WO2017099496A1 - Novel solvate of dapagliflozin and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel solvate of dapagliflozin, an SGLT-2 inhibitor, and a method for preparing the same.

Description

Novel Solvates of Dapagliflozin and Methods for Preparing the Same

The present invention relates to a novel solvate of Dapagliflozin, a SGLT-2 inhibitor, and a method for preparing the same.

Diabetes is a chronic metabolic disease that affects millions of patients around the world and is divided into type 1 and type 2. Among them, type 2 diabetes is caused by insulin resistance, which is caused by a decrease in the function of insulin, which lowers blood sugar.

Meanwhile, sodium / glucose cotransporter 2 (SGLT-2), together with sodium / glucose cotransporter 1 (SGLT-1), is a transporter responsible for excessive blood glucose resorption in the kidney, and SGLT-2 plays a major role. have. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood sugar released into the urine increases, and thus the blood sugar is lowered, and further, the calories contained in the blood sugar are released, thereby causing the weight loss effect. One of the drugs developed as an SGLT-2 inhibitor that can be usefully used as a treatment for type 2 diabetes is Dapagliflozin, and currently called Forxiga or Farxiga. It is sold all over the world under the brand name.

Dapagliflozin is a material having the following structure and has been disclosed for the first time in WO 2001/027128 (Patent Document 1).

However, the dapagliflozin crystal disclosed in Patent Document 1 is in an amorphous form, has poor stability, and has a disadvantage in that it is difficult to maintain a constant quality as a raw material pharmaceutical due to low melting point and high hygroscopicity, and thus is not useful in pharmaceutical form.

On the other hand, International Publication No. WO 2008/002824 (Patent Document 2) discloses (S) -propylene glycol solvate hydrate, (R) -propylene glycol solvate hydrate, ethanol solvate hydrate, ethylene glycol solvate hydrate, L Dapagle comprising a 1: 2 crystalline complex with proline, a 1: 1 crystalline complex with L-proline, a hemihydrate of a 1: 1 crystalline complex with L-proline, and a 1: 1 crystalline complex with L-phenylalanine Several crystalline forms of reflowazine have been disclosed, and dapagliflozin (S) -propylene glycol solvate hydrate (form SC-3), which is used as the actual active ingredient of pociga, is disclosed.

However, (S) -propylene glycol used as a solvent in Patent Document 2 is an expensive solvent, low economical efficiency, it is difficult to produce a smooth crystal when solvate production, it requires an additional seeding process to promote crystal production, this There is a difficult disadvantage such as the need to manufacture / manage seed as raw material. In addition, there is a problem of drying for a long time under specific drying conditions until it corresponds to the content of the hydrate during drying.

In order to improve the above problems, further research is being conducted on stable solvates exhibiting more advantageous hygroscopicity, solubility and stability.

It is an object of the present invention to provide a novel solvate of dapagliflozin, a SGLT2 inhibitor, and a method for preparing the same.

In order to solve the above problems, the present invention is a dapagliflozin 1,2-hexanediol solvate represented by the formula (1), dapagliflozin cis-1,2-cyclopentane represented by the formula (2) It provides a diol solvate hydrate, dapagliflozin 1,2-butanediol solvate hydrate represented by the following formula (3) and a method for preparing the same.

[Formula 1]

[Formula 2]

[Formula 3]

Solvate in the present invention means a complex or aggregate formed by one or more solute molecules and one or more solvent molecules, and may include a hydrate.

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

Dapagliflozin  1,2- Hexanediol  Solvent Preparation Method

Dapagliflozin  1,2- Hexanediol  Solvate A

The dapagliflozin 1,2-hexanediol solvate A of the present invention is a powder X-ray diffraction pattern from the group consisting of 284 (± 0.2 °) values of 3.841, 5.331, 7.668, 9.073, 14.715 and 17.902 It may comprise three or more diffraction peaks 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 7.967, 10.049, 15.653, 18.270, 18.906, 20.149 and 22.936. .

Dapagliflozin 1,2-hexanediol solvate A as described above, the step of dissolving dapagliflozin in butyl acetate and adding 1,2-hexanediol, to which n-heptane is added and stirred It may be prepared by a manufacturing method comprising the step of obtaining a solid by filtration.

Dapagliflozin  1,2- Hexanediol  Solvate B

Dapagliflozin 1,2-hexanediol solvate B of the present invention has a powder X-ray diffraction pattern from the group consisting of 2θ (± 0.2 °) values of 3.960, 5.421, 7.816, 9.322, 14.947 and 17.993 It may comprise three or more diffraction peaks 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. .

Dapagliflozin 1,2-hexanediol solvate B as described above, the step of dissolving dapagliflozin in isopropyl acetate and adding 1,2-hexanediol, to which cyclohexane was added and stirred It may be prepared by a manufacturing method comprising the step of obtaining a solid by filtration.

Dapagliflozin  1,2- Hexanediol  Solvate C

The dapagliflozin 1,2-hexanediol solvate C of the present invention has a powder X-ray diffraction pattern from the group consisting of 2θ (± 0.2 °) values of 3.877, 5.304, 7.617, 7.838, 14.869 and 17.796. It may comprise three or more diffraction peaks 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 9.053, 10.012, 15.058, 15.792, 19.006, 20.206 and 21.480. .

Dapagliflozin 1,2-hexanediol solvate C as described above, dissolving dapagliflozin in acetone and adding 1,2-hexanediol, n-heptane was added thereto, stirred and filtered It can be prepared by a manufacturing method comprising the step of obtaining a solid.

Dapagliflozin  cis-1,2- Cyclopentanediol  Solvate Hydrate and Method for Making the Same

The dapagliflozin cis-1,2-cyclopentanediol solvate hydrate of the present invention has a powder X-ray diffraction pattern with 2θ (± 0.2 °) values of 3.614, 14.316, 16.078, 16.407, 17.961 and 19.627. 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 2θ (± 0.2 °) values of 8.760, 16.877, 19.919, 20.186, 21.123, 24.329 and 28.114. .

The above dapagliflozin cis-1,2-cyclopentanediol solvate hydrate is a step of dissolving dapagliflozin in isopropyl acetate and adding cis-1,2-cyclopentanediol, to which cyclo It can be prepared by a manufacturing method comprising the step of adding hexane, stirring and filtering to obtain a solid.

Dapagliflozin  1,2- Butanediol  Solvate Hydrate and Method for Making the Same

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

As above, dapagliflozin 1,2-butanediol solvate hydrate is dissolved dapagliflozin in isopropyl acetate and 1,2-butanediol is added to the cyclohexane and stirred It may be prepared by a manufacturing method comprising the step of obtaining a solid by filtration.

The novel solvates provided by the present invention are well suited for formulation in crystalline forms that have a high melting point, low hygroscopicity and enable rapid dissolution. In addition, it showed excellent thermodynamic stability and preservation stability, excellent mechanical stability and fluidity, uniform particles, no tackiness, excellent purity, and confirmed that it was a suitable crystal as a raw material. Furthermore, the solvent used for the reaction is an inexpensive solvent that can establish an economical manufacturing process, does not require a seeding process during the reaction process, and can be industrialized by drying within a few hours at room temperature after the completion of the reaction. Solvates can be produced in high yield and are very suitable for industrial production.

Figure 1 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2- hexanediol solvate A.

Figure 2 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-hexanediol solvate B.

Figure 3 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-hexanediol solvate C.

Figure 4 shows the X-ray powder diffraction (XPRD) results of dapagliflozin cis-1,2-cyclopentanediol solvate hydrate.

Figure 5 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-butanediol solvate hydrate.

Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Measurement method>

The following measuring methods are commonly applied to each of the examples according to the present invention.

1. Measurement of nuclear magnetic resonance (NMR)

The structural analysis of the compound was measured by Agilent Technologies 600 MHz Nuclear Magnetic Resonance Instrument (NMR) and the solvent was DMSO-d ₆ .

2. Powder X-ray Diffraction

Powder X-ray diffraction patterns were obtained using a BRUKER D8 ADVANCE model using CuKα irradiation at 1.54178 kPa (40 kV, 40 mA) with a solid-state detector. The analysis was measured with a 0.02 ° step size over a range of 3 ° to 45 ° at 2θ angle.

3. Thermal Analysis

Differential Scanning Calorimetry (DSC) was performed using METTLER TOLEDO DSC1. About 1-10 mg of sample was weighed and placed in a capped aluminum pan. The sample was evaluated using a linear heating lamp of 10 ℃ / min in the range of 25 ℃ to 250 ℃.

4. Karl-Fischer ( K.F Moisture measurement

K.F moisture measurement was performed using a Metrohm 831 KF coulometer. Each weighed sample was analyzed using 100 ml of Coulometeric KF reagent Coulomet AG.

5. High performance liquid chromatography ( HPLC ) Measure

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

< Example  1> Dapagliflozin  1,2- Hexanediol  Preparation and Analysis of Solvate A

1 g of amorphous dapagliflozin 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 ( dd, 2H), 4.85 (d, 1H), 4.46 (t, 1H), 4.42 (t, 1H), 4.34 (d, 1H), 3.92-4.00 (m, 5H), 3.68 (ddd, 1H), 3.42 (dt, 1H), 3.35-3.37 (m, 1H), 3.19-3.25 (m, 4H), 3.13-3.16 (m, 1H), 3.09 (dt, 1H), 1.31-1.42 (m, 2H), 1.28 (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> Dapagliflozin  1,2- Hexanediol  Preparation and Analysis of Solvate B

1 g of amorphous dapagliflozin 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 is the same as in Example 1.

Its XPRD pattern is shown in Table 2 and FIG.

TABLE 2

< Example  3> Dapagliflozin  1,2- Hexanediol  Preparation and Analysis of Solvate C

1 g of amorphous dapagliflozin 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 ° C., stirred for 6 hours, filtered, washed with cyclohexane (5 mL), and dried under vacuum at room temperature for 6 hours to obtain the title solvate.

¹ H NMR is the same as in Example 1.

Its XPRD pattern is shown in Table 3 and FIG.

TABLE 3

< Example  4> Dapagliflozin  cis-1,2- Cyclopentanediol  Preparation and Analysis of Solvate Hydrates

1 g of amorphous dapagliflozin 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 ( dd, 2H), 4.85 (d, 1H), 4.46 (t, 1H), 4.24 (d, 2H), 3.93-4.00 (m, 5H), 3.72-3.76 (m, 2H), 3.68 (ddd, 1H) , 3.42 (dt, 1H), 3.19-3.26 (m, 2H), 3.13-3.16 (m, 1H), 3.10 (dt, 1H), 1.60-1.66 (m, 3H), 1.43-1.49 (m, 2H) , 1.34-1.39 (m, 1H), 1.28 (t, 3H)

Its XPRD pattern is shown in Table 4 and FIG.

TABLE 4

Peak List

< Example  5> Dapagliflozin  1,2- Butanediol  Preparation and Analysis of Solvate Hydrates

1 g of amorphous dapagliflozin 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 ( dd, 2H), 4.85 (d, 1H), 4.46 (t, 1H), 4.42 (t, 1H), 4.35 (d, 1H), 3.93-4.00 (m, 5H), 3.68 (ddd, 1H), 3.42 (dt, 1H), 3.26-3.30 (m, 1H), 3.19-3.25 (m, 4H), 3.12-3.16 (m, 1H), 3.08 (dt, 1H), 1.42-1.46 (m, 1H), 1.28 (t, 3H), 1.18-1.24 (m, 1H), 0.84 (t, 3H)

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

2. Melting point test

From the results of melting point measurement 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 drug substance.

Having described the specific part of the present invention in detail, it will be apparent to those skilled in the art that such a specific description is only a preferred embodiment, thereby not limiting the scope of the present invention. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

1. Dapagliflozin 1,2-hexanediol solvate of Formula 1:

    [Formula 1]

   

   .
2. The method of claim 1,

   Dapagliflozin 1,2-hexane wherein the powder X-ray diffraction pattern comprises at least three diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 3.841, 5.331, 7.668, 9.073, 14.715 and 17.902 Diol solvates.
3. The method of claim 2,

   Dapagliflozin 1, 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 7.967, 10.049, 15.653, 18.270, 18.906, 20.149, and 22.936 2-hexanediol solvate.
4. The method of claim 1,

   Dapagliflozin 1,2-hexane wherein the powder X-ray diffraction pattern comprises at least three diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 3.960, 5.421, 7.816, 9.322, 14.947 and 17.993 Diol solvates.
5. The method of claim 4, wherein

   Dapagliflozin 1, 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.
6. The method of claim 1,

   Dapagliflozin 1,2-hexane wherein the powder X-ray diffraction pattern comprises at least three diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 3.877, 5.304, 7.617, 7.838, 14.869 and 17.796 Diol solvates.
7. The method of claim 6,

   Dapagliflozin 1, 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 9.053, 10.012, 15.058, 15.792, 19.006, 20.206 and 21.480 2-hexanediol solvate.
8. Dapagliflozin cis-1,2-cyclopentanediol solvate hydrate of Formula 2:

   [Formula 2]

   

   .
9. The method of claim 8,

   Dapagliflozin cis-1,2 wherein the powder X-ray diffraction pattern comprises at least three diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 3.614, 14.316, 16.078, 16.407, 17.961 and 19.627 Cyclopentanediol solvate hydrate.
10. The method of claim 9,

    Dapagliflozin cis-1 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 8.760, 16.877, 19.919, 20.186, 21.123, 24.329 and 28.114 , 2-cyclopentanediol solvate hydrate.
11. Dapagliflozin 1,2-butanediol solvate hydrate of formula (3).

    [Formula 3]

    

    .
12. The method of claim 11,

    Dapagliflozin 1,2-butanedi wherein the powder X-ray diffraction pattern comprises at least three diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 3.788, 15.092, 15.604, 17.000, 18.891 and 19.760 All solvate hydrates.
13. The method of claim 12,

    Dapagliflo, 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 7.545, 8.003, 8.657, 20.084, 21.424, 22.727, 25.155, 25.883 and 30.451 True 1,2-butanediol solvate hydrate.

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