KR20170069943A - Novel Solvates of Dapagliflozin or Methods for Preparing the Same - Google Patents

Abstract

The present invention relates to a novel solvate of Dapagliflozin, an SGLT-2 inhibitor, and a process for its preparation.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel solvates of dapagliflozin and methods for preparing the same,

The present invention relates to a novel solvate of Dapagliflozin, an SGLT-2 inhibitor, and a process for its preparation.

Diabetes mellitus is a chronic metabolic disease that afflicts millions of patients around the world and is divided into Type 1 and Type 2. Type 2 diabetes is caused by the insulin resistance that causes the function of insulin to lower blood sugar.

On the other hand, SGLT-2 (sodium / glucose cotransporter 2) is the transporter responsible for excessive blood glucose reabsorption in the kidney with SGLT-1 (sodium / glucose cotransporter 1) have. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood glucose released into the urine is increased. As a result, the blood glucose is lowered, and furthermore, the calories contained in the blood glucose are discharged. One of the drugs developed as an SGLT-2 inhibitor that can be usefully used as a therapeutic agent for type 2 diabetes due to such an action is Dapagliflozin, which is currently called Forxiga or Farxiga It is sold worldwide as a product name.

Dapagliflozin is a substance having the following structure and has been disclosed for the first time in International Patent Publication No. WO 2001/027128 (Patent Document 1).

However, the dapagliflozin crystals disclosed in Patent Document 1 are amorphous, have poor stability, have a low melting point and high hygroscopicity, and are difficult to maintain a constant quality as a raw material drug, which is disadvantageous in terms of formulation.

On the other hand, International Patent Publication No. WO 2008/002824 (patent document 2) discloses a process for producing a poly (ethylene glycol) -caprolactone by reacting an (S) -propylene glycol solvate hydrate, (R) -propylene glycol solvate hydrate, ethanol solvate hydrate, ethylene glycol solvate hydrate, L Comprising a 1: 1 crystalline complex with proline, a 1: 1 crystalline complex with L-proline, a half-hydrate of a 1: 1 crystalline complex with L-proline and a 1: 1 crystalline complex with L-phenylalanine (S) -propylene glycol solvate hydrate (form SC-3) in which several crystalline forms of the reflux are disclosed and which are used as the actual active ingredients of the poisir.

However, (S) -propylene glycol used as a solvent in Patent Document 2 is not economical as an expensive solvent, and it is difficult to form crystals smoothly in the production of a solvate, and thus an additional seeding process is required to promote crystal formation. And the need to manufacture / manage the seed as a raw material. Further, there is a problem in that it must be dried for a long time under specific drying conditions until it corresponds to the content of the hydrate in drying.

Studies have been made on stable solvates which exhibit the above-mentioned problems and further exhibit a more hygroscopic hygroscopicity, solubility and stability characteristics in pharmaceutical formulations.

International Publication No. WO 2001/027128 (published on April 29, 2001) International Patent Publication No. WO 2008/002824 (published on Jan. 03, 2008)

It is an object of the present invention to provide a novel solvate of the dsPragriflozin which is an SGLT2 inhibitor and a process for its preparation.

In order to solve the above-mentioned problems, the present invention relates to a solvate of a dapagliflozin 1,2-hexanediol represented by the following general formula (1), a dapagliflozin cis-1,2-cyclopentane Diol solvate hydrate, a dipalmitoyl 1,2-butanediol solvate hydrate represented by the following formula 3, and a process for producing the same.

[Chemical Formula 1]

(2)

(3)

Solvates in the present invention refer to complexes or aggregates formed by one or more solute molecules and one or more solvent molecules, and may include hydrates.

Hereinafter, a novel solvate of dapagliflozin and a method for producing the same will be described in detail.

Da pagliprofrozen  1,2- Hexanediol  Method for preparing a solvate

Da pagliprofrozen  1,2- Hexanediol  Solvent A

The dipalmitoyl 1,2-hexanediol solvate A of the present invention has a powder X-ray diffraction pattern from the group consisting of 2θ (± 0.2 °) values of 3.841, 5.331, 7.668, 9.073, 14.715 and 17.902 And may include three or more diffraction peaks to be selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 7.967, 10.049, 15.653, 18.270, 18.906, 20.149 and 22.936 .

The above-described dapaglyplated 1,2-hexanediol solvate A is prepared by dissolving dapagliflozin in butyl acetate and adding 1,2-hexanediol, adding n-heptane thereto, stirring Followed by filtration to obtain a solid.

Da pagliprofrozen  1,2- Hexanediol  Solvate B

The polyparagloprolin 1,2-hexanediol solvate B of the present invention is characterized in that the powder X-ray diffraction pattern is from the group consisting of the 2? (± 0.2 °) values of 3.960, 5.421, 7.816, 9.322, 14.947 and 17.993 And may include three or more diffraction peaks to be selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 10.061, 15.748, 18.893, 19.275, 20.165, 21.799 and 23.346 .

The above-described dapaglyplated 1,2-hexanediol solvate B is prepared by dissolving dapagliflozin in isopropyl acetate and adding 1,2-hexanediol thereto, adding thereto cyclohexane, stirring Followed by filtration to obtain a solid.

Da pagliprofrozen  1,2- Hexanediol  Solvate C

Diffracted 1,2-hexanediol solvate C of the present invention has a powder X-ray diffraction pattern from the group consisting of 2? (± 0.2 °) values of 3.877, 5.304, 7.617, 7.838, 14.869 and 17.796 And may include three or more diffraction peaks to be selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of values of 2θ (± 0.2 °) of 9.053, 10.012, 15.058, 15.792, 19.006, 20.206 and 21.480 .

The above-described dapaglyphrolated 1,2-hexanediol solvate C is prepared by dissolving dapagliflozin in acetone and adding 1,2-hexanediol, adding n-heptane thereto, stirring the mixture, ≪ / RTI > to obtain a solid.

Da pagliprofrozen cis -1,2- Cyclopentane diol  Solvate hydrate and its Produce Way

The multiglycidyl cis-1,2-cyclopentanediol solvate hydrate of the present invention has a powder X-ray diffraction pattern with values of 2? (± 0.2 °) of 3.614, 14.316, 16.078, 16.407, 17.961 and 19.627 And three or more diffraction peaks selected from the group consisting of More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 8.760, 16.877, 19.919, 20.186, 21.123, 24.329 and 28.114 .

The above dapaglyplated cis-1,2-cyclopentanediol solvate hydrate is prepared by dissolving dapagliflozin in isopropyl acetate and adding cis-1,2-cyclopentanediol, Hexane is added and stirred, followed by filtration to obtain a solid.

Da pagliprofrozen  1,2- Butanediol  Solvate hydrate and method for its preparation

The multiglycidyl 1,2-butanediol solvate hydrate of the present invention has a powder X-ray diffraction pattern from the group consisting of the values of 2? (± 0.2 °) of 3.788, 15.092, 15.604, 17.000, 18.891 and 19.760 And may include three or more diffraction peaks to be selected. More preferably, the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of values of 2θ (± 0.2 °) of 7.545, 8.003, 8.657, 20.084, 21.424, 22.727, 25.155, 25.883 and 30.451 .

The dipalmitoyl 1,2-butanediol solvate hydrate as described above is prepared by dissolving dipalmitin in isopropyl acetate and adding 1,2-butanediol, adding cyclohexane thereto, stirring Followed by filtration to obtain a solid.

The novel solvates provided in the present invention are highly suitable for formulation in a crystalline form which has a high melting point, low hygroscopicity and allows rapid elution. In addition, it was confirmed that the crystals exhibit excellent thermodynamic stability and storage stability, are excellent in mechanical stability and fluidity, are uniform in particle, exhibit no tackiness, and are excellent in purity and are suitable crystals as a raw material. Furthermore, since the solvent used for the reaction is inexpensive, it is possible to establish an economical manufacturing process, and there is no need of a seeding process in the reaction process, and it can be industrialized by drying within a few hours at room temperature after completion of the reaction. Can be prepared in high yield, making them suitable for industrial production.

Figure 1 shows the X-ray powder diffraction (XPRD) results of the dipalmitoylated 1,2-hexanediol solvate A.
Figure 2 shows the X-ray powder diffraction (XPRD) results of the dipalmitoylated 1,2-hexanediol solvate B;
Figure 3 shows the X-ray powder diffraction (XPRD) results of the dipalmitoylated 1,2-hexanediol solvate C;
Figure 4 shows the X-ray powder diffraction (XPRD) results of the dasaglyphrolated cis-1,2-cyclopentanediol solvate hydrate.
Figure 5 shows the X-ray powder diffraction (XPRD) results of the dipalmitoyl 1,2-butanediol solvate hydrate.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Measurement method>

The following measurement method is commonly applied to each embodiment according to the present invention.

1. Nuclear magnetic resonance (NMR) measurement

Structural analysis of the compounds was carried out using Agilent Technologies 600 MHz nuclear magnetic resonance apparatus (NMR) and DMSO-d ₆ was used as the solvent.

2. Powder X-ray diffraction

The powder X-ray diffraction pattern was obtained using a BRUKER D8 ADVANCE model with a solid phase detector using CuKα irradiation at 1.54178 Å (40 kV, 40 mA). The analysis was carried out with a 0.02 ° step size ranging from 3 ° to 45 ° at 2θ angle.

3. Thermal analysis

Differential scanning calorimetry (DSC) was performed using METTLER TOLEDO DSC1. A sample of about 1-10 mg was weighed and placed in a capped aluminum pan. The samples were evaluated using a linear heating ramp at 10 [deg.] C / min from 25 [deg.] C to 250 [deg.] C.

4. Cal-Fischer (K.F) Moisture Measurement

K.F Moisture measurement was carried out using a Metrohm 831 KF coulometer. Each sample weighed was analyzed using 100 ml Coulometeric KF reagent Coulomet AG.

5. High Performance Liquid Chromatography ( HPLC ) Measure

The purity of the compounds was determined by high performance liquid chromatography (HPLC) using Agilent Technologies 1260 Infinity. (0.2% aqueous H ₃ PO ₄ ) and mobile phase B (90% CH ₃ CN / 10% H ₂ O) were used as the stationary phases (YMC ODS-A C-18 S3 and 4.6 X 50 mm).

< Example  1> Da pagliprofrozen  1,2- Hexanediol  Preparation and analysis of solvate A

1 g of amorphous dipalmitriol was dissolved in butyl acetate (7 mL) and 1,2-hexanediol (0.35 g) was added. After 10 minutes, n-heptane (20 mL) was added dropwise and stirred. After stirring at room temperature for 2 hours, the solid obtained by filtration was washed with cyclohexane (5 mL) and vacuum-dried at room temperature for 6 hours to obtain the title solvate.

^{1 H NMR (600 MHz, DMSO} -d 6) δ 7.36 (d, 1H), 7.31 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.81 (d, 2H), 4.98 ( (d, 1H), 3.42 (d, 1H), 4.42 (d, 1H) (m, 2H), 1.28 (d, 1H), 3.35-3.37 (m, 1H), 3.19-3.25 (m, 4H), 3.13-3.16 (t, 3H), 1.17-1.26 (m, 4H), 0.85 (t, 3H)

Its XPRD pattern is shown in Table 1 and Fig.

[Table 1]

< Example  2> Da pagliprofrozen  1,2- Hexanediol  Preparation and analysis of solvate B

1 g of amorphous dipalmitriol was dissolved in isopropyl acetate (7 mL) and 1,2-hexanediol (0.35 g) was added. After 10 minutes, c-hexane (49 mL) was added dropwise and stirred. After stirring at room temperature for 2 hours, the solid obtained by filtration was washed with cyclohexane (5 mL) and vacuum-dried at room temperature for 6 hours to obtain the title solvate.

¹ H NMR was the same as in Example 1.

Its XPRD pattern is shown in Table 2 and Fig.

[Table 2]

< Example  3> Da pagliprofrozen  1,2- Hexanediol  Preparation and analysis of solvate C

1 g of amorphous dipalmitriol was dissolved in acetone (7 mL) and 1,2-hexanediol (0.35 g) was added. After 10 minutes, n-heptane (50 mL) was added dropwise and stirred. The mixture was stirred at room temperature for 1 hour, cooled to 5 DEG C, stirred for 6 hours, filtered and washed with cyclohexane (5 mL) and vacuum-dried at room temperature for 6 hours to obtain the title solvate.

¹ H NMR was the same as in Example 1.

Its XPRD pattern is shown in Table 3 and Fig.

[Table 3]

< Example  4> Da pagliprofrozen  cis-1,2- Cyclopentane diol  Preparation and analysis of solvate hydrate

1 g of amorphous dipalmitriol was dissolved in isopropyl acetate (7 mL) and cis-1,2-cyclopentanediol (0.5 g) was added. After 10 minutes, cyclohexane (16 mL) was added dropwise and stirred. After stirring at room temperature for 2 hours, the solid obtained by filtration was washed with cyclohexane (5 mL) and vacuum-dried at room temperature for 6 hours to obtain the title solvate.

^{1 H NMR (600 MHz, DMSO} -d 6) δ 7.36 (d, 1H), 7.31 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.81 (d, 2H), 4.98 ( (m, 2H), 3.68 (d, 1H), 4.84 (d, 2H) 2H), 3.13-3.16 (m, 1H), 3.10 (dt, 1H), 1.60-1.66 (m, 3H), 1.43-1.49 , 1.34-1.39 (m, 1 H), 1.28 (t, 3 H)

Its XPRD pattern is shown in Table 4 and Fig.

[Table 4]

Peak List

< Example  5> Da pagliprofrozen  1,2- Butanediol  Preparation and analysis of solvate hydrate

1 g of amorphous dipalmitriol was dissolved in isopropyl acetate (7 mL) and 1,2-butanediol (0.44 g) was added. After 10 minutes, cyclohexane (21 mL) was added dropwise and stirred. After stirring at room temperature for 2 hours, the solid obtained by filtration was washed with cyclohexane (5 mL) and vacuum-dried at room temperature for 6 hours to obtain the title solvate.

^{1 H NMR (600 MHz, DMSO} -d 6) δ 7.36 (d, 1H), 7.31 (d, 1H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.81 (d, 2H), 4.98 ( (d, 1H), 3.42 (d, 1H), 4.42 (d, 1H) (d, 1H), 3.26-3.30 (m, 1H), 3.19-3.25 (m, 4H), 3.12-3.16 (t, 3 H), 1.18-1.24 (m, 1 H), 0.84 (t, 3 H)

Its XPRD pattern is shown in Table 5 and Fig.

[Table 5]

Peak List

< Experimental Example >

1. Hygroscopicity test

As a result of measuring hygroscopicity after storage at 25 ° C (relative humidity 80%) for 24 hours according to the European Pharmacopoeia Test, the solvate of the present invention exhibited non-hygroscopicity and thus is expected to have excellent storage stability.

2. Melting point test

As a result of measuring the melting point using differential scanning calorimetry (DSC), the solvate of the present invention is expected to be thermodynamically stable, and therefore excellent physical properties are expected as a raw material drug.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

A solvate of dapagliflozin 1,2-hexanediol of formula 1:
[Chemical Formula 1]

The method according to claim 1,
Wherein the powder X-ray diffraction pattern comprises three or more diffraction peaks selected from the group consisting of the values of 2θ (± 0.2 °) of 3.841, 5.331, 7.668, 9.073, 14.715 and 17.902, Diol solvate. 3. The method of claim 2,
Wherein the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 7.967, 10.049, 15.653, 18.270, 18.906, 20.149 and 22.936, 2-hexanediol solvate. The method according to claim 1,
Wherein the powder X-ray diffraction pattern comprises three or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 3.960, 5.421, 7.816, 9.322, 14.947 and 17.993, Diol solvate. 5. The method of claim 4,
Wherein the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 10.061, 15.748, 18.893, 19.275, 20.165, 21.799 and 23.346, 2-hexanediol solvate. The method according to claim 1,
Wherein the powder X-ray diffraction pattern comprises three or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 3.877, 5.304, 7.617, 7.838, 14.869 and 17.796, Diol solvate. The method according to claim 6,
Wherein the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 9.053, 10.012, 15.058, 15.792, 19.006, 20.206 and 21.480, 2-hexanediol solvate. Dasaglyphroline cis-1,2-cyclopentanediol solvate hydrate of Formula 2:
(2)

9. The method of claim 8,
Wherein the powder X-ray diffraction pattern comprises three or more diffraction peaks selected from the group consisting of values of 2θ (± 0.2 °) of 3.614, 14.316, 16.078, 16.407, 17.961 and 19.627, - cyclopentanediol solvate hydrate. 10. The method of claim 9,
Wherein the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of values of 2? (± 0.2 °) of 8.760, 16.877, 19.919, 20.186, 21.123, 24.329 and 28.114, , 2-cyclopentanediol solvate hydrate. Is a hydrate of a dipalmitoyl 1,2-butanediol solvate of Formula 3:
(3)

12. The method of claim 11,
Wherein the powder X-ray diffraction pattern comprises three or more diffraction peaks selected from the group consisting of the values of 2θ (± 0.2 °) of 3.788, 15.092, 15.604, 17.000, 18.891 and 19.760, All solvate hydrate. 13. The method of claim 12,
Wherein the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of values of 2θ (± 0.2 °) of 7.545, 8.003, 8.657, 20.084, 21.424, 22.727, 25.155, 25.883 and 30.451, 1,2-butanediol solvate hydrate.

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