction angles of type C crystal are reported to be 4.7°, 5.7°, 11.3°, 19.8°, 21.4°. Therefore, the crystalline Form I of the present invention shows distinctly different 2θ diffraction angles as shown in Table 1 when compared with conventional A-form crystals, B-form crystals, and C-form crystals.

teneligliptin ditosylate 2θ diffraction angle (°) Type I 4.4 6.1 13.3 18.0 18.3 18.8 20.4 21.8 type A 5.3 6.0 14.8 16.4 20.8 - - - type B 5.7 11.4 14.0 18.2 19.7 - - - type C 4.7 5.7 11.3 19.8 21.4 - - -

Hydrogen nuclear magnetic resonance analysis

Crystalline Form I of teneligliptin ditosylate dihydrate obtained in Example 1 was subjected to hydrogen nuclear magnetic resonance spectral analysis, and the results are attached in FIG. 2 . The Form I crystal has 9.67 (s, 1H), 9.07 (s, 1H), 7.76 (d, 2H), 7.49 (m, 6H), 7.31 (t, 1H), 7.12 (d, 4H), 5.89 (s , 1H), 4.69 (dd, 2H), 3.85 (m, 12H), 3.11 (t, 2H), 3.05 (t, 2H), 2.29 (s, 6H), and 2.13 (s, 3H) showed peaks, respectively. . The hydrogen nuclear magnetic resonance (NMR) measurement conditions are as follows.

1) Device: Agilent 400MR

2) Measurement range: -1.0 ∼ 15 ppm

3) Number of scans: 4 times

hygroscopicity test

The pharmaceutically preferred form of the compound is preferably a form that does not absorb moisture even in a high humidity environment while maintaining the initial form. Therefore, the hygroscopicity of teneligliptin ditosylate dihydrate crystalline form I obtained in Example 1, teneligliptin ditosylate anhydride, teneligliptin 2.5 hydrobromide (Comparative Example 1) and free base To confirm, the water content (K.F. moisture %) over time of each of the crystalline compounds was measured under the condition of 25° C. and 50% relative humidity. The results are shown in Table 2 and FIG. 3 below.

Early 4 hours 8 hours 12 hours 16 hours 20 hours 24 hours Teneligliptin 2.0 Tosylate Form I Crystals 4.48% 4.5% 4.51% 4.51% 4.52% 4.52% 4.52% Teneligliptin 2.0 Tosylate Anhydrous 0.21% 4.47% 4.52% 4.52% 4.53% 4.53% 4.53% Teneligliptin 2.5 hydrobromide 4.37% 4.9% 5.34% 5.50% 5.73% 5.80% 5.90% teneligliptin free base 0.23% 2.32% 4.10% 5.50% 6.01% 6.70% 7.81%

As shown in Table 2 above, teneligliptin ditosylate dihydrate crystalline Form I according to the present invention did not show hygroscopicity. That is, the water content was maintained at a similar level even after elapsed compared to the initial water content. On the other hand, in the case of teneligliptin 2tosylate anhydride, teneligliptin 2.5 bromide oxalate, and free base, it was confirmed that the water content increased over time by absorbing moisture in the air.

Specific rotation measurement

In the present invention, the specific optical rotation of teneligliptin ditosylate dihydrate crystalline form I and teneligliptin free base crystals were measured and are shown in Table 3 below. At this time, the specific rotation measurement method was as follows.

1) Device: JASCO P-1020

2) Ray: D line of sodium spectrum

3) Temperature: 25℃

4) Measuring tube: 100mm

specific rotation teneligliptin 2.0 tosylate dihydrate crystalline form I -26.2° teneligliptin free base -36.9°

HPLC analysis

In the present invention, teneligliptin ditosylate dihydrate crystalline Form I was analyzed by HPLC, and the graph is shown in FIG. 4 . At this time, the HPLC analysis method was as follows.

1) Device: Agilent techonologies 1260 infinity HPLC system

2) Column: octadecyl silylated silica gel (4.6x250mm, 5μm)

3) Column temperature: 30 ℃

4) Detector: Ultraviolet absorbance hygrometer

5) Measurement wavelength: 210nm

6) Measurement range: 15 minutes

7) Mobile phase: 0.01M NaH ₂ PO ₄ buffer solution: acetonitrile = 6:4

Claims (4)

delete crystallizing by adding teneligliptin free base and tosylic acid to an organic solvent mixed with water as a reaction solvent; And aging the crystals obtained in the process at 0 to 5 ° C.
The ratio (volume ratio) of the water and the organic solvent is 1:30,
The organic solvent is acetone,
Powder X-ray diffraction (XRD) analysis of teneligliptin ditosylate dihydrate crystalline Form I showed that the 2θ diffraction angles were 4.4±0.2°, 13.3±0.2°, 18.8±0.2°, 20.4±0.2°, and 24.3±0.2°. , 27.9±0.2°, and 33.7±0.2° diffraction patterns . delete Teneligliptin ditosylate dihydrate crystalline form I prepared by the method of claim 2.

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